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EFSA guidance on safety assessment of botanicals
2011-07-07T10:39:48Z
<p>Minttu: </p>
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<br />
EFSA Journal 2009; 7(9):1249<br />
For citation purposes: EFSA Scientific Committee; Guidance on safety assessment of botanicals and botanical preparations<br />
intended for use as ingredients in food supplements, on request of EFSA. EFSA Journal 2009; 7(9):1249. [19 pp.].<br />
doi:10.2093/j.efsa.2009.1249. Available online: www.efsa.europa.eu<br />
© European Food Safety Authority, 2009 1<ref>[http://www.efsa.europa.eu/de/scdocs/doc/1249.pdf]: EFSA Journal 2009; 7(9):1249<br />
For citation purposes: EFSA Scientific Committee; Guidance on safety assessment of botanicals and botanical preparations<br />
intended for use as ingredients in food supplements, on request of EFSA. EFSA Journal 2009; 7(9):1249. [19 pp.].<br />
doi:10.2093/j.efsa.2009.1249. Available online: www.efsa.europa.eu<br />
© European Food Safety Authority, 2009 1 </ref><br />
<br />
<br />
===SCIENTIFIC OPINION===<br />
<br />
<br />
''Guidance on Safety assessment of botanicals and botanical preparations intended for use as ingredients in food supplements''<br />
<br />
<br />
'''EFSA Scientific Committee'''<br />
<br />
<br />
European Food Safety Authority (EFSA), Parma, Italy<br />
<br />
<br />
This guidance document published on 9 September 2009, replaces the earlier version published on 20<br />
June 2008 with the Question Number: EFSA-Q-2005-233.<br />
<br />
<br />
===ABSTRACT===<br />
<br />
In this opinion, EFSA’s Scientific Committee provides guidance on the scientific data needed to carry out a safety assessments of a botanical or a botanical preparation. It also proposes a two-tiered scientific approach for the safety assessment depending on the available knowledge on a given botanical and the substance(s) it contains. The guidance also provides a set of criteria to help prioritise the safety assessment of botanical ingredients which<br />
are in use. EFSA has also compiled the available information on a large number of botanicals which have been reported to contain substances that may be of health concern when used in food or food supplements. The resulting compendium, which will be regularly updated, should be considered as part of this guidance document<br />
and is intended to assist manufacturers and food safety authorities by highlighting possible safety issues which may require further consideration.<br />
<br />
<br />
===KEY WORDS===<br />
<br />
Botanicals, botanical preparations, safety assessment, food supplements, toxicological properties, medicinal<br />
properties.<br />
<br />
<br />
===SUMMARY===<br />
<br />
Following the discussion paper of the Scientific Committee on botanicals and botanical preparations<br />
adopted on 23 June 2004, The European Food Safety Authority (EFSA) asked in August 2005 the<br />
Scientific Committee to develop a two-level tiered approach for the safety assessment of botanicals<br />
and botanical preparations. This approach consists of a first safety assessment level based on<br />
available knowledge and a subsequent level in which the safety assessment includes newly generated<br />
data.<br />
<br />
<br />
The present guidance document is focussed on botanicals and botanical preparations intended for use<br />
in food supplements, although the approach chosen is, in principle, applicable also to other uses of<br />
botanicals and botanical preparations in the food and feed areas.<br />
<br />
<br />
A general framework for safety assessment is proposed by the Scientific Committee, in which<br />
botanicals or botanical preparations for which an adequate body of knowledge exists could benefit<br />
from a “presumption of safety” without any need for further testing. Issues that should be carefully<br />
considered in order to reach such a conclusion are discussed in detail in the present guidance<br />
document. Botanicals and botanical preparations for which a presumption of safety is not possible<br />
based on available knowledge would be subject to a more extensive safety assessment, requiring<br />
additional data to be provided.<br />
<br />
<br />
It is not the objective of this opinion to produce a list of safe botanicals and botanical preparations<br />
intended for food supplement use, but only to provide guidance on how to assess safety of botanical<br />
ingredients.<br />
<br />
<br />
The Scientific Committee developed criteria for prioritising botanicals for safety assessment and has<br />
compiled a Compendium of botanicals that are reported to contain toxic, addictive, psychotropic or<br />
other substances that may be of concern. The main purpose of the Compendium, which should be<br />
considered as part of this guidance document, is to draw attention to issues that would need to be<br />
taken into account when assessing the safety of botanicals used as ingredients in food supplements,<br />
and to facilitate the establishment of priorities for safety assessment.<br />
<br />
<br />
The Scientific Committee recommends maintaining the Compendium up-to-date, making use of<br />
relevant available national lists of plants and of any other relevant data available, as well as of<br />
updated assessments carried out on botanicals by qualified bodies. The Scientific Committee also<br />
recommends to further expand the Compendium with botanicals not having any market history in<br />
Europe but having a documented history of use in their third country of origin.<br />
<br />
<br />
===TABLE OF CONTENTS===<br />
:*Abstract <br />
:*Summary <br />
:*Table of contents <br />
:*Background as provided by EFSA <br />
:*Terms of reference as provided by EFSA <br />
:*Acknowledgements <br />
:*Assessment <br />
:1.Introduction <br />
:2.Safety assessment of botanicals and botanical preparations intended for use as ingredients in<br />
food supplements <br />
:2.1Proposed data requirements for safety assessment of botanicals and botanical preparations<br />
used as ingredients in food supplements <br />
:2.1.1.Technical data<br />
::2.1.1.1. Identity and nature of the source material <br />
::2.1.1.2. Manufacturing process<br />
::2.1.1.3. Chemical composition <br />
::2.1.1.4. Specifications <br />
::2.1.1.5. Stability of the botanical or botanical preparation used as ingredient in food supplement <br />
::2.1.1.6. Proposed uses and use levels <br />
::2.1.1.7. Information on existing assessments <br />
:2.1.2. Exposure: extent and duration <br />
:2.1.3. Toxicological data <br />
2.2. Proposed general framework for assessing the safety of botanicals and botanical<br />
preparations used as ingredients in food supplement <br />
:2.2.1. Level A: Safety assessment based on available knowledge <br />
:2.2.2. Additional data required for the level B assessment <br />
3. Establishing a Compendium of botanicals and prioritising them to be considered for a safety<br />
assessment. <br />
:*Conclusions and recommendations <br />
:*References <br />
<br />
<br />
===BACKGROUND AS PROVIDED BY EFSA===<br />
<br />
A discussion paper by the Scientific Committee on botanicals and botanical preparations widely used<br />
in food supplements and related products was adopted on 23 June 2004 (SC document EFSA/SC/26<br />
Final3). In this paper, the Committee expressed concerns about quality and safety issues of botanicals<br />
and botanical preparations that have become widely available to consumers through several<br />
distribution channels in the EU. The use of botanicals and botanical preparations in food is regulated<br />
under the General Food Law (178/2002/EC), which attributes the primary legal responsibility for the<br />
safety of the products placed on the market to business operators. The Regulation however does not<br />
provide any guidance on how the safety of these products should be assessed. As the market volume<br />
and the variety of products expand, so does the need for a better characterisation of the range of<br />
botanicals and botanical preparations on the market, and for harmonising the risk assessment and<br />
consumer information approaches for these products. The paper aimed at increasing awareness of<br />
EFSA’s Advisory Forum on potential public health aspects associated with these products.<br />
<br />
<br />
The Secretariat brought the discussion paper to the attention of the Advisory Forum at its meeting of<br />
the 1st of October, 2004. Simultaneously, an invitation was sent to the members of the Advisory Forum to take note of the concerns<br />
raised by the Scientific Committee and to complete a questionnaire to provide a better understanding of the issue in Europe.<br />
<br />
<br />
By the end of January 2005, replies were received from twenty five countries, comprising twenty two<br />
EU Member States and three EFTA Countries. The members of the Advisory Forum underlined the<br />
importance of this issue for their countries and asked EFSA to initiate a self-task in order to develop<br />
some guidance on how to assess the safety of botanical ingredients.<br />
<br />
<br />
Following the mandate received by the Scientific Committee in August 2005 from EFSA, the<br />
Scientific Committee developed a two-level tiered approach for the safety assessment of botanicals<br />
and botanical preparations. A guidance document focussing on botanicals and botanical preparations<br />
intended for use as food supplements was published after public consultation.<br />
<br />
<br />
A conceptual framework for safety assessment was advocated, in which botanicals or botanical<br />
preparations for which an adequate body of knowledge exists could benefit from a “presumption of<br />
safety” without any need for further testing (first level of the framework). Issues that should be<br />
carefully considered in order to reach such a conclusion were discussed in detail in the guidance<br />
document. Botanicals and botanical preparations for which a presumption of safety is not possible<br />
would be subject to a more extensive safety assessment, based on additional data to be provided in<br />
accordance with the methodology described in the second level of the proposed framework.<br />
<br />
<br />
As a follow up, it was decided to test the adequacy of the above-mentioned approach described in the<br />
guidance document for safety assessment with a selected number of examples including botanicals<br />
known to contain toxic substances or having a reported toxic effect, botanicals with an established<br />
history of food use, and botanicals that are known to contain potentially genotoxic/carcinogenic<br />
substances. To this end, an EFSA Scientific Cooperation (ESCO) Working Group, composed of<br />
experts identified by the members of the Advisory Forum and by the Scientific Committee EFSA was<br />
established in April 2008. This working group was also given the task to finalise the Compendium of<br />
botanicals reported to contain toxic, addictive, psychotropic, or other substances of concern. The resulting ESCO report and Compendium9 were provided to the EFSA Executive Director in May<br />
2009.<br />
<br />
<br />
===TERMS OF REFERENCE AS PROVIDED BY EFSA===<br />
<br />
The Scientific Committee has been requested in May 2009 by the European Food Safety Authority<br />
to consider the recommendations made in the ESCO report for updating the guidance document for<br />
the safety assessment of botanicals and botanical preparations intended for use as ingredients in food<br />
supplements.<br />
<br />
<br />
===ACKNOWLEDGEMENTS===<br />
<br />
The European Food Safety Authority wishes to thank the members of the EFSA Scientific<br />
Cooperation (ESCO) Working Group on Botanicals and Botanical Preparations for the preparation of<br />
the ESCO Report, which was used by the Scientific Committee to update this guidance document.<br />
The European Food Safety Authority would also like to thank the members of the former Scientific<br />
Committee for their contributions to the present guidance document.<br />
<br />
<br />
===ASSESSMENT===<br />
<br />
====1. Introduction====<br />
The Scientific Committee decided to focus its work first on the safety assessment of botanicals and<br />
botanical preparations used as ingredients in food supplements (hereafter referred to, as botanical<br />
ingredients), although the approach chosen is, in principle, applicable also to other uses of botanicals<br />
and botanical preparations in the food and feed areas. It is not in the scope of the present guidance to<br />
address issues related to quality assurance and good hygienic practices currently regulated by the EU<br />
Food Legislation, nor to assess the safety of food supplements as end products. The present guidance<br />
does not therefore address hazards linked to the presence of contaminants and foodborne pathogens in<br />
the botanicals and botanicals preparations.<br />
<br />
<br />
A two-level tiered conceptual framework for safety assessment consisting of a safety assessment<br />
based on available knowledge and a subsequent level in which further testing and/or data are required<br />
is proposed by the Scientific Committee. Botanicals or botanical preparations for which an adequate<br />
body of knowledge exists, can benefit from a “presumption of safety” without any need for further<br />
testing. Based on reasonable evidence, they can then be assumed to be safe, sometimes under certain<br />
restrictions. The Scientific Committee used as an example the Qualified Presumption of Safety (QPS)<br />
approach developed for microorganisms in food and feed (EFSA, 2007a) to propose criteria for<br />
presuming a botanical or a botanical preparation safe. Botanicals and botanical preparations for which<br />
a presumption of safety is not possible should be subject to a more extensive safety assessment, based<br />
on additional data to be provided according to the methodology described by EFSA. By proposing a<br />
first safety assessment level based on available knowledge, the approach proposed by the Scientific<br />
Committee for the safety assessment of botanicals and botanical preparations is in line with EFSA’s<br />
policy to stimulate food and feed risk assessment approaches that minimise the number of<br />
experimental animals and any suffering (EFSA, 2009).<br />
<br />
<br />
In order to facilitate the implementation of the above-mentioned approach, EFSA has also compiled a<br />
Compendium of botanicals and botanical preparations that have been reported to contain toxic,<br />
addictive, psychotropic or other substances that may be of concern. This Compendium should be seen<br />
as a tool to gather relevant information and define priorities for safety assessment. The inclusion of a<br />
botanical in this Compendium does not imply that it is not safe for use in food supplements. Without<br />
prejudice to the existing legal framework, such Compendium has no legal status and may not be used<br />
as support or evidence in any disagreement or dispute pertaining to the legal classification of products<br />
or substances.<br />
<br />
<br />
Safety assessment of botanicals and botanical preparations<br />
EFSA Journal 2009; 7(9):1249 7<br />
<br />
<br />
====2. Safety assessment of botanicals and botanical preparations intended for use as<br />
ingredients in food supplements====<br />
<br />
It should be noted that Regulation 258/97/EC concerning novel foods and novel food ingredients<br />
applies to all foods, including food supplements, containing substances which have not been used for<br />
human consumption to a significant degree within the Community before 15 May 1997 and which fall<br />
under certain categories specified in the above-mentioned Regulation. In the case of a proposed use as<br />
a novel food, botanicals or botanical preparations should be assessed following the guidelines of the<br />
Commission Recommendation 97/618/EC of 29 July 1997 concerning the scientific aspects and the<br />
presentation of information necessary to support applications for the placing on the market of novel<br />
foods and novel food ingredients.<br />
<br />
<br />
Moreover, Regulation 1829/2003/EC on genetically modified food and feed would apply to any GMO<br />
ingredients used in food supplements. In the case of botanicals or botanical preparations derived from<br />
genetically modified plants, information should be provided in line with the guidance document of the<br />
EFSA Scientific Panel on Genetically Modified Organisms for the risk assessment of genetically<br />
modified plants and derived food (EFSA, 2006a).<br />
When the botanical or botanical preparation is intended for use as a food intended for particular<br />
nutritional uses (PARNUTS – Directive 89/398/EEC), the guidance document from the Scientific<br />
Committee on Food on submissions for safety evaluation of sources of nutrients or of other<br />
ingredients proposed for use in the manufacture of foods (SCF, 2001a) should also be consulted.<br />
<br />
<br />
It should also be underlined that this report only deals with guidance on safety assessment, whereas<br />
the scientific substantiation of any claims made on food supplements, as required by the Regulation<br />
on Nutrition and Health Claims, will be dealt with in separate EFSA documents, such as the<br />
“Scientific and technical guidance for the preparation and presentation of the application for<br />
authorisation of a health claim” (EFSA, 2007b).<br />
It is not the objective of this report to produce a list of safe botanicals and botanical preparations<br />
intended for food supplement use, but only to provide guidance on how to assess safety of botanical<br />
ingredients. Moreover, priority criteria are proposed, and a Compendium has been compiled to serve<br />
as a preliminary tool for risk assessors (see section 3).<br />
<br />
<br />
2.1. '''Proposed data requirements for safety assessment of botanicals and botanical<br />
preparations used as ingredients in food supplements'''<br />
<br />
It is understood that the use of botanicals and botanical preparations as ingredients in food<br />
supplements will have to be in compliance with the existing EU Food Legislation. This would<br />
include maximum permissible levels of chemical and biological contaminants (e.g. pesticides,<br />
mycotoxins, heavy metals and foodborne pathogens), modalities for ensuring quality, and application<br />
of good hygienic practice, including HACCP methodologies. The issues of controls needed to ensure<br />
constancy over time of the composition of botanical food supplements on the market and batch-tobatch<br />
variation are not addressed in this document as these are risk management aspects and therefore<br />
outside the scope of EFSA.<br />
<br />
The following sections aim at identifying data and information considered as necessary to assess the<br />
safety of botanical ingredients. These data are of: (i) technical; (ii) exposure and (iii) toxicological<br />
nature. The lists below are meant to give guidance on data requirements. They have been made as<br />
exhaustive as possible and should be adapted on a case-by-case basis, depending on the nature of the<br />
botanical or botanical preparation. This implies that not all the information listed below would be<br />
needed in all cases and that the amount of information available for a given botanical or botanical<br />
preparation may in some cases be sufficient without further testing (see section 2.2.1).<br />
<br />
<br />
2.1.1. '''Technical data'''<br />
<br />
2.1.1.1. Identity and nature of the source material<br />
<br />
It is recognized that identification of the botanical source and botanical preparation may in some cases<br />
be complicated. It is recommended to follow as much as possible the nomenclature of the European<br />
Pharmacopeia. Additional nomenclature sources are as follows:<br />
<br />
World Checklist of Selected Plant Families (Royal Botanic Garden, Kew); the books by Hanelt<br />
(2001) also available on the Internet as Mansfeld’s World Database of Agricultural and Horticultural<br />
Crops; and the database by United States Department of Agriculture. If a scientific name is not found<br />
in any of the above-named references, its existence may be checked in The International Plant Names<br />
Index.<br />
<br />
<br />
Since there have been many instances where species have been reclassified or renamed, a same<br />
species may be known by different scientific names. Common (vernacular) names may also be<br />
provided, but it should be noted that a common name used in one region to refer to a particular plant<br />
may be used elsewhere to refer to another quite unrelated species. Hence common names may not<br />
uniquely identify a species and are not as reliable as the scientific names.<br />
<br />
<br />
The following scheme summarizes the requirements for description of the identity of the botanical:<br />
<br />
<br />
;Scientific (Latin) name:<br />
:full systematic species name incl. botanical family, genus,<br />
species, variety, subspecies, author’s name, and chemotype if<br />
applicable<br />
<br />
;Synonyms: <br />
:botanical name(s) that may be used interchangeably with the<br />
preferred scientific name<br />
;Common names: <br />
:vernacular name(s)<br />
;Part used: <br />
:e.g. root, leaf, seed...<br />
;Geographical origin: <br />
:continent, country, region<br />
;Growth and harvesting conditions: <br />
:wild or cultivated, cultivation practices, time of harvest in relation<br />
to both season and stage of the plant growth.<br />
<br />
<br />
2.1.1.2. Manufacturing process<br />
<br />
The following information is considered necessary for assessing the safety of botanicals and botanical<br />
preparations:<br />
i):Information on the method(s) of manufacture (e.g. the process by which the raw material is<br />
converted into a preparation, such as extraction or other procedure(s), and plant extract ratio)<br />
<br />
ii):Information on substances entering the manufacturing process, e.g. identity of the extraction<br />
solvent, reagents, special precautions (light and temperature).<br />
<br />
iii):Standardization criteria (e.g. see European Pharmacopoeia).<br />
<br />
Botanicals or botanical preparations might become hazardous as a result of deviations in the<br />
production process (e.g. misclassification, switching of species). Therefore the safety of botanicals<br />
and botanical preparations should be ensured by following a Hazard Analysis and Critical Control<br />
Point (HACCP) approach (Codex Alimentarius 1997). The whole production chain, from primary<br />
production of botanicals to the storage and commercialisation of the botanical preparations should be<br />
taken into consideration. The HACCP system must be applied with the necessary flexibility and<br />
adapted to each botanical preparation on a case-by-case basis.<br />
<br />
<br />
2.1.1.3. Chemical composition<br />
<br />
Data on the chemical composition of the botanical ingredient should be provided with emphasis on<br />
the concentrations of constituent of relevance for the safety assessment; this includes the<br />
concentrations of:<br />
:*Compounds should be classified according to their chemical structure (e.g. flavonoids,<br />
terpenoids, alkaloids, etc.). Levels at which the constituents are present in the respective part<br />
of the botanical or botanical preparation should be given where available.<br />
:*Constituents to characterise the quality, chemical fingerprint, production process and/or<br />
biological activity of the preparation (markers).<br />
:*Constituents that provide reasons for concern due to their chemical, physiological or<br />
toxicological properties.<br />
In some cases, it may be difficult to identify the active principle responsible for an effect. Therefore<br />
the strength of the evidence underlying the concerns over a compound being reason for concern<br />
should also be given.<br />
<br />
<br />
2.1.1.4. Specifications<br />
<br />
Specifications of the botanicals or botanical preparations are required. They may be based on<br />
nutritional or biologically active components or, when these are not known, on selected chemical<br />
markers. Limits for or absence of specific undesirable / toxic substances should be specified. The<br />
proposed specifications should be modelled on recent European or other internationally accepted<br />
specifications (e.g. pharmacopoeia or the guidelines of the EMEA Committee on Herbal Medicinal<br />
Safety assessment of botanicals and botanical preparations<br />
<br />
Products (HMPC)). Where the proposed specifications differ from internationally recognised<br />
specifications, the latter specifications should be set out alongside the proposed new specifications,<br />
and any differences pointed out. Validated and well-established methods should be preferably used<br />
for the analysis of compounds considered in specifications.<br />
<br />
The specifications should include concentrations of major groups of constituents present in the<br />
botanical preparation including for example: amino acids, lipids, polysaccharides, volatile oil,<br />
inorganic ions, polyphenols, alkaloids, terpenes, alkenylbenzenes, lignin, saponins etc. as well as the<br />
major constituents within these classes.<br />
<br />
In addition, information on maximum levels for possible contaminants including e.g. heavy metals,<br />
mycotoxins, pesticide residues, and polycyclic aromatic hydrocarbon (PAH) residues should be<br />
provided.<br />
<br />
<br />
2.1.1.5. Stability of the botanical or botanical preparation used as ingredient in food supplement<br />
<br />
The stability of the botanical ingredient should be demonstrated over the shelf-life time. Any<br />
information concerning possible degradation should also be provided.<br />
<br />
<br />
2.1.1.6. Proposed uses and use levels<br />
<br />
Information on intended uses and recommended intakes for a product should specifically mention<br />
uses and use levels for the following categories:<br />
:* Common foods<br />
:* Food supplements<br />
:* Medicinal products<br />
<br />
Special attention should be given to population groups with specific uses like for example young<br />
children. Information on the duration of the proposed uses and use levels should also be provided<br />
<br />
<br />
2.1.1.7. Information on existing assessments<br />
<br />
Information on any existing assessments by international bodies or national competent authorities<br />
should be provided.<br />
<br />
<br />
2.1.2. '''Exposure: extent and duration'''<br />
<br />
Data and information should be provided on:<br />
:i) Anticipated human exposure to the botanical ingredient, including amount (e.g. maximum and<br />
average daily intake or exposure), frequency and duration. It is important to characterize as much as<br />
possible the expected human exposure to the botanical ingredient according to the recommended<br />
modalities of use in terms of extent and duration. Clear distinction should be made between intake of<br />
a botanical itself, intake of its essential oil and other preparations made of it.<br />
:ii) Possibility of additional / combined human exposure to the botanical or botanical preparation<br />
through different categories of food, food supplements and/or medicinal products that can be<br />
consumed together.<br />
:ii) Modality of use of the ingredient.<br />
:iv) Information on historical (food, food supplement and medicinal) use of the ingredient in<br />
human population groups in relation to the modalities of use and resulting exposure levels if known.<br />
Data derived from use outside of the European Union should also be considered.<br />
<br />
<br />
All data should be representative of the ingredient to be used for the European market. In this context,<br />
food use includes, in principle, the consumption of raw and cooked vegetables, spices, flavours, food<br />
supplements already in use for a long time16 and any other related food items.<br />
<br />
<br />
Estimates of average exposure ranges associated with the use of the botanical ingredient in the EU<br />
Member States should also be provided. Uncertainties associated with the food consumption data<br />
considered and anticipated exposure ranges should be clearly described (EFSA, 2006b).<br />
<br />
A matter to be specifically addressed in the evaluation is whether the proposed use and use levels will<br />
significantly increase already existing human exposure.<br />
<br />
<br />
2.1.3. '''Toxicological data'''<br />
<br />
Studies on toxicity and toxicokinetics including metabolism of botanicals and botanical preparations<br />
should be conducted using internationally agreed protocols. Test methods described by OECD or in<br />
European Commission Directives 87/432/EEC and 67/548/EC – Annex 5 are recommended. It is<br />
advisable to ensure that the most up-to-date version of any test guideline is followed. Use of any<br />
methods differing from internationally agreed protocols should be justified. Protocols for special<br />
studies differing from standard tests should be developed on a case-by-case basis.<br />
<br />
To ensure general acceptance of the data submitted, studies should be carried out according to the<br />
principles of Good Laboratory Practice (GLP) described in Council Directive 87/18/EEC and<br />
accompanied by a statement of GLP compliance. Adequate explanation should be provided for<br />
divergence from these principles.<br />
<br />
Council Directive 86/609/EEC, on the protection of animals used for experimental and other scientific<br />
purposes, requires that care is taken to avoid unnecessary use of animals. Studies carried out should<br />
be those necessary to demonstrate the safety of a botanical or botanical preparation and planned in<br />
accordance with the principles of reduction, refinement and replacement. However, where adequate<br />
data are not available for the safety assessment (see section 3.2.1), in vivo studies using experimental<br />
animals may be needed in order to assess possible risks to humans from the ingestion of botanicals or<br />
botanical preparations. Alternative validated methods involving fewer or no animals for toxicity<br />
endpoints may in the future be developed and should be considered on a case-by-case basis.<br />
<br />
If available, data on possible interactions (e.g. herbal-drug) should also be provided.<br />
<br />
<br />
2.2. '''Proposed general framework for assessing the safety of botanicals and botanical<br />
preparations used as ingredients in food supplement'''<br />
<br />
Several guidance documents (AFSSA, 2003; Council of Europe, 2005; Schilter et al., 2003) have been<br />
published on the principles for assessment of botanicals and botanical preparations in the food and<br />
feed area. The present guidance document is not intended to reiterate these, but to outline a<br />
framework that could be used by risk assessors when assessing the safety of a botanical or a botanical<br />
preparation. It also proposes a scientific approach to the assessment of available data.<br />
<br />
The aim of the assessment is to ensure that botanicals or botanical preparations, when used in food<br />
supplements in the manner, quantities and time period of intake proposed, would not pose a risk to the<br />
health of consumers. Data should provide not only information relevant to the healthy adult consumer,<br />
but also relevant to those population groups potentially vulnerable due to their pattern of food<br />
consumption or their physiological or health status, e.g. young age, elderly, pregnancy,<br />
immunocompromised etc.<br />
<br />
A general framework for assessing the safety with core tests and other tests is given, which should<br />
enable determination of what information is required to establish the safety-in-use of the botanical or<br />
botanical preparation. The application of this guidance to specific cases will depend on the nature of<br />
the botanical or botanical preparation, its intended uses and levels of use in food supplements and on<br />
whether the botanical or botanical preparation has a long term history of food use17, showing that, at<br />
proposed exposure levels, no adverse effect on human health has been reported. In addition to<br />
laboratory tests, it may be possible to use human data derived from medical use, epidemiology, or<br />
specific studies on volunteers (e.g. on absorption and metabolism), or any other data reporting<br />
possible adverse health effects, either anecdotal or on the basis of case reports of intoxication, e.g data<br />
related to toxicity on livestock animals, or on botanicals that closely resemble botanicals which are<br />
known to have caused toxic effects.<br />
<br />
However, it is recognized that for botanical ingredients lacking a history of food use, or for botanicals<br />
whose intended use levels will significantly exceed historical intake levels, an assessment of safety<br />
generally relies on experimental toxicity data largely derived from investigations in laboratory<br />
animals.<br />
<br />
The approach herein proposed for the safety assessment of botanicals and botanical preparations not<br />
regulated in the framework of specific regulations such as the one on novel foods, and illustrated by<br />
Figure 1, consists of the two following levels:<br />
:*Level A: Safety assessment based on available knowledge.<br />
:*Level B: Safety assessment including newly generated data.<br />
<br />
[[File:Proposed_tier_approach_botanical.png]]<br />
<br />
Figure 1: Proposed tiered approach for the safety assessment of botanicals and botanical<br />
preparations.<br />
<br />
<br />
2.1. '''Level A: Safety assessment based on available knowledge'''<br />
<br />
Depending on the botanical ingredient and its uses, there are circumstances under which no additional<br />
data are judged necessary for the safety evaluation, i.e. a presumption of safety would be applied.<br />
This would be the case whenever available data would allow to conclude that exposure to known<br />
levels of the botanical ingredient has occurred in large population groups for many years without<br />
reported adverse effects.<br />
<br />
Therefore, an important requirement is that the data as outlined in chapter 2.1 are provided and that<br />
no significant increase of intake compared to historical levels is to be expected due to the intended<br />
levels of use in food supplements. This implies that not only use levels but also chemotypes of<br />
botanicals and the chemical composition of the botanical preparations should be in line with<br />
historically used ones. This approach can only be applied when intakes due to the intended levels of<br />
use are within the range of intake levels derived from the European Member States’ average diets or<br />
from studies on specific subgroups. It is recognized that the acceptability of such an approach relies<br />
mainly on the objective of not significantly increasing exposures beyond the levels linked to the safe<br />
history of use.<br />
<br />
If compounds of concern can be well defined, evaluations can focus on these specific compounds. In<br />
some cases, it may be difficult to identify the active principle responsible for an effect. In such cases<br />
the strength of the evidence underlying the concerns over a compound taken as the reference<br />
compound for the safety evaluation should also be given.<br />
<br />
For botanicals and botanical preparations with a potential to contain toxic, addictive, psychotropic or<br />
other substances that may be of concern (see also the Compendium and section 3), presumption of<br />
safety can be applied only if there is convincing evidence that these undesirable substances in the<br />
specific plant parts or preparations are either absent in the source material, or significantly reduced if<br />
not excluded, or inactivated during processing.<br />
<br />
In cases where the above-mentioned substances are known to be present in the botanical ingredient<br />
under evaluation (see attached Compendium), additional consideration should be given to support the<br />
presumption of safety of the botanical preparation. The significance of overall exposure to such<br />
substances should be assessed and compared with existing health-based guidance values such as the<br />
acceptable / tolerable daily intake (ADI/TDI). Consideration of exposure to the substance of concern<br />
in relation to the Threshold of Toxicological Concern (TTC) values may also be helpful.<br />
<br />
In cases where no health-based guidance values are available or where the botanical ingredient<br />
contains substances that are both genotoxic and carcinogenic, the “Margin of Exposure” (MOE)<br />
approach (EFSA, 2005) could be applied covering the botanical(s) under examination and any other<br />
dietary sources of exposure. The MOE approach compares toxic effect levels with human exposure<br />
levels. Alternatively, it could be evaluated whether the expected exposure to the genotoxic and<br />
carcinogenic ingredient is likely to be increased, compared to the intake from other sources.<br />
<br />
It is plausible that the kinetics as well as the expression of the inherent toxicity of a naturally<br />
occurring substance could be modified by the matrix in which it is present. Depending on the<br />
mechanism of action, this could result in the toxicity being unchanged, reduced or even increased.<br />
Research on individual substance/matrix interactions or botanical preparations cannot be used to draw<br />
general conclusions about intact botanicals, herbs and spices under all conditions of use, ingestion and<br />
metabolism. Where a matrix effect is advocated to support the safety of specific levels of substances<br />
(e.g. that data from a pure substance may overestimate effects of the substance in the botanical<br />
matrix), testing and/or other data should be provided to demonstrate the occurrence of the matrix<br />
effect of the preparation and its magnitude. A matrix effect should be judged on a case-by-case basis.<br />
<br />
Extrapolating from one preparation to another and/or from one botanical to another with respect to the<br />
same substance of toxicological concern can only been considered when accompanied by evidence of<br />
their composition with respect to the substance of concern and pattern of consumption.<br />
<br />
For food supplements consisting of complex mixtures of different botanicals, the above-mentioned<br />
assessment could be carried out on the levels of individual substances of concern known to be present<br />
(see also the Compendium), with the understanding of the limitation that such an approach does not<br />
generally allow the assessment of possible synergistic or antagonistic effects.Any data on possible<br />
herb-drug interaction should be carefully considered.<br />
<br />
In the case of a botanical ingredient whose anticipated intake is significantly higher than the estimated<br />
historical intake level, or for which the historical intake level cannot be assessed, additional data<br />
should be provided for the safety assessment, as described in the following sections.<br />
<br />
<br />
2.2.2. '''Additional data required for the level B assessment'''<br />
<br />
The reasons for carrying out toxicological studies should be stated, as should the reasons for not<br />
submitting a study that might be expected. The studies that might be expected can be seen from the<br />
“Guidance on submissions for food additive evaluations by the Scientific Committee on Food” (SCF<br />
2001b). All the important results should be presented and discussed and the original study reports<br />
should be submitted in order to allow independent, critical appraisal.<br />
<br />
The toxicology section of the dossier should start with a section describing in detail the specifications<br />
and identity criteria for the botanical preparation(s) used for the toxicity studies and their relationship<br />
to the final product to be used in the food supplement. It should be demonstrated unambiguously that<br />
these characteristics are in compliance with the technical details specified for the botanical<br />
preparation in this report.<br />
<br />
The toxicological tests should, as far as possible, follow the recommendations for data reporting given<br />
in the relevant guidelines (e.g. OECD, 1998). The material to be tested, with lot or batch number,<br />
should be well identified, characterized and standardized. It is important that for each study performed<br />
it is stated whether the test material conforms to the proposed specifications. If it does not conform,<br />
then the specifications of the test material should be given together with a rationale for using these<br />
data in the safety assessment of the product intended for the market.<br />
<br />
<br />
*''Toxicokinetics including metabolism''<br />
<br />
Information on toxicokinetics of relevant biologically active constituents present in the botanical or<br />
botanical preparation should be provided whenever available from the literature. Not all aspects need<br />
to be investigated in every case. Additional issues that may deserve consideration are:<br />
:*The possibility of interactions among constituents of the botanical or botanical<br />
preparation that can alter bioavailability, metabolism, and toxicity.<br />
:*The possibility of interactions with medicinal products.<br />
*''Genotoxicity testing''<br />
For the genotoxicity testing of botanicals and botanical preparations, in vitro tests covering effects<br />
both at gene and chromosome levels are required19. Specific tests are likely to include the Ames test<br />
(OECD guideline 471) and an in vitro test for the detection of chromosomal aberrations (OECD<br />
guideline 473) or an in vitro micronucleus assay (draft OECD guideline 487), and possibly the mouse<br />
lymphoma tk assay (OECD 476). The particular test strategy may depend upon the test material<br />
considered.<br />
<br />
There may be circumstances under which it may be justified to deviate from the above-mentioned<br />
core set. In such cases a scientific justification should be provided and additional types of<br />
considerations or mechanistic studies may be needed.<br />
<br />
A positive in vitro test normally requires follow-up by in vivo testing, unless it can be adequately<br />
demonstrated that the positive in vitro findings are not relevant for the in vivo situation. The choice of the appropriate in vivo test is critical, due to different sensitivities, different endpoints and other<br />
variables. It requires expert judgement based on all available information, to be applied case-by-case.<br />
For this reason, a flexible approach is preferable to a fixed decision tree.<br />
<br />
<br />
*''Subchronic toxicity testing''<br />
<br />
A 90-day study in the rat with the test material administered via the diet is the minimum requirement<br />
to establish a no-observed-adverse-effect level. Subchronic toxicity testing should be carried out<br />
independently of the results of the in vitro and in vivo genotoxicity testing.<br />
<br />
*''Other studies''<br />
<br />
Depending on the outcome of the genotoxicity and subchronic toxicity studies, or other specific<br />
relevant information, further studies may be required (e.g. reproductive toxicity, developmental<br />
toxicity, neurotoxicity, immunotoxicity, chronic toxicity/carcinogenicity).<br />
<br />
<br />
====3. Establishing a Compendium of botanicals and prioritising them to be considered for a<br />
safety assessment.====<br />
<br />
A Compendium of botanicals reported to contain toxic, addictive, psychotropic or other substances<br />
that may be of concern has been produced to complement the present guidance document.<br />
<br />
The Compendium contains the following information:<br />
:*The botanical (binomial) denomination of the plant (genus, species and in some cases variety or<br />
subspecies when relevant), with synonyms in use.<br />
:*The plant parts and substances of possible toxicological concern<br />
:*Additional specific information of relevance for the risk assessment, e.g. adulterations<br />
:*References, either to existing international / national list of plants that were used to populate the<br />
Compendium, or to published literature when specific information has been added.<br />
<br />
The Compendium aims at flagging plants or part of plants or substances of possible concern for<br />
human heath naturally present in the listed botanicals and that, therefore, require specific attention<br />
while assessing the safety of the product(s) containing such botanical(s). For some botanicals in the<br />
Compendium, adverse (toxic) effect(s) are mentioned although sometimes based on anecdotal reports<br />
and even though the constituent(s) of concern are not elucidated in the literature. In some cases the<br />
whole genus was flagged because of the likely presence of substances of concern characteristic for the<br />
toxicity of that genus.<br />
<br />
The presence of a substance of concern in a given botanical does not mean that this substance will<br />
also be present in the botanical preparation. This depends largely on the plant part used, as well as the<br />
preparation method.<br />
<br />
The Compendium contains also an “insufficient information” list regrouping botanicals that appear in<br />
one of the sources of information, but for which sufficient information could not be found on possible<br />
substances of concern, or for which the information available could not be verified.<br />
<br />
Without prejudice to the existing legal framework, it should be noted that this Compendium has no<br />
legal status and should not be used as support or evidence in any disagreement or dispute pertaining to<br />
the legal classification of products or substances.<br />
<br />
The Compendium is a living document which should be periodically updated by EFSA. As a<br />
consequence, the absence of a given species in this Compendium cannot be interpreted as meaning<br />
that the species is devoid of substances hazardous for human health. In the same way, not mentioning<br />
a specific part of plant, does not imply absence of substance(s) of concern in this part. Botanicals that<br />
have not been reported as having been considered for food or food supplement use in the European<br />
countries or botanicals classified as novel foods or GMOs will not appear in the Compendium.<br />
<br />
<br />
''Priority setting for safety assessment:''<br />
The botanicals in the above-mentioned Compendium should be assessed according to the following<br />
recommendations:<br />
<br />
Priority should be given to botanicals and botanical preparations:<br />
:*known to have an established history of food use and that have been identified to contain<br />
significant levels of substances of concern.<br />
:*that are not allowed/recommended for food use in some European countries, but which are<br />
still in use in some other EU countries, particularly when the intended use levels in food are<br />
known or expected to be high.<br />
:*for which some adverse health effects have been reported, either anecdotally, or on the basis<br />
of case reports of intoxication, epidemiological data or any toxicity data from livestock<br />
animals or experimental animals, or for botanicals that closely resemble botanicals which are<br />
known to have caused toxic effects.<br />
:*for which consumption has significantly increased during recent years in Member States.<br />
:*for which there are both limited history of use and toxicity data available, and for which the<br />
intended use levels are expected to be relatively high (e.g. high interest to the food industry).<br />
<br />
Botanical ingredients that are reported to have a low toxic potential, and for which the intended<br />
intake/exposure levels are within the range of intake levels resulting from the European Member<br />
States average diet would be given a low priority.<br />
<br />
<br />
===CONCLUSIONS AND RECOMMENDATIONS===<br />
<br />
A two-level tiered approach for the safety assessment of botanical ingredients intended for use in food<br />
supplements is proposed. This approach consists of a safety assessment based on available knowledge<br />
and a subsequent level in which further testing and/or data are required. It allows the recognition of<br />
presumption of safety without further testing, based on long-term history of use with no reported<br />
adverse effect and with no significant increased exposure. For those botanical ingredients for which a<br />
presumption of safety based on available data cannot be established, it introduces a framework for<br />
assessing their safety, including the types of testing that would be most useful. Recommendations for<br />
prioritising botanicals for safety assessment are also made.<br />
<br />
The Compendium of botanicals reported to contain toxic, addictive, psychotropic or other substances<br />
that may be of concern, is considered to facilitate the assessment by flagging possible safety issues,<br />
and should therefore be considered as an essential part of this guidance document. The Scientific<br />
Committee recommends to maintain it up-to-date, making use of relevant available national lists of<br />
plants and of any other relevant data available, as well as of updated assessments carried out on<br />
botanicals by qualified bodies. The Scientific Committee also recommends to further expand the<br />
Compendium with botanicals not having any market history in Europe in order to prepare the<br />
implementation of the new Novel Food Regulation, which foresees a notification process for<br />
botanicals and botanical preparations having a history of safe use in the third country of origin.<br />
<br />
<br />
'''European Food Safety Authority'''<br />
<br />
''SCIENTIFIC COMMITTEE''<br />
Discussion Paper on “Botanicals and Botanical Preparations widely used<br />
as food supplements and related products: Coherent and Comprehensive<br />
Risk Assessment and Consumer Information Approaches”<br />
<br />
(adopted by written procedure on 23 June 2004)<br />
<br />
1. In view of the fact that botanicals and botanical preparations intended for human<br />
consumption as food supplements and related products are very widely marketed<br />
with a variety of claims, the present discussion paper aims at increasing awareness<br />
of some key issues to improve comprehensiveness and coherence of current<br />
approaches to risk assessment and consumer information on these products.<br />
<br />
2. A large number of botanical materials (e.g. whole, fragmented or cut plants, algae,<br />
fungi, lichens), and botanical preparations obtained from these materials by various<br />
processes (e.g. extraction, distillation, purification, concentration and fermentation)<br />
readily find their way onto the food supplements market. These materials are also<br />
often labelled as natural foods, largely organic, and foods specifically intended to<br />
support sport activities. Personal care products and the so-called “traditional herbal<br />
medicinal products” represent additional sources of exposure of consumers to<br />
botanical products. New products are also emerging, consisting of substances that<br />
commonly occur at low levels in botanical components of the diet, which are then<br />
extracted and re-introduced at much higher levels in specific products.<br />
<br />
3. Botanicals and botanical preparations are widely available to consumers through<br />
several distribution channels in the E.U. and elsewhere. In particular, they are sold<br />
over the counter in pharmacies and can be bought in supermarkets, herbalist’s<br />
shops and other shops, or via the Internet. They are currently available and used in<br />
such a way that they are almost becoming part of the common diet, thus providing<br />
for a significant human exposure from a public health point of view.<br />
<br />
4. There are some general concerns with respect to botanicals and botanical<br />
preparations mainly relating to quality and safety issues:<br />
:*Contamination (both chemical and microbiological) is a documented problem.<br />
It has been associated, for example, with botanical products originating from<br />
Asia. Deaths through poisoning following consumption of such products have<br />
been reported in Europe and the US arising from contamination with heavy<br />
metals, synthetic drugs and other undesirable substances (Ernst, 2002).<br />
Misidentification of plants harvested from the wild is also a continuing<br />
problem. When sales of traditional herbal products remained restricted to<br />
particular ethnic groups, which are familiar with the products and able to exert a<br />
local control on quality, problems were more rarely encountered. The growing<br />
volume of sales in the European Union with products obtained from suppliers<br />
based in Asia or elsewhere and the move towards widespread outlets for the<br />
products of traditional medicine call for more formal pre-marketing assessment<br />
and more stringent controls than the occasional random checks and analyses<br />
often carried out by individual national or local authorities on what is already<br />
out in the market.<br />
:*There is world-wide recognition of potential problems associated with<br />
botanicals and botanical products, not only in terms of safety, but also in terms<br />
of the claimed amounts and stability of the active ingredients. For example, the<br />
US Pharmacopeia, which considers the safety of food supplements as well as<br />
medicines, announced in December 2002 the establishment of an advisory<br />
panel specifically to advice on improving the quality of botanical products.<br />
:*Any efficacy shown by botanical products is usually a product of one or more<br />
plant secondary metabolites. Secondary metabolism responds to stress imposed<br />
by biotic and abiotic factors and, as a consequence, patterns and concentrations<br />
of metabolites can show considerable variation among plants belonging to the<br />
same species and variety. For instance, it is not unusual for metabolites<br />
produced in response to pathogen attack to vary in concentration one thousandfold<br />
over short time periods. While consistency of product is more easily<br />
controlled in cultivated plants, particularly those grown in containment,<br />
collections from the wild make it difficult to ensure that concentrations of<br />
bioactive agents meet specifications and are within safe limits.<br />
:*A very large literature exists on toxic substances naturally-occurring in plants.<br />
Of particular concern are plant products consumed in concentrated forms.<br />
Concerns can relate directly to the toxicological profile of the active agent(s). It<br />
has been the case with kava-kava (Piper methysticum), its withdrawal from the<br />
market being advised recently because of the association of its consumption with acute liver failure (Kraft et al., 2001). In June 2001, the US FDA,<br />
following action by the UK and Australia, advised manufacturers of dietary<br />
supplements to avoid the use of the various types of comfrey (Symphytum spp.)<br />
because of the health concerns associated with the presence of pyrrolizidine<br />
alkaloids. Moreover, since 1993, cases of nephrotoxicity and carcinogenicity<br />
have been reported in Belgium, France and United Kingdom as a result of<br />
inadvertent exposure to Aristolochia species in unlicensed herbal medicines<br />
(EMEA, 2000).<br />
:*Interactions of herbal products with prescription products are well recognised,<br />
although widely under-reported (Ernst, 2000; Sorensen, 2002). In the past,<br />
when such products were usually obtained from outlets run by knowledgeable<br />
individuals, advice on use and contra-indications was often available. Currently,<br />
contra-indications do not usually appear on the labels or any associated<br />
documentation when herbal products are sold through supermarkets and other<br />
retail outlets. Yet, a survey of the available information on interactions with<br />
medicinal compounds of the more commonly purchased botanical products<br />
(e.g. ginkgo, garlic, St. John’s Wort and ginseng) found recorded adverse<br />
interactions for all but Echinacea and saw palmetto (Izzo and Ernst, 2001).<br />
Incidence and severity of effects associated with prescription drug-dietary<br />
supplement interactions in a small group of primary care patients have also<br />
been investigated by Peng et al. (2004); the most common botanical products<br />
included garlic, ginkgo biloba, saw palmetto and ginseng. While most<br />
interactions were judged not to be serious, an incidence of 6% of potentially<br />
severe health consequences was recorded among patients taking at the same<br />
time specific drugs and specific botanical products.<br />
<br />
5. This heterogeneous group of commodities includes products which, mainly<br />
depending on their intended uses and presentations, fall under different Community<br />
regulatory frameworks and for some types of products legal provisions for a<br />
preliminary risk assessment do not exist yet. The main legislations to be considered<br />
in this context are Directive 2002/46/EC on food supplements and Directive<br />
2004/27/EC on traditional herbal medicinal products:<br />
<br />
:*Directive 2002/46/EC foresees the use as food supplements of vitamins and<br />
minerals listed in the Annexes to the Directive. It also allows the use for the<br />
same purpose of still undetermined substances with a nutritional or<br />
physiological effect, but definition of such effects is not provided for.<br />
According to Art. 4, para 8, the European Commission shall produce, not later<br />
than 12 July 2007, a report on the advisability of establishing specific rules,<br />
including, where appropriate, categories of additional vitamins and minerals or<br />
of substances with a nutritional or physiological effect, accompanied by any proposals for amendments to Directive 2002/46/EC**. Thus a regulatory<br />
framework for further developments in this area already exists.<br />
:*Directive 2004/27/EC on “traditional herbal medicinal products” provides for<br />
definitions of (i) traditional herbal medicinal products, (ii) herbal medicinal<br />
products, (iii) herbal preparations and (iv) herbal substances. The directive<br />
introduces a simplified registration procedure, based on “traditional use”, but<br />
ensuring quality and safety as for any other medicinal product. Community lists<br />
will have to be prepared of traditional herbal medicinal products, herbal<br />
preparations and herbal products. On the other hand, traditional herbal<br />
materials, which are authorised for use in medicinal products, will continue to<br />
contribute to the dietary intake of bioactive agents as long as they comply with<br />
the general food regulations and make no medicinal claim.<br />
<br />
6. Also relevant in this context are the Directives 1989/398/EEC and 96/84/EC on<br />
“Food for special purposes” and the Regulation 1997/258/CE on “novel foods” that<br />
provide additional channels for some botanicals and botanical preparations to enter<br />
the food market, and the proposed Directives on “nutritional and health claims” and<br />
“food fortification” at present under consideration by the European Parliament and<br />
Council.<br />
<br />
7. As the market volume expands, so does the need for a better characterisation of<br />
botanicals and botanical preparations, and for harmonising the scientific assessment<br />
of risks from exposure of consumers to these products.<br />
<br />
8. It is important, therefore, from a public health point of view, to achieve a<br />
comprehensive and coherent approach to risk assessment and consumer<br />
information on botanicals and botanical preparations widely present in different<br />
categories of commodities. Such an approach would, in time, overcome the existing<br />
information gaps on many of these products and bring together the fragmentary<br />
provisions for risk assessment on botanicals and botanical preparations in the<br />
current relevant regulations. To this end, the present paper aims at increasing<br />
awareness on these issues and at facilitating a critical analysis of the present<br />
situation. It is intended to lead to a stronger partnership and collaboration among all<br />
the stakeholders who have a role in this important sector.<br />
<br />
9. Although it is not the objective of this discussion paper to provide a detailed<br />
analysis of the way forward, the following reflections address some issues in order<br />
to facilitate an open discussion particularly in the frame of future developments of<br />
the above-mentioned Directive 2002/46/EC:<br />
<br />
:*As systematic information about the range of botanicals and botanical products<br />
present on the market is lacking, consideration could be given, to carrying out a<br />
survey to identify the main product categories currently marketed and a study to<br />
clarify the potential health-related issues that may need to be addressed.<br />
:*In view of the difficulty of compiling a full inventory of botanicals and<br />
botanical products, the possibility could also be considered of adopting and<br />
regularly updating a list of plants or parts of plants which should not be used or<br />
could be put under scrutiny because of the presence of undesirable substances,<br />
especially if effective reduction or removal of such substances can not be<br />
ensured.<br />
:*As purity specifications for all botanicals and botanical preparations are very<br />
difficult to define, the development of ad hoc manufacturing guidelines, could<br />
be considered in order to improve their characterisation and safety. Experience<br />
already existing in the pharmaceutical sector could be helpful to this end.<br />
:*Considering the importance of providing to consumers adequate information to<br />
allow the safe use of botanicals and botanical preparations, the possibility of<br />
establishing accredited information sources easily accessible to consumers on<br />
these products also deserves attention. A complicating issue in this respect is<br />
the diffusion of misleading claims which are very difficult to counterbalance by<br />
means of reliable consumer information. However, in this respect, the situation<br />
is likely to improve when the proposal for a Community Directive providing for<br />
a clear evaluation procedure of “Nutritional and Health Claims” will be<br />
adopted.<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
http://www.efsa.europa.eu/de/scdocs/doc/1249.pdf</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=EFSA_guidance_on_safety_assessment_of_botanicals&diff=22000
EFSA guidance on safety assessment of botanicals
2011-07-07T10:33:03Z
<p>Minttu: </p>
<hr />
<div>{{nugget<br />
|authors= <br />
|reference= <br />
|urn= <br />
|ethics= <br />
|journal=<br />
|moderator=Minttu<br />
|stub=Yes}}<br />
<br />
EFSA Journal 2009; 7(9):1249<br />
For citation purposes: EFSA Scientific Committee; Guidance on safety assessment of botanicals and botanical preparations<br />
intended for use as ingredients in food supplements, on request of EFSA. EFSA Journal 2009; 7(9):1249. [19 pp.].<br />
doi:10.2093/j.efsa.2009.1249. Available online: www.efsa.europa.eu<br />
© European Food Safety Authority, 2009 1<ref>[http://www.efsa.europa.eu/de/scdocs/doc/1249.pdf]: EFSA Journal 2009; 7(9):1249<br />
For citation purposes: EFSA Scientific Committee; Guidance on safety assessment of botanicals and botanical preparations<br />
intended for use as ingredients in food supplements, on request of EFSA. EFSA Journal 2009; 7(9):1249. [19 pp.].<br />
doi:10.2093/j.efsa.2009.1249. Available online: www.efsa.europa.eu<br />
© European Food Safety Authority, 2009 1 </ref><br />
<br />
<br />
'''''SCIENTIFIC OPINION'''''<br />
<br />
<br />
''Guidance on Safety assessment of botanicals and botanical preparations intended for use as ingredients in food supplements''<br />
<br />
<br />
'''EFSA Scientific Committee'''<br />
<br />
<br />
European Food Safety Authority (EFSA), Parma, Italy<br />
<br />
<br />
This guidance document published on 9 September 2009, replaces the earlier version published on 20<br />
June 2008 with the Question Number: EFSA-Q-2005-233.<br />
<br />
<br />
''ABSTRACT''<br />
<br />
In this opinion, EFSA’s Scientific Committee provides guidance on the scientific data needed to carry out a safety assessments of a botanical or a botanical preparation. It also proposes a two-tiered scientific approach for the safety assessment depending on the available knowledge on a given botanical and the substance(s) it contains. The guidance also provides a set of criteria to help prioritise the safety assessment of botanical ingredients which<br />
are in use. EFSA has also compiled the available information on a large number of botanicals which have been reported to contain substances that may be of health concern when used in food or food supplements. The resulting compendium, which will be regularly updated, should be considered as part of this guidance document<br />
and is intended to assist manufacturers and food safety authorities by highlighting possible safety issues which may require further consideration.<br />
<br />
<br />
''KEY WORDS''<br />
<br />
Botanicals, botanical preparations, safety assessment, food supplements, toxicological properties, medicinal<br />
properties.<br />
<br />
<br />
''SUMMARY''<br />
<br />
Following the discussion paper of the Scientific Committee on botanicals and botanical preparations<br />
adopted on 23 June 2004, The European Food Safety Authority (EFSA) asked in August 2005 the<br />
Scientific Committee to develop a two-level tiered approach for the safety assessment of botanicals<br />
and botanical preparations. This approach consists of a first safety assessment level based on<br />
available knowledge and a subsequent level in which the safety assessment includes newly generated<br />
data.<br />
<br />
<br />
The present guidance document is focussed on botanicals and botanical preparations intended for use<br />
in food supplements, although the approach chosen is, in principle, applicable also to other uses of<br />
botanicals and botanical preparations in the food and feed areas.<br />
<br />
<br />
A general framework for safety assessment is proposed by the Scientific Committee, in which<br />
botanicals or botanical preparations for which an adequate body of knowledge exists could benefit<br />
from a “presumption of safety” without any need for further testing. Issues that should be carefully<br />
considered in order to reach such a conclusion are discussed in detail in the present guidance<br />
document. Botanicals and botanical preparations for which a presumption of safety is not possible<br />
based on available knowledge would be subject to a more extensive safety assessment, requiring<br />
additional data to be provided.<br />
<br />
<br />
It is not the objective of this opinion to produce a list of safe botanicals and botanical preparations<br />
intended for food supplement use, but only to provide guidance on how to assess safety of botanical<br />
ingredients.<br />
<br />
<br />
The Scientific Committee developed criteria for prioritising botanicals for safety assessment and has<br />
compiled a Compendium of botanicals that are reported to contain toxic, addictive, psychotropic or<br />
other substances that may be of concern. The main purpose of the Compendium, which should be<br />
considered as part of this guidance document, is to draw attention to issues that would need to be<br />
taken into account when assessing the safety of botanicals used as ingredients in food supplements,<br />
and to facilitate the establishment of priorities for safety assessment.<br />
<br />
<br />
The Scientific Committee recommends maintaining the Compendium up-to-date, making use of<br />
relevant available national lists of plants and of any other relevant data available, as well as of<br />
updated assessments carried out on botanicals by qualified bodies. The Scientific Committee also<br />
recommends to further expand the Compendium with botanicals not having any market history in<br />
Europe but having a documented history of use in their third country of origin.<br />
<br />
<br />
TABLE OF CONTENTS<br />
:*Abstract <br />
:*Summary <br />
:*Table of contents <br />
:*Background as provided by EFSA <br />
:*Terms of reference as provided by EFSA <br />
:*Acknowledgements <br />
:*Assessment <br />
:1.Introduction <br />
:2.Safety assessment of botanicals and botanical preparations intended for use as ingredients in<br />
food supplements <br />
:2.1Proposed data requirements for safety assessment of botanicals and botanical preparations<br />
used as ingredients in food supplements <br />
:2.1.1.Technical data<br />
::2.1.1.1. Identity and nature of the source material <br />
::2.1.1.2. Manufacturing process<br />
::2.1.1.3. Chemical composition <br />
::2.1.1.4. Specifications <br />
::2.1.1.5. Stability of the botanical or botanical preparation used as ingredient in food supplement <br />
::2.1.1.6. Proposed uses and use levels <br />
::2.1.1.7. Information on existing assessments <br />
:2.1.2. Exposure: extent and duration <br />
:2.1.3. Toxicological data <br />
2.2. Proposed general framework for assessing the safety of botanicals and botanical<br />
preparations used as ingredients in food supplement <br />
:2.2.1. Level A: Safety assessment based on available knowledge <br />
:2.2.2. Additional data required for the level B assessment <br />
3. Establishing a Compendium of botanicals and prioritising them to be considered for a safety<br />
assessment. <br />
:*Conclusions and recommendations <br />
:*References <br />
<br />
<br />
''BACKGROUND AS PROVIDED BY EFSA''<br />
<br />
A discussion paper by the Scientific Committee on botanicals and botanical preparations widely used<br />
in food supplements and related products was adopted on 23 June 2004 (SC document EFSA/SC/26<br />
Final3). In this paper, the Committee expressed concerns about quality and safety issues of botanicals<br />
and botanical preparations that have become widely available to consumers through several<br />
distribution channels in the EU. The use of botanicals and botanical preparations in food is regulated<br />
under the General Food Law (178/2002/EC), which attributes the primary legal responsibility for the<br />
safety of the products placed on the market to business operators. The Regulation however does not<br />
provide any guidance on how the safety of these products should be assessed. As the market volume<br />
and the variety of products expand, so does the need for a better characterisation of the range of<br />
botanicals and botanical preparations on the market, and for harmonising the risk assessment and<br />
consumer information approaches for these products. The paper aimed at increasing awareness of<br />
EFSA’s Advisory Forum on potential public health aspects associated with these products.<br />
<br />
<br />
The Secretariat brought the discussion paper to the attention of the Advisory Forum at its meeting of<br />
the 1st of October, 2004. Simultaneously, an invitation was sent to the members of the Advisory Forum to take note of the concerns<br />
raised by the Scientific Committee and to complete a questionnaire to provide a better understanding of the issue in Europe.<br />
<br />
<br />
By the end of January 2005, replies were received from twenty five countries, comprising twenty two<br />
EU Member States and three EFTA Countries. The members of the Advisory Forum underlined the<br />
importance of this issue for their countries and asked EFSA to initiate a self-task in order to develop<br />
some guidance on how to assess the safety of botanical ingredients.<br />
<br />
<br />
Following the mandate received by the Scientific Committee in August 2005 from EFSA, the<br />
Scientific Committee developed a two-level tiered approach for the safety assessment of botanicals<br />
and botanical preparations. A guidance document focussing on botanicals and botanical preparations<br />
intended for use as food supplements was published after public consultation.<br />
<br />
<br />
A conceptual framework for safety assessment was advocated, in which botanicals or botanical<br />
preparations for which an adequate body of knowledge exists could benefit from a “presumption of<br />
safety” without any need for further testing (first level of the framework). Issues that should be<br />
carefully considered in order to reach such a conclusion were discussed in detail in the guidance<br />
document. Botanicals and botanical preparations for which a presumption of safety is not possible<br />
would be subject to a more extensive safety assessment, based on additional data to be provided in<br />
accordance with the methodology described in the second level of the proposed framework.<br />
<br />
<br />
As a follow up, it was decided to test the adequacy of the above-mentioned approach described in the<br />
guidance document for safety assessment with a selected number of examples including botanicals<br />
known to contain toxic substances or having a reported toxic effect, botanicals with an established<br />
history of food use, and botanicals that are known to contain potentially genotoxic/carcinogenic<br />
substances. To this end, an EFSA Scientific Cooperation (ESCO) Working Group, composed of<br />
experts identified by the members of the Advisory Forum and by the Scientific Committee EFSA was<br />
established in April 2008. This working group was also given the task to finalise the Compendium of<br />
botanicals reported to contain toxic, addictive, psychotropic, or other substances of concern. The resulting ESCO report and Compendium9 were provided to the EFSA Executive Director in May<br />
2009.<br />
<br />
<br />
''TERMS OF REFERENCE AS PROVIDED BY EFSA''<br />
<br />
The Scientific Committee has been requested in May 2009 by the European Food Safety Authority<br />
to consider the recommendations made in the ESCO report for updating the guidance document for<br />
the safety assessment of botanicals and botanical preparations intended for use as ingredients in food<br />
supplements.<br />
<br />
<br />
''ACKNOWLEDGEMENTS''<br />
<br />
The European Food Safety Authority wishes to thank the members of the EFSA Scientific<br />
Cooperation (ESCO) Working Group on Botanicals and Botanical Preparations for the preparation of<br />
the ESCO Report, which was used by the Scientific Committee to update this guidance document.<br />
The European Food Safety Authority would also like to thank the members of the former Scientific<br />
Committee for their contributions to the present guidance document.<br />
<br />
<br />
''ASSESSMENT''<br />
<br />
1. '''Introduction'''<br />
The Scientific Committee decided to focus its work first on the safety assessment of botanicals and<br />
botanical preparations used as ingredients in food supplements (hereafter referred to, as botanical<br />
ingredients), although the approach chosen is, in principle, applicable also to other uses of botanicals<br />
and botanical preparations in the food and feed areas. It is not in the scope of the present guidance to<br />
address issues related to quality assurance and good hygienic practices currently regulated by the EU<br />
Food Legislation, nor to assess the safety of food supplements as end products. The present guidance<br />
does not therefore address hazards linked to the presence of contaminants and foodborne pathogens in<br />
the botanicals and botanicals preparations.<br />
<br />
<br />
A two-level tiered conceptual framework for safety assessment consisting of a safety assessment<br />
based on available knowledge and a subsequent level in which further testing and/or data are required<br />
is proposed by the Scientific Committee. Botanicals or botanical preparations for which an adequate<br />
body of knowledge exists, can benefit from a “presumption of safety” without any need for further<br />
testing. Based on reasonable evidence, they can then be assumed to be safe, sometimes under certain<br />
restrictions. The Scientific Committee used as an example the Qualified Presumption of Safety (QPS)<br />
approach developed for microorganisms in food and feed (EFSA, 2007a) to propose criteria for<br />
presuming a botanical or a botanical preparation safe. Botanicals and botanical preparations for which<br />
a presumption of safety is not possible should be subject to a more extensive safety assessment, based<br />
on additional data to be provided according to the methodology described by EFSA. By proposing a<br />
first safety assessment level based on available knowledge, the approach proposed by the Scientific<br />
Committee for the safety assessment of botanicals and botanical preparations is in line with EFSA’s<br />
policy to stimulate food and feed risk assessment approaches that minimise the number of<br />
experimental animals and any suffering (EFSA, 2009).<br />
<br />
<br />
In order to facilitate the implementation of the above-mentioned approach, EFSA has also compiled a<br />
Compendium of botanicals and botanical preparations that have been reported to contain toxic,<br />
addictive, psychotropic or other substances that may be of concern. This Compendium should be seen<br />
as a tool to gather relevant information and define priorities for safety assessment. The inclusion of a<br />
botanical in this Compendium does not imply that it is not safe for use in food supplements. Without<br />
prejudice to the existing legal framework, such Compendium has no legal status and may not be used<br />
as support or evidence in any disagreement or dispute pertaining to the legal classification of products<br />
or substances.<br />
<br />
<br />
Safety assessment of botanicals and botanical preparations<br />
EFSA Journal 2009; 7(9):1249 7<br />
<br />
<br />
2. '''Safety assessment of botanicals and botanical preparations intended for use as<br />
ingredients in food supplements'''<br />
<br />
It should be noted that Regulation 258/97/EC concerning novel foods and novel food ingredients<br />
applies to all foods, including food supplements, containing substances which have not been used for<br />
human consumption to a significant degree within the Community before 15 May 1997 and which fall<br />
under certain categories specified in the above-mentioned Regulation. In the case of a proposed use as<br />
a novel food, botanicals or botanical preparations should be assessed following the guidelines of the<br />
Commission Recommendation 97/618/EC of 29 July 1997 concerning the scientific aspects and the<br />
presentation of information necessary to support applications for the placing on the market of novel<br />
foods and novel food ingredients.<br />
<br />
<br />
Moreover, Regulation 1829/2003/EC on genetically modified food and feed would apply to any GMO<br />
ingredients used in food supplements. In the case of botanicals or botanical preparations derived from<br />
genetically modified plants, information should be provided in line with the guidance document of the<br />
EFSA Scientific Panel on Genetically Modified Organisms for the risk assessment of genetically<br />
modified plants and derived food (EFSA, 2006a).<br />
When the botanical or botanical preparation is intended for use as a food intended for particular<br />
nutritional uses (PARNUTS – Directive 89/398/EEC), the guidance document from the Scientific<br />
Committee on Food on submissions for safety evaluation of sources of nutrients or of other<br />
ingredients proposed for use in the manufacture of foods (SCF, 2001a) should also be consulted.<br />
<br />
<br />
It should also be underlined that this report only deals with guidance on safety assessment, whereas<br />
the scientific substantiation of any claims made on food supplements, as required by the Regulation<br />
on Nutrition and Health Claims, will be dealt with in separate EFSA documents, such as the<br />
“Scientific and technical guidance for the preparation and presentation of the application for<br />
authorisation of a health claim” (EFSA, 2007b).<br />
It is not the objective of this report to produce a list of safe botanicals and botanical preparations<br />
intended for food supplement use, but only to provide guidance on how to assess safety of botanical<br />
ingredients. Moreover, priority criteria are proposed, and a Compendium has been compiled to serve<br />
as a preliminary tool for risk assessors (see section 3).<br />
<br />
<br />
2.1. '''Proposed data requirements for safety assessment of botanicals and botanical<br />
preparations used as ingredients in food supplements'''<br />
<br />
It is understood that the use of botanicals and botanical preparations as ingredients in food<br />
supplements will have to be in compliance with the existing EU Food Legislation. This would<br />
include maximum permissible levels of chemical and biological contaminants (e.g. pesticides,<br />
mycotoxins, heavy metals and foodborne pathogens), modalities for ensuring quality, and application<br />
of good hygienic practice, including HACCP methodologies. The issues of controls needed to ensure<br />
constancy over time of the composition of botanical food supplements on the market and batch-tobatch<br />
variation are not addressed in this document as these are risk management aspects and therefore<br />
outside the scope of EFSA.<br />
<br />
The following sections aim at identifying data and information considered as necessary to assess the<br />
safety of botanical ingredients. These data are of: (i) technical; (ii) exposure and (iii) toxicological<br />
nature. The lists below are meant to give guidance on data requirements. They have been made as<br />
exhaustive as possible and should be adapted on a case-by-case basis, depending on the nature of the<br />
botanical or botanical preparation. This implies that not all the information listed below would be<br />
needed in all cases and that the amount of information available for a given botanical or botanical<br />
preparation may in some cases be sufficient without further testing (see section 2.2.1).<br />
<br />
<br />
2.1.1. '''Technical data'''<br />
<br />
2.1.1.1. Identity and nature of the source material<br />
<br />
It is recognized that identification of the botanical source and botanical preparation may in some cases<br />
be complicated. It is recommended to follow as much as possible the nomenclature of the European<br />
Pharmacopeia. Additional nomenclature sources are as follows:<br />
<br />
World Checklist of Selected Plant Families (Royal Botanic Garden, Kew); the books by Hanelt<br />
(2001) also available on the Internet as Mansfeld’s World Database of Agricultural and Horticultural<br />
Crops; and the database by United States Department of Agriculture. If a scientific name is not found<br />
in any of the above-named references, its existence may be checked in The International Plant Names<br />
Index.<br />
<br />
<br />
Since there have been many instances where species have been reclassified or renamed, a same<br />
species may be known by different scientific names. Common (vernacular) names may also be<br />
provided, but it should be noted that a common name used in one region to refer to a particular plant<br />
may be used elsewhere to refer to another quite unrelated species. Hence common names may not<br />
uniquely identify a species and are not as reliable as the scientific names.<br />
<br />
<br />
The following scheme summarizes the requirements for description of the identity of the botanical:<br />
<br />
<br />
;Scientific (Latin) name:<br />
:full systematic species name incl. botanical family, genus,<br />
species, variety, subspecies, author’s name, and chemotype if<br />
applicable<br />
<br />
;Synonyms: <br />
:botanical name(s) that may be used interchangeably with the<br />
preferred scientific name<br />
;Common names: <br />
:vernacular name(s)<br />
;Part used: <br />
:e.g. root, leaf, seed...<br />
;Geographical origin: <br />
:continent, country, region<br />
;Growth and harvesting conditions: <br />
:wild or cultivated, cultivation practices, time of harvest in relation<br />
to both season and stage of the plant growth.<br />
<br />
<br />
2.1.1.2. Manufacturing process<br />
<br />
The following information is considered necessary for assessing the safety of botanicals and botanical<br />
preparations:<br />
i):Information on the method(s) of manufacture (e.g. the process by which the raw material is<br />
converted into a preparation, such as extraction or other procedure(s), and plant extract ratio)<br />
<br />
ii):Information on substances entering the manufacturing process, e.g. identity of the extraction<br />
solvent, reagents, special precautions (light and temperature).<br />
<br />
iii):Standardization criteria (e.g. see European Pharmacopoeia).<br />
<br />
Botanicals or botanical preparations might become hazardous as a result of deviations in the<br />
production process (e.g. misclassification, switching of species). Therefore the safety of botanicals<br />
and botanical preparations should be ensured by following a Hazard Analysis and Critical Control<br />
Point (HACCP) approach (Codex Alimentarius 1997). The whole production chain, from primary<br />
production of botanicals to the storage and commercialisation of the botanical preparations should be<br />
taken into consideration. The HACCP system must be applied with the necessary flexibility and<br />
adapted to each botanical preparation on a case-by-case basis.<br />
<br />
<br />
2.1.1.3. Chemical composition<br />
<br />
Data on the chemical composition of the botanical ingredient should be provided with emphasis on<br />
the concentrations of constituent of relevance for the safety assessment; this includes the<br />
concentrations of:<br />
:*Compounds should be classified according to their chemical structure (e.g. flavonoids,<br />
terpenoids, alkaloids, etc.). Levels at which the constituents are present in the respective part<br />
of the botanical or botanical preparation should be given where available.<br />
:*Constituents to characterise the quality, chemical fingerprint, production process and/or<br />
biological activity of the preparation (markers).<br />
:*Constituents that provide reasons for concern due to their chemical, physiological or<br />
toxicological properties.<br />
In some cases, it may be difficult to identify the active principle responsible for an effect. Therefore<br />
the strength of the evidence underlying the concerns over a compound being reason for concern<br />
should also be given.<br />
<br />
<br />
2.1.1.4. Specifications<br />
<br />
Specifications of the botanicals or botanical preparations are required. They may be based on<br />
nutritional or biologically active components or, when these are not known, on selected chemical<br />
markers. Limits for or absence of specific undesirable / toxic substances should be specified. The<br />
proposed specifications should be modelled on recent European or other internationally accepted<br />
specifications (e.g. pharmacopoeia or the guidelines of the EMEA Committee on Herbal Medicinal<br />
Safety assessment of botanicals and botanical preparations<br />
<br />
Products (HMPC)). Where the proposed specifications differ from internationally recognised<br />
specifications, the latter specifications should be set out alongside the proposed new specifications,<br />
and any differences pointed out. Validated and well-established methods should be preferably used<br />
for the analysis of compounds considered in specifications.<br />
<br />
The specifications should include concentrations of major groups of constituents present in the<br />
botanical preparation including for example: amino acids, lipids, polysaccharides, volatile oil,<br />
inorganic ions, polyphenols, alkaloids, terpenes, alkenylbenzenes, lignin, saponins etc. as well as the<br />
major constituents within these classes.<br />
<br />
In addition, information on maximum levels for possible contaminants including e.g. heavy metals,<br />
mycotoxins, pesticide residues, and polycyclic aromatic hydrocarbon (PAH) residues should be<br />
provided.<br />
<br />
<br />
2.1.1.5. Stability of the botanical or botanical preparation used as ingredient in food supplement<br />
<br />
The stability of the botanical ingredient should be demonstrated over the shelf-life time. Any<br />
information concerning possible degradation should also be provided.<br />
<br />
<br />
2.1.1.6. Proposed uses and use levels<br />
<br />
Information on intended uses and recommended intakes for a product should specifically mention<br />
uses and use levels for the following categories:<br />
:* Common foods<br />
:* Food supplements<br />
:* Medicinal products<br />
<br />
Special attention should be given to population groups with specific uses like for example young<br />
children. Information on the duration of the proposed uses and use levels should also be provided<br />
<br />
<br />
2.1.1.7. Information on existing assessments<br />
<br />
Information on any existing assessments by international bodies or national competent authorities<br />
should be provided.<br />
<br />
<br />
2.1.2. '''Exposure: extent and duration'''<br />
<br />
Data and information should be provided on:<br />
:i) Anticipated human exposure to the botanical ingredient, including amount (e.g. maximum and<br />
average daily intake or exposure), frequency and duration. It is important to characterize as much as<br />
possible the expected human exposure to the botanical ingredient according to the recommended<br />
modalities of use in terms of extent and duration. Clear distinction should be made between intake of<br />
a botanical itself, intake of its essential oil and other preparations made of it.<br />
:ii) Possibility of additional / combined human exposure to the botanical or botanical preparation<br />
through different categories of food, food supplements and/or medicinal products that can be<br />
consumed together.<br />
:ii) Modality of use of the ingredient.<br />
:iv) Information on historical (food, food supplement and medicinal) use of the ingredient in<br />
human population groups in relation to the modalities of use and resulting exposure levels if known.<br />
Data derived from use outside of the European Union should also be considered.<br />
<br />
<br />
All data should be representative of the ingredient to be used for the European market. In this context,<br />
food use includes, in principle, the consumption of raw and cooked vegetables, spices, flavours, food<br />
supplements already in use for a long time16 and any other related food items.<br />
<br />
<br />
Estimates of average exposure ranges associated with the use of the botanical ingredient in the EU<br />
Member States should also be provided. Uncertainties associated with the food consumption data<br />
considered and anticipated exposure ranges should be clearly described (EFSA, 2006b).<br />
<br />
A matter to be specifically addressed in the evaluation is whether the proposed use and use levels will<br />
significantly increase already existing human exposure.<br />
<br />
<br />
2.1.3. '''Toxicological data'''<br />
<br />
Studies on toxicity and toxicokinetics including metabolism of botanicals and botanical preparations<br />
should be conducted using internationally agreed protocols. Test methods described by OECD or in<br />
European Commission Directives 87/432/EEC and 67/548/EC – Annex 5 are recommended. It is<br />
advisable to ensure that the most up-to-date version of any test guideline is followed. Use of any<br />
methods differing from internationally agreed protocols should be justified. Protocols for special<br />
studies differing from standard tests should be developed on a case-by-case basis.<br />
<br />
To ensure general acceptance of the data submitted, studies should be carried out according to the<br />
principles of Good Laboratory Practice (GLP) described in Council Directive 87/18/EEC and<br />
accompanied by a statement of GLP compliance. Adequate explanation should be provided for<br />
divergence from these principles.<br />
<br />
Council Directive 86/609/EEC, on the protection of animals used for experimental and other scientific<br />
purposes, requires that care is taken to avoid unnecessary use of animals. Studies carried out should<br />
be those necessary to demonstrate the safety of a botanical or botanical preparation and planned in<br />
accordance with the principles of reduction, refinement and replacement. However, where adequate<br />
data are not available for the safety assessment (see section 3.2.1), in vivo studies using experimental<br />
animals may be needed in order to assess possible risks to humans from the ingestion of botanicals or<br />
botanical preparations. Alternative validated methods involving fewer or no animals for toxicity<br />
endpoints may in the future be developed and should be considered on a case-by-case basis.<br />
<br />
If available, data on possible interactions (e.g. herbal-drug) should also be provided.<br />
<br />
<br />
2.2. '''Proposed general framework for assessing the safety of botanicals and botanical<br />
preparations used as ingredients in food supplement'''<br />
<br />
Several guidance documents (AFSSA, 2003; Council of Europe, 2005; Schilter et al., 2003) have been<br />
published on the principles for assessment of botanicals and botanical preparations in the food and<br />
feed area. The present guidance document is not intended to reiterate these, but to outline a<br />
framework that could be used by risk assessors when assessing the safety of a botanical or a botanical<br />
preparation. It also proposes a scientific approach to the assessment of available data.<br />
<br />
The aim of the assessment is to ensure that botanicals or botanical preparations, when used in food<br />
supplements in the manner, quantities and time period of intake proposed, would not pose a risk to the<br />
health of consumers. Data should provide not only information relevant to the healthy adult consumer,<br />
but also relevant to those population groups potentially vulnerable due to their pattern of food<br />
consumption or their physiological or health status, e.g. young age, elderly, pregnancy,<br />
immunocompromised etc.<br />
<br />
A general framework for assessing the safety with core tests and other tests is given, which should<br />
enable determination of what information is required to establish the safety-in-use of the botanical or<br />
botanical preparation. The application of this guidance to specific cases will depend on the nature of<br />
the botanical or botanical preparation, its intended uses and levels of use in food supplements and on<br />
whether the botanical or botanical preparation has a long term history of food use17, showing that, at<br />
proposed exposure levels, no adverse effect on human health has been reported. In addition to<br />
laboratory tests, it may be possible to use human data derived from medical use, epidemiology, or<br />
specific studies on volunteers (e.g. on absorption and metabolism), or any other data reporting<br />
possible adverse health effects, either anecdotal or on the basis of case reports of intoxication, e.g data<br />
related to toxicity on livestock animals, or on botanicals that closely resemble botanicals which are<br />
known to have caused toxic effects.<br />
<br />
However, it is recognized that for botanical ingredients lacking a history of food use, or for botanicals<br />
whose intended use levels will significantly exceed historical intake levels, an assessment of safety<br />
generally relies on experimental toxicity data largely derived from investigations in laboratory<br />
animals.<br />
<br />
The approach herein proposed for the safety assessment of botanicals and botanical preparations not<br />
regulated in the framework of specific regulations such as the one on novel foods, and illustrated by<br />
Figure 1, consists of the two following levels:<br />
:*Level A: Safety assessment based on available knowledge.<br />
:*Level B: Safety assessment including newly generated data.<br />
<br />
[[File:Proposed_tier_approach_botanical.png]]<br />
<br />
Figure 1: Proposed tiered approach for the safety assessment of botanicals and botanical<br />
preparations.<br />
<br />
<br />
2.1. '''Level A: Safety assessment based on available knowledge'''<br />
<br />
Depending on the botanical ingredient and its uses, there are circumstances under which no additional<br />
data are judged necessary for the safety evaluation, i.e. a presumption of safety would be applied.<br />
This would be the case whenever available data would allow to conclude that exposure to known<br />
levels of the botanical ingredient has occurred in large population groups for many years without<br />
reported adverse effects.<br />
<br />
Therefore, an important requirement is that the data as outlined in chapter 2.1 are provided and that<br />
no significant increase of intake compared to historical levels is to be expected due to the intended<br />
levels of use in food supplements. This implies that not only use levels but also chemotypes of<br />
botanicals and the chemical composition of the botanical preparations should be in line with<br />
historically used ones. This approach can only be applied when intakes due to the intended levels of<br />
use are within the range of intake levels derived from the European Member States’ average diets or<br />
from studies on specific subgroups. It is recognized that the acceptability of such an approach relies<br />
mainly on the objective of not significantly increasing exposures beyond the levels linked to the safe<br />
history of use.<br />
<br />
If compounds of concern can be well defined, evaluations can focus on these specific compounds. In<br />
some cases, it may be difficult to identify the active principle responsible for an effect. In such cases<br />
the strength of the evidence underlying the concerns over a compound taken as the reference<br />
compound for the safety evaluation should also be given.<br />
<br />
For botanicals and botanical preparations with a potential to contain toxic, addictive, psychotropic or<br />
other substances that may be of concern (see also the Compendium and section 3), presumption of<br />
safety can be applied only if there is convincing evidence that these undesirable substances in the<br />
specific plant parts or preparations are either absent in the source material, or significantly reduced if<br />
not excluded, or inactivated during processing.<br />
<br />
In cases where the above-mentioned substances are known to be present in the botanical ingredient<br />
under evaluation (see attached Compendium), additional consideration should be given to support the<br />
presumption of safety of the botanical preparation. The significance of overall exposure to such<br />
substances should be assessed and compared with existing health-based guidance values such as the<br />
acceptable / tolerable daily intake (ADI/TDI). Consideration of exposure to the substance of concern<br />
in relation to the Threshold of Toxicological Concern (TTC) values may also be helpful.<br />
<br />
In cases where no health-based guidance values are available or where the botanical ingredient<br />
contains substances that are both genotoxic and carcinogenic, the “Margin of Exposure” (MOE)<br />
approach (EFSA, 2005) could be applied covering the botanical(s) under examination and any other<br />
dietary sources of exposure. The MOE approach compares toxic effect levels with human exposure<br />
levels. Alternatively, it could be evaluated whether the expected exposure to the genotoxic and<br />
carcinogenic ingredient is likely to be increased, compared to the intake from other sources.<br />
<br />
It is plausible that the kinetics as well as the expression of the inherent toxicity of a naturally<br />
occurring substance could be modified by the matrix in which it is present. Depending on the<br />
mechanism of action, this could result in the toxicity being unchanged, reduced or even increased.<br />
Research on individual substance/matrix interactions or botanical preparations cannot be used to draw<br />
general conclusions about intact botanicals, herbs and spices under all conditions of use, ingestion and<br />
metabolism. Where a matrix effect is advocated to support the safety of specific levels of substances<br />
(e.g. that data from a pure substance may overestimate effects of the substance in the botanical<br />
matrix), testing and/or other data should be provided to demonstrate the occurrence of the matrix<br />
effect of the preparation and its magnitude. A matrix effect should be judged on a case-by-case basis.<br />
<br />
Extrapolating from one preparation to another and/or from one botanical to another with respect to the<br />
same substance of toxicological concern can only been considered when accompanied by evidence of<br />
their composition with respect to the substance of concern and pattern of consumption.<br />
<br />
For food supplements consisting of complex mixtures of different botanicals, the above-mentioned<br />
assessment could be carried out on the levels of individual substances of concern known to be present<br />
(see also the Compendium), with the understanding of the limitation that such an approach does not<br />
generally allow the assessment of possible synergistic or antagonistic effects.Any data on possible<br />
herb-drug interaction should be carefully considered.<br />
<br />
In the case of a botanical ingredient whose anticipated intake is significantly higher than the estimated<br />
historical intake level, or for which the historical intake level cannot be assessed, additional data<br />
should be provided for the safety assessment, as described in the following sections.<br />
<br />
<br />
2.2.2. '''Additional data required for the level B assessment'''<br />
<br />
The reasons for carrying out toxicological studies should be stated, as should the reasons for not<br />
submitting a study that might be expected. The studies that might be expected can be seen from the<br />
“Guidance on submissions for food additive evaluations by the Scientific Committee on Food” (SCF<br />
2001b). All the important results should be presented and discussed and the original study reports<br />
should be submitted in order to allow independent, critical appraisal.<br />
<br />
The toxicology section of the dossier should start with a section describing in detail the specifications<br />
and identity criteria for the botanical preparation(s) used for the toxicity studies and their relationship<br />
to the final product to be used in the food supplement. It should be demonstrated unambiguously that<br />
these characteristics are in compliance with the technical details specified for the botanical<br />
preparation in this report.<br />
<br />
The toxicological tests should, as far as possible, follow the recommendations for data reporting given<br />
in the relevant guidelines (e.g. OECD, 1998). The material to be tested, with lot or batch number,<br />
should be well identified, characterized and standardized. It is important that for each study performed<br />
it is stated whether the test material conforms to the proposed specifications. If it does not conform,<br />
then the specifications of the test material should be given together with a rationale for using these<br />
data in the safety assessment of the product intended for the market.<br />
<br />
<br />
*''Toxicokinetics including metabolism''<br />
<br />
Information on toxicokinetics of relevant biologically active constituents present in the botanical or<br />
botanical preparation should be provided whenever available from the literature. Not all aspects need<br />
to be investigated in every case. Additional issues that may deserve consideration are:<br />
:*The possibility of interactions among constituents of the botanical or botanical<br />
preparation that can alter bioavailability, metabolism, and toxicity.<br />
:*The possibility of interactions with medicinal products.<br />
*''Genotoxicity testing''<br />
For the genotoxicity testing of botanicals and botanical preparations, in vitro tests covering effects<br />
both at gene and chromosome levels are required19. Specific tests are likely to include the Ames test<br />
(OECD guideline 471) and an in vitro test for the detection of chromosomal aberrations (OECD<br />
guideline 473) or an in vitro micronucleus assay (draft OECD guideline 487), and possibly the mouse<br />
lymphoma tk assay (OECD 476). The particular test strategy may depend upon the test material<br />
considered.<br />
<br />
There may be circumstances under which it may be justified to deviate from the above-mentioned<br />
core set. In such cases a scientific justification should be provided and additional types of<br />
considerations or mechanistic studies may be needed.<br />
<br />
A positive in vitro test normally requires follow-up by in vivo testing, unless it can be adequately<br />
demonstrated that the positive in vitro findings are not relevant for the in vivo situation. The choice of the appropriate in vivo test is critical, due to different sensitivities, different endpoints and other<br />
variables. It requires expert judgement based on all available information, to be applied case-by-case.<br />
For this reason, a flexible approach is preferable to a fixed decision tree.<br />
<br />
<br />
*''Subchronic toxicity testing''<br />
<br />
A 90-day study in the rat with the test material administered via the diet is the minimum requirement<br />
to establish a no-observed-adverse-effect level. Subchronic toxicity testing should be carried out<br />
independently of the results of the in vitro and in vivo genotoxicity testing.<br />
<br />
*''Other studies''<br />
<br />
Depending on the outcome of the genotoxicity and subchronic toxicity studies, or other specific<br />
relevant information, further studies may be required (e.g. reproductive toxicity, developmental<br />
toxicity, neurotoxicity, immunotoxicity, chronic toxicity/carcinogenicity).<br />
<br />
<br />
3. ''Establishing a Compendium of botanicals and prioritising them to be considered for a<br />
safety assessment.''<br />
<br />
A Compendium of botanicals reported to contain toxic, addictive, psychotropic or other substances<br />
that may be of concern has been produced to complement the present guidance document.<br />
<br />
The Compendium contains the following information:<br />
:*The botanical (binomial) denomination of the plant (genus, species and in some cases variety or<br />
subspecies when relevant), with synonyms in use.<br />
:*The plant parts and substances of possible toxicological concern<br />
:*Additional specific information of relevance for the risk assessment, e.g. adulterations<br />
:*References, either to existing international / national list of plants that were used to populate the<br />
Compendium, or to published literature when specific information has been added.<br />
<br />
The Compendium aims at flagging plants or part of plants or substances of possible concern for<br />
human heath naturally present in the listed botanicals and that, therefore, require specific attention<br />
while assessing the safety of the product(s) containing such botanical(s). For some botanicals in the<br />
Compendium, adverse (toxic) effect(s) are mentioned although sometimes based on anecdotal reports<br />
and even though the constituent(s) of concern are not elucidated in the literature. In some cases the<br />
whole genus was flagged because of the likely presence of substances of concern characteristic for the<br />
toxicity of that genus.<br />
<br />
The presence of a substance of concern in a given botanical does not mean that this substance will<br />
also be present in the botanical preparation. This depends largely on the plant part used, as well as the<br />
preparation method.<br />
<br />
The Compendium contains also an “insufficient information” list regrouping botanicals that appear in<br />
one of the sources of information, but for which sufficient information could not be found on possible<br />
substances of concern, or for which the information available could not be verified.<br />
<br />
Without prejudice to the existing legal framework, it should be noted that this Compendium has no<br />
legal status and should not be used as support or evidence in any disagreement or dispute pertaining to<br />
the legal classification of products or substances.<br />
<br />
The Compendium is a living document which should be periodically updated by EFSA. As a<br />
consequence, the absence of a given species in this Compendium cannot be interpreted as meaning<br />
that the species is devoid of substances hazardous for human health. In the same way, not mentioning<br />
a specific part of plant, does not imply absence of substance(s) of concern in this part. Botanicals that<br />
have not been reported as having been considered for food or food supplement use in the European<br />
countries or botanicals classified as novel foods or GMOs will not appear in the Compendium.<br />
<br />
<br />
''Priority setting for safety assessment:''<br />
The botanicals in the above-mentioned Compendium should be assessed according to the following<br />
recommendations:<br />
<br />
Priority should be given to botanicals and botanical preparations:<br />
:*known to have an established history of food use and that have been identified to contain<br />
significant levels of substances of concern.<br />
:*that are not allowed/recommended for food use in some European countries, but which are<br />
still in use in some other EU countries, particularly when the intended use levels in food are<br />
known or expected to be high.<br />
:*for which some adverse health effects have been reported, either anecdotally, or on the basis<br />
of case reports of intoxication, epidemiological data or any toxicity data from livestock<br />
animals or experimental animals, or for botanicals that closely resemble botanicals which are<br />
known to have caused toxic effects.<br />
:*for which consumption has significantly increased during recent years in Member States.<br />
:*for which there are both limited history of use and toxicity data available, and for which the<br />
intended use levels are expected to be relatively high (e.g. high interest to the food industry).<br />
<br />
Botanical ingredients that are reported to have a low toxic potential, and for which the intended<br />
intake/exposure levels are within the range of intake levels resulting from the European Member<br />
States average diet would be given a low priority.<br />
<br />
<br />
'''''CONCLUSIONS AND RECOMMENDATIONS'''''<br />
<br />
A two-level tiered approach for the safety assessment of botanical ingredients intended for use in food<br />
supplements is proposed. This approach consists of a safety assessment based on available knowledge<br />
and a subsequent level in which further testing and/or data are required. It allows the recognition of<br />
presumption of safety without further testing, based on long-term history of use with no reported<br />
adverse effect and with no significant increased exposure. For those botanical ingredients for which a<br />
presumption of safety based on available data cannot be established, it introduces a framework for<br />
assessing their safety, including the types of testing that would be most useful. Recommendations for<br />
prioritising botanicals for safety assessment are also made.<br />
<br />
The Compendium of botanicals reported to contain toxic, addictive, psychotropic or other substances<br />
that may be of concern, is considered to facilitate the assessment by flagging possible safety issues,<br />
and should therefore be considered as an essential part of this guidance document. The Scientific<br />
Committee recommends to maintain it up-to-date, making use of relevant available national lists of<br />
plants and of any other relevant data available, as well as of updated assessments carried out on<br />
botanicals by qualified bodies. The Scientific Committee also recommends to further expand the<br />
Compendium with botanicals not having any market history in Europe in order to prepare the<br />
implementation of the new Novel Food Regulation, which foresees a notification process for<br />
botanicals and botanical preparations having a history of safe use in the third country of origin.<br />
<br />
<br />
'''European Food Safety Authority'''<br />
<br />
''SCIENTIFIC COMMITTEE''<br />
Discussion Paper on “Botanicals and Botanical Preparations widely used<br />
as food supplements and related products: Coherent and Comprehensive<br />
Risk Assessment and Consumer Information Approaches”<br />
<br />
(adopted by written procedure on 23 June 2004)<br />
<br />
1. In view of the fact that botanicals and botanical preparations intended for human<br />
consumption as food supplements and related products are very widely marketed<br />
with a variety of claims, the present discussion paper aims at increasing awareness<br />
of some key issues to improve comprehensiveness and coherence of current<br />
approaches to risk assessment and consumer information on these products.<br />
<br />
2. A large number of botanical materials (e.g. whole, fragmented or cut plants, algae,<br />
fungi, lichens), and botanical preparations obtained from these materials by various<br />
processes (e.g. extraction, distillation, purification, concentration and fermentation)<br />
readily find their way onto the food supplements market. These materials are also<br />
often labelled as natural foods, largely organic, and foods specifically intended to<br />
support sport activities. Personal care products and the so-called “traditional herbal<br />
medicinal products” represent additional sources of exposure of consumers to<br />
botanical products. New products are also emerging, consisting of substances that<br />
commonly occur at low levels in botanical components of the diet, which are then<br />
extracted and re-introduced at much higher levels in specific products.<br />
<br />
3. Botanicals and botanical preparations are widely available to consumers through<br />
several distribution channels in the E.U. and elsewhere. In particular, they are sold<br />
over the counter in pharmacies and can be bought in supermarkets, herbalist’s<br />
shops and other shops, or via the Internet. They are currently available and used in<br />
such a way that they are almost becoming part of the common diet, thus providing<br />
for a significant human exposure from a public health point of view.<br />
<br />
4. There are some general concerns with respect to botanicals and botanical<br />
preparations mainly relating to quality and safety issues:<br />
:*Contamination (both chemical and microbiological) is a documented problem.<br />
It has been associated, for example, with botanical products originating from<br />
Asia. Deaths through poisoning following consumption of such products have<br />
been reported in Europe and the US arising from contamination with heavy<br />
metals, synthetic drugs and other undesirable substances (Ernst, 2002).<br />
Misidentification of plants harvested from the wild is also a continuing<br />
problem. When sales of traditional herbal products remained restricted to<br />
particular ethnic groups, which are familiar with the products and able to exert a<br />
local control on quality, problems were more rarely encountered. The growing<br />
volume of sales in the European Union with products obtained from suppliers<br />
based in Asia or elsewhere and the move towards widespread outlets for the<br />
products of traditional medicine call for more formal pre-marketing assessment<br />
and more stringent controls than the occasional random checks and analyses<br />
often carried out by individual national or local authorities on what is already<br />
out in the market.<br />
:*There is world-wide recognition of potential problems associated with<br />
botanicals and botanical products, not only in terms of safety, but also in terms<br />
of the claimed amounts and stability of the active ingredients. For example, the<br />
US Pharmacopeia, which considers the safety of food supplements as well as<br />
medicines, announced in December 2002 the establishment of an advisory<br />
panel specifically to advice on improving the quality of botanical products.<br />
:*Any efficacy shown by botanical products is usually a product of one or more<br />
plant secondary metabolites. Secondary metabolism responds to stress imposed<br />
by biotic and abiotic factors and, as a consequence, patterns and concentrations<br />
of metabolites can show considerable variation among plants belonging to the<br />
same species and variety. For instance, it is not unusual for metabolites<br />
produced in response to pathogen attack to vary in concentration one thousandfold<br />
over short time periods. While consistency of product is more easily<br />
controlled in cultivated plants, particularly those grown in containment,<br />
collections from the wild make it difficult to ensure that concentrations of<br />
bioactive agents meet specifications and are within safe limits.<br />
:*A very large literature exists on toxic substances naturally-occurring in plants.<br />
Of particular concern are plant products consumed in concentrated forms.<br />
Concerns can relate directly to the toxicological profile of the active agent(s). It<br />
has been the case with kava-kava (Piper methysticum), its withdrawal from the<br />
market being advised recently because of the association of its consumption with acute liver failure (Kraft et al., 2001). In June 2001, the US FDA,<br />
following action by the UK and Australia, advised manufacturers of dietary<br />
supplements to avoid the use of the various types of comfrey (Symphytum spp.)<br />
because of the health concerns associated with the presence of pyrrolizidine<br />
alkaloids. Moreover, since 1993, cases of nephrotoxicity and carcinogenicity<br />
have been reported in Belgium, France and United Kingdom as a result of<br />
inadvertent exposure to Aristolochia species in unlicensed herbal medicines<br />
(EMEA, 2000).<br />
:*Interactions of herbal products with prescription products are well recognised,<br />
although widely under-reported (Ernst, 2000; Sorensen, 2002). In the past,<br />
when such products were usually obtained from outlets run by knowledgeable<br />
individuals, advice on use and contra-indications was often available. Currently,<br />
contra-indications do not usually appear on the labels or any associated<br />
documentation when herbal products are sold through supermarkets and other<br />
retail outlets. Yet, a survey of the available information on interactions with<br />
medicinal compounds of the more commonly purchased botanical products<br />
(e.g. ginkgo, garlic, St. John’s Wort and ginseng) found recorded adverse<br />
interactions for all but Echinacea and saw palmetto (Izzo and Ernst, 2001).<br />
Incidence and severity of effects associated with prescription drug-dietary<br />
supplement interactions in a small group of primary care patients have also<br />
been investigated by Peng et al. (2004); the most common botanical products<br />
included garlic, ginkgo biloba, saw palmetto and ginseng. While most<br />
interactions were judged not to be serious, an incidence of 6% of potentially<br />
severe health consequences was recorded among patients taking at the same<br />
time specific drugs and specific botanical products.<br />
<br />
5. This heterogeneous group of commodities includes products which, mainly<br />
depending on their intended uses and presentations, fall under different Community<br />
regulatory frameworks and for some types of products legal provisions for a<br />
preliminary risk assessment do not exist yet. The main legislations to be considered<br />
in this context are Directive 2002/46/EC on food supplements and Directive<br />
2004/27/EC on traditional herbal medicinal products:<br />
<br />
:*Directive 2002/46/EC foresees the use as food supplements of vitamins and<br />
minerals listed in the Annexes to the Directive. It also allows the use for the<br />
same purpose of still undetermined substances with a nutritional or<br />
physiological effect, but definition of such effects is not provided for.<br />
According to Art. 4, para 8, the European Commission shall produce, not later<br />
than 12 July 2007, a report on the advisability of establishing specific rules,<br />
including, where appropriate, categories of additional vitamins and minerals or<br />
of substances with a nutritional or physiological effect, accompanied by any proposals for amendments to Directive 2002/46/EC**. Thus a regulatory<br />
framework for further developments in this area already exists.<br />
:*Directive 2004/27/EC on “traditional herbal medicinal products” provides for<br />
definitions of (i) traditional herbal medicinal products, (ii) herbal medicinal<br />
products, (iii) herbal preparations and (iv) herbal substances. The directive<br />
introduces a simplified registration procedure, based on “traditional use”, but<br />
ensuring quality and safety as for any other medicinal product. Community lists<br />
will have to be prepared of traditional herbal medicinal products, herbal<br />
preparations and herbal products. On the other hand, traditional herbal<br />
materials, which are authorised for use in medicinal products, will continue to<br />
contribute to the dietary intake of bioactive agents as long as they comply with<br />
the general food regulations and make no medicinal claim.<br />
<br />
6. Also relevant in this context are the Directives 1989/398/EEC and 96/84/EC on<br />
“Food for special purposes” and the Regulation 1997/258/CE on “novel foods” that<br />
provide additional channels for some botanicals and botanical preparations to enter<br />
the food market, and the proposed Directives on “nutritional and health claims” and<br />
“food fortification” at present under consideration by the European Parliament and<br />
Council.<br />
<br />
7. As the market volume expands, so does the need for a better characterisation of<br />
botanicals and botanical preparations, and for harmonising the scientific assessment<br />
of risks from exposure of consumers to these products.<br />
<br />
8. It is important, therefore, from a public health point of view, to achieve a<br />
comprehensive and coherent approach to risk assessment and consumer<br />
information on botanicals and botanical preparations widely present in different<br />
categories of commodities. Such an approach would, in time, overcome the existing<br />
information gaps on many of these products and bring together the fragmentary<br />
provisions for risk assessment on botanicals and botanical preparations in the<br />
current relevant regulations. To this end, the present paper aims at increasing<br />
awareness on these issues and at facilitating a critical analysis of the present<br />
situation. It is intended to lead to a stronger partnership and collaboration among all<br />
the stakeholders who have a role in this important sector.<br />
<br />
9. Although it is not the objective of this discussion paper to provide a detailed<br />
analysis of the way forward, the following reflections address some issues in order<br />
to facilitate an open discussion particularly in the frame of future developments of<br />
the above-mentioned Directive 2002/46/EC:<br />
<br />
:*As systematic information about the range of botanicals and botanical products<br />
present on the market is lacking, consideration could be given, to carrying out a<br />
survey to identify the main product categories currently marketed and a study to<br />
clarify the potential health-related issues that may need to be addressed.<br />
:*In view of the difficulty of compiling a full inventory of botanicals and<br />
botanical products, the possibility could also be considered of adopting and<br />
regularly updating a list of plants or parts of plants which should not be used or<br />
could be put under scrutiny because of the presence of undesirable substances,<br />
especially if effective reduction or removal of such substances can not be<br />
ensured.<br />
:*As purity specifications for all botanicals and botanical preparations are very<br />
difficult to define, the development of ad hoc manufacturing guidelines, could<br />
be considered in order to improve their characterisation and safety. Experience<br />
already existing in the pharmaceutical sector could be helpful to this end.<br />
:*Considering the importance of providing to consumers adequate information to<br />
allow the safe use of botanicals and botanical preparations, the possibility of<br />
establishing accredited information sources easily accessible to consumers on<br />
these products also deserves attention. A complicating issue in this respect is<br />
the diffusion of misleading claims which are very difficult to counterbalance by<br />
means of reliable consumer information. However, in this respect, the situation<br />
is likely to improve when the proposal for a Community Directive providing for<br />
a clear evaluation procedure of “Nutritional and Health Claims” will be<br />
adopted.<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
http://www.efsa.europa.eu/de/scdocs/doc/1249.pdf</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=EFSA_guidance_on_safety_assessment_of_botanicals&diff=21998
EFSA guidance on safety assessment of botanicals
2011-07-07T10:24:55Z
<p>Minttu: </p>
<hr />
<div>{{nugget<br />
|authors= <br />
|reference= <br />
|urn= <br />
|ethics= <br />
|journal=<br />
|moderator=Minttu<br />
|stub=Yes}}<br />
<br />
EFSA Journal 2009; 7(9):1249<br />
For citation purposes: EFSA Scientific Committee; Guidance on safety assessment of botanicals and botanical preparations<br />
intended for use as ingredients in food supplements, on request of EFSA. EFSA Journal 2009; 7(9):1249. [19 pp.].<br />
doi:10.2093/j.efsa.2009.1249. Available online: www.efsa.europa.eu<br />
© European Food Safety Authority, 2009 1<ref>[http://www.efsa.europa.eu/de/scdocs/doc/1249.pdf]: EFSA Journal 2009; 7(9):1249<br />
For citation purposes: EFSA Scientific Committee; Guidance on safety assessment of botanicals and botanical preparations<br />
intended for use as ingredients in food supplements, on request of EFSA. EFSA Journal 2009; 7(9):1249. [19 pp.].<br />
doi:10.2093/j.efsa.2009.1249. Available online: www.efsa.europa.eu<br />
© European Food Safety Authority, 2009 1 </ref><br />
<br />
<br />
'''''SCIENTIFIC OPINION'''''<br />
<br />
<br />
''Guidance on Safety assessment of botanicals and botanical preparations intended for use as ingredients in food supplements''<br />
<br />
<br />
'''EFSA Scientific Committee'''<br />
<br />
<br />
European Food Safety Authority (EFSA), Parma, Italy<br />
<br />
<br />
This guidance document published on 9 September 2009, replaces the earlier version published on 20<br />
June 2008 with the Question Number: EFSA-Q-2005-233.<br />
<br />
<br />
''ABSTRACT''<br />
<br />
In this opinion, EFSA’s Scientific Committee provides guidance on the scientific data needed to carry out a safety assessments of a botanical or a botanical preparation. It also proposes a two-tiered scientific approach for the safety assessment depending on the available knowledge on a given botanical and the substance(s) it contains. The guidance also provides a set of criteria to help prioritise the safety assessment of botanical ingredients which<br />
are in use. EFSA has also compiled the available information on a large number of botanicals which have been reported to contain substances that may be of health concern when used in food or food supplements. The resulting compendium, which will be regularly updated, should be considered as part of this guidance document<br />
and is intended to assist manufacturers and food safety authorities by highlighting possible safety issues which may require further consideration.<br />
<br />
<br />
''KEY WORDS''<br />
<br />
Botanicals, botanical preparations, safety assessment, food supplements, toxicological properties, medicinal<br />
properties.<br />
<br />
<br />
''SUMMARY''<br />
<br />
Following the discussion paper of the Scientific Committee on botanicals and botanical preparations<br />
adopted on 23 June 2004, The European Food Safety Authority (EFSA) asked in August 2005 the<br />
Scientific Committee to develop a two-level tiered approach for the safety assessment of botanicals<br />
and botanical preparations. This approach consists of a first safety assessment level based on<br />
available knowledge and a subsequent level in which the safety assessment includes newly generated<br />
data.<br />
<br />
<br />
The present guidance document is focussed on botanicals and botanical preparations intended for use<br />
in food supplements, although the approach chosen is, in principle, applicable also to other uses of<br />
botanicals and botanical preparations in the food and feed areas.<br />
<br />
<br />
A general framework for safety assessment is proposed by the Scientific Committee, in which<br />
botanicals or botanical preparations for which an adequate body of knowledge exists could benefit<br />
from a “presumption of safety” without any need for further testing. Issues that should be carefully<br />
considered in order to reach such a conclusion are discussed in detail in the present guidance<br />
document. Botanicals and botanical preparations for which a presumption of safety is not possible<br />
based on available knowledge would be subject to a more extensive safety assessment, requiring<br />
additional data to be provided.<br />
<br />
<br />
It is not the objective of this opinion to produce a list of safe botanicals and botanical preparations<br />
intended for food supplement use, but only to provide guidance on how to assess safety of botanical<br />
ingredients.<br />
<br />
<br />
The Scientific Committee developed criteria for prioritising botanicals for safety assessment and has<br />
compiled a Compendium of botanicals that are reported to contain toxic, addictive, psychotropic or<br />
other substances that may be of concern. The main purpose of the Compendium, which should be<br />
considered as part of this guidance document, is to draw attention to issues that would need to be<br />
taken into account when assessing the safety of botanicals used as ingredients in food supplements,<br />
and to facilitate the establishment of priorities for safety assessment.<br />
<br />
<br />
The Scientific Committee recommends maintaining the Compendium up-to-date, making use of<br />
relevant available national lists of plants and of any other relevant data available, as well as of<br />
updated assessments carried out on botanicals by qualified bodies. The Scientific Committee also<br />
recommends to further expand the Compendium with botanicals not having any market history in<br />
Europe but having a documented history of use in their third country of origin.<br />
<br />
<br />
TABLE OF CONTENTS<br />
:*Abstract <br />
:*Summary <br />
:*Table of contents <br />
:*Background as provided by EFSA <br />
:*Terms of reference as provided by EFSA <br />
:*Acknowledgements <br />
:*Assessment <br />
:1.Introduction <br />
:2.Safety assessment of botanicals and botanical preparations intended for use as ingredients in<br />
food supplements <br />
:2.1Proposed data requirements for safety assessment of botanicals and botanical preparations<br />
used as ingredients in food supplements <br />
:2.1.1.Technical data<br />
::2.1.1.1. Identity and nature of the source material <br />
::2.1.1.2. Manufacturing process<br />
::2.1.1.3. Chemical composition <br />
::2.1.1.4. Specifications <br />
::2.1.1.5. Stability of the botanical or botanical preparation used as ingredient in food supplement <br />
::2.1.1.6. Proposed uses and use levels <br />
::2.1.1.7. Information on existing assessments <br />
:2.1.2. Exposure: extent and duration <br />
:2.1.3. Toxicological data <br />
2.2. Proposed general framework for assessing the safety of botanicals and botanical<br />
preparations used as ingredients in food supplement <br />
:2.2.1. Level A: Safety assessment based on available knowledge <br />
:2.2.2. Additional data required for the level B assessment <br />
3. Establishing a Compendium of botanicals and prioritising them to be considered for a safety<br />
assessment. <br />
:*Conclusions and recommendations <br />
:*References <br />
<br />
<br />
''BACKGROUND AS PROVIDED BY EFSA''<br />
<br />
A discussion paper by the Scientific Committee on botanicals and botanical preparations widely used<br />
in food supplements and related products was adopted on 23 June 2004 (SC document EFSA/SC/26<br />
Final3). In this paper, the Committee expressed concerns about quality and safety issues of botanicals<br />
and botanical preparations that have become widely available to consumers through several<br />
distribution channels in the EU. The use of botanicals and botanical preparations in food is regulated<br />
under the General Food Law (178/2002/EC), which attributes the primary legal responsibility for the<br />
safety of the products placed on the market to business operators. The Regulation however does not<br />
provide any guidance on how the safety of these products should be assessed. As the market volume<br />
and the variety of products expand, so does the need for a better characterisation of the range of<br />
botanicals and botanical preparations on the market, and for harmonising the risk assessment and<br />
consumer information approaches for these products. The paper aimed at increasing awareness of<br />
EFSA’s Advisory Forum on potential public health aspects associated with these products.<br />
<br />
<br />
The Secretariat brought the discussion paper to the attention of the Advisory Forum at its meeting of<br />
the 1st of October, 2004. Simultaneously, an invitation was sent to the members of the Advisory Forum to take note of the concerns<br />
raised by the Scientific Committee and to complete a questionnaire to provide a better understanding of the issue in Europe.<br />
<br />
<br />
By the end of January 2005, replies were received from twenty five countries, comprising twenty two<br />
EU Member States and three EFTA Countries. The members of the Advisory Forum underlined the<br />
importance of this issue for their countries and asked EFSA to initiate a self-task in order to develop<br />
some guidance on how to assess the safety of botanical ingredients.<br />
<br />
<br />
Following the mandate received by the Scientific Committee in August 2005 from EFSA, the<br />
Scientific Committee developed a two-level tiered approach for the safety assessment of botanicals<br />
and botanical preparations. A guidance document focussing on botanicals and botanical preparations<br />
intended for use as food supplements was published after public consultation.<br />
<br />
<br />
A conceptual framework for safety assessment was advocated, in which botanicals or botanical<br />
preparations for which an adequate body of knowledge exists could benefit from a “presumption of<br />
safety” without any need for further testing (first level of the framework). Issues that should be<br />
carefully considered in order to reach such a conclusion were discussed in detail in the guidance<br />
document. Botanicals and botanical preparations for which a presumption of safety is not possible<br />
would be subject to a more extensive safety assessment, based on additional data to be provided in<br />
accordance with the methodology described in the second level of the proposed framework.<br />
<br />
<br />
As a follow up, it was decided to test the adequacy of the above-mentioned approach described in the<br />
guidance document for safety assessment with a selected number of examples including botanicals<br />
known to contain toxic substances or having a reported toxic effect, botanicals with an established<br />
history of food use, and botanicals that are known to contain potentially genotoxic/carcinogenic<br />
substances. To this end, an EFSA Scientific Cooperation (ESCO) Working Group, composed of<br />
experts identified by the members of the Advisory Forum and by the Scientific Committee EFSA was<br />
established in April 2008. This working group was also given the task to finalise the Compendium of<br />
botanicals reported to contain toxic, addictive, psychotropic, or other substances of concern. The resulting ESCO report and Compendium9 were provided to the EFSA Executive Director in May<br />
2009.<br />
<br />
<br />
''TERMS OF REFERENCE AS PROVIDED BY EFSA''<br />
<br />
The Scientific Committee has been requested in May 2009 by the European Food Safety Authority<br />
to consider the recommendations made in the ESCO report for updating the guidance document for<br />
the safety assessment of botanicals and botanical preparations intended for use as ingredients in food<br />
supplements.<br />
<br />
<br />
''ACKNOWLEDGEMENTS''<br />
<br />
The European Food Safety Authority wishes to thank the members of the EFSA Scientific<br />
Cooperation (ESCO) Working Group on Botanicals and Botanical Preparations for the preparation of<br />
the ESCO Report, which was used by the Scientific Committee to update this guidance document.<br />
The European Food Safety Authority would also like to thank the members of the former Scientific<br />
Committee for their contributions to the present guidance document.<br />
<br />
<br />
''ASSESSMENT''<br />
<br />
1. '''Introduction'''<br />
The Scientific Committee decided to focus its work first on the safety assessment of botanicals and<br />
botanical preparations used as ingredients in food supplements (hereafter referred to, as botanical<br />
ingredients), although the approach chosen is, in principle, applicable also to other uses of botanicals<br />
and botanical preparations in the food and feed areas. It is not in the scope of the present guidance to<br />
address issues related to quality assurance and good hygienic practices currently regulated by the EU<br />
Food Legislation, nor to assess the safety of food supplements as end products. The present guidance<br />
does not therefore address hazards linked to the presence of contaminants and foodborne pathogens in<br />
the botanicals and botanicals preparations.<br />
<br />
<br />
A two-level tiered conceptual framework for safety assessment consisting of a safety assessment<br />
based on available knowledge and a subsequent level in which further testing and/or data are required<br />
is proposed by the Scientific Committee. Botanicals or botanical preparations for which an adequate<br />
body of knowledge exists, can benefit from a “presumption of safety” without any need for further<br />
testing. Based on reasonable evidence, they can then be assumed to be safe, sometimes under certain<br />
restrictions. The Scientific Committee used as an example the Qualified Presumption of Safety (QPS)<br />
approach developed for microorganisms in food and feed (EFSA, 2007a) to propose criteria for<br />
presuming a botanical or a botanical preparation safe. Botanicals and botanical preparations for which<br />
a presumption of safety is not possible should be subject to a more extensive safety assessment, based<br />
on additional data to be provided according to the methodology described by EFSA. By proposing a<br />
first safety assessment level based on available knowledge, the approach proposed by the Scientific<br />
Committee for the safety assessment of botanicals and botanical preparations is in line with EFSA’s<br />
policy to stimulate food and feed risk assessment approaches that minimise the number of<br />
experimental animals and any suffering (EFSA, 2009).<br />
<br />
<br />
In order to facilitate the implementation of the above-mentioned approach, EFSA has also compiled a<br />
Compendium of botanicals and botanical preparations that have been reported to contain toxic,<br />
addictive, psychotropic or other substances that may be of concern. This Compendium should be seen<br />
as a tool to gather relevant information and define priorities for safety assessment. The inclusion of a<br />
botanical in this Compendium does not imply that it is not safe for use in food supplements. Without<br />
prejudice to the existing legal framework, such Compendium has no legal status and may not be used<br />
as support or evidence in any disagreement or dispute pertaining to the legal classification of products<br />
or substances.<br />
<br />
<br />
Safety assessment of botanicals and botanical preparations<br />
EFSA Journal 2009; 7(9):1249 7<br />
<br />
<br />
2. '''Safety assessment of botanicals and botanical preparations intended for use as<br />
ingredients in food supplements'''<br />
<br />
It should be noted that Regulation 258/97/EC concerning novel foods and novel food ingredients<br />
applies to all foods, including food supplements, containing substances which have not been used for<br />
human consumption to a significant degree within the Community before 15 May 1997 and which fall<br />
under certain categories specified in the above-mentioned Regulation. In the case of a proposed use as<br />
a novel food, botanicals or botanical preparations should be assessed following the guidelines of the<br />
Commission Recommendation 97/618/EC of 29 July 1997 concerning the scientific aspects and the<br />
presentation of information necessary to support applications for the placing on the market of novel<br />
foods and novel food ingredients.<br />
<br />
<br />
Moreover, Regulation 1829/2003/EC on genetically modified food and feed would apply to any GMO<br />
ingredients used in food supplements. In the case of botanicals or botanical preparations derived from<br />
genetically modified plants, information should be provided in line with the guidance document of the<br />
EFSA Scientific Panel on Genetically Modified Organisms for the risk assessment of genetically<br />
modified plants and derived food (EFSA, 2006a).<br />
When the botanical or botanical preparation is intended for use as a food intended for particular<br />
nutritional uses (PARNUTS – Directive 89/398/EEC), the guidance document from the Scientific<br />
Committee on Food on submissions for safety evaluation of sources of nutrients or of other<br />
ingredients proposed for use in the manufacture of foods (SCF, 2001a) should also be consulted.<br />
<br />
<br />
It should also be underlined that this report only deals with guidance on safety assessment, whereas<br />
the scientific substantiation of any claims made on food supplements, as required by the Regulation<br />
on Nutrition and Health Claims, will be dealt with in separate EFSA documents, such as the<br />
“Scientific and technical guidance for the preparation and presentation of the application for<br />
authorisation of a health claim” (EFSA, 2007b).<br />
It is not the objective of this report to produce a list of safe botanicals and botanical preparations<br />
intended for food supplement use, but only to provide guidance on how to assess safety of botanical<br />
ingredients. Moreover, priority criteria are proposed, and a Compendium has been compiled to serve<br />
as a preliminary tool for risk assessors (see section 3).<br />
<br />
<br />
2.1. '''Proposed data requirements for safety assessment of botanicals and botanical<br />
preparations used as ingredients in food supplements'''<br />
<br />
It is understood that the use of botanicals and botanical preparations as ingredients in food<br />
supplements will have to be in compliance with the existing EU Food Legislation. This would<br />
include maximum permissible levels of chemical and biological contaminants (e.g. pesticides,<br />
mycotoxins, heavy metals and foodborne pathogens), modalities for ensuring quality, and application<br />
of good hygienic practice, including HACCP methodologies. The issues of controls needed to ensure<br />
constancy over time of the composition of botanical food supplements on the market and batch-tobatch<br />
variation are not addressed in this document as these are risk management aspects and therefore<br />
outside the scope of EFSA.<br />
<br />
The following sections aim at identifying data and information considered as necessary to assess the<br />
safety of botanical ingredients. These data are of: (i) technical; (ii) exposure and (iii) toxicological<br />
nature. The lists below are meant to give guidance on data requirements. They have been made as<br />
exhaustive as possible and should be adapted on a case-by-case basis, depending on the nature of the<br />
botanical or botanical preparation. This implies that not all the information listed below would be<br />
needed in all cases and that the amount of information available for a given botanical or botanical<br />
preparation may in some cases be sufficient without further testing (see section 2.2.1).<br />
<br />
<br />
2.1.1. '''Technical data'''<br />
<br />
2.1.1.1. Identity and nature of the source material<br />
<br />
It is recognized that identification of the botanical source and botanical preparation may in some cases<br />
be complicated. It is recommended to follow as much as possible the nomenclature of the European<br />
Pharmacopeia. Additional nomenclature sources are as follows:<br />
<br />
World Checklist of Selected Plant Families (Royal Botanic Garden, Kew); the books by Hanelt<br />
(2001) also available on the Internet as Mansfeld’s World Database of Agricultural and Horticultural<br />
Crops; and the database by United States Department of Agriculture. If a scientific name is not found<br />
in any of the above-named references, its existence may be checked in The International Plant Names<br />
Index.<br />
<br />
<br />
Since there have been many instances where species have been reclassified or renamed, a same<br />
species may be known by different scientific names. Common (vernacular) names may also be<br />
provided, but it should be noted that a common name used in one region to refer to a particular plant<br />
may be used elsewhere to refer to another quite unrelated species. Hence common names may not<br />
uniquely identify a species and are not as reliable as the scientific names.<br />
<br />
<br />
The following scheme summarizes the requirements for description of the identity of the botanical:<br />
<br />
<br />
;Scientific (Latin) name:<br />
:full systematic species name incl. botanical family, genus,<br />
species, variety, subspecies, author’s name, and chemotype if<br />
applicable<br />
<br />
;Synonyms: <br />
:botanical name(s) that may be used interchangeably with the<br />
preferred scientific name<br />
;Common names: <br />
:vernacular name(s)<br />
;Part used: <br />
:e.g. root, leaf, seed...<br />
;Geographical origin: <br />
:continent, country, region<br />
;Growth and harvesting conditions: <br />
:wild or cultivated, cultivation practices, time of harvest in relation<br />
to both season and stage of the plant growth.<br />
<br />
<br />
2.1.1.2. Manufacturing process<br />
<br />
The following information is considered necessary for assessing the safety of botanicals and botanical<br />
preparations:<br />
i):Information on the method(s) of manufacture (e.g. the process by which the raw material is<br />
converted into a preparation, such as extraction or other procedure(s), and plant extract ratio)<br />
<br />
ii):Information on substances entering the manufacturing process, e.g. identity of the extraction<br />
solvent, reagents, special precautions (light and temperature).<br />
<br />
iii):Standardization criteria (e.g. see European Pharmacopoeia).<br />
<br />
Botanicals or botanical preparations might become hazardous as a result of deviations in the<br />
production process (e.g. misclassification, switching of species). Therefore the safety of botanicals<br />
and botanical preparations should be ensured by following a Hazard Analysis and Critical Control<br />
Point (HACCP) approach (Codex Alimentarius 1997). The whole production chain, from primary<br />
production of botanicals to the storage and commercialisation of the botanical preparations should be<br />
taken into consideration. The HACCP system must be applied with the necessary flexibility and<br />
adapted to each botanical preparation on a case-by-case basis.<br />
<br />
<br />
2.1.1.3. Chemical composition<br />
<br />
Data on the chemical composition of the botanical ingredient should be provided with emphasis on<br />
the concentrations of constituent of relevance for the safety assessment; this includes the<br />
concentrations of:<br />
:*Compounds should be classified according to their chemical structure (e.g. flavonoids,<br />
terpenoids, alkaloids, etc.). Levels at which the constituents are present in the respective part<br />
of the botanical or botanical preparation should be given where available.<br />
:*Constituents to characterise the quality, chemical fingerprint, production process and/or<br />
biological activity of the preparation (markers).<br />
:*Constituents that provide reasons for concern due to their chemical, physiological or<br />
toxicological properties.<br />
In some cases, it may be difficult to identify the active principle responsible for an effect. Therefore<br />
the strength of the evidence underlying the concerns over a compound being reason for concern<br />
should also be given.<br />
<br />
<br />
2.1.1.4. Specifications<br />
<br />
Specifications of the botanicals or botanical preparations are required. They may be based on<br />
nutritional or biologically active components or, when these are not known, on selected chemical<br />
markers. Limits for or absence of specific undesirable / toxic substances should be specified. The<br />
proposed specifications should be modelled on recent European or other internationally accepted<br />
specifications (e.g. pharmacopoeia or the guidelines of the EMEA Committee on Herbal Medicinal<br />
Safety assessment of botanicals and botanical preparations<br />
<br />
Products (HMPC)). Where the proposed specifications differ from internationally recognised<br />
specifications, the latter specifications should be set out alongside the proposed new specifications,<br />
and any differences pointed out. Validated and well-established methods should be preferably used<br />
for the analysis of compounds considered in specifications.<br />
<br />
The specifications should include concentrations of major groups of constituents present in the<br />
botanical preparation including for example: amino acids, lipids, polysaccharides, volatile oil,<br />
inorganic ions, polyphenols, alkaloids, terpenes, alkenylbenzenes, lignin, saponins etc. as well as the<br />
major constituents within these classes.<br />
<br />
In addition, information on maximum levels for possible contaminants including e.g. heavy metals,<br />
mycotoxins, pesticide residues, and polycyclic aromatic hydrocarbon (PAH) residues should be<br />
provided.<br />
<br />
<br />
2.1.1.5. Stability of the botanical or botanical preparation used as ingredient in food supplement<br />
<br />
The stability of the botanical ingredient should be demonstrated over the shelf-life time. Any<br />
information concerning possible degradation should also be provided.<br />
<br />
<br />
2.1.1.6. Proposed uses and use levels<br />
<br />
Information on intended uses and recommended intakes for a product should specifically mention<br />
uses and use levels for the following categories:<br />
:* Common foods<br />
:* Food supplements<br />
:* Medicinal products<br />
<br />
Special attention should be given to population groups with specific uses like for example young<br />
children. Information on the duration of the proposed uses and use levels should also be provided<br />
<br />
<br />
2.1.1.7. Information on existing assessments<br />
<br />
Information on any existing assessments by international bodies or national competent authorities<br />
should be provided.<br />
<br />
<br />
2.1.2. '''Exposure: extent and duration'''<br />
<br />
Data and information should be provided on:<br />
:i) Anticipated human exposure to the botanical ingredient, including amount (e.g. maximum and<br />
average daily intake or exposure), frequency and duration. It is important to characterize as much as<br />
possible the expected human exposure to the botanical ingredient according to the recommended<br />
modalities of use in terms of extent and duration. Clear distinction should be made between intake of<br />
a botanical itself, intake of its essential oil and other preparations made of it.<br />
:ii) Possibility of additional / combined human exposure to the botanical or botanical preparation<br />
through different categories of food, food supplements and/or medicinal products that can be<br />
consumed together.<br />
:ii) Modality of use of the ingredient.<br />
:iv) Information on historical (food, food supplement and medicinal) use of the ingredient in<br />
human population groups in relation to the modalities of use and resulting exposure levels if known.<br />
Data derived from use outside of the European Union should also be considered.<br />
<br />
<br />
All data should be representative of the ingredient to be used for the European market. In this context,<br />
food use includes, in principle, the consumption of raw and cooked vegetables, spices, flavours, food<br />
supplements already in use for a long time16 and any other related food items.<br />
<br />
<br />
Estimates of average exposure ranges associated with the use of the botanical ingredient in the EU<br />
Member States should also be provided. Uncertainties associated with the food consumption data<br />
considered and anticipated exposure ranges should be clearly described (EFSA, 2006b).<br />
<br />
A matter to be specifically addressed in the evaluation is whether the proposed use and use levels will<br />
significantly increase already existing human exposure.<br />
<br />
<br />
2.1.3. '''Toxicological data'''<br />
<br />
Studies on toxicity and toxicokinetics including metabolism of botanicals and botanical preparations<br />
should be conducted using internationally agreed protocols. Test methods described by OECD or in<br />
European Commission Directives 87/432/EEC and 67/548/EC – Annex 5 are recommended. It is<br />
advisable to ensure that the most up-to-date version of any test guideline is followed. Use of any<br />
methods differing from internationally agreed protocols should be justified. Protocols for special<br />
studies differing from standard tests should be developed on a case-by-case basis.<br />
<br />
To ensure general acceptance of the data submitted, studies should be carried out according to the<br />
principles of Good Laboratory Practice (GLP) described in Council Directive 87/18/EEC and<br />
accompanied by a statement of GLP compliance. Adequate explanation should be provided for<br />
divergence from these principles.<br />
<br />
Council Directive 86/609/EEC, on the protection of animals used for experimental and other scientific<br />
purposes, requires that care is taken to avoid unnecessary use of animals. Studies carried out should<br />
be those necessary to demonstrate the safety of a botanical or botanical preparation and planned in<br />
accordance with the principles of reduction, refinement and replacement. However, where adequate<br />
data are not available for the safety assessment (see section 3.2.1), in vivo studies using experimental<br />
animals may be needed in order to assess possible risks to humans from the ingestion of botanicals or<br />
botanical preparations. Alternative validated methods involving fewer or no animals for toxicity<br />
endpoints may in the future be developed and should be considered on a case-by-case basis.<br />
<br />
If available, data on possible interactions (e.g. herbal-drug) should also be provided.<br />
<br />
<br />
2.2. '''Proposed general framework for assessing the safety of botanicals and botanical<br />
preparations used as ingredients in food supplement'''<br />
<br />
Several guidance documents (AFSSA, 2003; Council of Europe, 2005; Schilter et al., 2003) have been<br />
published on the principles for assessment of botanicals and botanical preparations in the food and<br />
feed area. The present guidance document is not intended to reiterate these, but to outline a<br />
framework that could be used by risk assessors when assessing the safety of a botanical or a botanical<br />
preparation. It also proposes a scientific approach to the assessment of available data.<br />
<br />
The aim of the assessment is to ensure that botanicals or botanical preparations, when used in food<br />
supplements in the manner, quantities and time period of intake proposed, would not pose a risk to the<br />
health of consumers. Data should provide not only information relevant to the healthy adult consumer,<br />
but also relevant to those population groups potentially vulnerable due to their pattern of food<br />
consumption or their physiological or health status, e.g. young age, elderly, pregnancy,<br />
immunocompromised etc.<br />
<br />
A general framework for assessing the safety with core tests and other tests is given, which should<br />
enable determination of what information is required to establish the safety-in-use of the botanical or<br />
botanical preparation. The application of this guidance to specific cases will depend on the nature of<br />
the botanical or botanical preparation, its intended uses and levels of use in food supplements and on<br />
whether the botanical or botanical preparation has a long term history of food use17, showing that, at<br />
proposed exposure levels, no adverse effect on human health has been reported. In addition to<br />
laboratory tests, it may be possible to use human data derived from medical use, epidemiology, or<br />
specific studies on volunteers (e.g. on absorption and metabolism), or any other data reporting<br />
possible adverse health effects, either anecdotal or on the basis of case reports of intoxication, e.g data<br />
related to toxicity on livestock animals, or on botanicals that closely resemble botanicals which are<br />
known to have caused toxic effects.<br />
<br />
However, it is recognized that for botanical ingredients lacking a history of food use, or for botanicals<br />
whose intended use levels will significantly exceed historical intake levels, an assessment of safety<br />
generally relies on experimental toxicity data largely derived from investigations in laboratory<br />
animals.<br />
<br />
The approach herein proposed for the safety assessment of botanicals and botanical preparations not<br />
regulated in the framework of specific regulations such as the one on novel foods, and illustrated by<br />
Figure 1, consists of the two following levels:<br />
:*Level A: Safety assessment based on available knowledge.<br />
:*Level B: Safety assessment including newly generated data.<br />
<br />
Figure 1: Proposed tiered approach for the safety assessment of botanicals and botanical<br />
preparations.<br />
<br />
<br />
2.1. '''Level A: Safety assessment based on available knowledge'''<br />
<br />
Depending on the botanical ingredient and its uses, there are circumstances under which no additional<br />
data are judged necessary for the safety evaluation, i.e. a presumption of safety would be applied.<br />
This would be the case whenever available data would allow to conclude that exposure to known<br />
levels of the botanical ingredient has occurred in large population groups for many years without<br />
reported adverse effects.<br />
<br />
Therefore, an important requirement is that the data as outlined in chapter 2.1 are provided and that<br />
no significant increase of intake compared to historical levels is to be expected due to the intended<br />
levels of use in food supplements. This implies that not only use levels but also chemotypes of<br />
botanicals and the chemical composition of the botanical preparations should be in line with<br />
historically used ones. This approach can only be applied when intakes due to the intended levels of<br />
use are within the range of intake levels derived from the European Member States’ average diets or<br />
from studies on specific subgroups. It is recognized that the acceptability of such an approach relies<br />
mainly on the objective of not significantly increasing exposures beyond the levels linked to the safe<br />
history of use.<br />
<br />
If compounds of concern can be well defined, evaluations can focus on these specific compounds. In<br />
some cases, it may be difficult to identify the active principle responsible for an effect. In such cases<br />
the strength of the evidence underlying the concerns over a compound taken as the reference<br />
compound for the safety evaluation should also be given.<br />
<br />
For botanicals and botanical preparations with a potential to contain toxic, addictive, psychotropic or<br />
other substances that may be of concern (see also the Compendium and section 3), presumption of<br />
safety can be applied only if there is convincing evidence that these undesirable substances in the<br />
specific plant parts or preparations are either absent in the source material, or significantly reduced if<br />
not excluded, or inactivated during processing.<br />
<br />
In cases where the above-mentioned substances are known to be present in the botanical ingredient<br />
under evaluation (see attached Compendium), additional consideration should be given to support the<br />
presumption of safety of the botanical preparation. The significance of overall exposure to such<br />
substances should be assessed and compared with existing health-based guidance values such as the<br />
acceptable / tolerable daily intake (ADI/TDI). Consideration of exposure to the substance of concern<br />
in relation to the Threshold of Toxicological Concern (TTC) values may also be helpful.<br />
<br />
In cases where no health-based guidance values are available or where the botanical ingredient<br />
contains substances that are both genotoxic and carcinogenic, the “Margin of Exposure” (MOE)<br />
approach (EFSA, 2005) could be applied covering the botanical(s) under examination and any other<br />
dietary sources of exposure. The MOE approach compares toxic effect levels with human exposure<br />
levels. Alternatively, it could be evaluated whether the expected exposure to the genotoxic and<br />
carcinogenic ingredient is likely to be increased, compared to the intake from other sources.<br />
<br />
It is plausible that the kinetics as well as the expression of the inherent toxicity of a naturally<br />
occurring substance could be modified by the matrix in which it is present. Depending on the<br />
mechanism of action, this could result in the toxicity being unchanged, reduced or even increased.<br />
Research on individual substance/matrix interactions or botanical preparations cannot be used to draw<br />
general conclusions about intact botanicals, herbs and spices under all conditions of use, ingestion and<br />
metabolism. Where a matrix effect is advocated to support the safety of specific levels of substances<br />
(e.g. that data from a pure substance may overestimate effects of the substance in the botanical<br />
matrix), testing and/or other data should be provided to demonstrate the occurrence of the matrix<br />
effect of the preparation and its magnitude. A matrix effect should be judged on a case-by-case basis.<br />
<br />
Extrapolating from one preparation to another and/or from one botanical to another with respect to the<br />
same substance of toxicological concern can only been considered when accompanied by evidence of<br />
their composition with respect to the substance of concern and pattern of consumption.<br />
<br />
For food supplements consisting of complex mixtures of different botanicals, the above-mentioned<br />
assessment could be carried out on the levels of individual substances of concern known to be present<br />
(see also the Compendium), with the understanding of the limitation that such an approach does not<br />
generally allow the assessment of possible synergistic or antagonistic effects.Any data on possible<br />
herb-drug interaction should be carefully considered.<br />
<br />
In the case of a botanical ingredient whose anticipated intake is significantly higher than the estimated<br />
historical intake level, or for which the historical intake level cannot be assessed, additional data<br />
should be provided for the safety assessment, as described in the following sections.<br />
<br />
<br />
2.2.2. '''Additional data required for the level B assessment'''<br />
<br />
The reasons for carrying out toxicological studies should be stated, as should the reasons for not<br />
submitting a study that might be expected. The studies that might be expected can be seen from the<br />
“Guidance on submissions for food additive evaluations by the Scientific Committee on Food” (SCF<br />
2001b). All the important results should be presented and discussed and the original study reports<br />
should be submitted in order to allow independent, critical appraisal.<br />
<br />
The toxicology section of the dossier should start with a section describing in detail the specifications<br />
and identity criteria for the botanical preparation(s) used for the toxicity studies and their relationship<br />
to the final product to be used in the food supplement. It should be demonstrated unambiguously that<br />
these characteristics are in compliance with the technical details specified for the botanical<br />
preparation in this report.<br />
<br />
The toxicological tests should, as far as possible, follow the recommendations for data reporting given<br />
in the relevant guidelines (e.g. OECD, 1998). The material to be tested, with lot or batch number,<br />
should be well identified, characterized and standardized. It is important that for each study performed<br />
it is stated whether the test material conforms to the proposed specifications. If it does not conform,<br />
then the specifications of the test material should be given together with a rationale for using these<br />
data in the safety assessment of the product intended for the market.<br />
<br />
<br />
*''Toxicokinetics including metabolism''<br />
<br />
Information on toxicokinetics of relevant biologically active constituents present in the botanical or<br />
botanical preparation should be provided whenever available from the literature. Not all aspects need<br />
to be investigated in every case. Additional issues that may deserve consideration are:<br />
:*The possibility of interactions among constituents of the botanical or botanical<br />
preparation that can alter bioavailability, metabolism, and toxicity.<br />
:*The possibility of interactions with medicinal products.<br />
*''Genotoxicity testing''<br />
For the genotoxicity testing of botanicals and botanical preparations, in vitro tests covering effects<br />
both at gene and chromosome levels are required19. Specific tests are likely to include the Ames test<br />
(OECD guideline 471) and an in vitro test for the detection of chromosomal aberrations (OECD<br />
guideline 473) or an in vitro micronucleus assay (draft OECD guideline 487), and possibly the mouse<br />
lymphoma tk assay (OECD 476). The particular test strategy may depend upon the test material<br />
considered.<br />
<br />
There may be circumstances under which it may be justified to deviate from the above-mentioned<br />
core set. In such cases a scientific justification should be provided and additional types of<br />
considerations or mechanistic studies may be needed.<br />
<br />
A positive in vitro test normally requires follow-up by in vivo testing, unless it can be adequately<br />
demonstrated that the positive in vitro findings are not relevant for the in vivo situation. The choice of the appropriate in vivo test is critical, due to different sensitivities, different endpoints and other<br />
variables. It requires expert judgement based on all available information, to be applied case-by-case.<br />
For this reason, a flexible approach is preferable to a fixed decision tree.<br />
<br />
<br />
*''Subchronic toxicity testing''<br />
<br />
A 90-day study in the rat with the test material administered via the diet is the minimum requirement<br />
to establish a no-observed-adverse-effect level. Subchronic toxicity testing should be carried out<br />
independently of the results of the in vitro and in vivo genotoxicity testing.<br />
<br />
*''Other studies''<br />
<br />
Depending on the outcome of the genotoxicity and subchronic toxicity studies, or other specific<br />
relevant information, further studies may be required (e.g. reproductive toxicity, developmental<br />
toxicity, neurotoxicity, immunotoxicity, chronic toxicity/carcinogenicity).<br />
<br />
<br />
3. ''Establishing a Compendium of botanicals and prioritising them to be considered for a<br />
safety assessment.''<br />
<br />
A Compendium of botanicals reported to contain toxic, addictive, psychotropic or other substances<br />
that may be of concern has been produced to complement the present guidance document.<br />
<br />
The Compendium contains the following information:<br />
:*The botanical (binomial) denomination of the plant (genus, species and in some cases variety or<br />
subspecies when relevant), with synonyms in use.<br />
:*The plant parts and substances of possible toxicological concern<br />
:*Additional specific information of relevance for the risk assessment, e.g. adulterations<br />
:*References, either to existing international / national list of plants that were used to populate the<br />
Compendium, or to published literature when specific information has been added.<br />
<br />
The Compendium aims at flagging plants or part of plants or substances of possible concern for<br />
human heath naturally present in the listed botanicals and that, therefore, require specific attention<br />
while assessing the safety of the product(s) containing such botanical(s). For some botanicals in the<br />
Compendium, adverse (toxic) effect(s) are mentioned although sometimes based on anecdotal reports<br />
and even though the constituent(s) of concern are not elucidated in the literature. In some cases the<br />
whole genus was flagged because of the likely presence of substances of concern characteristic for the<br />
toxicity of that genus.<br />
<br />
The presence of a substance of concern in a given botanical does not mean that this substance will<br />
also be present in the botanical preparation. This depends largely on the plant part used, as well as the<br />
preparation method.<br />
<br />
The Compendium contains also an “insufficient information” list regrouping botanicals that appear in<br />
one of the sources of information, but for which sufficient information could not be found on possible<br />
substances of concern, or for which the information available could not be verified.<br />
<br />
Without prejudice to the existing legal framework, it should be noted that this Compendium has no<br />
legal status and should not be used as support or evidence in any disagreement or dispute pertaining to<br />
the legal classification of products or substances.<br />
<br />
The Compendium is a living document which should be periodically updated by EFSA. As a<br />
consequence, the absence of a given species in this Compendium cannot be interpreted as meaning<br />
that the species is devoid of substances hazardous for human health. In the same way, not mentioning<br />
a specific part of plant, does not imply absence of substance(s) of concern in this part. Botanicals that<br />
have not been reported as having been considered for food or food supplement use in the European<br />
countries or botanicals classified as novel foods or GMOs will not appear in the Compendium.<br />
<br />
<br />
''Priority setting for safety assessment:''<br />
The botanicals in the above-mentioned Compendium should be assessed according to the following<br />
recommendations:<br />
<br />
Priority should be given to botanicals and botanical preparations:<br />
:*known to have an established history of food use and that have been identified to contain<br />
significant levels of substances of concern.<br />
:*that are not allowed/recommended for food use in some European countries, but which are<br />
still in use in some other EU countries, particularly when the intended use levels in food are<br />
known or expected to be high.<br />
:*for which some adverse health effects have been reported, either anecdotally, or on the basis<br />
of case reports of intoxication, epidemiological data or any toxicity data from livestock<br />
animals or experimental animals, or for botanicals that closely resemble botanicals which are<br />
known to have caused toxic effects.<br />
:*for which consumption has significantly increased during recent years in Member States.<br />
:*for which there are both limited history of use and toxicity data available, and for which the<br />
intended use levels are expected to be relatively high (e.g. high interest to the food industry).<br />
<br />
Botanical ingredients that are reported to have a low toxic potential, and for which the intended<br />
intake/exposure levels are within the range of intake levels resulting from the European Member<br />
States average diet would be given a low priority.<br />
<br />
<br />
'''''CONCLUSIONS AND RECOMMENDATIONS'''''<br />
<br />
A two-level tiered approach for the safety assessment of botanical ingredients intended for use in food<br />
supplements is proposed. This approach consists of a safety assessment based on available knowledge<br />
and a subsequent level in which further testing and/or data are required. It allows the recognition of<br />
presumption of safety without further testing, based on long-term history of use with no reported<br />
adverse effect and with no significant increased exposure. For those botanical ingredients for which a<br />
presumption of safety based on available data cannot be established, it introduces a framework for<br />
assessing their safety, including the types of testing that would be most useful. Recommendations for<br />
prioritising botanicals for safety assessment are also made.<br />
<br />
The Compendium of botanicals reported to contain toxic, addictive, psychotropic or other substances<br />
that may be of concern, is considered to facilitate the assessment by flagging possible safety issues,<br />
and should therefore be considered as an essential part of this guidance document. The Scientific<br />
Committee recommends to maintain it up-to-date, making use of relevant available national lists of<br />
plants and of any other relevant data available, as well as of updated assessments carried out on<br />
botanicals by qualified bodies. The Scientific Committee also recommends to further expand the<br />
Compendium with botanicals not having any market history in Europe in order to prepare the<br />
implementation of the new Novel Food Regulation, which foresees a notification process for<br />
botanicals and botanical preparations having a history of safe use in the third country of origin.<br />
<br />
<br />
'''European Food Safety Authority'''<br />
<br />
''SCIENTIFIC COMMITTEE''<br />
Discussion Paper on “Botanicals and Botanical Preparations widely used<br />
as food supplements and related products: Coherent and Comprehensive<br />
Risk Assessment and Consumer Information Approaches”<br />
<br />
(adopted by written procedure on 23 June 2004)<br />
<br />
1. In view of the fact that botanicals and botanical preparations intended for human<br />
consumption as food supplements and related products are very widely marketed<br />
with a variety of claims, the present discussion paper aims at increasing awareness<br />
of some key issues to improve comprehensiveness and coherence of current<br />
approaches to risk assessment and consumer information on these products.<br />
<br />
2. A large number of botanical materials (e.g. whole, fragmented or cut plants, algae,<br />
fungi, lichens), and botanical preparations obtained from these materials by various<br />
processes (e.g. extraction, distillation, purification, concentration and fermentation)<br />
readily find their way onto the food supplements market. These materials are also<br />
often labelled as natural foods, largely organic, and foods specifically intended to<br />
support sport activities. Personal care products and the so-called “traditional herbal<br />
medicinal products” represent additional sources of exposure of consumers to<br />
botanical products. New products are also emerging, consisting of substances that<br />
commonly occur at low levels in botanical components of the diet, which are then<br />
extracted and re-introduced at much higher levels in specific products.<br />
<br />
3. Botanicals and botanical preparations are widely available to consumers through<br />
several distribution channels in the E.U. and elsewhere. In particular, they are sold<br />
over the counter in pharmacies and can be bought in supermarkets, herbalist’s<br />
shops and other shops, or via the Internet. They are currently available and used in<br />
such a way that they are almost becoming part of the common diet, thus providing<br />
for a significant human exposure from a public health point of view.<br />
<br />
4. There are some general concerns with respect to botanicals and botanical<br />
preparations mainly relating to quality and safety issues:<br />
:*Contamination (both chemical and microbiological) is a documented problem.<br />
It has been associated, for example, with botanical products originating from<br />
Asia. Deaths through poisoning following consumption of such products have<br />
been reported in Europe and the US arising from contamination with heavy<br />
metals, synthetic drugs and other undesirable substances (Ernst, 2002).<br />
Misidentification of plants harvested from the wild is also a continuing<br />
problem. When sales of traditional herbal products remained restricted to<br />
particular ethnic groups, which are familiar with the products and able to exert a<br />
local control on quality, problems were more rarely encountered. The growing<br />
volume of sales in the European Union with products obtained from suppliers<br />
based in Asia or elsewhere and the move towards widespread outlets for the<br />
products of traditional medicine call for more formal pre-marketing assessment<br />
and more stringent controls than the occasional random checks and analyses<br />
often carried out by individual national or local authorities on what is already<br />
out in the market.<br />
:*There is world-wide recognition of potential problems associated with<br />
botanicals and botanical products, not only in terms of safety, but also in terms<br />
of the claimed amounts and stability of the active ingredients. For example, the<br />
US Pharmacopeia, which considers the safety of food supplements as well as<br />
medicines, announced in December 2002 the establishment of an advisory<br />
panel specifically to advice on improving the quality of botanical products.<br />
:*Any efficacy shown by botanical products is usually a product of one or more<br />
plant secondary metabolites. Secondary metabolism responds to stress imposed<br />
by biotic and abiotic factors and, as a consequence, patterns and concentrations<br />
of metabolites can show considerable variation among plants belonging to the<br />
same species and variety. For instance, it is not unusual for metabolites<br />
produced in response to pathogen attack to vary in concentration one thousandfold<br />
over short time periods. While consistency of product is more easily<br />
controlled in cultivated plants, particularly those grown in containment,<br />
collections from the wild make it difficult to ensure that concentrations of<br />
bioactive agents meet specifications and are within safe limits.<br />
:*A very large literature exists on toxic substances naturally-occurring in plants.<br />
Of particular concern are plant products consumed in concentrated forms.<br />
Concerns can relate directly to the toxicological profile of the active agent(s). It<br />
has been the case with kava-kava (Piper methysticum), its withdrawal from the<br />
market being advised recently because of the association of its consumption with acute liver failure (Kraft et al., 2001). In June 2001, the US FDA,<br />
following action by the UK and Australia, advised manufacturers of dietary<br />
supplements to avoid the use of the various types of comfrey (Symphytum spp.)<br />
because of the health concerns associated with the presence of pyrrolizidine<br />
alkaloids. Moreover, since 1993, cases of nephrotoxicity and carcinogenicity<br />
have been reported in Belgium, France and United Kingdom as a result of<br />
inadvertent exposure to Aristolochia species in unlicensed herbal medicines<br />
(EMEA, 2000).<br />
:*Interactions of herbal products with prescription products are well recognised,<br />
although widely under-reported (Ernst, 2000; Sorensen, 2002). In the past,<br />
when such products were usually obtained from outlets run by knowledgeable<br />
individuals, advice on use and contra-indications was often available. Currently,<br />
contra-indications do not usually appear on the labels or any associated<br />
documentation when herbal products are sold through supermarkets and other<br />
retail outlets. Yet, a survey of the available information on interactions with<br />
medicinal compounds of the more commonly purchased botanical products<br />
(e.g. ginkgo, garlic, St. John’s Wort and ginseng) found recorded adverse<br />
interactions for all but Echinacea and saw palmetto (Izzo and Ernst, 2001).<br />
Incidence and severity of effects associated with prescription drug-dietary<br />
supplement interactions in a small group of primary care patients have also<br />
been investigated by Peng et al. (2004); the most common botanical products<br />
included garlic, ginkgo biloba, saw palmetto and ginseng. While most<br />
interactions were judged not to be serious, an incidence of 6% of potentially<br />
severe health consequences was recorded among patients taking at the same<br />
time specific drugs and specific botanical products.<br />
<br />
5. This heterogeneous group of commodities includes products which, mainly<br />
depending on their intended uses and presentations, fall under different Community<br />
regulatory frameworks and for some types of products legal provisions for a<br />
preliminary risk assessment do not exist yet. The main legislations to be considered<br />
in this context are Directive 2002/46/EC on food supplements and Directive<br />
2004/27/EC on traditional herbal medicinal products:<br />
<br />
:*Directive 2002/46/EC foresees the use as food supplements of vitamins and<br />
minerals listed in the Annexes to the Directive. It also allows the use for the<br />
same purpose of still undetermined substances with a nutritional or<br />
physiological effect, but definition of such effects is not provided for.<br />
According to Art. 4, para 8, the European Commission shall produce, not later<br />
than 12 July 2007, a report on the advisability of establishing specific rules,<br />
including, where appropriate, categories of additional vitamins and minerals or<br />
of substances with a nutritional or physiological effect, accompanied by any proposals for amendments to Directive 2002/46/EC**. Thus a regulatory<br />
framework for further developments in this area already exists.<br />
:*Directive 2004/27/EC on “traditional herbal medicinal products” provides for<br />
definitions of (i) traditional herbal medicinal products, (ii) herbal medicinal<br />
products, (iii) herbal preparations and (iv) herbal substances. The directive<br />
introduces a simplified registration procedure, based on “traditional use”, but<br />
ensuring quality and safety as for any other medicinal product. Community lists<br />
will have to be prepared of traditional herbal medicinal products, herbal<br />
preparations and herbal products. On the other hand, traditional herbal<br />
materials, which are authorised for use in medicinal products, will continue to<br />
contribute to the dietary intake of bioactive agents as long as they comply with<br />
the general food regulations and make no medicinal claim.<br />
<br />
6. Also relevant in this context are the Directives 1989/398/EEC and 96/84/EC on<br />
“Food for special purposes” and the Regulation 1997/258/CE on “novel foods” that<br />
provide additional channels for some botanicals and botanical preparations to enter<br />
the food market, and the proposed Directives on “nutritional and health claims” and<br />
“food fortification” at present under consideration by the European Parliament and<br />
Council.<br />
<br />
7. As the market volume expands, so does the need for a better characterisation of<br />
botanicals and botanical preparations, and for harmonising the scientific assessment<br />
of risks from exposure of consumers to these products.<br />
<br />
8. It is important, therefore, from a public health point of view, to achieve a<br />
comprehensive and coherent approach to risk assessment and consumer<br />
information on botanicals and botanical preparations widely present in different<br />
categories of commodities. Such an approach would, in time, overcome the existing<br />
information gaps on many of these products and bring together the fragmentary<br />
provisions for risk assessment on botanicals and botanical preparations in the<br />
current relevant regulations. To this end, the present paper aims at increasing<br />
awareness on these issues and at facilitating a critical analysis of the present<br />
situation. It is intended to lead to a stronger partnership and collaboration among all<br />
the stakeholders who have a role in this important sector.<br />
<br />
9. Although it is not the objective of this discussion paper to provide a detailed<br />
analysis of the way forward, the following reflections address some issues in order<br />
to facilitate an open discussion particularly in the frame of future developments of<br />
the above-mentioned Directive 2002/46/EC:<br />
<br />
:*As systematic information about the range of botanicals and botanical products<br />
present on the market is lacking, consideration could be given, to carrying out a<br />
survey to identify the main product categories currently marketed and a study to<br />
clarify the potential health-related issues that may need to be addressed.<br />
:*In view of the difficulty of compiling a full inventory of botanicals and<br />
botanical products, the possibility could also be considered of adopting and<br />
regularly updating a list of plants or parts of plants which should not be used or<br />
could be put under scrutiny because of the presence of undesirable substances,<br />
especially if effective reduction or removal of such substances can not be<br />
ensured.<br />
:*As purity specifications for all botanicals and botanical preparations are very<br />
difficult to define, the development of ad hoc manufacturing guidelines, could<br />
be considered in order to improve their characterisation and safety. Experience<br />
already existing in the pharmaceutical sector could be helpful to this end.<br />
:*Considering the importance of providing to consumers adequate information to<br />
allow the safe use of botanicals and botanical preparations, the possibility of<br />
establishing accredited information sources easily accessible to consumers on<br />
these products also deserves attention. A complicating issue in this respect is<br />
the diffusion of misleading claims which are very difficult to counterbalance by<br />
means of reliable consumer information. However, in this respect, the situation<br />
is likely to improve when the proposal for a Community Directive providing for<br />
a clear evaluation procedure of “Nutritional and Health Claims” will be<br />
adopted.<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
http://www.efsa.europa.eu/de/scdocs/doc/1249.pdf</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=EFSA_guidance_on_safety_assessment_of_botanicals&diff=21997
EFSA guidance on safety assessment of botanicals
2011-07-07T10:17:04Z
<p>Minttu: </p>
<hr />
<div>{{nugget<br />
|authors= <br />
|reference= <br />
|urn= <br />
|ethics= <br />
|journal=<br />
|moderator=Minttu<br />
|stub=Yes}}<br />
<br />
EFSA Journal 2009; 7(9):1249<br />
For citation purposes: EFSA Scientific Committee; Guidance on safety assessment of botanicals and botanical preparations<br />
intended for use as ingredients in food supplements, on request of EFSA. EFSA Journal 2009; 7(9):1249. [19 pp.].<br />
doi:10.2093/j.efsa.2009.1249. Available online: www.efsa.europa.eu<br />
© European Food Safety Authority, 2009 1<ref>[http://www.efsa.europa.eu/de/scdocs/doc/1249.pdf]: EFSA Journal 2009; 7(9):1249<br />
For citation purposes: EFSA Scientific Committee; Guidance on safety assessment of botanicals and botanical preparations<br />
intended for use as ingredients in food supplements, on request of EFSA. EFSA Journal 2009; 7(9):1249. [19 pp.].<br />
doi:10.2093/j.efsa.2009.1249. Available online: www.efsa.europa.eu<br />
© European Food Safety Authority, 2009 1 </ref><br />
<br />
<br />
'''''SCIENTIFIC OPINION'''''<br />
<br />
<br />
''Guidance on Safety assessment of botanicals and botanical preparations intended for use as ingredients in food supplements''<br />
<br />
<br />
'''EFSA Scientific Committee'''<br />
<br />
<br />
European Food Safety Authority (EFSA), Parma, Italy<br />
<br />
<br />
This guidance document published on 9 September 2009, replaces the earlier version published on 20<br />
June 2008 with the Question Number: EFSA-Q-2005-233.<br />
<br />
<br />
''ABSTRACT''<br />
<br />
In this opinion, EFSA’s Scientific Committee provides guidance on the scientific data needed to carry out a safety assessments of a botanical or a botanical preparation. It also proposes a two-tiered scientific approach for the safety assessment depending on the available knowledge on a given botanical and the substance(s) it contains. The guidance also provides a set of criteria to help prioritise the safety assessment of botanical ingredients which<br />
are in use. EFSA has also compiled the available information on a large number of botanicals which have been reported to contain substances that may be of health concern when used in food or food supplements. The resulting compendium, which will be regularly updated, should be considered as part of this guidance document<br />
and is intended to assist manufacturers and food safety authorities by highlighting possible safety issues which may require further consideration.<br />
<br />
<br />
''KEY WORDS''<br />
<br />
Botanicals, botanical preparations, safety assessment, food supplements, toxicological properties, medicinal<br />
properties.<br />
<br />
<br />
''SUMMARY''<br />
<br />
Following the discussion paper of the Scientific Committee on botanicals and botanical preparations<br />
adopted on 23 June 2004, The European Food Safety Authority (EFSA) asked in August 2005 the<br />
Scientific Committee to develop a two-level tiered approach for the safety assessment of botanicals<br />
and botanical preparations. This approach consists of a first safety assessment level based on<br />
available knowledge and a subsequent level in which the safety assessment includes newly generated<br />
data.<br />
<br />
<br />
The present guidance document is focussed on botanicals and botanical preparations intended for use<br />
in food supplements, although the approach chosen is, in principle, applicable also to other uses of<br />
botanicals and botanical preparations in the food and feed areas.<br />
<br />
<br />
A general framework for safety assessment is proposed by the Scientific Committee, in which<br />
botanicals or botanical preparations for which an adequate body of knowledge exists could benefit<br />
from a “presumption of safety” without any need for further testing. Issues that should be carefully<br />
considered in order to reach such a conclusion are discussed in detail in the present guidance<br />
document. Botanicals and botanical preparations for which a presumption of safety is not possible<br />
based on available knowledge would be subject to a more extensive safety assessment, requiring<br />
additional data to be provided.<br />
<br />
<br />
It is not the objective of this opinion to produce a list of safe botanicals and botanical preparations<br />
intended for food supplement use, but only to provide guidance on how to assess safety of botanical<br />
ingredients.<br />
<br />
<br />
The Scientific Committee developed criteria for prioritising botanicals for safety assessment and has<br />
compiled a Compendium of botanicals that are reported to contain toxic, addictive, psychotropic or<br />
other substances that may be of concern. The main purpose of the Compendium, which should be<br />
considered as part of this guidance document, is to draw attention to issues that would need to be<br />
taken into account when assessing the safety of botanicals used as ingredients in food supplements,<br />
and to facilitate the establishment of priorities for safety assessment.<br />
<br />
<br />
The Scientific Committee recommends maintaining the Compendium up-to-date, making use of<br />
relevant available national lists of plants and of any other relevant data available, as well as of<br />
updated assessments carried out on botanicals by qualified bodies. The Scientific Committee also<br />
recommends to further expand the Compendium with botanicals not having any market history in<br />
Europe but having a documented history of use in their third country of origin.<br />
<br />
<br />
TABLE OF CONTENTS<br />
:*Abstract <br />
:*Summary <br />
:*Table of contents <br />
:*Background as provided by EFSA <br />
:*Terms of reference as provided by EFSA <br />
:*Acknowledgements <br />
:*Assessment <br />
:1.Introduction <br />
:2.Safety assessment of botanicals and botanical preparations intended for use as ingredients in<br />
food supplements <br />
:2.1Proposed data requirements for safety assessment of botanicals and botanical preparations<br />
used as ingredients in food supplements <br />
:2.1.1.Technical data<br />
::2.1.1.1. Identity and nature of the source material <br />
::2.1.1.2. Manufacturing process<br />
::2.1.1.3. Chemical composition <br />
::2.1.1.4. Specifications <br />
::2.1.1.5. Stability of the botanical or botanical preparation used as ingredient in food supplement <br />
::2.1.1.6. Proposed uses and use levels <br />
::2.1.1.7. Information on existing assessments <br />
:2.1.2. Exposure: extent and duration <br />
:2.1.3. Toxicological data <br />
2.2. Proposed general framework for assessing the safety of botanicals and botanical<br />
preparations used as ingredients in food supplement <br />
:2.2.1. Level A: Safety assessment based on available knowledge <br />
:2.2.2. Additional data required for the level B assessment <br />
3. Establishing a Compendium of botanicals and prioritising them to be considered for a safety<br />
assessment. <br />
:*Conclusions and recommendations <br />
:*References <br />
<br />
<br />
''BACKGROUND AS PROVIDED BY EFSA''<br />
<br />
A discussion paper by the Scientific Committee on botanicals and botanical preparations widely used<br />
in food supplements and related products was adopted on 23 June 2004 (SC document EFSA/SC/26<br />
Final3). In this paper, the Committee expressed concerns about quality and safety issues of botanicals<br />
and botanical preparations that have become widely available to consumers through several<br />
distribution channels in the EU. The use of botanicals and botanical preparations in food is regulated<br />
under the General Food Law (178/2002/EC), which attributes the primary legal responsibility for the<br />
safety of the products placed on the market to business operators. The Regulation however does not<br />
provide any guidance on how the safety of these products should be assessed. As the market volume<br />
and the variety of products expand, so does the need for a better characterisation of the range of<br />
botanicals and botanical preparations on the market, and for harmonising the risk assessment and<br />
consumer information approaches for these products. The paper aimed at increasing awareness of<br />
EFSA’s Advisory Forum on potential public health aspects associated with these products.<br />
<br />
<br />
The Secretariat brought the discussion paper to the attention of the Advisory Forum at its meeting of<br />
the 1st of October, 2004. Simultaneously, an invitation was sent to the members of the Advisory Forum to take note of the concerns<br />
raised by the Scientific Committee and to complete a questionnaire to provide a better understanding of the issue in Europe.<br />
<br />
<br />
By the end of January 2005, replies were received from twenty five countries, comprising twenty two<br />
EU Member States and three EFTA Countries. The members of the Advisory Forum underlined the<br />
importance of this issue for their countries and asked EFSA to initiate a self-task in order to develop<br />
some guidance on how to assess the safety of botanical ingredients.<br />
<br />
<br />
Following the mandate received by the Scientific Committee in August 2005 from EFSA, the<br />
Scientific Committee developed a two-level tiered approach for the safety assessment of botanicals<br />
and botanical preparations. A guidance document focussing on botanicals and botanical preparations<br />
intended for use as food supplements was published after public consultation.<br />
<br />
<br />
A conceptual framework for safety assessment was advocated, in which botanicals or botanical<br />
preparations for which an adequate body of knowledge exists could benefit from a “presumption of<br />
safety” without any need for further testing (first level of the framework). Issues that should be<br />
carefully considered in order to reach such a conclusion were discussed in detail in the guidance<br />
document. Botanicals and botanical preparations for which a presumption of safety is not possible<br />
would be subject to a more extensive safety assessment, based on additional data to be provided in<br />
accordance with the methodology described in the second level of the proposed framework.<br />
<br />
<br />
As a follow up, it was decided to test the adequacy of the above-mentioned approach described in the<br />
guidance document for safety assessment with a selected number of examples including botanicals<br />
known to contain toxic substances or having a reported toxic effect, botanicals with an established<br />
history of food use, and botanicals that are known to contain potentially genotoxic/carcinogenic<br />
substances. To this end, an EFSA Scientific Cooperation (ESCO) Working Group, composed of<br />
experts identified by the members of the Advisory Forum and by the Scientific Committee EFSA was<br />
established in April 2008. This working group was also given the task to finalise the Compendium of<br />
botanicals reported to contain toxic, addictive, psychotropic, or other substances of concern. The resulting ESCO report and Compendium9 were provided to the EFSA Executive Director in May<br />
2009.<br />
<br />
<br />
''TERMS OF REFERENCE AS PROVIDED BY EFSA''<br />
<br />
The Scientific Committee has been requested in May 2009 by the European Food Safety Authority<br />
to consider the recommendations made in the ESCO report for updating the guidance document for<br />
the safety assessment of botanicals and botanical preparations intended for use as ingredients in food<br />
supplements.<br />
<br />
<br />
''ACKNOWLEDGEMENTS''<br />
<br />
The European Food Safety Authority wishes to thank the members of the EFSA Scientific<br />
Cooperation (ESCO) Working Group on Botanicals and Botanical Preparations for the preparation of<br />
the ESCO Report, which was used by the Scientific Committee to update this guidance document.<br />
The European Food Safety Authority would also like to thank the members of the former Scientific<br />
Committee for their contributions to the present guidance document.<br />
<br />
<br />
''ASSESSMENT''<br />
<br />
1. '''Introduction'''<br />
The Scientific Committee decided to focus its work first on the safety assessment of botanicals and<br />
botanical preparations used as ingredients in food supplements (hereafter referred to, as botanical<br />
ingredients), although the approach chosen is, in principle, applicable also to other uses of botanicals<br />
and botanical preparations in the food and feed areas. It is not in the scope of the present guidance to<br />
address issues related to quality assurance and good hygienic practices currently regulated by the EU<br />
Food Legislation, nor to assess the safety of food supplements as end products. The present guidance<br />
does not therefore address hazards linked to the presence of contaminants and foodborne pathogens in<br />
the botanicals and botanicals preparations.<br />
<br />
<br />
A two-level tiered conceptual framework for safety assessment consisting of a safety assessment<br />
based on available knowledge and a subsequent level in which further testing and/or data are required<br />
is proposed by the Scientific Committee. Botanicals or botanical preparations for which an adequate<br />
body of knowledge exists, can benefit from a “presumption of safety” without any need for further<br />
testing. Based on reasonable evidence, they can then be assumed to be safe, sometimes under certain<br />
restrictions. The Scientific Committee used as an example the Qualified Presumption of Safety (QPS)<br />
approach developed for microorganisms in food and feed (EFSA, 2007a) to propose criteria for<br />
presuming a botanical or a botanical preparation safe. Botanicals and botanical preparations for which<br />
a presumption of safety is not possible should be subject to a more extensive safety assessment, based<br />
on additional data to be provided according to the methodology described by EFSA. By proposing a<br />
first safety assessment level based on available knowledge, the approach proposed by the Scientific<br />
Committee for the safety assessment of botanicals and botanical preparations is in line with EFSA’s<br />
policy to stimulate food and feed risk assessment approaches that minimise the number of<br />
experimental animals and any suffering (EFSA, 2009).<br />
<br />
<br />
In order to facilitate the implementation of the above-mentioned approach, EFSA has also compiled a<br />
Compendium of botanicals and botanical preparations that have been reported to contain toxic,<br />
addictive, psychotropic or other substances that may be of concern. This Compendium should be seen<br />
as a tool to gather relevant information and define priorities for safety assessment. The inclusion of a<br />
botanical in this Compendium does not imply that it is not safe for use in food supplements. Without<br />
prejudice to the existing legal framework, such Compendium has no legal status and may not be used<br />
as support or evidence in any disagreement or dispute pertaining to the legal classification of products<br />
or substances.<br />
<br />
<br />
Safety assessment of botanicals and botanical preparations<br />
EFSA Journal 2009; 7(9):1249 7<br />
<br />
2. '''Safety assessment of botanicals and botanical preparations intended for use as<br />
ingredients in food supplements'''<br />
<br />
It should be noted that Regulation 258/97/EC concerning novel foods and novel food ingredients<br />
applies to all foods, including food supplements, containing substances which have not been used for<br />
human consumption to a significant degree within the Community before 15 May 1997 and which fall<br />
under certain categories specified in the above-mentioned Regulation. In the case of a proposed use as<br />
a novel food, botanicals or botanical preparations should be assessed following the guidelines of the<br />
Commission Recommendation 97/618/EC of 29 July 1997 concerning the scientific aspects and the<br />
presentation of information necessary to support applications for the placing on the market of novel<br />
foods and novel food ingredients.<br />
<br />
<br />
Moreover, Regulation 1829/2003/EC on genetically modified food and feed would apply to any GMO<br />
ingredients used in food supplements. In the case of botanicals or botanical preparations derived from<br />
genetically modified plants, information should be provided in line with the guidance document of the<br />
EFSA Scientific Panel on Genetically Modified Organisms for the risk assessment of genetically<br />
modified plants and derived food (EFSA, 2006a).<br />
When the botanical or botanical preparation is intended for use as a food intended for particular<br />
nutritional uses (PARNUTS – Directive 89/398/EEC), the guidance document from the Scientific<br />
Committee on Food on submissions for safety evaluation of sources of nutrients or of other<br />
ingredients proposed for use in the manufacture of foods (SCF, 2001a) should also be consulted.<br />
<br />
<br />
It should also be underlined that this report only deals with guidance on safety assessment, whereas<br />
the scientific substantiation of any claims made on food supplements, as required by the Regulation<br />
on Nutrition and Health Claims, will be dealt with in separate EFSA documents, such as the<br />
“Scientific and technical guidance for the preparation and presentation of the application for<br />
authorisation of a health claim” (EFSA, 2007b).<br />
It is not the objective of this report to produce a list of safe botanicals and botanical preparations<br />
intended for food supplement use, but only to provide guidance on how to assess safety of botanical<br />
ingredients. Moreover, priority criteria are proposed, and a Compendium has been compiled to serve<br />
as a preliminary tool for risk assessors (see section 3).<br />
<br />
<br />
2.1. '''Proposed data requirements for safety assessment of botanicals and botanical<br />
preparations used as ingredients in food supplements'''<br />
<br />
It is understood that the use of botanicals and botanical preparations as ingredients in food<br />
supplements will have to be in compliance with the existing EU Food Legislation. This would<br />
include maximum permissible levels of chemical and biological contaminants (e.g. pesticides,<br />
mycotoxins, heavy metals and foodborne pathogens), modalities for ensuring quality, and application<br />
of good hygienic practice, including HACCP methodologies. The issues of controls needed to ensure<br />
constancy over time of the composition of botanical food supplements on the market and batch-tobatch<br />
variation are not addressed in this document as these are risk management aspects and therefore<br />
outside the scope of EFSA.<br />
<br />
The following sections aim at identifying data and information considered as necessary to assess the<br />
safety of botanical ingredients. These data are of: (i) technical; (ii) exposure and (iii) toxicological<br />
nature. The lists below are meant to give guidance on data requirements. They have been made as<br />
exhaustive as possible and should be adapted on a case-by-case basis, depending on the nature of the<br />
botanical or botanical preparation. This implies that not all the information listed below would be<br />
needed in all cases and that the amount of information available for a given botanical or botanical<br />
preparation may in some cases be sufficient without further testing (see section 2.2.1).<br />
<br />
<br />
2.1.1. '''Technical data'''<br />
<br />
<br />
2.1.1.1. Identity and nature of the source material<br />
<br />
It is recognized that identification of the botanical source and botanical preparation may in some cases<br />
be complicated. It is recommended to follow as much as possible the nomenclature of the European<br />
Pharmacopeia. Additional nomenclature sources are as follows:<br />
<br />
World Checklist of Selected Plant Families (Royal Botanic Garden, Kew); the books by Hanelt<br />
(2001) also available on the Internet as Mansfeld’s World Database of Agricultural and Horticultural<br />
Crops; and the database by United States Department of Agriculture. If a scientific name is not found<br />
in any of the above-named references, its existence may be checked in The International Plant Names<br />
Index.<br />
<br />
<br />
Since there have been many instances where species have been reclassified or renamed, a same<br />
species may be known by different scientific names. Common (vernacular) names may also be<br />
provided, but it should be noted that a common name used in one region to refer to a particular plant<br />
may be used elsewhere to refer to another quite unrelated species. Hence common names may not<br />
uniquely identify a species and are not as reliable as the scientific names.<br />
<br />
<br />
The following scheme summarizes the requirements for description of the identity of the botanical:<br />
<br />
<br />
;Scientific (Latin) name:<br />
:full systematic species name incl. botanical family, genus,<br />
species, variety, subspecies, author’s name, and chemotype if<br />
applicable<br />
<br />
;Synonyms: <br />
:botanical name(s) that may be used interchangeably with the<br />
preferred scientific name<br />
;Common names: <br />
:vernacular name(s)<br />
;Part used: <br />
;e.g. root, leaf, seed …<br />
;Geographical origin: <br />
:continent, country, region<br />
;Growth and harvesting conditions: <br />
:wild or cultivated, cultivation practices, time of harvest in relation<br />
to both season and stage of the plant growth.<br />
<br />
2.1.1.2. Manufacturing process<br />
<br />
The following information is considered necessary for assessing the safety of botanicals and botanical<br />
preparations:<br />
i):Information on the method(s) of manufacture (e.g. the process by which the raw material is<br />
converted into a preparation, such as extraction or other procedure(s), and plant extract ratio)<br />
<br />
ii):Information on substances entering the manufacturing process, e.g. identity of the extraction<br />
solvent, reagents, special precautions (light and temperature).<br />
<br />
iii):Standardization criteria (e.g. see European Pharmacopoeia).<br />
<br />
Botanicals or botanical preparations might become hazardous as a result of deviations in the<br />
production process (e.g. misclassification, switching of species). Therefore the safety of botanicals<br />
and botanical preparations should be ensured by following a Hazard Analysis and Critical Control<br />
Point (HACCP) approach (Codex Alimentarius 1997). The whole production chain, from primary<br />
production of botanicals to the storage and commercialisation of the botanical preparations should be<br />
taken into consideration. The HACCP system must be applied with the necessary flexibility and<br />
adapted to each botanical preparation on a case-by-case basis.<br />
<br />
<br />
2.1.1.3. Chemical composition<br />
<br />
Data on the chemical composition of the botanical ingredient should be provided with emphasis on<br />
the concentrations of constituent of relevance for the safety assessment; this includes the<br />
concentrations of:<br />
:*Compounds should be classified according to their chemical structure (e.g. flavonoids,<br />
terpenoids, alkaloids, etc.). Levels at which the constituents are present in the respective part<br />
of the botanical or botanical preparation should be given where available.<br />
:*Constituents to characterise the quality, chemical fingerprint, production process and/or<br />
biological activity of the preparation (markers).<br />
:*Constituents that provide reasons for concern due to their chemical, physiological or<br />
toxicological properties.<br />
In some cases, it may be difficult to identify the active principle responsible for an effect. Therefore<br />
the strength of the evidence underlying the concerns over a compound being reason for concern<br />
should also be given.<br />
<br />
<br />
2.1.1.4. Specifications<br />
<br />
Specifications of the botanicals or botanical preparations are required. They may be based on<br />
nutritional or biologically active components or, when these are not known, on selected chemical<br />
markers. Limits for or absence of specific undesirable / toxic substances should be specified. The<br />
proposed specifications should be modelled on recent European or other internationally accepted<br />
specifications (e.g. pharmacopoeia or the guidelines of the EMEA Committee on Herbal Medicinal<br />
Safety assessment of botanicals and botanical preparations<br />
<br />
Products (HMPC)). Where the proposed specifications differ from internationally recognised<br />
specifications, the latter specifications should be set out alongside the proposed new specifications,<br />
and any differences pointed out. Validated and well-established methods should be preferably used<br />
for the analysis of compounds considered in specifications.<br />
<br />
The specifications should include concentrations of major groups of constituents present in the<br />
botanical preparation including for example: amino acids, lipids, polysaccharides, volatile oil,<br />
inorganic ions, polyphenols, alkaloids, terpenes, alkenylbenzenes, lignin, saponins etc. as well as the<br />
major constituents within these classes.<br />
<br />
In addition, information on maximum levels for possible contaminants including e.g. heavy metals,<br />
mycotoxins, pesticide residues, and polycyclic aromatic hydrocarbon (PAH) residues should be<br />
provided.<br />
<br />
<br />
2.1.1.5. Stability of the botanical or botanical preparation used as ingredient in food supplement<br />
<br />
The stability of the botanical ingredient should be demonstrated over the shelf-life time. Any<br />
information concerning possible degradation should also be provided.<br />
<br />
<br />
2.1.1.6. Proposed uses and use levels<br />
<br />
Information on intended uses and recommended intakes for a product should specifically mention<br />
uses and use levels for the following categories:<br />
:* Common foods<br />
:* Food supplements<br />
:* Medicinal products<br />
<br />
Special attention should be given to population groups with specific uses like for example young<br />
children. Information on the duration of the proposed uses and use levels should also be provided<br />
<br />
<br />
2.1.1.7. Information on existing assessments<br />
<br />
Information on any existing assessments by international bodies or national competent authorities<br />
should be provided.<br />
<br />
<br />
2.1.2. '''Exposure: extent and duration'''<br />
<br />
Data and information should be provided on:<br />
:i) Anticipated human exposure to the botanical ingredient, including amount (e.g. maximum and<br />
average daily intake or exposure), frequency and duration. It is important to characterize as much as<br />
possible the expected human exposure to the botanical ingredient according to the recommended<br />
modalities of use in terms of extent and duration. Clear distinction should be made between intake of<br />
a botanical itself, intake of its essential oil and other preparations made of it.<br />
:ii) Possibility of additional / combined human exposure to the botanical or botanical preparation<br />
through different categories of food, food supplements and/or medicinal products that can be<br />
consumed together.<br />
:ii) Modality of use of the ingredient.<br />
:iv) Information on historical (food, food supplement and medicinal) use of the ingredient in<br />
human population groups in relation to the modalities of use and resulting exposure levels if known.<br />
Data derived from use outside of the European Union should also be considered.<br />
<br />
<br />
All data should be representative of the ingredient to be used for the European market. In this context,<br />
food use includes, in principle, the consumption of raw and cooked vegetables, spices, flavours, food<br />
supplements already in use for a long time16 and any other related food items.<br />
<br />
<br />
Estimates of average exposure ranges associated with the use of the botanical ingredient in the EU<br />
Member States should also be provided. Uncertainties associated with the food consumption data<br />
considered and anticipated exposure ranges should be clearly described (EFSA, 2006b).<br />
<br />
A matter to be specifically addressed in the evaluation is whether the proposed use and use levels will<br />
significantly increase already existing human exposure.<br />
<br />
<br />
2.1.3. '''Toxicological data'''<br />
<br />
Studies on toxicity and toxicokinetics including metabolism of botanicals and botanical preparations<br />
should be conducted using internationally agreed protocols. Test methods described by OECD or in<br />
European Commission Directives 87/432/EEC and 67/548/EC – Annex 5 are recommended. It is<br />
advisable to ensure that the most up-to-date version of any test guideline is followed. Use of any<br />
methods differing from internationally agreed protocols should be justified. Protocols for special<br />
studies differing from standard tests should be developed on a case-by-case basis.<br />
<br />
To ensure general acceptance of the data submitted, studies should be carried out according to the<br />
principles of Good Laboratory Practice (GLP) described in Council Directive 87/18/EEC and<br />
accompanied by a statement of GLP compliance. Adequate explanation should be provided for<br />
divergence from these principles.<br />
<br />
Council Directive 86/609/EEC, on the protection of animals used for experimental and other scientific<br />
purposes, requires that care is taken to avoid unnecessary use of animals. Studies carried out should<br />
be those necessary to demonstrate the safety of a botanical or botanical preparation and planned in<br />
accordance with the principles of reduction, refinement and replacement. However, where adequate<br />
data are not available for the safety assessment (see section 3.2.1), in vivo studies using experimental<br />
animals may be needed in order to assess possible risks to humans from the ingestion of botanicals or<br />
botanical preparations. Alternative validated methods involving fewer or no animals for toxicity<br />
endpoints may in the future be developed and should be considered on a case-by-case basis.<br />
<br />
If available, data on possible interactions (e.g. herbal-drug) should also be provided.<br />
<br />
<br />
2.2. '''Proposed general framework for assessing the safety of botanicals and botanical<br />
preparations used as ingredients in food supplement'''<br />
<br />
Several guidance documents (AFSSA, 2003; Council of Europe, 2005; Schilter et al., 2003) have been<br />
published on the principles for assessment of botanicals and botanical preparations in the food and<br />
feed area. The present guidance document is not intended to reiterate these, but to outline a<br />
framework that could be used by risk assessors when assessing the safety of a botanical or a botanical<br />
preparation. It also proposes a scientific approach to the assessment of available data.<br />
<br />
The aim of the assessment is to ensure that botanicals or botanical preparations, when used in food<br />
supplements in the manner, quantities and time period of intake proposed, would not pose a risk to the<br />
health of consumers. Data should provide not only information relevant to the healthy adult consumer,<br />
but also relevant to those population groups potentially vulnerable due to their pattern of food<br />
consumption or their physiological or health status, e.g. young age, elderly, pregnancy,<br />
immunocompromised etc.<br />
<br />
A general framework for assessing the safety with core tests and other tests is given, which should<br />
enable determination of what information is required to establish the safety-in-use of the botanical or<br />
botanical preparation. The application of this guidance to specific cases will depend on the nature of<br />
the botanical or botanical preparation, its intended uses and levels of use in food supplements and on<br />
whether the botanical or botanical preparation has a long term history of food use17, showing that, at<br />
proposed exposure levels, no adverse effect on human health has been reported. In addition to<br />
laboratory tests, it may be possible to use human data derived from medical use, epidemiology, or<br />
specific studies on volunteers (e.g. on absorption and metabolism), or any other data reporting<br />
possible adverse health effects, either anecdotal or on the basis of case reports of intoxication, e.g data<br />
related to toxicity on livestock animals, or on botanicals that closely resemble botanicals which are<br />
known to have caused toxic effects.<br />
<br />
However, it is recognized that for botanical ingredients lacking a history of food use, or for botanicals<br />
whose intended use levels will significantly exceed historical intake levels, an assessment of safety<br />
generally relies on experimental toxicity data largely derived from investigations in laboratory<br />
animals.<br />
<br />
The approach herein proposed for the safety assessment of botanicals and botanical preparations not<br />
regulated in the framework of specific regulations such as the one on novel foods, and illustrated by<br />
Figure 1, consists of the two following levels:<br />
:*Level A: Safety assessment based on available knowledge.<br />
:*Level B: Safety assessment including newly generated data.<br />
<br />
Figure 1: Proposed tiered approach for the safety assessment of botanicals and botanical<br />
preparations.<br />
<br />
<br />
2.1. '''Level A: Safety assessment based on available knowledge'''<br />
<br />
Depending on the botanical ingredient and its uses, there are circumstances under which no additional<br />
data are judged necessary for the safety evaluation, i.e. a presumption of safety would be applied.<br />
This would be the case whenever available data would allow to conclude that exposure to known<br />
levels of the botanical ingredient has occurred in large population groups for many years without<br />
reported adverse effects.<br />
<br />
Therefore, an important requirement is that the data as outlined in chapter 2.1 are provided and that<br />
no significant increase of intake compared to historical levels is to be expected due to the intended<br />
levels of use in food supplements. This implies that not only use levels but also chemotypes of<br />
botanicals and the chemical composition of the botanical preparations should be in line with<br />
historically used ones. This approach can only be applied when intakes due to the intended levels of<br />
use are within the range of intake levels derived from the European Member States’ average diets or<br />
from studies on specific subgroups. It is recognized that the acceptability of such an approach relies<br />
mainly on the objective of not significantly increasing exposures beyond the levels linked to the safe<br />
history of use.<br />
<br />
If compounds of concern can be well defined, evaluations can focus on these specific compounds. In<br />
some cases, it may be difficult to identify the active principle responsible for an effect. In such cases<br />
the strength of the evidence underlying the concerns over a compound taken as the reference<br />
compound for the safety evaluation should also be given.<br />
<br />
For botanicals and botanical preparations with a potential to contain toxic, addictive, psychotropic or<br />
other substances that may be of concern (see also the Compendium and section 3), presumption of<br />
safety can be applied only if there is convincing evidence that these undesirable substances in the<br />
specific plant parts or preparations are either absent in the source material, or significantly reduced if<br />
not excluded, or inactivated during processing.<br />
<br />
In cases where the above-mentioned substances are known to be present in the botanical ingredient<br />
under evaluation (see attached Compendium), additional consideration should be given to support the<br />
presumption of safety of the botanical preparation. The significance of overall exposure to such<br />
substances should be assessed and compared with existing health-based guidance values such as the<br />
acceptable / tolerable daily intake (ADI/TDI). Consideration of exposure to the substance of concern<br />
in relation to the Threshold of Toxicological Concern (TTC) values may also be helpful.<br />
<br />
In cases where no health-based guidance values are available or where the botanical ingredient<br />
contains substances that are both genotoxic and carcinogenic, the “Margin of Exposure” (MOE)<br />
approach (EFSA, 2005) could be applied covering the botanical(s) under examination and any other<br />
dietary sources of exposure. The MOE approach compares toxic effect levels with human exposure<br />
levels. Alternatively, it could be evaluated whether the expected exposure to the genotoxic and<br />
carcinogenic ingredient is likely to be increased, compared to the intake from other sources.<br />
<br />
It is plausible that the kinetics as well as the expression of the inherent toxicity of a naturally<br />
occurring substance could be modified by the matrix in which it is present. Depending on the<br />
mechanism of action, this could result in the toxicity being unchanged, reduced or even increased.<br />
Research on individual substance/matrix interactions or botanical preparations cannot be used to draw<br />
general conclusions about intact botanicals, herbs and spices under all conditions of use, ingestion and<br />
metabolism. Where a matrix effect is advocated to support the safety of specific levels of substances<br />
(e.g. that data from a pure substance may overestimate effects of the substance in the botanical<br />
matrix), testing and/or other data should be provided to demonstrate the occurrence of the matrix<br />
effect of the preparation and its magnitude. A matrix effect should be judged on a case-by-case basis.<br />
<br />
Extrapolating from one preparation to another and/or from one botanical to another with respect to the<br />
same substance of toxicological concern can only been considered when accompanied by evidence of<br />
their composition with respect to the substance of concern and pattern of consumption.<br />
<br />
For food supplements consisting of complex mixtures of different botanicals, the above-mentioned<br />
assessment could be carried out on the levels of individual substances of concern known to be present<br />
(see also the Compendium), with the understanding of the limitation that such an approach does not<br />
generally allow the assessment of possible synergistic or antagonistic effects.Any data on possible<br />
herb-drug interaction should be carefully considered.<br />
<br />
In the case of a botanical ingredient whose anticipated intake is significantly higher than the estimated<br />
historical intake level, or for which the historical intake level cannot be assessed, additional data<br />
should be provided for the safety assessment, as described in the following sections.<br />
<br />
2.2.2. '''Additional data required for the level B assessment'''<br />
<br />
The reasons for carrying out toxicological studies should be stated, as should the reasons for not<br />
submitting a study that might be expected. The studies that might be expected can be seen from the<br />
“Guidance on submissions for food additive evaluations by the Scientific Committee on Food” (SCF<br />
2001b). All the important results should be presented and discussed and the original study reports<br />
should be submitted in order to allow independent, critical appraisal.<br />
<br />
The toxicology section of the dossier should start with a section describing in detail the specifications<br />
and identity criteria for the botanical preparation(s) used for the toxicity studies and their relationship<br />
to the final product to be used in the food supplement. It should be demonstrated unambiguously that<br />
these characteristics are in compliance with the technical details specified for the botanical<br />
preparation in this report.<br />
<br />
The toxicological tests should, as far as possible, follow the recommendations for data reporting given<br />
in the relevant guidelines (e.g. OECD, 1998). The material to be tested, with lot or batch number,<br />
should be well identified, characterized and standardized. It is important that for each study performed<br />
it is stated whether the test material conforms to the proposed specifications. If it does not conform,<br />
then the specifications of the test material should be given together with a rationale for using these<br />
data in the safety assessment of the product intended for the market.<br />
<br />
<br />
*''Toxicokinetics including metabolism''<br />
<br />
Information on toxicokinetics of relevant biologically active constituents present in the botanical or<br />
botanical preparation should be provided whenever available from the literature. Not all aspects need<br />
to be investigated in every case. Additional issues that may deserve consideration are:<br />
:*The possibility of interactions among constituents of the botanical or botanical<br />
preparation that can alter bioavailability, metabolism, and toxicity.<br />
:*The possibility of interactions with medicinal products.<br />
*''Genotoxicity testing''<br />
For the genotoxicity testing of botanicals and botanical preparations, in vitro tests covering effects<br />
both at gene and chromosome levels are required19. Specific tests are likely to include the Ames test<br />
(OECD guideline 471) and an in vitro test for the detection of chromosomal aberrations (OECD<br />
guideline 473) or an in vitro micronucleus assay (draft OECD guideline 487), and possibly the mouse<br />
lymphoma tk assay (OECD 476). The particular test strategy may depend upon the test material<br />
considered.<br />
<br />
There may be circumstances under which it may be justified to deviate from the above-mentioned<br />
core set. In such cases a scientific justification should be provided and additional types of<br />
considerations or mechanistic studies may be needed.<br />
<br />
A positive in vitro test normally requires follow-up by in vivo testing, unless it can be adequately<br />
demonstrated that the positive in vitro findings are not relevant for the in vivo situation. The choice of the appropriate in vivo test is critical, due to different sensitivities, different endpoints and other<br />
variables. It requires expert judgement based on all available information, to be applied case-by-case.<br />
For this reason, a flexible approach is preferable to a fixed decision tree.<br />
<br />
<br />
*''Subchronic toxicity testing''<br />
<br />
A 90-day study in the rat with the test material administered via the diet is the minimum requirement<br />
to establish a no-observed-adverse-effect level. Subchronic toxicity testing should be carried out<br />
independently of the results of the in vitro and in vivo genotoxicity testing.<br />
<br />
*''Other studies''<br />
<br />
Depending on the outcome of the genotoxicity and subchronic toxicity studies, or other specific<br />
relevant information, further studies may be required (e.g. reproductive toxicity, developmental<br />
toxicity, neurotoxicity, immunotoxicity, chronic toxicity/carcinogenicity).<br />
<br />
<br />
3. ''Establishing a Compendium of botanicals and prioritising them to be considered for a<br />
safety assessment.''<br />
<br />
A Compendium of botanicals reported to contain toxic, addictive, psychotropic or other substances<br />
that may be of concern has been produced to complement the present guidance document.<br />
<br />
The Compendium contains the following information:<br />
:*The botanical (binomial) denomination of the plant (genus, species and in some cases variety or<br />
subspecies when relevant), with synonyms in use.<br />
:*The plant parts and substances of possible toxicological concern<br />
:*Additional specific information of relevance for the risk assessment, e.g. adulterations<br />
:*References, either to existing international / national list of plants that were used to populate the<br />
Compendium, or to published literature when specific information has been added.<br />
<br />
The Compendium aims at flagging plants or part of plants or substances of possible concern for<br />
human heath naturally present in the listed botanicals and that, therefore, require specific attention<br />
while assessing the safety of the product(s) containing such botanical(s). For some botanicals in the<br />
Compendium, adverse (toxic) effect(s) are mentioned although sometimes based on anecdotal reports<br />
and even though the constituent(s) of concern are not elucidated in the literature. In some cases the<br />
whole genus was flagged because of the likely presence of substances of concern characteristic for the<br />
toxicity of that genus.<br />
<br />
The presence of a substance of concern in a given botanical does not mean that this substance will<br />
also be present in the botanical preparation. This depends largely on the plant part used, as well as the<br />
preparation method.<br />
<br />
The Compendium contains also an “insufficient information” list regrouping botanicals that appear in<br />
one of the sources of information, but for which sufficient information could not be found on possible<br />
substances of concern, or for which the information available could not be verified.<br />
<br />
Without prejudice to the existing legal framework, it should be noted that this Compendium has no<br />
legal status and should not be used as support or evidence in any disagreement or dispute pertaining to<br />
the legal classification of products or substances.<br />
<br />
The Compendium is a living document which should be periodically updated by EFSA. As a<br />
consequence, the absence of a given species in this Compendium cannot be interpreted as meaning<br />
that the species is devoid of substances hazardous for human health. In the same way, not mentioning<br />
a specific part of plant, does not imply absence of substance(s) of concern in this part. Botanicals that<br />
have not been reported as having been considered for food or food supplement use in the European<br />
countries or botanicals classified as novel foods or GMOs will not appear in the Compendium.<br />
<br />
''Priority setting for safety assessment:''<br />
The botanicals in the above-mentioned Compendium should be assessed according to the following<br />
recommendations:<br />
<br />
Priority should be given to botanicals and botanical preparations:<br />
:*known to have an established history of food use and that have been identified to contain<br />
significant levels of substances of concern.<br />
:*that are not allowed/recommended for food use in some European countries, but which are<br />
still in use in some other EU countries, particularly when the intended use levels in food are<br />
known or expected to be high.<br />
:*for which some adverse health effects have been reported, either anecdotally, or on the basis<br />
of case reports of intoxication, epidemiological data or any toxicity data from livestock<br />
animals or experimental animals, or for botanicals that closely resemble botanicals which are<br />
known to have caused toxic effects.<br />
:*for which consumption has significantly increased during recent years in Member States.<br />
:*for which there are both limited history of use and toxicity data available, and for which the<br />
intended use levels are expected to be relatively high (e.g. high interest to the food industry).<br />
<br />
Botanical ingredients that are reported to have a low toxic potential, and for which the intended<br />
intake/exposure levels are within the range of intake levels resulting from the European Member<br />
States average diet would be given a low priority.<br />
<br />
'''''CONCLUSIONS AND RECOMMENDATIONS'''''<br />
<br />
A two-level tiered approach for the safety assessment of botanical ingredients intended for use in food<br />
supplements is proposed. This approach consists of a safety assessment based on available knowledge<br />
and a subsequent level in which further testing and/or data are required. It allows the recognition of<br />
presumption of safety without further testing, based on long-term history of use with no reported<br />
adverse effect and with no significant increased exposure. For those botanical ingredients for which a<br />
presumption of safety based on available data cannot be established, it introduces a framework for<br />
assessing their safety, including the types of testing that would be most useful. Recommendations for<br />
prioritising botanicals for safety assessment are also made.<br />
<br />
The Compendium of botanicals reported to contain toxic, addictive, psychotropic or other substances<br />
that may be of concern, is considered to facilitate the assessment by flagging possible safety issues,<br />
and should therefore be considered as an essential part of this guidance document. The Scientific<br />
Committee recommends to maintain it up-to-date, making use of relevant available national lists of<br />
plants and of any other relevant data available, as well as of updated assessments carried out on<br />
botanicals by qualified bodies. The Scientific Committee also recommends to further expand the<br />
Compendium with botanicals not having any market history in Europe in order to prepare the<br />
implementation of the new Novel Food Regulation, which foresees a notification process for<br />
botanicals and botanical preparations having a history of safe use in the third country of origin.<br />
<br />
<br />
'''European Food Safety Authority'''<br />
<br />
''SCIENTIFIC COMMITTEE''<br />
Discussion Paper on “Botanicals and Botanical Preparations widely used<br />
as food supplements and related products: Coherent and Comprehensive<br />
Risk Assessment and Consumer Information Approaches”<br />
<br />
(adopted by written procedure on 23 June 2004)<br />
<br />
1. In view of the fact that botanicals and botanical preparations intended for human<br />
consumption as food supplements and related products are very widely marketed<br />
with a variety of claims, the present discussion paper aims at increasing awareness<br />
of some key issues to improve comprehensiveness and coherence of current<br />
approaches to risk assessment and consumer information on these products.<br />
<br />
2. A large number of botanical materials (e.g. whole, fragmented or cut plants, algae,<br />
fungi, lichens), and botanical preparations obtained from these materials by various<br />
processes (e.g. extraction, distillation, purification, concentration and fermentation)<br />
readily find their way onto the food supplements market. These materials are also<br />
often labelled as natural foods, largely organic, and foods specifically intended to<br />
support sport activities. Personal care products and the so-called “traditional herbal<br />
medicinal products” represent additional sources of exposure of consumers to<br />
botanical products. New products are also emerging, consisting of substances that<br />
commonly occur at low levels in botanical components of the diet, which are then<br />
extracted and re-introduced at much higher levels in specific products.<br />
<br />
3. Botanicals and botanical preparations are widely available to consumers through<br />
several distribution channels in the E.U. and elsewhere. In particular, they are sold<br />
over the counter in pharmacies and can be bought in supermarkets, herbalist’s<br />
shops and other shops, or via the Internet. They are currently available and used in<br />
such a way that they are almost becoming part of the common diet, thus providing<br />
for a significant human exposure from a public health point of view.<br />
<br />
4. There are some general concerns with respect to botanicals and botanical<br />
preparations mainly relating to quality and safety issues:<br />
:*Contamination (both chemical and microbiological) is a documented problem.<br />
It has been associated, for example, with botanical products originating from<br />
Asia. Deaths through poisoning following consumption of such products have<br />
been reported in Europe and the US arising from contamination with heavy<br />
metals, synthetic drugs and other undesirable substances (Ernst, 2002).<br />
Misidentification of plants harvested from the wild is also a continuing<br />
problem. When sales of traditional herbal products remained restricted to<br />
particular ethnic groups, which are familiar with the products and able to exert a<br />
local control on quality, problems were more rarely encountered. The growing<br />
volume of sales in the European Union with products obtained from suppliers<br />
based in Asia or elsewhere and the move towards widespread outlets for the<br />
products of traditional medicine call for more formal pre-marketing assessment<br />
and more stringent controls than the occasional random checks and analyses<br />
often carried out by individual national or local authorities on what is already<br />
out in the market.<br />
:*There is world-wide recognition of potential problems associated with<br />
botanicals and botanical products, not only in terms of safety, but also in terms<br />
of the claimed amounts and stability of the active ingredients. For example, the<br />
US Pharmacopeia, which considers the safety of food supplements as well as<br />
medicines, announced in December 2002 the establishment of an advisory<br />
panel specifically to advice on improving the quality of botanical products.<br />
:*Any efficacy shown by botanical products is usually a product of one or more<br />
plant secondary metabolites. Secondary metabolism responds to stress imposed<br />
by biotic and abiotic factors and, as a consequence, patterns and concentrations<br />
of metabolites can show considerable variation among plants belonging to the<br />
same species and variety. For instance, it is not unusual for metabolites<br />
produced in response to pathogen attack to vary in concentration one thousandfold<br />
over short time periods. While consistency of product is more easily<br />
controlled in cultivated plants, particularly those grown in containment,<br />
collections from the wild make it difficult to ensure that concentrations of<br />
bioactive agents meet specifications and are within safe limits.<br />
:*A very large literature exists on toxic substances naturally-occurring in plants.<br />
Of particular concern are plant products consumed in concentrated forms.<br />
Concerns can relate directly to the toxicological profile of the active agent(s). It<br />
has been the case with kava-kava (Piper methysticum), its withdrawal from the<br />
market being advised recently because of the association of its consumption with acute liver failure (Kraft et al., 2001). In June 2001, the US FDA,<br />
following action by the UK and Australia, advised manufacturers of dietary<br />
supplements to avoid the use of the various types of comfrey (Symphytum spp.)<br />
because of the health concerns associated with the presence of pyrrolizidine<br />
alkaloids. Moreover, since 1993, cases of nephrotoxicity and carcinogenicity<br />
have been reported in Belgium, France and United Kingdom as a result of<br />
inadvertent exposure to Aristolochia species in unlicensed herbal medicines<br />
(EMEA, 2000).<br />
:*Interactions of herbal products with prescription products are well recognised,<br />
although widely under-reported (Ernst, 2000; Sorensen, 2002). In the past,<br />
when such products were usually obtained from outlets run by knowledgeable<br />
individuals, advice on use and contra-indications was often available. Currently,<br />
contra-indications do not usually appear on the labels or any associated<br />
documentation when herbal products are sold through supermarkets and other<br />
retail outlets. Yet, a survey of the available information on interactions with<br />
medicinal compounds of the more commonly purchased botanical products<br />
(e.g. ginkgo, garlic, St. John’s Wort and ginseng) found recorded adverse<br />
interactions for all but Echinacea and saw palmetto (Izzo and Ernst, 2001).<br />
Incidence and severity of effects associated with prescription drug-dietary<br />
supplement interactions in a small group of primary care patients have also<br />
been investigated by Peng et al. (2004); the most common botanical products<br />
included garlic, ginkgo biloba, saw palmetto and ginseng. While most<br />
interactions were judged not to be serious, an incidence of 6% of potentially<br />
severe health consequences was recorded among patients taking at the same<br />
time specific drugs and specific botanical products.<br />
<br />
5. This heterogeneous group of commodities includes products which, mainly<br />
depending on their intended uses and presentations, fall under different Community<br />
regulatory frameworks and for some types of products legal provisions for a<br />
preliminary risk assessment do not exist yet. The main legislations to be considered<br />
in this context are Directive 2002/46/EC on food supplements and Directive<br />
2004/27/EC on traditional herbal medicinal products:<br />
<br />
:*Directive 2002/46/EC foresees the use as food supplements of vitamins and<br />
minerals listed in the Annexes to the Directive. It also allows the use for the<br />
same purpose of still undetermined substances with a nutritional or<br />
physiological effect, but definition of such effects is not provided for.<br />
According to Art. 4, para 8, the European Commission shall produce, not later<br />
than 12 July 2007, a report on the advisability of establishing specific rules,<br />
including, where appropriate, categories of additional vitamins and minerals or<br />
of substances with a nutritional or physiological effect, accompanied by any proposals for amendments to Directive 2002/46/EC**. Thus a regulatory<br />
framework for further developments in this area already exists.<br />
:*Directive 2004/27/EC on “traditional herbal medicinal products” provides for<br />
definitions of (i) traditional herbal medicinal products, (ii) herbal medicinal<br />
products, (iii) herbal preparations and (iv) herbal substances. The directive<br />
introduces a simplified registration procedure, based on “traditional use”, but<br />
ensuring quality and safety as for any other medicinal product. Community lists<br />
will have to be prepared of traditional herbal medicinal products, herbal<br />
preparations and herbal products. On the other hand, traditional herbal<br />
materials, which are authorised for use in medicinal products, will continue to<br />
contribute to the dietary intake of bioactive agents as long as they comply with<br />
the general food regulations and make no medicinal claim.<br />
<br />
6. Also relevant in this context are the Directives 1989/398/EEC and 96/84/EC on<br />
“Food for special purposes” and the Regulation 1997/258/CE on “novel foods” that<br />
provide additional channels for some botanicals and botanical preparations to enter<br />
the food market, and the proposed Directives on “nutritional and health claims” and<br />
“food fortification” at present under consideration by the European Parliament and<br />
Council.<br />
<br />
7. As the market volume expands, so does the need for a better characterisation of<br />
botanicals and botanical preparations, and for harmonising the scientific assessment<br />
of risks from exposure of consumers to these products.<br />
<br />
8. It is important, therefore, from a public health point of view, to achieve a<br />
comprehensive and coherent approach to risk assessment and consumer<br />
information on botanicals and botanical preparations widely present in different<br />
categories of commodities. Such an approach would, in time, overcome the existing<br />
information gaps on many of these products and bring together the fragmentary<br />
provisions for risk assessment on botanicals and botanical preparations in the<br />
current relevant regulations. To this end, the present paper aims at increasing<br />
awareness on these issues and at facilitating a critical analysis of the present<br />
situation. It is intended to lead to a stronger partnership and collaboration among all<br />
the stakeholders who have a role in this important sector.<br />
<br />
9. Although it is not the objective of this discussion paper to provide a detailed<br />
analysis of the way forward, the following reflections address some issues in order<br />
to facilitate an open discussion particularly in the frame of future developments of<br />
the above-mentioned Directive 2002/46/EC:<br />
<br />
:*As systematic information about the range of botanicals and botanical products<br />
present on the market is lacking, consideration could be given, to carrying out a<br />
survey to identify the main product categories currently marketed and a study to<br />
clarify the potential health-related issues that may need to be addressed.<br />
:*In view of the difficulty of compiling a full inventory of botanicals and<br />
botanical products, the possibility could also be considered of adopting and<br />
regularly updating a list of plants or parts of plants which should not be used or<br />
could be put under scrutiny because of the presence of undesirable substances,<br />
especially if effective reduction or removal of such substances can not be<br />
ensured.<br />
:*As purity specifications for all botanicals and botanical preparations are very<br />
difficult to define, the development of ad hoc manufacturing guidelines, could<br />
be considered in order to improve their characterisation and safety. Experience<br />
already existing in the pharmaceutical sector could be helpful to this end.<br />
:*Considering the importance of providing to consumers adequate information to<br />
allow the safe use of botanicals and botanical preparations, the possibility of<br />
establishing accredited information sources easily accessible to consumers on<br />
these products also deserves attention. A complicating issue in this respect is<br />
the diffusion of misleading claims which are very difficult to counterbalance by<br />
means of reliable consumer information. However, in this respect, the situation<br />
is likely to improve when the proposal for a Community Directive providing for<br />
a clear evaluation procedure of “Nutritional and Health Claims” will be<br />
adopted.<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
http://www.efsa.europa.eu/de/scdocs/doc/1249.pdf</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=EFSA_guidance_on_safety_assessment_of_botanicals&diff=21996
EFSA guidance on safety assessment of botanicals
2011-07-07T10:16:14Z
<p>Minttu: </p>
<hr />
<div>{{nugget<br />
|authors= <br />
|reference= <br />
|urn= <br />
|ethics= <br />
|journal=<br />
|moderator=Minttu<br />
|stub=Yes}}<br />
<br />
EFSA Journal 2009; 7(9):1249<br />
For citation purposes: EFSA Scientific Committee; Guidance on safety assessment of botanicals and botanical preparations<br />
intended for use as ingredients in food supplements, on request of EFSA. EFSA Journal 2009; 7(9):1249. [19 pp.].<br />
doi:10.2093/j.efsa.2009.1249. Available online: www.efsa.europa.eu<br />
© European Food Safety Authority, 2009 1<ref>[http://www.efsa.europa.eu/de/scdocs/doc/1249.pdf]: EFSA Journal 2009; 7(9):1249<br />
For citation purposes: EFSA Scientific Committee; Guidance on safety assessment of botanicals and botanical preparations<br />
intended for use as ingredients in food supplements, on request of EFSA. EFSA Journal 2009; 7(9):1249. [19 pp.].<br />
doi:10.2093/j.efsa.2009.1249. Available online: www.efsa.europa.eu<br />
© European Food Safety Authority, 2009 1 </ref><br />
<br />
<br />
'''''SCIENTIFIC OPINION'''''<br />
<br />
<br />
''Guidance on Safety assessment of botanicals and botanical preparations intended for use as ingredients in food supplements''<br />
<br />
<br />
'''EFSA Scientific Committee'''<br />
<br />
<br />
European Food Safety Authority (EFSA), Parma, Italy<br />
<br />
<br />
This guidance document published on 9 September 2009, replaces the earlier version published on 20<br />
June 2008 with the Question Number: EFSA-Q-2005-233.<br />
<br />
<br />
''ABSTRACT''<br />
<br />
In this opinion, EFSA’s Scientific Committee provides guidance on the scientific data needed to carry out a safety assessments of a botanical or a botanical preparation. It also proposes a two-tiered scientific approach for the safety assessment depending on the available knowledge on a given botanical and the substance(s) it contains. The guidance also provides a set of criteria to help prioritise the safety assessment of botanical ingredients which<br />
are in use. EFSA has also compiled the available information on a large number of botanicals which have been reported to contain substances that may be of health concern when used in food or food supplements. The resulting compendium, which will be regularly updated, should be considered as part of this guidance document<br />
and is intended to assist manufacturers and food safety authorities by highlighting possible safety issues which may require further consideration.<br />
<br />
<br />
''KEY WORDS''<br />
<br />
Botanicals, botanical preparations, safety assessment, food supplements, toxicological properties, medicinal<br />
properties.<br />
<br />
<br />
''SUMMARY''<br />
<br />
Following the discussion paper of the Scientific Committee on botanicals and botanical preparations<br />
adopted on 23 June 2004, The European Food Safety Authority (EFSA) asked in August 2005 the<br />
Scientific Committee to develop a two-level tiered approach for the safety assessment of botanicals<br />
and botanical preparations. This approach consists of a first safety assessment level based on<br />
available knowledge and a subsequent level in which the safety assessment includes newly generated<br />
data.<br />
<br />
<br />
The present guidance document is focussed on botanicals and botanical preparations intended for use<br />
in food supplements, although the approach chosen is, in principle, applicable also to other uses of<br />
botanicals and botanical preparations in the food and feed areas.<br />
<br />
<br />
A general framework for safety assessment is proposed by the Scientific Committee, in which<br />
botanicals or botanical preparations for which an adequate body of knowledge exists could benefit<br />
from a “presumption of safety” without any need for further testing. Issues that should be carefully<br />
considered in order to reach such a conclusion are discussed in detail in the present guidance<br />
document. Botanicals and botanical preparations for which a presumption of safety is not possible<br />
based on available knowledge would be subject to a more extensive safety assessment, requiring<br />
additional data to be provided.<br />
<br />
<br />
It is not the objective of this opinion to produce a list of safe botanicals and botanical preparations<br />
intended for food supplement use, but only to provide guidance on how to assess safety of botanical<br />
ingredients.<br />
<br />
<br />
The Scientific Committee developed criteria for prioritising botanicals for safety assessment and has<br />
compiled a Compendium of botanicals that are reported to contain toxic, addictive, psychotropic or<br />
other substances that may be of concern. The main purpose of the Compendium, which should be<br />
considered as part of this guidance document, is to draw attention to issues that would need to be<br />
taken into account when assessing the safety of botanicals used as ingredients in food supplements,<br />
and to facilitate the establishment of priorities for safety assessment.<br />
<br />
<br />
The Scientific Committee recommends maintaining the Compendium up-to-date, making use of<br />
relevant available national lists of plants and of any other relevant data available, as well as of<br />
updated assessments carried out on botanicals by qualified bodies. The Scientific Committee also<br />
recommends to further expand the Compendium with botanicals not having any market history in<br />
Europe but having a documented history of use in their third country of origin.<br />
<br />
<br />
TABLE OF CONTENTS<br />
:*Abstract <br />
:*Summary <br />
:*Table of contents <br />
:*Background as provided by EFSA <br />
:*Terms of reference as provided by EFSA <br />
:*Acknowledgements <br />
:*Assessment <br />
:1.Introduction <br />
:2.Safety assessment of botanicals and botanical preparations intended for use as ingredients in<br />
food supplements <br />
:2.1Proposed data requirements for safety assessment of botanicals and botanical preparations<br />
used as ingredients in food supplements <br />
:2.1.1.Technical data<br />
::2.1.1.1. Identity and nature of the source material <br />
::2.1.1.2. Manufacturing process<br />
::2.1.1.3. Chemical composition <br />
::2.1.1.4. Specifications <br />
::2.1.1.5. Stability of the botanical or botanical preparation used as ingredient in food supplement <br />
::2.1.1.6. Proposed uses and use levels <br />
::2.1.1.7. Information on existing assessments <br />
:2.1.2. Exposure: extent and duration <br />
:2.1.3. Toxicological data <br />
2.2. Proposed general framework for assessing the safety of botanicals and botanical<br />
preparations used as ingredients in food supplement <br />
:2.2.1. Level A: Safety assessment based on available knowledge <br />
:2.2.2. Additional data required for the level B assessment <br />
3. Establishing a Compendium of botanicals and prioritising them to be considered for a safety<br />
assessment. <br />
:*Conclusions and recommendations <br />
:*References <br />
<br />
<br />
''BACKGROUND AS PROVIDED BY EFSA''<br />
<br />
A discussion paper by the Scientific Committee on botanicals and botanical preparations widely used<br />
in food supplements and related products was adopted on 23 June 2004 (SC document EFSA/SC/26<br />
Final3). In this paper, the Committee expressed concerns about quality and safety issues of botanicals<br />
and botanical preparations that have become widely available to consumers through several<br />
distribution channels in the EU. The use of botanicals and botanical preparations in food is regulated<br />
under the General Food Law (178/2002/EC), which attributes the primary legal responsibility for the<br />
safety of the products placed on the market to business operators. The Regulation however does not<br />
provide any guidance on how the safety of these products should be assessed. As the market volume<br />
and the variety of products expand, so does the need for a better characterisation of the range of<br />
botanicals and botanical preparations on the market, and for harmonising the risk assessment and<br />
consumer information approaches for these products. The paper aimed at increasing awareness of<br />
EFSA’s Advisory Forum on potential public health aspects associated with these products.<br />
<br />
<br />
The Secretariat brought the discussion paper to the attention of the Advisory Forum at its meeting of<br />
the 1st of October, 2004. Simultaneously, an invitation was sent to the members of the Advisory Forum to take note of the concerns<br />
raised by the Scientific Committee and to complete a questionnaire to provide a better understanding of the issue in Europe.<br />
<br />
<br />
By the end of January 2005, replies were received from twenty five countries, comprising twenty two<br />
EU Member States and three EFTA Countries. The members of the Advisory Forum underlined the<br />
importance of this issue for their countries and asked EFSA to initiate a self-task in order to develop<br />
some guidance on how to assess the safety of botanical ingredients.<br />
<br />
<br />
Following the mandate received by the Scientific Committee in August 2005 from EFSA, the<br />
Scientific Committee developed a two-level tiered approach for the safety assessment of botanicals<br />
and botanical preparations. A guidance document focussing on botanicals and botanical preparations<br />
intended for use as food supplements was published after public consultation.<br />
<br />
<br />
A conceptual framework for safety assessment was advocated, in which botanicals or botanical<br />
preparations for which an adequate body of knowledge exists could benefit from a “presumption of<br />
safety” without any need for further testing (first level of the framework). Issues that should be<br />
carefully considered in order to reach such a conclusion were discussed in detail in the guidance<br />
document. Botanicals and botanical preparations for which a presumption of safety is not possible<br />
would be subject to a more extensive safety assessment, based on additional data to be provided in<br />
accordance with the methodology described in the second level of the proposed framework.<br />
<br />
<br />
As a follow up, it was decided to test the adequacy of the above-mentioned approach described in the<br />
guidance document for safety assessment with a selected number of examples including botanicals<br />
known to contain toxic substances or having a reported toxic effect, botanicals with an established<br />
history of food use, and botanicals that are known to contain potentially genotoxic/carcinogenic<br />
substances. To this end, an EFSA Scientific Cooperation (ESCO) Working Group, composed of<br />
experts identified by the members of the Advisory Forum and by the Scientific Committee EFSA was<br />
established in April 2008. This working group was also given the task to finalise the Compendium of<br />
botanicals reported to contain toxic, addictive, psychotropic, or other substances of concern. The resulting ESCO report and Compendium9 were provided to the EFSA Executive Director in May<br />
2009.<br />
<br />
<br />
''TERMS OF REFERENCE AS PROVIDED BY EFSA''<br />
<br />
The Scientific Committee has been requested in May 2009 by the European Food Safety Authority<br />
to consider the recommendations made in the ESCO report for updating the guidance document for<br />
the safety assessment of botanicals and botanical preparations intended for use as ingredients in food<br />
supplements.<br />
<br />
<br />
''ACKNOWLEDGEMENTS''<br />
<br />
The European Food Safety Authority wishes to thank the members of the EFSA Scientific<br />
Cooperation (ESCO) Working Group on Botanicals and Botanical Preparations for the preparation of<br />
the ESCO Report, which was used by the Scientific Committee to update this guidance document.<br />
The European Food Safety Authority would also like to thank the members of the former Scientific<br />
Committee for their contributions to the present guidance document.<br />
<br />
<br />
''ASSESSMENT''<br />
<br />
1. '''Introduction'''<br />
The Scientific Committee decided to focus its work first on the safety assessment of botanicals and<br />
botanical preparations used as ingredients in food supplements (hereafter referred to, as botanical<br />
ingredients), although the approach chosen is, in principle, applicable also to other uses of botanicals<br />
and botanical preparations in the food and feed areas. It is not in the scope of the present guidance to<br />
address issues related to quality assurance and good hygienic practices currently regulated by the EU<br />
Food Legislation, nor to assess the safety of food supplements as end products. The present guidance<br />
does not therefore address hazards linked to the presence of contaminants and foodborne pathogens in<br />
the botanicals and botanicals preparations.<br />
<br />
<br />
A two-level tiered conceptual framework for safety assessment consisting of a safety assessment<br />
based on available knowledge and a subsequent level in which further testing and/or data are required<br />
is proposed by the Scientific Committee. Botanicals or botanical preparations for which an adequate<br />
body of knowledge exists, can benefit from a “presumption of safety” without any need for further<br />
testing. Based on reasonable evidence, they can then be assumed to be safe, sometimes under certain<br />
restrictions. The Scientific Committee used as an example the Qualified Presumption of Safety (QPS)<br />
approach developed for microorganisms in food and feed (EFSA, 2007a) to propose criteria for<br />
presuming a botanical or a botanical preparation safe. Botanicals and botanical preparations for which<br />
a presumption of safety is not possible should be subject to a more extensive safety assessment, based<br />
on additional data to be provided according to the methodology described by EFSA. By proposing a<br />
first safety assessment level based on available knowledge, the approach proposed by the Scientific<br />
Committee for the safety assessment of botanicals and botanical preparations is in line with EFSA’s<br />
policy to stimulate food and feed risk assessment approaches that minimise the number of<br />
experimental animals and any suffering (EFSA, 2009).<br />
<br />
<br />
In order to facilitate the implementation of the above-mentioned approach, EFSA has also compiled a<br />
Compendium of botanicals and botanical preparations that have been reported to contain toxic,<br />
addictive, psychotropic or other substances that may be of concern. This Compendium should be seen<br />
as a tool to gather relevant information and define priorities for safety assessment. The inclusion of a<br />
botanical in this Compendium does not imply that it is not safe for use in food supplements. Without<br />
prejudice to the existing legal framework, such Compendium has no legal status and may not be used<br />
as support or evidence in any disagreement or dispute pertaining to the legal classification of products<br />
or substances.<br />
<br />
<br />
Safety assessment of botanicals and botanical preparations<br />
EFSA Journal 2009; 7(9):1249 7<br />
2. '''Safety assessment of botanicals and botanical preparations intended for use as<br />
ingredients in food supplements'''<br />
<br />
It should be noted that Regulation 258/97/EC concerning novel foods and novel food ingredients<br />
applies to all foods, including food supplements, containing substances which have not been used for<br />
human consumption to a significant degree within the Community before 15 May 1997 and which fall<br />
under certain categories specified in the above-mentioned Regulation. In the case of a proposed use as<br />
a novel food, botanicals or botanical preparations should be assessed following the guidelines of the<br />
Commission Recommendation 97/618/EC of 29 July 1997 concerning the scientific aspects and the<br />
presentation of information necessary to support applications for the placing on the market of novel<br />
foods and novel food ingredients.<br />
<br />
<br />
Moreover, Regulation 1829/2003/EC on genetically modified food and feed would apply to any GMO<br />
ingredients used in food supplements. In the case of botanicals or botanical preparations derived from<br />
genetically modified plants, information should be provided in line with the guidance document of the<br />
EFSA Scientific Panel on Genetically Modified Organisms for the risk assessment of genetically<br />
modified plants and derived food (EFSA, 2006a).<br />
When the botanical or botanical preparation is intended for use as a food intended for particular<br />
nutritional uses (PARNUTS – Directive 89/398/EEC), the guidance document from the Scientific<br />
Committee on Food on submissions for safety evaluation of sources of nutrients or of other<br />
ingredients proposed for use in the manufacture of foods (SCF, 2001a) should also be consulted.<br />
<br />
<br />
It should also be underlined that this report only deals with guidance on safety assessment, whereas<br />
the scientific substantiation of any claims made on food supplements, as required by the Regulation<br />
on Nutrition and Health Claims, will be dealt with in separate EFSA documents, such as the<br />
“Scientific and technical guidance for the preparation and presentation of the application for<br />
authorisation of a health claim” (EFSA, 2007b).<br />
It is not the objective of this report to produce a list of safe botanicals and botanical preparations<br />
intended for food supplement use, but only to provide guidance on how to assess safety of botanical<br />
ingredients. Moreover, priority criteria are proposed, and a Compendium has been compiled to serve<br />
as a preliminary tool for risk assessors (see section 3).<br />
<br />
<br />
2.1. '''Proposed data requirements for safety assessment of botanicals and botanical<br />
preparations used as ingredients in food supplements'''<br />
<br />
It is understood that the use of botanicals and botanical preparations as ingredients in food<br />
supplements will have to be in compliance with the existing EU Food Legislation. This would<br />
include maximum permissible levels of chemical and biological contaminants (e.g. pesticides,<br />
mycotoxins, heavy metals and foodborne pathogens), modalities for ensuring quality, and application<br />
of good hygienic practice, including HACCP methodologies. The issues of controls needed to ensure<br />
constancy over time of the composition of botanical food supplements on the market and batch-tobatch<br />
variation are not addressed in this document as these are risk management aspects and therefore<br />
outside the scope of EFSA.<br />
<br />
The following sections aim at identifying data and information considered as necessary to assess the<br />
safety of botanical ingredients. These data are of: (i) technical; (ii) exposure and (iii) toxicological<br />
nature. The lists below are meant to give guidance on data requirements. They have been made as<br />
exhaustive as possible and should be adapted on a case-by-case basis, depending on the nature of the<br />
botanical or botanical preparation. This implies that not all the information listed below would be<br />
needed in all cases and that the amount of information available for a given botanical or botanical<br />
preparation may in some cases be sufficient without further testing (see section 2.2.1).<br />
<br />
<br />
2.1.1. '''Technical data'''<br />
<br />
<br />
2.1.1.1. Identity and nature of the source material<br />
<br />
It is recognized that identification of the botanical source and botanical preparation may in some cases<br />
be complicated. It is recommended to follow as much as possible the nomenclature of the European<br />
Pharmacopeia. Additional nomenclature sources are as follows:<br />
<br />
World Checklist of Selected Plant Families (Royal Botanic Garden, Kew); the books by Hanelt<br />
(2001) also available on the Internet as Mansfeld’s World Database of Agricultural and Horticultural<br />
Crops; and the database by United States Department of Agriculture. If a scientific name is not found<br />
in any of the above-named references, its existence may be checked in The International Plant Names<br />
Index.<br />
<br />
<br />
Since there have been many instances where species have been reclassified or renamed, a same<br />
species may be known by different scientific names. Common (vernacular) names may also be<br />
provided, but it should be noted that a common name used in one region to refer to a particular plant<br />
may be used elsewhere to refer to another quite unrelated species. Hence common names may not<br />
uniquely identify a species and are not as reliable as the scientific names.<br />
<br />
<br />
The following scheme summarizes the requirements for description of the identity of the botanical:<br />
<br />
<br />
;Scientific (Latin) name:<br />
:full systematic species name incl. botanical family, genus,<br />
species, variety, subspecies, author’s name, and chemotype if<br />
applicable<br />
<br />
;Synonyms: <br />
:botanical name(s) that may be used interchangeably with the<br />
preferred scientific name<br />
;Common names: <br />
:vernacular name(s)<br />
;Part used: <br />
;e.g. root, leaf, seed …<br />
;Geographical origin: <br />
:continent, country, region<br />
;Growth and harvesting conditions: <br />
:wild or cultivated, cultivation practices, time of harvest in relation<br />
to both season and stage of the plant growth.<br />
<br />
2.1.1.2. Manufacturing process<br />
<br />
The following information is considered necessary for assessing the safety of botanicals and botanical<br />
preparations:<br />
i):Information on the method(s) of manufacture (e.g. the process by which the raw material is<br />
converted into a preparation, such as extraction or other procedure(s), and plant extract ratio)<br />
<br />
ii):Information on substances entering the manufacturing process, e.g. identity of the extraction<br />
solvent, reagents, special precautions (light and temperature).<br />
<br />
iii):Standardization criteria (e.g. see European Pharmacopoeia).<br />
<br />
Botanicals or botanical preparations might become hazardous as a result of deviations in the<br />
production process (e.g. misclassification, switching of species). Therefore the safety of botanicals<br />
and botanical preparations should be ensured by following a Hazard Analysis and Critical Control<br />
Point (HACCP) approach (Codex Alimentarius 1997). The whole production chain, from primary<br />
production of botanicals to the storage and commercialisation of the botanical preparations should be<br />
taken into consideration. The HACCP system must be applied with the necessary flexibility and<br />
adapted to each botanical preparation on a case-by-case basis.<br />
<br />
<br />
2.1.1.3. Chemical composition<br />
<br />
Data on the chemical composition of the botanical ingredient should be provided with emphasis on<br />
the concentrations of constituent of relevance for the safety assessment; this includes the<br />
concentrations of:<br />
:*Compounds should be classified according to their chemical structure (e.g. flavonoids,<br />
terpenoids, alkaloids, etc.). Levels at which the constituents are present in the respective part<br />
of the botanical or botanical preparation should be given where available.<br />
:*Constituents to characterise the quality, chemical fingerprint, production process and/or<br />
biological activity of the preparation (markers).<br />
:*Constituents that provide reasons for concern due to their chemical, physiological or<br />
toxicological properties.<br />
In some cases, it may be difficult to identify the active principle responsible for an effect. Therefore<br />
the strength of the evidence underlying the concerns over a compound being reason for concern<br />
should also be given.<br />
<br />
<br />
2.1.1.4. Specifications<br />
<br />
Specifications of the botanicals or botanical preparations are required. They may be based on<br />
nutritional or biologically active components or, when these are not known, on selected chemical<br />
markers. Limits for or absence of specific undesirable / toxic substances should be specified. The<br />
proposed specifications should be modelled on recent European or other internationally accepted<br />
specifications (e.g. pharmacopoeia or the guidelines of the EMEA Committee on Herbal Medicinal<br />
Safety assessment of botanicals and botanical preparations<br />
<br />
Products (HMPC)). Where the proposed specifications differ from internationally recognised<br />
specifications, the latter specifications should be set out alongside the proposed new specifications,<br />
and any differences pointed out. Validated and well-established methods should be preferably used<br />
for the analysis of compounds considered in specifications.<br />
<br />
The specifications should include concentrations of major groups of constituents present in the<br />
botanical preparation including for example: amino acids, lipids, polysaccharides, volatile oil,<br />
inorganic ions, polyphenols, alkaloids, terpenes, alkenylbenzenes, lignin, saponins etc. as well as the<br />
major constituents within these classes.<br />
<br />
In addition, information on maximum levels for possible contaminants including e.g. heavy metals,<br />
mycotoxins, pesticide residues, and polycyclic aromatic hydrocarbon (PAH) residues should be<br />
provided.<br />
<br />
<br />
2.1.1.5. Stability of the botanical or botanical preparation used as ingredient in food supplement<br />
<br />
The stability of the botanical ingredient should be demonstrated over the shelf-life time. Any<br />
information concerning possible degradation should also be provided.<br />
<br />
<br />
2.1.1.6. Proposed uses and use levels<br />
<br />
Information on intended uses and recommended intakes for a product should specifically mention<br />
uses and use levels for the following categories:<br />
:* Common foods<br />
:* Food supplements<br />
:* Medicinal products<br />
<br />
Special attention should be given to population groups with specific uses like for example young<br />
children. Information on the duration of the proposed uses and use levels should also be provided<br />
<br />
<br />
2.1.1.7. Information on existing assessments<br />
<br />
Information on any existing assessments by international bodies or national competent authorities<br />
should be provided.<br />
<br />
<br />
2.1.2. '''Exposure: extent and duration'''<br />
<br />
Data and information should be provided on:<br />
:i) Anticipated human exposure to the botanical ingredient, including amount (e.g. maximum and<br />
average daily intake or exposure), frequency and duration. It is important to characterize as much as<br />
possible the expected human exposure to the botanical ingredient according to the recommended<br />
modalities of use in terms of extent and duration. Clear distinction should be made between intake of<br />
a botanical itself, intake of its essential oil and other preparations made of it.<br />
:ii) Possibility of additional / combined human exposure to the botanical or botanical preparation<br />
through different categories of food, food supplements and/or medicinal products that can be<br />
consumed together.<br />
:ii) Modality of use of the ingredient.<br />
:iv) Information on historical (food, food supplement and medicinal) use of the ingredient in<br />
human population groups in relation to the modalities of use and resulting exposure levels if known.<br />
Data derived from use outside of the European Union should also be considered.<br />
<br />
<br />
All data should be representative of the ingredient to be used for the European market. In this context,<br />
food use includes, in principle, the consumption of raw and cooked vegetables, spices, flavours, food<br />
supplements already in use for a long time16 and any other related food items.<br />
<br />
<br />
Estimates of average exposure ranges associated with the use of the botanical ingredient in the EU<br />
Member States should also be provided. Uncertainties associated with the food consumption data<br />
considered and anticipated exposure ranges should be clearly described (EFSA, 2006b).<br />
<br />
A matter to be specifically addressed in the evaluation is whether the proposed use and use levels will<br />
significantly increase already existing human exposure.<br />
<br />
<br />
2.1.3. '''Toxicological data'''<br />
<br />
Studies on toxicity and toxicokinetics including metabolism of botanicals and botanical preparations<br />
should be conducted using internationally agreed protocols. Test methods described by OECD or in<br />
European Commission Directives 87/432/EEC and 67/548/EC – Annex 5 are recommended. It is<br />
advisable to ensure that the most up-to-date version of any test guideline is followed. Use of any<br />
methods differing from internationally agreed protocols should be justified. Protocols for special<br />
studies differing from standard tests should be developed on a case-by-case basis.<br />
<br />
To ensure general acceptance of the data submitted, studies should be carried out according to the<br />
principles of Good Laboratory Practice (GLP) described in Council Directive 87/18/EEC and<br />
accompanied by a statement of GLP compliance. Adequate explanation should be provided for<br />
divergence from these principles.<br />
<br />
Council Directive 86/609/EEC, on the protection of animals used for experimental and other scientific<br />
purposes, requires that care is taken to avoid unnecessary use of animals. Studies carried out should<br />
be those necessary to demonstrate the safety of a botanical or botanical preparation and planned in<br />
accordance with the principles of reduction, refinement and replacement. However, where adequate<br />
data are not available for the safety assessment (see section 3.2.1), in vivo studies using experimental<br />
animals may be needed in order to assess possible risks to humans from the ingestion of botanicals or<br />
botanical preparations. Alternative validated methods involving fewer or no animals for toxicity<br />
endpoints may in the future be developed and should be considered on a case-by-case basis.<br />
<br />
If available, data on possible interactions (e.g. herbal-drug) should also be provided.<br />
<br />
<br />
2.2. '''Proposed general framework for assessing the safety of botanicals and botanical<br />
preparations used as ingredients in food supplement'''<br />
<br />
Several guidance documents (AFSSA, 2003; Council of Europe, 2005; Schilter et al., 2003) have been<br />
published on the principles for assessment of botanicals and botanical preparations in the food and<br />
feed area. The present guidance document is not intended to reiterate these, but to outline a<br />
framework that could be used by risk assessors when assessing the safety of a botanical or a botanical<br />
preparation. It also proposes a scientific approach to the assessment of available data.<br />
<br />
The aim of the assessment is to ensure that botanicals or botanical preparations, when used in food<br />
supplements in the manner, quantities and time period of intake proposed, would not pose a risk to the<br />
health of consumers. Data should provide not only information relevant to the healthy adult consumer,<br />
but also relevant to those population groups potentially vulnerable due to their pattern of food<br />
consumption or their physiological or health status, e.g. young age, elderly, pregnancy,<br />
immunocompromised etc.<br />
<br />
A general framework for assessing the safety with core tests and other tests is given, which should<br />
enable determination of what information is required to establish the safety-in-use of the botanical or<br />
botanical preparation. The application of this guidance to specific cases will depend on the nature of<br />
the botanical or botanical preparation, its intended uses and levels of use in food supplements and on<br />
whether the botanical or botanical preparation has a long term history of food use17, showing that, at<br />
proposed exposure levels, no adverse effect on human health has been reported. In addition to<br />
laboratory tests, it may be possible to use human data derived from medical use, epidemiology, or<br />
specific studies on volunteers (e.g. on absorption and metabolism), or any other data reporting<br />
possible adverse health effects, either anecdotal or on the basis of case reports of intoxication, e.g data<br />
related to toxicity on livestock animals, or on botanicals that closely resemble botanicals which are<br />
known to have caused toxic effects.<br />
<br />
However, it is recognized that for botanical ingredients lacking a history of food use, or for botanicals<br />
whose intended use levels will significantly exceed historical intake levels, an assessment of safety<br />
generally relies on experimental toxicity data largely derived from investigations in laboratory<br />
animals.<br />
<br />
The approach herein proposed for the safety assessment of botanicals and botanical preparations not<br />
regulated in the framework of specific regulations such as the one on novel foods, and illustrated by<br />
Figure 1, consists of the two following levels:<br />
:*Level A: Safety assessment based on available knowledge.<br />
:*Level B: Safety assessment including newly generated data.<br />
<br />
Figure 1: Proposed tiered approach for the safety assessment of botanicals and botanical<br />
preparations.<br />
<br />
<br />
2.1. '''Level A: Safety assessment based on available knowledge'''<br />
<br />
Depending on the botanical ingredient and its uses, there are circumstances under which no additional<br />
data are judged necessary for the safety evaluation, i.e. a presumption of safety would be applied.<br />
This would be the case whenever available data would allow to conclude that exposure to known<br />
levels of the botanical ingredient has occurred in large population groups for many years without<br />
reported adverse effects.<br />
<br />
Therefore, an important requirement is that the data as outlined in chapter 2.1 are provided and that<br />
no significant increase of intake compared to historical levels is to be expected due to the intended<br />
levels of use in food supplements. This implies that not only use levels but also chemotypes of<br />
botanicals and the chemical composition of the botanical preparations should be in line with<br />
historically used ones. This approach can only be applied when intakes due to the intended levels of<br />
use are within the range of intake levels derived from the European Member States’ average diets or<br />
from studies on specific subgroups. It is recognized that the acceptability of such an approach relies<br />
mainly on the objective of not significantly increasing exposures beyond the levels linked to the safe<br />
history of use.<br />
<br />
If compounds of concern can be well defined, evaluations can focus on these specific compounds. In<br />
some cases, it may be difficult to identify the active principle responsible for an effect. In such cases<br />
the strength of the evidence underlying the concerns over a compound taken as the reference<br />
compound for the safety evaluation should also be given.<br />
<br />
For botanicals and botanical preparations with a potential to contain toxic, addictive, psychotropic or<br />
other substances that may be of concern (see also the Compendium and section 3), presumption of<br />
safety can be applied only if there is convincing evidence that these undesirable substances in the<br />
specific plant parts or preparations are either absent in the source material, or significantly reduced if<br />
not excluded, or inactivated during processing.<br />
<br />
In cases where the above-mentioned substances are known to be present in the botanical ingredient<br />
under evaluation (see attached Compendium), additional consideration should be given to support the<br />
presumption of safety of the botanical preparation. The significance of overall exposure to such<br />
substances should be assessed and compared with existing health-based guidance values such as the<br />
acceptable / tolerable daily intake (ADI/TDI). Consideration of exposure to the substance of concern<br />
in relation to the Threshold of Toxicological Concern (TTC) values may also be helpful.<br />
<br />
In cases where no health-based guidance values are available or where the botanical ingredient<br />
contains substances that are both genotoxic and carcinogenic, the “Margin of Exposure” (MOE)<br />
approach (EFSA, 2005) could be applied covering the botanical(s) under examination and any other<br />
dietary sources of exposure. The MOE approach compares toxic effect levels with human exposure<br />
levels. Alternatively, it could be evaluated whether the expected exposure to the genotoxic and<br />
carcinogenic ingredient is likely to be increased, compared to the intake from other sources.<br />
<br />
It is plausible that the kinetics as well as the expression of the inherent toxicity of a naturally<br />
occurring substance could be modified by the matrix in which it is present. Depending on the<br />
mechanism of action, this could result in the toxicity being unchanged, reduced or even increased.<br />
Research on individual substance/matrix interactions or botanical preparations cannot be used to draw<br />
general conclusions about intact botanicals, herbs and spices under all conditions of use, ingestion and<br />
metabolism. Where a matrix effect is advocated to support the safety of specific levels of substances<br />
(e.g. that data from a pure substance may overestimate effects of the substance in the botanical<br />
matrix), testing and/or other data should be provided to demonstrate the occurrence of the matrix<br />
effect of the preparation and its magnitude. A matrix effect should be judged on a case-by-case basis.<br />
<br />
Extrapolating from one preparation to another and/or from one botanical to another with respect to the<br />
same substance of toxicological concern can only been considered when accompanied by evidence of<br />
their composition with respect to the substance of concern and pattern of consumption.<br />
<br />
For food supplements consisting of complex mixtures of different botanicals, the above-mentioned<br />
assessment could be carried out on the levels of individual substances of concern known to be present<br />
(see also the Compendium), with the understanding of the limitation that such an approach does not<br />
generally allow the assessment of possible synergistic or antagonistic effects.Any data on possible<br />
herb-drug interaction should be carefully considered.<br />
<br />
In the case of a botanical ingredient whose anticipated intake is significantly higher than the estimated<br />
historical intake level, or for which the historical intake level cannot be assessed, additional data<br />
should be provided for the safety assessment, as described in the following sections.<br />
<br />
2.2.2. '''Additional data required for the level B assessment'''<br />
<br />
The reasons for carrying out toxicological studies should be stated, as should the reasons for not<br />
submitting a study that might be expected. The studies that might be expected can be seen from the<br />
“Guidance on submissions for food additive evaluations by the Scientific Committee on Food” (SCF<br />
2001b). All the important results should be presented and discussed and the original study reports<br />
should be submitted in order to allow independent, critical appraisal.<br />
<br />
The toxicology section of the dossier should start with a section describing in detail the specifications<br />
and identity criteria for the botanical preparation(s) used for the toxicity studies and their relationship<br />
to the final product to be used in the food supplement. It should be demonstrated unambiguously that<br />
these characteristics are in compliance with the technical details specified for the botanical<br />
preparation in this report.<br />
<br />
The toxicological tests should, as far as possible, follow the recommendations for data reporting given<br />
in the relevant guidelines (e.g. OECD, 1998). The material to be tested, with lot or batch number,<br />
should be well identified, characterized and standardized. It is important that for each study performed<br />
it is stated whether the test material conforms to the proposed specifications. If it does not conform,<br />
then the specifications of the test material should be given together with a rationale for using these<br />
data in the safety assessment of the product intended for the market.<br />
<br />
<br />
*''Toxicokinetics including metabolism''<br />
<br />
Information on toxicokinetics of relevant biologically active constituents present in the botanical or<br />
botanical preparation should be provided whenever available from the literature. Not all aspects need<br />
to be investigated in every case. Additional issues that may deserve consideration are:<br />
:*The possibility of interactions among constituents of the botanical or botanical<br />
preparation that can alter bioavailability, metabolism, and toxicity.<br />
:*The possibility of interactions with medicinal products.<br />
*''Genotoxicity testing''<br />
For the genotoxicity testing of botanicals and botanical preparations, in vitro tests covering effects<br />
both at gene and chromosome levels are required19. Specific tests are likely to include the Ames test<br />
(OECD guideline 471) and an in vitro test for the detection of chromosomal aberrations (OECD<br />
guideline 473) or an in vitro micronucleus assay (draft OECD guideline 487), and possibly the mouse<br />
lymphoma tk assay (OECD 476). The particular test strategy may depend upon the test material<br />
considered.<br />
<br />
There may be circumstances under which it may be justified to deviate from the above-mentioned<br />
core set. In such cases a scientific justification should be provided and additional types of<br />
considerations or mechanistic studies may be needed.<br />
<br />
A positive in vitro test normally requires follow-up by in vivo testing, unless it can be adequately<br />
demonstrated that the positive in vitro findings are not relevant for the in vivo situation. The choice of the appropriate in vivo test is critical, due to different sensitivities, different endpoints and other<br />
variables. It requires expert judgement based on all available information, to be applied case-by-case.<br />
For this reason, a flexible approach is preferable to a fixed decision tree.<br />
<br />
<br />
*''Subchronic toxicity testing''<br />
<br />
A 90-day study in the rat with the test material administered via the diet is the minimum requirement<br />
to establish a no-observed-adverse-effect level. Subchronic toxicity testing should be carried out<br />
independently of the results of the in vitro and in vivo genotoxicity testing.<br />
<br />
*''Other studies''<br />
<br />
Depending on the outcome of the genotoxicity and subchronic toxicity studies, or other specific<br />
relevant information, further studies may be required (e.g. reproductive toxicity, developmental<br />
toxicity, neurotoxicity, immunotoxicity, chronic toxicity/carcinogenicity).<br />
<br />
<br />
3. ''Establishing a Compendium of botanicals and prioritising them to be considered for a<br />
safety assessment.''<br />
<br />
A Compendium of botanicals reported to contain toxic, addictive, psychotropic or other substances<br />
that may be of concern has been produced to complement the present guidance document.<br />
<br />
The Compendium contains the following information:<br />
:*The botanical (binomial) denomination of the plant (genus, species and in some cases variety or<br />
subspecies when relevant), with synonyms in use.<br />
:*The plant parts and substances of possible toxicological concern<br />
:*Additional specific information of relevance for the risk assessment, e.g. adulterations<br />
:*References, either to existing international / national list of plants that were used to populate the<br />
Compendium, or to published literature when specific information has been added.<br />
<br />
The Compendium aims at flagging plants or part of plants or substances of possible concern for<br />
human heath naturally present in the listed botanicals and that, therefore, require specific attention<br />
while assessing the safety of the product(s) containing such botanical(s). For some botanicals in the<br />
Compendium, adverse (toxic) effect(s) are mentioned although sometimes based on anecdotal reports<br />
and even though the constituent(s) of concern are not elucidated in the literature. In some cases the<br />
whole genus was flagged because of the likely presence of substances of concern characteristic for the<br />
toxicity of that genus.<br />
<br />
The presence of a substance of concern in a given botanical does not mean that this substance will<br />
also be present in the botanical preparation. This depends largely on the plant part used, as well as the<br />
preparation method.<br />
<br />
The Compendium contains also an “insufficient information” list regrouping botanicals that appear in<br />
one of the sources of information, but for which sufficient information could not be found on possible<br />
substances of concern, or for which the information available could not be verified.<br />
<br />
Without prejudice to the existing legal framework, it should be noted that this Compendium has no<br />
legal status and should not be used as support or evidence in any disagreement or dispute pertaining to<br />
the legal classification of products or substances.<br />
<br />
The Compendium is a living document which should be periodically updated by EFSA. As a<br />
consequence, the absence of a given species in this Compendium cannot be interpreted as meaning<br />
that the species is devoid of substances hazardous for human health. In the same way, not mentioning<br />
a specific part of plant, does not imply absence of substance(s) of concern in this part. Botanicals that<br />
have not been reported as having been considered for food or food supplement use in the European<br />
countries or botanicals classified as novel foods or GMOs will not appear in the Compendium.<br />
<br />
''Priority setting for safety assessment:''<br />
The botanicals in the above-mentioned Compendium should be assessed according to the following<br />
recommendations:<br />
<br />
Priority should be given to botanicals and botanical preparations:<br />
:*known to have an established history of food use and that have been identified to contain<br />
significant levels of substances of concern.<br />
:*that are not allowed/recommended for food use in some European countries, but which are<br />
still in use in some other EU countries, particularly when the intended use levels in food are<br />
known or expected to be high.<br />
:*for which some adverse health effects have been reported, either anecdotally, or on the basis<br />
of case reports of intoxication, epidemiological data or any toxicity data from livestock<br />
animals or experimental animals, or for botanicals that closely resemble botanicals which are<br />
known to have caused toxic effects.<br />
:*for which consumption has significantly increased during recent years in Member States.<br />
:*for which there are both limited history of use and toxicity data available, and for which the<br />
intended use levels are expected to be relatively high (e.g. high interest to the food industry).<br />
<br />
Botanical ingredients that are reported to have a low toxic potential, and for which the intended<br />
intake/exposure levels are within the range of intake levels resulting from the European Member<br />
States average diet would be given a low priority.<br />
<br />
'''''CONCLUSIONS AND RECOMMENDATIONS'''''<br />
<br />
A two-level tiered approach for the safety assessment of botanical ingredients intended for use in food<br />
supplements is proposed. This approach consists of a safety assessment based on available knowledge<br />
and a subsequent level in which further testing and/or data are required. It allows the recognition of<br />
presumption of safety without further testing, based on long-term history of use with no reported<br />
adverse effect and with no significant increased exposure. For those botanical ingredients for which a<br />
presumption of safety based on available data cannot be established, it introduces a framework for<br />
assessing their safety, including the types of testing that would be most useful. Recommendations for<br />
prioritising botanicals for safety assessment are also made.<br />
<br />
The Compendium of botanicals reported to contain toxic, addictive, psychotropic or other substances<br />
that may be of concern, is considered to facilitate the assessment by flagging possible safety issues,<br />
and should therefore be considered as an essential part of this guidance document. The Scientific<br />
Committee recommends to maintain it up-to-date, making use of relevant available national lists of<br />
plants and of any other relevant data available, as well as of updated assessments carried out on<br />
botanicals by qualified bodies. The Scientific Committee also recommends to further expand the<br />
Compendium with botanicals not having any market history in Europe in order to prepare the<br />
implementation of the new Novel Food Regulation, which foresees a notification process for<br />
botanicals and botanical preparations having a history of safe use in the third country of origin.<br />
<br />
<br />
'''European Food Safety Authority'''<br />
<br />
''SCIENTIFIC COMMITTEE''<br />
Discussion Paper on “Botanicals and Botanical Preparations widely used<br />
as food supplements and related products: Coherent and Comprehensive<br />
Risk Assessment and Consumer Information Approaches”<br />
<br />
(adopted by written procedure on 23 June 2004)<br />
<br />
1. In view of the fact that botanicals and botanical preparations intended for human<br />
consumption as food supplements and related products are very widely marketed<br />
with a variety of claims, the present discussion paper aims at increasing awareness<br />
of some key issues to improve comprehensiveness and coherence of current<br />
approaches to risk assessment and consumer information on these products.<br />
<br />
2. A large number of botanical materials (e.g. whole, fragmented or cut plants, algae,<br />
fungi, lichens), and botanical preparations obtained from these materials by various<br />
processes (e.g. extraction, distillation, purification, concentration and fermentation)<br />
readily find their way onto the food supplements market. These materials are also<br />
often labelled as natural foods, largely organic, and foods specifically intended to<br />
support sport activities. Personal care products and the so-called “traditional herbal<br />
medicinal products” represent additional sources of exposure of consumers to<br />
botanical products. New products are also emerging, consisting of substances that<br />
commonly occur at low levels in botanical components of the diet, which are then<br />
extracted and re-introduced at much higher levels in specific products.<br />
<br />
3. Botanicals and botanical preparations are widely available to consumers through<br />
several distribution channels in the E.U. and elsewhere. In particular, they are sold<br />
over the counter in pharmacies and can be bought in supermarkets, herbalist’s<br />
shops and other shops, or via the Internet. They are currently available and used in<br />
such a way that they are almost becoming part of the common diet, thus providing<br />
for a significant human exposure from a public health point of view.<br />
<br />
4. There are some general concerns with respect to botanicals and botanical<br />
preparations mainly relating to quality and safety issues:<br />
:*Contamination (both chemical and microbiological) is a documented problem.<br />
It has been associated, for example, with botanical products originating from<br />
Asia. Deaths through poisoning following consumption of such products have<br />
been reported in Europe and the US arising from contamination with heavy<br />
metals, synthetic drugs and other undesirable substances (Ernst, 2002).<br />
Misidentification of plants harvested from the wild is also a continuing<br />
problem. When sales of traditional herbal products remained restricted to<br />
particular ethnic groups, which are familiar with the products and able to exert a<br />
local control on quality, problems were more rarely encountered. The growing<br />
volume of sales in the European Union with products obtained from suppliers<br />
based in Asia or elsewhere and the move towards widespread outlets for the<br />
products of traditional medicine call for more formal pre-marketing assessment<br />
and more stringent controls than the occasional random checks and analyses<br />
often carried out by individual national or local authorities on what is already<br />
out in the market.<br />
:*There is world-wide recognition of potential problems associated with<br />
botanicals and botanical products, not only in terms of safety, but also in terms<br />
of the claimed amounts and stability of the active ingredients. For example, the<br />
US Pharmacopeia, which considers the safety of food supplements as well as<br />
medicines, announced in December 2002 the establishment of an advisory<br />
panel specifically to advice on improving the quality of botanical products.<br />
:*Any efficacy shown by botanical products is usually a product of one or more<br />
plant secondary metabolites. Secondary metabolism responds to stress imposed<br />
by biotic and abiotic factors and, as a consequence, patterns and concentrations<br />
of metabolites can show considerable variation among plants belonging to the<br />
same species and variety. For instance, it is not unusual for metabolites<br />
produced in response to pathogen attack to vary in concentration one thousandfold<br />
over short time periods. While consistency of product is more easily<br />
controlled in cultivated plants, particularly those grown in containment,<br />
collections from the wild make it difficult to ensure that concentrations of<br />
bioactive agents meet specifications and are within safe limits.<br />
:*A very large literature exists on toxic substances naturally-occurring in plants.<br />
Of particular concern are plant products consumed in concentrated forms.<br />
Concerns can relate directly to the toxicological profile of the active agent(s). It<br />
has been the case with kava-kava (Piper methysticum), its withdrawal from the<br />
market being advised recently because of the association of its consumption with acute liver failure (Kraft et al., 2001). In June 2001, the US FDA,<br />
following action by the UK and Australia, advised manufacturers of dietary<br />
supplements to avoid the use of the various types of comfrey (Symphytum spp.)<br />
because of the health concerns associated with the presence of pyrrolizidine<br />
alkaloids. Moreover, since 1993, cases of nephrotoxicity and carcinogenicity<br />
have been reported in Belgium, France and United Kingdom as a result of<br />
inadvertent exposure to Aristolochia species in unlicensed herbal medicines<br />
(EMEA, 2000).<br />
:*Interactions of herbal products with prescription products are well recognised,<br />
although widely under-reported (Ernst, 2000; Sorensen, 2002). In the past,<br />
when such products were usually obtained from outlets run by knowledgeable<br />
individuals, advice on use and contra-indications was often available. Currently,<br />
contra-indications do not usually appear on the labels or any associated<br />
documentation when herbal products are sold through supermarkets and other<br />
retail outlets. Yet, a survey of the available information on interactions with<br />
medicinal compounds of the more commonly purchased botanical products<br />
(e.g. ginkgo, garlic, St. John’s Wort and ginseng) found recorded adverse<br />
interactions for all but Echinacea and saw palmetto (Izzo and Ernst, 2001).<br />
Incidence and severity of effects associated with prescription drug-dietary<br />
supplement interactions in a small group of primary care patients have also<br />
been investigated by Peng et al. (2004); the most common botanical products<br />
included garlic, ginkgo biloba, saw palmetto and ginseng. While most<br />
interactions were judged not to be serious, an incidence of 6% of potentially<br />
severe health consequences was recorded among patients taking at the same<br />
time specific drugs and specific botanical products.<br />
<br />
5. This heterogeneous group of commodities includes products which, mainly<br />
depending on their intended uses and presentations, fall under different Community<br />
regulatory frameworks and for some types of products legal provisions for a<br />
preliminary risk assessment do not exist yet. The main legislations to be considered<br />
in this context are Directive 2002/46/EC on food supplements and Directive<br />
2004/27/EC on traditional herbal medicinal products:<br />
<br />
:*Directive 2002/46/EC foresees the use as food supplements of vitamins and<br />
minerals listed in the Annexes to the Directive. It also allows the use for the<br />
same purpose of still undetermined substances with a nutritional or<br />
physiological effect, but definition of such effects is not provided for.<br />
According to Art. 4, para 8, the European Commission shall produce, not later<br />
than 12 July 2007, a report on the advisability of establishing specific rules,<br />
including, where appropriate, categories of additional vitamins and minerals or<br />
of substances with a nutritional or physiological effect, accompanied by any proposals for amendments to Directive 2002/46/EC**. Thus a regulatory<br />
framework for further developments in this area already exists.<br />
:*Directive 2004/27/EC on “traditional herbal medicinal products” provides for<br />
definitions of (i) traditional herbal medicinal products, (ii) herbal medicinal<br />
products, (iii) herbal preparations and (iv) herbal substances. The directive<br />
introduces a simplified registration procedure, based on “traditional use”, but<br />
ensuring quality and safety as for any other medicinal product. Community lists<br />
will have to be prepared of traditional herbal medicinal products, herbal<br />
preparations and herbal products. On the other hand, traditional herbal<br />
materials, which are authorised for use in medicinal products, will continue to<br />
contribute to the dietary intake of bioactive agents as long as they comply with<br />
the general food regulations and make no medicinal claim.<br />
<br />
6. Also relevant in this context are the Directives 1989/398/EEC and 96/84/EC on<br />
“Food for special purposes” and the Regulation 1997/258/CE on “novel foods” that<br />
provide additional channels for some botanicals and botanical preparations to enter<br />
the food market, and the proposed Directives on “nutritional and health claims” and<br />
“food fortification” at present under consideration by the European Parliament and<br />
Council.<br />
<br />
7. As the market volume expands, so does the need for a better characterisation of<br />
botanicals and botanical preparations, and for harmonising the scientific assessment<br />
of risks from exposure of consumers to these products.<br />
<br />
8. It is important, therefore, from a public health point of view, to achieve a<br />
comprehensive and coherent approach to risk assessment and consumer<br />
information on botanicals and botanical preparations widely present in different<br />
categories of commodities. Such an approach would, in time, overcome the existing<br />
information gaps on many of these products and bring together the fragmentary<br />
provisions for risk assessment on botanicals and botanical preparations in the<br />
current relevant regulations. To this end, the present paper aims at increasing<br />
awareness on these issues and at facilitating a critical analysis of the present<br />
situation. It is intended to lead to a stronger partnership and collaboration among all<br />
the stakeholders who have a role in this important sector.<br />
<br />
9. Although it is not the objective of this discussion paper to provide a detailed<br />
analysis of the way forward, the following reflections address some issues in order<br />
to facilitate an open discussion particularly in the frame of future developments of<br />
the above-mentioned Directive 2002/46/EC:<br />
<br />
:*As systematic information about the range of botanicals and botanical products<br />
present on the market is lacking, consideration could be given, to carrying out a<br />
survey to identify the main product categories currently marketed and a study to<br />
clarify the potential health-related issues that may need to be addressed.<br />
:*In view of the difficulty of compiling a full inventory of botanicals and<br />
botanical products, the possibility could also be considered of adopting and<br />
regularly updating a list of plants or parts of plants which should not be used or<br />
could be put under scrutiny because of the presence of undesirable substances,<br />
especially if effective reduction or removal of such substances can not be<br />
ensured.<br />
:*As purity specifications for all botanicals and botanical preparations are very<br />
difficult to define, the development of ad hoc manufacturing guidelines, could<br />
be considered in order to improve their characterisation and safety. Experience<br />
already existing in the pharmaceutical sector could be helpful to this end.<br />
:*Considering the importance of providing to consumers adequate information to<br />
allow the safe use of botanicals and botanical preparations, the possibility of<br />
establishing accredited information sources easily accessible to consumers on<br />
these products also deserves attention. A complicating issue in this respect is<br />
the diffusion of misleading claims which are very difficult to counterbalance by<br />
means of reliable consumer information. However, in this respect, the situation<br />
is likely to improve when the proposal for a Community Directive providing for<br />
a clear evaluation procedure of “Nutritional and Health Claims” will be<br />
adopted.<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
http://www.efsa.europa.eu/de/scdocs/doc/1249.pdf</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=EFSA_guidance_on_safety_assessment_of_botanicals&diff=21995
EFSA guidance on safety assessment of botanicals
2011-07-07T10:13:49Z
<p>Minttu: </p>
<hr />
<div>{{nugget<br />
|authors= <br />
|reference= <br />
|urn= <br />
|ethics= <br />
|journal=<br />
|moderator=Minttu<br />
|stub=Yes}}<br />
<br />
EFSA Journal 2009; 7(9):1249<br />
For citation purposes: EFSA Scientific Committee; Guidance on safety assessment of botanicals and botanical preparations<br />
intended for use as ingredients in food supplements, on request of EFSA. EFSA Journal 2009; 7(9):1249. [19 pp.].<br />
doi:10.2093/j.efsa.2009.1249. Available online: www.efsa.europa.eu<br />
© European Food Safety Authority, 2009 1<ref>[http://www.efsa.europa.eu/de/scdocs/doc/1249.pdf]: EFSA Journal 2009; 7(9):1249<br />
For citation purposes: EFSA Scientific Committee; Guidance on safety assessment of botanicals and botanical preparations<br />
intended for use as ingredients in food supplements, on request of EFSA. EFSA Journal 2009; 7(9):1249. [19 pp.].<br />
doi:10.2093/j.efsa.2009.1249. Available online: www.efsa.europa.eu<br />
© European Food Safety Authority, 2009 1 </ref><br />
<br />
<br />
'''''SCIENTIFIC OPINION'''''<br />
<br />
<br />
''Guidance on Safety assessment of botanicals and botanical preparations intended for use as ingredients in food supplements''<br />
<br />
<br />
'''EFSA Scientific Committee'''<br />
<br />
<br />
European Food Safety Authority (EFSA), Parma, Italy<br />
<br />
<br />
This guidance document published on 9 September 2009, replaces the earlier version published on 20<br />
June 2008 with the Question Number: EFSA-Q-2005-233.<br />
<br />
<br />
''ABSTRACT''<br />
<br />
In this opinion, EFSA’s Scientific Committee provides guidance on the scientific data needed to carry out a safety assessments of a botanical or a botanical preparation. It also proposes a two-tiered scientific approach for the safety assessment depending on the available knowledge on a given botanical and the substance(s) it contains. The guidance also provides a set of criteria to help prioritise the safety assessment of botanical ingredients which<br />
are in use. EFSA has also compiled the available information on a large number of botanicals which have been reported to contain substances that may be of health concern when used in food or food supplements. The resulting compendium, which will be regularly updated, should be considered as part of this guidance document<br />
and is intended to assist manufacturers and food safety authorities by highlighting possible safety issues which may require further consideration.<br />
<br />
<br />
''KEY WORDS''<br />
<br />
Botanicals, botanical preparations, safety assessment, food supplements, toxicological properties, medicinal<br />
properties.<br />
<br />
<br />
''SUMMARY''<br />
<br />
Following the discussion paper of the Scientific Committee on botanicals and botanical preparations<br />
adopted on 23 June 2004, The European Food Safety Authority (EFSA) asked in August 2005 the<br />
Scientific Committee to develop a two-level tiered approach for the safety assessment of botanicals<br />
and botanical preparations. This approach consists of a first safety assessment level based on<br />
available knowledge and a subsequent level in which the safety assessment includes newly generated<br />
data.<br />
<br />
<br />
The present guidance document is focussed on botanicals and botanical preparations intended for use<br />
in food supplements, although the approach chosen is, in principle, applicable also to other uses of<br />
botanicals and botanical preparations in the food and feed areas.<br />
<br />
<br />
A general framework for safety assessment is proposed by the Scientific Committee, in which<br />
botanicals or botanical preparations for which an adequate body of knowledge exists could benefit<br />
from a “presumption of safety” without any need for further testing. Issues that should be carefully<br />
considered in order to reach such a conclusion are discussed in detail in the present guidance<br />
document. Botanicals and botanical preparations for which a presumption of safety is not possible<br />
based on available knowledge would be subject to a more extensive safety assessment, requiring<br />
additional data to be provided.<br />
<br />
<br />
It is not the objective of this opinion to produce a list of safe botanicals and botanical preparations<br />
intended for food supplement use, but only to provide guidance on how to assess safety of botanical<br />
ingredients.<br />
<br />
<br />
The Scientific Committee developed criteria for prioritising botanicals for safety assessment and has<br />
compiled a Compendium of botanicals that are reported to contain toxic, addictive, psychotropic or<br />
other substances that may be of concern. The main purpose of the Compendium, which should be<br />
considered as part of this guidance document, is to draw attention to issues that would need to be<br />
taken into account when assessing the safety of botanicals used as ingredients in food supplements,<br />
and to facilitate the establishment of priorities for safety assessment.<br />
<br />
<br />
The Scientific Committee recommends maintaining the Compendium up-to-date, making use of<br />
relevant available national lists of plants and of any other relevant data available, as well as of<br />
updated assessments carried out on botanicals by qualified bodies. The Scientific Committee also<br />
recommends to further expand the Compendium with botanicals not having any market history in<br />
Europe but having a documented history of use in their third country of origin.<br />
<br />
<br />
TABLE OF CONTENTS<br />
:*Abstract <br />
:*Summary <br />
:*Table of contents <br />
:*Background as provided by EFSA <br />
:*Terms of reference as provided by EFSA <br />
:*Acknowledgements <br />
:*Assessment <br />
:1.Introduction <br />
:2.Safety assessment of botanicals and botanical preparations intended for use as ingredients in<br />
food supplements <br />
:2.1Proposed data requirements for safety assessment of botanicals and botanical preparations<br />
used as ingredients in food supplements <br />
:2.1.1.Technical data<br />
::2.1.1.1. Identity and nature of the source material <br />
::2.1.1.2. Manufacturing process<br />
::2.1.1.3. Chemical composition <br />
::2.1.1.4. Specifications <br />
::2.1.1.5. Stability of the botanical or botanical preparation used as ingredient in food supplement <br />
::2.1.1.6. Proposed uses and use levels <br />
::2.1.1.7. Information on existing assessments <br />
:2.1.2. Exposure: extent and duration <br />
:2.1.3. Toxicological data <br />
2.2. Proposed general framework for assessing the safety of botanicals and botanical<br />
preparations used as ingredients in food supplement <br />
:2.2.1. Level A: Safety assessment based on available knowledge <br />
:2.2.2. Additional data required for the level B assessment <br />
3. Establishing a Compendium of botanicals and prioritising them to be considered for a safety<br />
assessment. <br />
:*Conclusions and recommendations <br />
:*References <br />
<br />
<br />
''BACKGROUND AS PROVIDED BY EFSA''<br />
<br />
A discussion paper by the Scientific Committee on botanicals and botanical preparations widely used<br />
in food supplements and related products was adopted on 23 June 2004 (SC document EFSA/SC/26<br />
Final3). In this paper, the Committee expressed concerns about quality and safety issues of botanicals<br />
and botanical preparations that have become widely available to consumers through several<br />
distribution channels in the EU. The use of botanicals and botanical preparations in food is regulated<br />
under the General Food Law (178/2002/EC), which attributes the primary legal responsibility for the<br />
safety of the products placed on the market to business operators. The Regulation however does not<br />
provide any guidance on how the safety of these products should be assessed. As the market volume<br />
and the variety of products expand, so does the need for a better characterisation of the range of<br />
botanicals and botanical preparations on the market, and for harmonising the risk assessment and<br />
consumer information approaches for these products. The paper aimed at increasing awareness of<br />
EFSA’s Advisory Forum on potential public health aspects associated with these products.<br />
<br />
<br />
The Secretariat brought the discussion paper to the attention of the Advisory Forum at its meeting of<br />
the 1st of October, 2004. Simultaneously, an invitation was sent to the members of the Advisory Forum to take note of the concerns<br />
raised by the Scientific Committee and to complete a questionnaire to provide a better understanding of the issue in Europe.<br />
<br />
<br />
By the end of January 2005, replies were received from twenty five countries, comprising twenty two<br />
EU Member States and three EFTA Countries. The members of the Advisory Forum underlined the<br />
importance of this issue for their countries and asked EFSA to initiate a self-task in order to develop<br />
some guidance on how to assess the safety of botanical ingredients.<br />
<br />
<br />
Following the mandate received by the Scientific Committee in August 2005 from EFSA, the<br />
Scientific Committee developed a two-level tiered approach for the safety assessment of botanicals<br />
and botanical preparations. A guidance document focussing on botanicals and botanical preparations<br />
intended for use as food supplements was published after public consultation.<br />
<br />
<br />
A conceptual framework for safety assessment was advocated, in which botanicals or botanical<br />
preparations for which an adequate body of knowledge exists could benefit from a “presumption of<br />
safety” without any need for further testing (first level of the framework). Issues that should be<br />
carefully considered in order to reach such a conclusion were discussed in detail in the guidance<br />
document. Botanicals and botanical preparations for which a presumption of safety is not possible<br />
would be subject to a more extensive safety assessment, based on additional data to be provided in<br />
accordance with the methodology described in the second level of the proposed framework.<br />
<br />
<br />
As a follow up, it was decided to test the adequacy of the above-mentioned approach described in the<br />
guidance document for safety assessment with a selected number of examples including botanicals<br />
known to contain toxic substances or having a reported toxic effect, botanicals with an established<br />
history of food use, and botanicals that are known to contain potentially genotoxic/carcinogenic<br />
substances. To this end, an EFSA Scientific Cooperation (ESCO) Working Group, composed of<br />
experts identified by the members of the Advisory Forum and by the Scientific Committee EFSA was<br />
established in April 2008. This working group was also given the task to finalise the Compendium of<br />
botanicals reported to contain toxic, addictive, psychotropic, or other substances of concern. The resulting ESCO report and Compendium9 were provided to the EFSA Executive Director in May<br />
2009.<br />
<br />
<br />
''TERMS OF REFERENCE AS PROVIDED BY EFSA''<br />
<br />
The Scientific Committee has been requested in May 2009 by the European Food Safety Authority<br />
to consider the recommendations made in the ESCO report for updating the guidance document for<br />
the safety assessment of botanicals and botanical preparations intended for use as ingredients in food<br />
supplements.<br />
<br />
<br />
''ACKNOWLEDGEMENTS''<br />
<br />
The European Food Safety Authority wishes to thank the members of the EFSA Scientific<br />
Cooperation (ESCO) Working Group on Botanicals and Botanical Preparations for the preparation of<br />
the ESCO Report, which was used by the Scientific Committee to update this guidance document.<br />
The European Food Safety Authority would also like to thank the members of the former Scientific<br />
Committee for their contributions to the present guidance document.<br />
<br />
<br />
''ASSESSMENT''<br />
<br />
1. '''Introduction'''<br />
The Scientific Committee decided to focus its work first on the safety assessment of botanicals and<br />
botanical preparations used as ingredients in food supplements (hereafter referred to, as botanical<br />
ingredients), although the approach chosen is, in principle, applicable also to other uses of botanicals<br />
and botanical preparations in the food and feed areas. It is not in the scope of the present guidance to<br />
address issues related to quality assurance and good hygienic practices currently regulated by the EU<br />
Food Legislation, nor to assess the safety of food supplements as end products. The present guidance<br />
does not therefore address hazards linked to the presence of contaminants and foodborne pathogens in<br />
the botanicals and botanicals preparations.<br />
<br />
<br />
A two-level tiered conceptual framework for safety assessment consisting of a safety assessment<br />
based on available knowledge and a subsequent level in which further testing and/or data are required<br />
is proposed by the Scientific Committee. Botanicals or botanical preparations for which an adequate<br />
body of knowledge exists, can benefit from a “presumption of safety” without any need for further<br />
testing. Based on reasonable evidence, they can then be assumed to be safe, sometimes under certain<br />
restrictions. The Scientific Committee used as an example the Qualified Presumption of Safety (QPS)<br />
approach developed for microorganisms in food and feed (EFSA, 2007a) to propose criteria for<br />
presuming a botanical or a botanical preparation safe. Botanicals and botanical preparations for which<br />
a presumption of safety is not possible should be subject to a more extensive safety assessment, based<br />
on additional data to be provided according to the methodology described by EFSA. By proposing a<br />
first safety assessment level based on available knowledge, the approach proposed by the Scientific<br />
Committee for the safety assessment of botanicals and botanical preparations is in line with EFSA’s<br />
policy to stimulate food and feed risk assessment approaches that minimise the number of<br />
experimental animals and any suffering (EFSA, 2009).<br />
<br />
<br />
In order to facilitate the implementation of the above-mentioned approach, EFSA has also compiled a<br />
Compendium of botanicals and botanical preparations that have been reported to contain toxic,<br />
addictive, psychotropic or other substances that may be of concern. This Compendium should be seen<br />
as a tool to gather relevant information and define priorities for safety assessment. The inclusion of a<br />
botanical in this Compendium does not imply that it is not safe for use in food supplements. Without<br />
prejudice to the existing legal framework, such Compendium has no legal status and may not be used<br />
as support or evidence in any disagreement or dispute pertaining to the legal classification of products<br />
or substances.<br />
<br />
<br />
Safety assessment of botanicals and botanical preparations<br />
EFSA Journal 2009; 7(9):1249 7<br />
2. '''Safety assessment of botanicals and botanical preparations intended for use as<br />
ingredients in food supplements'''<br />
<br />
It should be noted that Regulation 258/97/EC concerning novel foods and novel food ingredients<br />
applies to all foods, including food supplements, containing substances which have not been used for<br />
human consumption to a significant degree within the Community before 15 May 1997 and which fall<br />
under certain categories specified in the above-mentioned Regulation. In the case of a proposed use as<br />
a novel food, botanicals or botanical preparations should be assessed following the guidelines of the<br />
Commission Recommendation 97/618/EC of 29 July 1997 concerning the scientific aspects and the<br />
presentation of information necessary to support applications for the placing on the market of novel<br />
foods and novel food ingredients.<br />
<br />
<br />
Moreover, Regulation 1829/2003/EC on genetically modified food and feed would apply to any GMO<br />
ingredients used in food supplements. In the case of botanicals or botanical preparations derived from<br />
genetically modified plants, information should be provided in line with the guidance document of the<br />
EFSA Scientific Panel on Genetically Modified Organisms for the risk assessment of genetically<br />
modified plants and derived food (EFSA, 2006a).<br />
When the botanical or botanical preparation is intended for use as a food intended for particular<br />
nutritional uses (PARNUTS – Directive 89/398/EEC), the guidance document from the Scientific<br />
Committee on Food on submissions for safety evaluation of sources of nutrients or of other<br />
ingredients proposed for use in the manufacture of foods (SCF, 2001a) should also be consulted.<br />
<br />
<br />
It should also be underlined that this report only deals with guidance on safety assessment, whereas<br />
the scientific substantiation of any claims made on food supplements, as required by the Regulation<br />
on Nutrition and Health Claims, will be dealt with in separate EFSA documents, such as the<br />
“Scientific and technical guidance for the preparation and presentation of the application for<br />
authorisation of a health claim” (EFSA, 2007b).<br />
It is not the objective of this report to produce a list of safe botanicals and botanical preparations<br />
intended for food supplement use, but only to provide guidance on how to assess safety of botanical<br />
ingredients. Moreover, priority criteria are proposed, and a Compendium has been compiled to serve<br />
as a preliminary tool for risk assessors (see section 3).<br />
<br />
<br />
2.1. '''Proposed data requirements for safety assessment of botanicals and botanical<br />
preparations used as ingredients in food supplements'''<br />
<br />
It is understood that the use of botanicals and botanical preparations as ingredients in food<br />
supplements will have to be in compliance with the existing EU Food Legislation. This would<br />
include maximum permissible levels of chemical and biological contaminants (e.g. pesticides,<br />
mycotoxins, heavy metals and foodborne pathogens), modalities for ensuring quality, and application<br />
of good hygienic practice, including HACCP methodologies. The issues of controls needed to ensure<br />
constancy over time of the composition of botanical food supplements on the market and batch-tobatch<br />
variation are not addressed in this document as these are risk management aspects and therefore<br />
outside the scope of EFSA.<br />
<br />
The following sections aim at identifying data and information considered as necessary to assess the<br />
safety of botanical ingredients. These data are of: (i) technical; (ii) exposure and (iii) toxicological<br />
nature. The lists below are meant to give guidance on data requirements. They have been made as<br />
exhaustive as possible and should be adapted on a case-by-case basis, depending on the nature of the<br />
botanical or botanical preparation. This implies that not all the information listed below would be<br />
needed in all cases and that the amount of information available for a given botanical or botanical<br />
preparation may in some cases be sufficient without further testing (see section 2.2.1).<br />
<br />
<br />
'''2.1.1. Technical data'''<br />
<br />
<br />
2.1.1.1. Identity and nature of the source material<br />
<br />
It is recognized that identification of the botanical source and botanical preparation may in some cases<br />
be complicated. It is recommended to follow as much as possible the nomenclature of the European<br />
Pharmacopeia. Additional nomenclature sources are as follows:<br />
<br />
World Checklist of Selected Plant Families (Royal Botanic Garden, Kew); the books by Hanelt<br />
(2001) also available on the Internet as Mansfeld’s World Database of Agricultural and Horticultural<br />
Crops; and the database by United States Department of Agriculture. If a scientific name is not found<br />
in any of the above-named references, its existence may be checked in The International Plant Names<br />
Index.<br />
<br />
<br />
Since there have been many instances where species have been reclassified or renamed, a same<br />
species may be known by different scientific names. Common (vernacular) names may also be<br />
provided, but it should be noted that a common name used in one region to refer to a particular plant<br />
may be used elsewhere to refer to another quite unrelated species. Hence common names may not<br />
uniquely identify a species and are not as reliable as the scientific names.<br />
<br />
<br />
The following scheme summarizes the requirements for description of the identity of the botanical:<br />
<br />
<br />
;Scientific (Latin) name:<br />
:full systematic species name incl. botanical family, genus,<br />
species, variety, subspecies, author’s name, and chemotype if<br />
applicable<br />
<br />
;Synonyms: <br />
:botanical name(s) that may be used interchangeably with the<br />
preferred scientific name<br />
;Common names: <br />
:vernacular name(s)<br />
;Part used: <br />
;e.g. root, leaf, seed …<br />
;Geographical origin: <br />
:continent, country, region<br />
;Growth and harvesting conditions: <br />
:wild or cultivated, cultivation practices, time of harvest in relation<br />
to both season and stage of the plant growth.<br />
<br />
2.1.1.2. Manufacturing process<br />
<br />
The following information is considered necessary for assessing the safety of botanicals and botanical<br />
preparations:<br />
i):Information on the method(s) of manufacture (e.g. the process by which the raw material is<br />
converted into a preparation, such as extraction or other procedure(s), and plant extract ratio)<br />
<br />
ii):Information on substances entering the manufacturing process, e.g. identity of the extraction<br />
solvent, reagents, special precautions (light and temperature).<br />
<br />
iii):Standardization criteria (e.g. see European Pharmacopoeia).<br />
<br />
Botanicals or botanical preparations might become hazardous as a result of deviations in the<br />
production process (e.g. misclassification, switching of species). Therefore the safety of botanicals<br />
and botanical preparations should be ensured by following a Hazard Analysis and Critical Control<br />
Point (HACCP) approach (Codex Alimentarius 1997). The whole production chain, from primary<br />
production of botanicals to the storage and commercialisation of the botanical preparations should be<br />
taken into consideration. The HACCP system must be applied with the necessary flexibility and<br />
adapted to each botanical preparation on a case-by-case basis.<br />
<br />
<br />
2.1.1.3. Chemical composition<br />
<br />
Data on the chemical composition of the botanical ingredient should be provided with emphasis on<br />
the concentrations of constituent of relevance for the safety assessment; this includes the<br />
concentrations of:<br />
:*Compounds should be classified according to their chemical structure (e.g. flavonoids,<br />
terpenoids, alkaloids, etc.). Levels at which the constituents are present in the respective part<br />
of the botanical or botanical preparation should be given where available.<br />
:*Constituents to characterise the quality, chemical fingerprint, production process and/or<br />
biological activity of the preparation (markers).<br />
:*Constituents that provide reasons for concern due to their chemical, physiological or<br />
toxicological properties.<br />
In some cases, it may be difficult to identify the active principle responsible for an effect. Therefore<br />
the strength of the evidence underlying the concerns over a compound being reason for concern<br />
should also be given.<br />
<br />
<br />
2.1.1.4. Specifications<br />
<br />
Specifications of the botanicals or botanical preparations are required. They may be based on<br />
nutritional or biologically active components or, when these are not known, on selected chemical<br />
markers. Limits for or absence of specific undesirable / toxic substances should be specified. The<br />
proposed specifications should be modelled on recent European or other internationally accepted<br />
specifications (e.g. pharmacopoeia or the guidelines of the EMEA Committee on Herbal Medicinal<br />
Safety assessment of botanicals and botanical preparations<br />
<br />
Products (HMPC)). Where the proposed specifications differ from internationally recognised<br />
specifications, the latter specifications should be set out alongside the proposed new specifications,<br />
and any differences pointed out. Validated and well-established methods should be preferably used<br />
for the analysis of compounds considered in specifications.<br />
<br />
The specifications should include concentrations of major groups of constituents present in the<br />
botanical preparation including for example: amino acids, lipids, polysaccharides, volatile oil,<br />
inorganic ions, polyphenols, alkaloids, terpenes, alkenylbenzenes, lignin, saponins etc. as well as the<br />
major constituents within these classes.<br />
<br />
In addition, information on maximum levels for possible contaminants including e.g. heavy metals,<br />
mycotoxins, pesticide residues, and polycyclic aromatic hydrocarbon (PAH) residues should be<br />
provided.<br />
<br />
<br />
2.1.1.5. Stability of the botanical or botanical preparation used as ingredient in food supplement<br />
<br />
The stability of the botanical ingredient should be demonstrated over the shelf-life time. Any<br />
information concerning possible degradation should also be provided.<br />
<br />
<br />
2.1.1.6. Proposed uses and use levels<br />
<br />
Information on intended uses and recommended intakes for a product should specifically mention<br />
uses and use levels for the following categories:<br />
:* Common foods<br />
:* Food supplements<br />
:* Medicinal products<br />
<br />
Special attention should be given to population groups with specific uses like for example young<br />
children. Information on the duration of the proposed uses and use levels should also be provided<br />
<br />
<br />
2.1.1.7. Information on existing assessments<br />
<br />
Information on any existing assessments by international bodies or national competent authorities<br />
should be provided.<br />
<br />
<br />
2.1.2. Exposure: extent and duration<br />
<br />
Data and information should be provided on:<br />
:i) Anticipated human exposure to the botanical ingredient, including amount (e.g. maximum and<br />
average daily intake or exposure), frequency and duration. It is important to characterize as much as<br />
possible the expected human exposure to the botanical ingredient according to the recommended<br />
modalities of use in terms of extent and duration. Clear distinction should be made between intake of<br />
a botanical itself, intake of its essential oil and other preparations made of it.<br />
:ii) Possibility of additional / combined human exposure to the botanical or botanical preparation<br />
through different categories of food, food supplements and/or medicinal products that can be<br />
consumed together.<br />
:ii) Modality of use of the ingredient.<br />
:iv) Information on historical (food, food supplement and medicinal) use of the ingredient in<br />
human population groups in relation to the modalities of use and resulting exposure levels if known.<br />
Data derived from use outside of the European Union should also be considered.<br />
<br />
<br />
All data should be representative of the ingredient to be used for the European market. In this context,<br />
food use includes, in principle, the consumption of raw and cooked vegetables, spices, flavours, food<br />
supplements already in use for a long time16 and any other related food items.<br />
<br />
<br />
Estimates of average exposure ranges associated with the use of the botanical ingredient in the EU<br />
Member States should also be provided. Uncertainties associated with the food consumption data<br />
considered and anticipated exposure ranges should be clearly described (EFSA, 2006b).<br />
<br />
A matter to be specifically addressed in the evaluation is whether the proposed use and use levels will<br />
significantly increase already existing human exposure.<br />
<br />
<br />
'''2.1.3. Toxicological data'''<br />
<br />
Studies on toxicity and toxicokinetics including metabolism of botanicals and botanical preparations<br />
should be conducted using internationally agreed protocols. Test methods described by OECD or in<br />
European Commission Directives 87/432/EEC and 67/548/EC – Annex 5 are recommended. It is<br />
advisable to ensure that the most up-to-date version of any test guideline is followed. Use of any<br />
methods differing from internationally agreed protocols should be justified. Protocols for special<br />
studies differing from standard tests should be developed on a case-by-case basis.<br />
<br />
To ensure general acceptance of the data submitted, studies should be carried out according to the<br />
principles of Good Laboratory Practice (GLP) described in Council Directive 87/18/EEC and<br />
accompanied by a statement of GLP compliance. Adequate explanation should be provided for<br />
divergence from these principles.<br />
<br />
Council Directive 86/609/EEC, on the protection of animals used for experimental and other scientific<br />
purposes, requires that care is taken to avoid unnecessary use of animals. Studies carried out should<br />
be those necessary to demonstrate the safety of a botanical or botanical preparation and planned in<br />
accordance with the principles of reduction, refinement and replacement. However, where adequate<br />
data are not available for the safety assessment (see section 3.2.1), in vivo studies using experimental<br />
animals may be needed in order to assess possible risks to humans from the ingestion of botanicals or<br />
botanical preparations. Alternative validated methods involving fewer or no animals for toxicity<br />
endpoints may in the future be developed and should be considered on a case-by-case basis.<br />
<br />
If available, data on possible interactions (e.g. herbal-drug) should also be provided.<br />
<br />
<br />
'''2.2. Proposed general framework for assessing the safety of botanicals and botanical<br />
preparations used as ingredients in food supplement'''<br />
<br />
Several guidance documents (AFSSA, 2003; Council of Europe, 2005; Schilter et al., 2003) have been<br />
published on the principles for assessment of botanicals and botanical preparations in the food and<br />
feed area. The present guidance document is not intended to reiterate these, but to outline a<br />
framework that could be used by risk assessors when assessing the safety of a botanical or a botanical<br />
preparation. It also proposes a scientific approach to the assessment of available data.<br />
<br />
The aim of the assessment is to ensure that botanicals or botanical preparations, when used in food<br />
supplements in the manner, quantities and time period of intake proposed, would not pose a risk to the<br />
health of consumers. Data should provide not only information relevant to the healthy adult consumer,<br />
but also relevant to those population groups potentially vulnerable due to their pattern of food<br />
consumption or their physiological or health status, e.g. young age, elderly, pregnancy,<br />
immunocompromised etc.<br />
<br />
A general framework for assessing the safety with core tests and other tests is given, which should<br />
enable determination of what information is required to establish the safety-in-use of the botanical or<br />
botanical preparation. The application of this guidance to specific cases will depend on the nature of<br />
the botanical or botanical preparation, its intended uses and levels of use in food supplements and on<br />
whether the botanical or botanical preparation has a long term history of food use17, showing that, at<br />
proposed exposure levels, no adverse effect on human health has been reported. In addition to<br />
laboratory tests, it may be possible to use human data derived from medical use, epidemiology, or<br />
specific studies on volunteers (e.g. on absorption and metabolism), or any other data reporting<br />
possible adverse health effects, either anecdotal or on the basis of case reports of intoxication, e.g data<br />
related to toxicity on livestock animals, or on botanicals that closely resemble botanicals which are<br />
known to have caused toxic effects.<br />
<br />
However, it is recognized that for botanical ingredients lacking a history of food use, or for botanicals<br />
whose intended use levels will significantly exceed historical intake levels, an assessment of safety<br />
generally relies on experimental toxicity data largely derived from investigations in laboratory<br />
animals.<br />
<br />
The approach herein proposed for the safety assessment of botanicals and botanical preparations not<br />
regulated in the framework of specific regulations such as the one on novel foods, and illustrated by<br />
Figure 1, consists of the two following levels:<br />
:*Level A: Safety assessment based on available knowledge.<br />
:*Level B: Safety assessment including newly generated data.<br />
<br />
Figure 1: Proposed tiered approach for the safety assessment of botanicals and botanical<br />
preparations.<br />
<br />
<br />
'''.2.1. Level A: Safety assessment based on available knowledge'''<br />
<br />
Depending on the botanical ingredient and its uses, there are circumstances under which no additional<br />
data are judged necessary for the safety evaluation, i.e. a presumption of safety would be applied.<br />
This would be the case whenever available data would allow to conclude that exposure to known<br />
levels of the botanical ingredient has occurred in large population groups for many years without<br />
reported adverse effects.<br />
<br />
Therefore, an important requirement is that the data as outlined in chapter 2.1 are provided and that<br />
no significant increase of intake compared to historical levels is to be expected due to the intended<br />
levels of use in food supplements. This implies that not only use levels but also chemotypes of<br />
botanicals and the chemical composition of the botanical preparations should be in line with<br />
historically used ones. This approach can only be applied when intakes due to the intended levels of<br />
use are within the range of intake levels derived from the European Member States’ average diets or<br />
from studies on specific subgroups. It is recognized that the acceptability of such an approach relies<br />
mainly on the objective of not significantly increasing exposures beyond the levels linked to the safe<br />
history of use.<br />
<br />
If compounds of concern can be well defined, evaluations can focus on these specific compounds. In<br />
some cases, it may be difficult to identify the active principle responsible for an effect. In such cases<br />
the strength of the evidence underlying the concerns over a compound taken as the reference<br />
compound for the safety evaluation should also be given.<br />
<br />
For botanicals and botanical preparations with a potential to contain toxic, addictive, psychotropic or<br />
other substances that may be of concern (see also the Compendium and section 3), presumption of<br />
safety can be applied only if there is convincing evidence that these undesirable substances in the<br />
specific plant parts or preparations are either absent in the source material, or significantly reduced if<br />
not excluded, or inactivated during processing.<br />
<br />
In cases where the above-mentioned substances are known to be present in the botanical ingredient<br />
under evaluation (see attached Compendium), additional consideration should be given to support the<br />
presumption of safety of the botanical preparation. The significance of overall exposure to such<br />
substances should be assessed and compared with existing health-based guidance values such as the<br />
acceptable / tolerable daily intake (ADI/TDI). Consideration of exposure to the substance of concern<br />
in relation to the Threshold of Toxicological Concern (TTC) values may also be helpful.<br />
<br />
In cases where no health-based guidance values are available or where the botanical ingredient<br />
contains substances that are both genotoxic and carcinogenic, the “Margin of Exposure” (MOE)<br />
approach (EFSA, 2005) could be applied covering the botanical(s) under examination and any other<br />
dietary sources of exposure. The MOE approach compares toxic effect levels with human exposure<br />
levels. Alternatively, it could be evaluated whether the expected exposure to the genotoxic and<br />
carcinogenic ingredient is likely to be increased, compared to the intake from other sources.<br />
<br />
It is plausible that the kinetics as well as the expression of the inherent toxicity of a naturally<br />
occurring substance could be modified by the matrix in which it is present. Depending on the<br />
mechanism of action, this could result in the toxicity being unchanged, reduced or even increased.<br />
Research on individual substance/matrix interactions or botanical preparations cannot be used to draw<br />
general conclusions about intact botanicals, herbs and spices under all conditions of use, ingestion and<br />
metabolism. Where a matrix effect is advocated to support the safety of specific levels of substances<br />
(e.g. that data from a pure substance may overestimate effects of the substance in the botanical<br />
matrix), testing and/or other data should be provided to demonstrate the occurrence of the matrix<br />
effect of the preparation and its magnitude. A matrix effect should be judged on a case-by-case basis.<br />
<br />
Extrapolating from one preparation to another and/or from one botanical to another with respect to the<br />
same substance of toxicological concern can only been considered when accompanied by evidence of<br />
their composition with respect to the substance of concern and pattern of consumption.<br />
<br />
For food supplements consisting of complex mixtures of different botanicals, the above-mentioned<br />
assessment could be carried out on the levels of individual substances of concern known to be present<br />
(see also the Compendium), with the understanding of the limitation that such an approach does not<br />
generally allow the assessment of possible synergistic or antagonistic effects.Any data on possible<br />
herb-drug interaction should be carefully considered.<br />
<br />
In the case of a botanical ingredient whose anticipated intake is significantly higher than the estimated<br />
historical intake level, or for which the historical intake level cannot be assessed, additional data<br />
should be provided for the safety assessment, as described in the following sections.<br />
<br />
'''2.2.2. Additional data required for the level B assessment'''<br />
<br />
The reasons for carrying out toxicological studies should be stated, as should the reasons for not<br />
submitting a study that might be expected. The studies that might be expected can be seen from the<br />
“Guidance on submissions for food additive evaluations by the Scientific Committee on Food” (SCF<br />
2001b). All the important results should be presented and discussed and the original study reports<br />
should be submitted in order to allow independent, critical appraisal.<br />
<br />
The toxicology section of the dossier should start with a section describing in detail the specifications<br />
and identity criteria for the botanical preparation(s) used for the toxicity studies and their relationship<br />
to the final product to be used in the food supplement. It should be demonstrated unambiguously that<br />
these characteristics are in compliance with the technical details specified for the botanical<br />
preparation in this report.<br />
<br />
The toxicological tests should, as far as possible, follow the recommendations for data reporting given<br />
in the relevant guidelines (e.g. OECD, 1998). The material to be tested, with lot or batch number,<br />
should be well identified, characterized and standardized. It is important that for each study performed<br />
it is stated whether the test material conforms to the proposed specifications. If it does not conform,<br />
then the specifications of the test material should be given together with a rationale for using these<br />
data in the safety assessment of the product intended for the market.<br />
<br />
<br />
*''Toxicokinetics including metabolism''<br />
<br />
Information on toxicokinetics of relevant biologically active constituents present in the botanical or<br />
botanical preparation should be provided whenever available from the literature. Not all aspects need<br />
to be investigated in every case. Additional issues that may deserve consideration are:<br />
:*The possibility of interactions among constituents of the botanical or botanical<br />
preparation that can alter bioavailability, metabolism, and toxicity.<br />
:*The possibility of interactions with medicinal products.<br />
*''Genotoxicity testing''<br />
For the genotoxicity testing of botanicals and botanical preparations, in vitro tests covering effects<br />
both at gene and chromosome levels are required19. Specific tests are likely to include the Ames test<br />
(OECD guideline 471) and an in vitro test for the detection of chromosomal aberrations (OECD<br />
guideline 473) or an in vitro micronucleus assay (draft OECD guideline 487), and possibly the mouse<br />
lymphoma tk assay (OECD 476). The particular test strategy may depend upon the test material<br />
considered.<br />
<br />
There may be circumstances under which it may be justified to deviate from the above-mentioned<br />
core set. In such cases a scientific justification should be provided and additional types of<br />
considerations or mechanistic studies may be needed.<br />
<br />
A positive in vitro test normally requires follow-up by in vivo testing, unless it can be adequately<br />
demonstrated that the positive in vitro findings are not relevant for the in vivo situation. The choice of the appropriate in vivo test is critical, due to different sensitivities, different endpoints and other<br />
variables. It requires expert judgement based on all available information, to be applied case-by-case.<br />
For this reason, a flexible approach is preferable to a fixed decision tree.<br />
<br />
<br />
*''Subchronic toxicity testing''<br />
<br />
A 90-day study in the rat with the test material administered via the diet is the minimum requirement<br />
to establish a no-observed-adverse-effect level. Subchronic toxicity testing should be carried out<br />
independently of the results of the in vitro and in vivo genotoxicity testing.<br />
<br />
*''Other studies''<br />
<br />
Depending on the outcome of the genotoxicity and subchronic toxicity studies, or other specific<br />
relevant information, further studies may be required (e.g. reproductive toxicity, developmental<br />
toxicity, neurotoxicity, immunotoxicity, chronic toxicity/carcinogenicity).<br />
<br />
<br />
''3. Establishing a Compendium of botanicals and prioritising them to be considered for a<br />
safety assessment.''<br />
<br />
A Compendium of botanicals reported to contain toxic, addictive, psychotropic or other substances<br />
that may be of concern has been produced to complement the present guidance document.<br />
<br />
The Compendium contains the following information:<br />
:*The botanical (binomial) denomination of the plant (genus, species and in some cases variety or<br />
subspecies when relevant), with synonyms in use.<br />
:*The plant parts and substances of possible toxicological concern<br />
:*Additional specific information of relevance for the risk assessment, e.g. adulterations<br />
:*References, either to existing international / national list of plants that were used to populate the<br />
Compendium, or to published literature when specific information has been added.<br />
<br />
The Compendium aims at flagging plants or part of plants or substances of possible concern for<br />
human heath naturally present in the listed botanicals and that, therefore, require specific attention<br />
while assessing the safety of the product(s) containing such botanical(s). For some botanicals in the<br />
Compendium, adverse (toxic) effect(s) are mentioned although sometimes based on anecdotal reports<br />
and even though the constituent(s) of concern are not elucidated in the literature. In some cases the<br />
whole genus was flagged because of the likely presence of substances of concern characteristic for the<br />
toxicity of that genus.<br />
<br />
The presence of a substance of concern in a given botanical does not mean that this substance will<br />
also be present in the botanical preparation. This depends largely on the plant part used, as well as the<br />
preparation method.<br />
<br />
The Compendium contains also an “insufficient information” list regrouping botanicals that appear in<br />
one of the sources of information, but for which sufficient information could not be found on possible<br />
substances of concern, or for which the information available could not be verified.<br />
<br />
Without prejudice to the existing legal framework, it should be noted that this Compendium has no<br />
legal status and should not be used as support or evidence in any disagreement or dispute pertaining to<br />
the legal classification of products or substances.<br />
<br />
The Compendium is a living document which should be periodically updated by EFSA. As a<br />
consequence, the absence of a given species in this Compendium cannot be interpreted as meaning<br />
that the species is devoid of substances hazardous for human health. In the same way, not mentioning<br />
a specific part of plant, does not imply absence of substance(s) of concern in this part. Botanicals that<br />
have not been reported as having been considered for food or food supplement use in the European<br />
countries or botanicals classified as novel foods or GMOs will not appear in the Compendium.<br />
<br />
''Priority setting for safety assessment:''<br />
The botanicals in the above-mentioned Compendium should be assessed according to the following<br />
recommendations:<br />
<br />
Priority should be given to botanicals and botanical preparations:<br />
:*known to have an established history of food use and that have been identified to contain<br />
significant levels of substances of concern.<br />
:*that are not allowed/recommended for food use in some European countries, but which are<br />
still in use in some other EU countries, particularly when the intended use levels in food are<br />
known or expected to be high.<br />
:*for which some adverse health effects have been reported, either anecdotally, or on the basis<br />
of case reports of intoxication, epidemiological data or any toxicity data from livestock<br />
animals or experimental animals, or for botanicals that closely resemble botanicals which are<br />
known to have caused toxic effects.<br />
:*for which consumption has significantly increased during recent years in Member States.<br />
:*for which there are both limited history of use and toxicity data available, and for which the<br />
intended use levels are expected to be relatively high (e.g. high interest to the food industry).<br />
<br />
Botanical ingredients that are reported to have a low toxic potential, and for which the intended<br />
intake/exposure levels are within the range of intake levels resulting from the European Member<br />
States average diet would be given a low priority.<br />
<br />
'''''CONCLUSIONS AND RECOMMENDATIONS'''''<br />
<br />
A two-level tiered approach for the safety assessment of botanical ingredients intended for use in food<br />
supplements is proposed. This approach consists of a safety assessment based on available knowledge<br />
and a subsequent level in which further testing and/or data are required. It allows the recognition of<br />
presumption of safety without further testing, based on long-term history of use with no reported<br />
adverse effect and with no significant increased exposure. For those botanical ingredients for which a<br />
presumption of safety based on available data cannot be established, it introduces a framework for<br />
assessing their safety, including the types of testing that would be most useful. Recommendations for<br />
prioritising botanicals for safety assessment are also made.<br />
<br />
The Compendium of botanicals reported to contain toxic, addictive, psychotropic or other substances<br />
that may be of concern, is considered to facilitate the assessment by flagging possible safety issues,<br />
and should therefore be considered as an essential part of this guidance document. The Scientific<br />
Committee recommends to maintain it up-to-date, making use of relevant available national lists of<br />
plants and of any other relevant data available, as well as of updated assessments carried out on<br />
botanicals by qualified bodies. The Scientific Committee also recommends to further expand the<br />
Compendium with botanicals not having any market history in Europe in order to prepare the<br />
implementation of the new Novel Food Regulation, which foresees a notification process for<br />
botanicals and botanical preparations having a history of safe use in the third country of origin.<br />
<br />
<br />
'''European Food Safety Authority'''<br />
<br />
''SCIENTIFIC COMMITTEE''<br />
Discussion Paper on “Botanicals and Botanical Preparations widely used<br />
as food supplements and related products: Coherent and Comprehensive<br />
Risk Assessment and Consumer Information Approaches”<br />
<br />
(adopted by written procedure on 23 June 2004)<br />
<br />
1. In view of the fact that botanicals and botanical preparations intended for human<br />
consumption as food supplements and related products are very widely marketed<br />
with a variety of claims, the present discussion paper aims at increasing awareness<br />
of some key issues to improve comprehensiveness and coherence of current<br />
approaches to risk assessment and consumer information on these products.<br />
<br />
2. A large number of botanical materials (e.g. whole, fragmented or cut plants, algae,<br />
fungi, lichens), and botanical preparations obtained from these materials by various<br />
processes (e.g. extraction, distillation, purification, concentration and fermentation)<br />
readily find their way onto the food supplements market. These materials are also<br />
often labelled as natural foods, largely organic, and foods specifically intended to<br />
support sport activities. Personal care products and the so-called “traditional herbal<br />
medicinal products” represent additional sources of exposure of consumers to<br />
botanical products. New products are also emerging, consisting of substances that<br />
commonly occur at low levels in botanical components of the diet, which are then<br />
extracted and re-introduced at much higher levels in specific products.<br />
<br />
3. Botanicals and botanical preparations are widely available to consumers through<br />
several distribution channels in the E.U. and elsewhere. In particular, they are sold<br />
over the counter in pharmacies and can be bought in supermarkets, herbalist’s<br />
shops and other shops, or via the Internet. They are currently available and used in<br />
such a way that they are almost becoming part of the common diet, thus providing<br />
for a significant human exposure from a public health point of view.<br />
<br />
4. There are some general concerns with respect to botanicals and botanical<br />
preparations mainly relating to quality and safety issues:<br />
:*Contamination (both chemical and microbiological) is a documented problem.<br />
It has been associated, for example, with botanical products originating from<br />
Asia. Deaths through poisoning following consumption of such products have<br />
been reported in Europe and the US arising from contamination with heavy<br />
metals, synthetic drugs and other undesirable substances (Ernst, 2002).<br />
Misidentification of plants harvested from the wild is also a continuing<br />
problem. When sales of traditional herbal products remained restricted to<br />
particular ethnic groups, which are familiar with the products and able to exert a<br />
local control on quality, problems were more rarely encountered. The growing<br />
volume of sales in the European Union with products obtained from suppliers<br />
based in Asia or elsewhere and the move towards widespread outlets for the<br />
products of traditional medicine call for more formal pre-marketing assessment<br />
and more stringent controls than the occasional random checks and analyses<br />
often carried out by individual national or local authorities on what is already<br />
out in the market.<br />
:*There is world-wide recognition of potential problems associated with<br />
botanicals and botanical products, not only in terms of safety, but also in terms<br />
of the claimed amounts and stability of the active ingredients. For example, the<br />
US Pharmacopeia, which considers the safety of food supplements as well as<br />
medicines, announced in December 2002 the establishment of an advisory<br />
panel specifically to advice on improving the quality of botanical products.<br />
:*Any efficacy shown by botanical products is usually a product of one or more<br />
plant secondary metabolites. Secondary metabolism responds to stress imposed<br />
by biotic and abiotic factors and, as a consequence, patterns and concentrations<br />
of metabolites can show considerable variation among plants belonging to the<br />
same species and variety. For instance, it is not unusual for metabolites<br />
produced in response to pathogen attack to vary in concentration one thousandfold<br />
over short time periods. While consistency of product is more easily<br />
controlled in cultivated plants, particularly those grown in containment,<br />
collections from the wild make it difficult to ensure that concentrations of<br />
bioactive agents meet specifications and are within safe limits.<br />
:*A very large literature exists on toxic substances naturally-occurring in plants.<br />
Of particular concern are plant products consumed in concentrated forms.<br />
Concerns can relate directly to the toxicological profile of the active agent(s). It<br />
has been the case with kava-kava (Piper methysticum), its withdrawal from the<br />
market being advised recently because of the association of its consumption with acute liver failure (Kraft et al., 2001). In June 2001, the US FDA,<br />
following action by the UK and Australia, advised manufacturers of dietary<br />
supplements to avoid the use of the various types of comfrey (Symphytum spp.)<br />
because of the health concerns associated with the presence of pyrrolizidine<br />
alkaloids. Moreover, since 1993, cases of nephrotoxicity and carcinogenicity<br />
have been reported in Belgium, France and United Kingdom as a result of<br />
inadvertent exposure to Aristolochia species in unlicensed herbal medicines<br />
(EMEA, 2000).<br />
:*Interactions of herbal products with prescription products are well recognised,<br />
although widely under-reported (Ernst, 2000; Sorensen, 2002). In the past,<br />
when such products were usually obtained from outlets run by knowledgeable<br />
individuals, advice on use and contra-indications was often available. Currently,<br />
contra-indications do not usually appear on the labels or any associated<br />
documentation when herbal products are sold through supermarkets and other<br />
retail outlets. Yet, a survey of the available information on interactions with<br />
medicinal compounds of the more commonly purchased botanical products<br />
(e.g. ginkgo, garlic, St. John’s Wort and ginseng) found recorded adverse<br />
interactions for all but Echinacea and saw palmetto (Izzo and Ernst, 2001).<br />
Incidence and severity of effects associated with prescription drug-dietary<br />
supplement interactions in a small group of primary care patients have also<br />
been investigated by Peng et al. (2004); the most common botanical products<br />
included garlic, ginkgo biloba, saw palmetto and ginseng. While most<br />
interactions were judged not to be serious, an incidence of 6% of potentially<br />
severe health consequences was recorded among patients taking at the same<br />
time specific drugs and specific botanical products.<br />
<br />
5. This heterogeneous group of commodities includes products which, mainly<br />
depending on their intended uses and presentations, fall under different Community<br />
regulatory frameworks and for some types of products legal provisions for a<br />
preliminary risk assessment do not exist yet. The main legislations to be considered<br />
in this context are Directive 2002/46/EC on food supplements and Directive<br />
2004/27/EC on traditional herbal medicinal products:<br />
<br />
:*Directive 2002/46/EC foresees the use as food supplements of vitamins and<br />
minerals listed in the Annexes to the Directive. It also allows the use for the<br />
same purpose of still undetermined substances with a nutritional or<br />
physiological effect, but definition of such effects is not provided for.<br />
According to Art. 4, para 8, the European Commission shall produce, not later<br />
than 12 July 2007, a report on the advisability of establishing specific rules,<br />
including, where appropriate, categories of additional vitamins and minerals or<br />
of substances with a nutritional or physiological effect, accompanied by any proposals for amendments to Directive 2002/46/EC**. Thus a regulatory<br />
framework for further developments in this area already exists.<br />
:*Directive 2004/27/EC on “traditional herbal medicinal products” provides for<br />
definitions of (i) traditional herbal medicinal products, (ii) herbal medicinal<br />
products, (iii) herbal preparations and (iv) herbal substances. The directive<br />
introduces a simplified registration procedure, based on “traditional use”, but<br />
ensuring quality and safety as for any other medicinal product. Community lists<br />
will have to be prepared of traditional herbal medicinal products, herbal<br />
preparations and herbal products. On the other hand, traditional herbal<br />
materials, which are authorised for use in medicinal products, will continue to<br />
contribute to the dietary intake of bioactive agents as long as they comply with<br />
the general food regulations and make no medicinal claim.<br />
<br />
6. Also relevant in this context are the Directives 1989/398/EEC and 96/84/EC on<br />
“Food for special purposes” and the Regulation 1997/258/CE on “novel foods” that<br />
provide additional channels for some botanicals and botanical preparations to enter<br />
the food market, and the proposed Directives on “nutritional and health claims” and<br />
“food fortification” at present under consideration by the European Parliament and<br />
Council.<br />
<br />
7. As the market volume expands, so does the need for a better characterisation of<br />
botanicals and botanical preparations, and for harmonising the scientific assessment<br />
of risks from exposure of consumers to these products.<br />
<br />
8. It is important, therefore, from a public health point of view, to achieve a<br />
comprehensive and coherent approach to risk assessment and consumer<br />
information on botanicals and botanical preparations widely present in different<br />
categories of commodities. Such an approach would, in time, overcome the existing<br />
information gaps on many of these products and bring together the fragmentary<br />
provisions for risk assessment on botanicals and botanical preparations in the<br />
current relevant regulations. To this end, the present paper aims at increasing<br />
awareness on these issues and at facilitating a critical analysis of the present<br />
situation. It is intended to lead to a stronger partnership and collaboration among all<br />
the stakeholders who have a role in this important sector.<br />
<br />
9. Although it is not the objective of this discussion paper to provide a detailed<br />
analysis of the way forward, the following reflections address some issues in order<br />
to facilitate an open discussion particularly in the frame of future developments of<br />
the above-mentioned Directive 2002/46/EC:<br />
<br />
:*As systematic information about the range of botanicals and botanical products<br />
present on the market is lacking, consideration could be given, to carrying out a<br />
survey to identify the main product categories currently marketed and a study to<br />
clarify the potential health-related issues that may need to be addressed.<br />
:*In view of the difficulty of compiling a full inventory of botanicals and<br />
botanical products, the possibility could also be considered of adopting and<br />
regularly updating a list of plants or parts of plants which should not be used or<br />
could be put under scrutiny because of the presence of undesirable substances,<br />
especially if effective reduction or removal of such substances can not be<br />
ensured.<br />
:*As purity specifications for all botanicals and botanical preparations are very<br />
difficult to define, the development of ad hoc manufacturing guidelines, could<br />
be considered in order to improve their characterisation and safety. Experience<br />
already existing in the pharmaceutical sector could be helpful to this end.<br />
:*Considering the importance of providing to consumers adequate information to<br />
allow the safe use of botanicals and botanical preparations, the possibility of<br />
establishing accredited information sources easily accessible to consumers on<br />
these products also deserves attention. A complicating issue in this respect is<br />
the diffusion of misleading claims which are very difficult to counterbalance by<br />
means of reliable consumer information. However, in this respect, the situation<br />
is likely to improve when the proposal for a Community Directive providing for<br />
a clear evaluation procedure of “Nutritional and Health Claims” will be<br />
adopted.<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
http://www.efsa.europa.eu/de/scdocs/doc/1249.pdf</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=EFSA_guidance_on_safety_assessment_of_botanicals&diff=21994
EFSA guidance on safety assessment of botanicals
2011-07-07T10:11:51Z
<p>Minttu: </p>
<hr />
<div>{{nugget<br />
|authors= <br />
|reference= <br />
|urn= <br />
|ethics= <br />
|journal=<br />
|moderator=Minttu<br />
|stub=Yes}}<br />
<br />
EFSA Journal 2009; 7(9):1249<br />
For citation purposes: EFSA Scientific Committee; Guidance on safety assessment of botanicals and botanical preparations<br />
intended for use as ingredients in food supplements, on request of EFSA. EFSA Journal 2009; 7(9):1249. [19 pp.].<br />
doi:10.2093/j.efsa.2009.1249. Available online: www.efsa.europa.eu<br />
© European Food Safety Authority, 2009 1<ref>[http://www.efsa.europa.eu/de/scdocs/doc/1249.pdf]: EFSA Journal 2009; 7(9):1249<br />
For citation purposes: EFSA Scientific Committee; Guidance on safety assessment of botanicals and botanical preparations<br />
intended for use as ingredients in food supplements, on request of EFSA. EFSA Journal 2009; 7(9):1249. [19 pp.].<br />
doi:10.2093/j.efsa.2009.1249. Available online: www.efsa.europa.eu<br />
© European Food Safety Authority, 2009 1 </ref><br />
<br />
<br />
'''''SCIENTIFIC OPINION'''''<br />
<br />
<br />
''Guidance on Safety assessment of botanicals and botanical preparations intended for use as ingredients in food supplements''<br />
<br />
<br />
'''EFSA Scientific Committee'''<br />
<br />
<br />
European Food Safety Authority (EFSA), Parma, Italy<br />
<br />
<br />
This guidance document published on 9 September 2009, replaces the earlier version published on 20<br />
June 2008 with the Question Number: EFSA-Q-2005-233.<br />
<br />
<br />
''ABSTRACT''<br />
<br />
In this opinion, EFSA’s Scientific Committee provides guidance on the scientific data needed to carry out a safety assessments of a botanical or a botanical preparation. It also proposes a two-tiered scientific approach for the safety assessment depending on the available knowledge on a given botanical and the substance(s) it contains. The guidance also provides a set of criteria to help prioritise the safety assessment of botanical ingredients which<br />
are in use. EFSA has also compiled the available information on a large number of botanicals which have been reported to contain substances that may be of health concern when used in food or food supplements. The resulting compendium, which will be regularly updated, should be considered as part of this guidance document<br />
and is intended to assist manufacturers and food safety authorities by highlighting possible safety issues which may require further consideration.<br />
<br />
<br />
''KEY WORDS''<br />
<br />
Botanicals, botanical preparations, safety assessment, food supplements, toxicological properties, medicinal<br />
properties.<br />
<br />
<br />
''SUMMARY''<br />
<br />
Following the discussion paper of the Scientific Committee on botanicals and botanical preparations<br />
adopted on 23 June 2004, The European Food Safety Authority (EFSA) asked in August 2005 the<br />
Scientific Committee to develop a two-level tiered approach for the safety assessment of botanicals<br />
and botanical preparations. This approach consists of a first safety assessment level based on<br />
available knowledge and a subsequent level in which the safety assessment includes newly generated<br />
data.<br />
<br />
<br />
The present guidance document is focussed on botanicals and botanical preparations intended for use<br />
in food supplements, although the approach chosen is, in principle, applicable also to other uses of<br />
botanicals and botanical preparations in the food and feed areas.<br />
<br />
<br />
A general framework for safety assessment is proposed by the Scientific Committee, in which<br />
botanicals or botanical preparations for which an adequate body of knowledge exists could benefit<br />
from a “presumption of safety” without any need for further testing. Issues that should be carefully<br />
considered in order to reach such a conclusion are discussed in detail in the present guidance<br />
document. Botanicals and botanical preparations for which a presumption of safety is not possible<br />
based on available knowledge would be subject to a more extensive safety assessment, requiring<br />
additional data to be provided.<br />
<br />
<br />
It is not the objective of this opinion to produce a list of safe botanicals and botanical preparations<br />
intended for food supplement use, but only to provide guidance on how to assess safety of botanical<br />
ingredients.<br />
<br />
<br />
The Scientific Committee developed criteria for prioritising botanicals for safety assessment and has<br />
compiled a Compendium of botanicals that are reported to contain toxic, addictive, psychotropic or<br />
other substances that may be of concern. The main purpose of the Compendium, which should be<br />
considered as part of this guidance document, is to draw attention to issues that would need to be<br />
taken into account when assessing the safety of botanicals used as ingredients in food supplements,<br />
and to facilitate the establishment of priorities for safety assessment.<br />
<br />
<br />
The Scientific Committee recommends maintaining the Compendium up-to-date, making use of<br />
relevant available national lists of plants and of any other relevant data available, as well as of<br />
updated assessments carried out on botanicals by qualified bodies. The Scientific Committee also<br />
recommends to further expand the Compendium with botanicals not having any market history in<br />
Europe but having a documented history of use in their third country of origin.<br />
<br />
<br />
TABLE OF CONTENTS<br />
:*Abstract <br />
:*Summary <br />
:*Table of contents <br />
:*Background as provided by EFSA <br />
:*Terms of reference as provided by EFSA <br />
:*Acknowledgements <br />
:*Assessment <br />
:1.Introduction <br />
:2.Safety assessment of botanicals and botanical preparations intended for use as ingredients in<br />
food supplements <br />
:2.1Proposed data requirements for safety assessment of botanicals and botanical preparations<br />
used as ingredients in food supplements <br />
:2.1.1.Technical data<br />
::2.1.1.1. Identity and nature of the source material <br />
::2.1.1.2. Manufacturing process<br />
::2.1.1.3. Chemical composition <br />
::2.1.1.4. Specifications <br />
::2.1.1.5. Stability of the botanical or botanical preparation used as ingredient in food supplement <br />
::2.1.1.6. Proposed uses and use levels <br />
::2.1.1.7. Information on existing assessments <br />
:2.1.2. Exposure: extent and duration <br />
:2.1.3. Toxicological data <br />
2.2. Proposed general framework for assessing the safety of botanicals and botanical<br />
preparations used as ingredients in food supplement <br />
:2.2.1. Level A: Safety assessment based on available knowledge <br />
:2.2.2. Additional data required for the level B assessment <br />
3. Establishing a Compendium of botanicals and prioritising them to be considered for a safety<br />
assessment. <br />
:*Conclusions and recommendations <br />
:*References <br />
<br />
<br />
''BACKGROUND AS PROVIDED BY EFSA''<br />
A discussion paper by the Scientific Committee on botanicals and botanical preparations widely used<br />
in food supplements and related products was adopted on 23 June 2004 (SC document EFSA/SC/26<br />
Final3). In this paper, the Committee expressed concerns about quality and safety issues of botanicals<br />
and botanical preparations that have become widely available to consumers through several<br />
distribution channels in the EU. The use of botanicals and botanical preparations in food is regulated<br />
under the General Food Law (178/2002/EC), which attributes the primary legal responsibility for the<br />
safety of the products placed on the market to business operators. The Regulation however does not<br />
provide any guidance on how the safety of these products should be assessed. As the market volume<br />
and the variety of products expand, so does the need for a better characterisation of the range of<br />
botanicals and botanical preparations on the market, and for harmonising the risk assessment and<br />
consumer information approaches for these products. The paper aimed at increasing awareness of<br />
EFSA’s Advisory Forum on potential public health aspects associated with these products.<br />
<br />
<br />
The Secretariat brought the discussion paper to the attention of the Advisory Forum at its meeting of<br />
the 1st of October, 2004. Simultaneously, an invitation was sent to the members of the Advisory Forum to take note of the concerns<br />
raised by the Scientific Committee and to complete a questionnaire to provide a better understanding of the issue in Europe.<br />
<br />
<br />
By the end of January 2005, replies were received from twenty five countries, comprising twenty two<br />
EU Member States and three EFTA Countries. The members of the Advisory Forum underlined the<br />
importance of this issue for their countries and asked EFSA to initiate a self-task in order to develop<br />
some guidance on how to assess the safety of botanical ingredients.<br />
<br />
<br />
Following the mandate received by the Scientific Committee in August 2005 from EFSA, the<br />
Scientific Committee developed a two-level tiered approach for the safety assessment of botanicals<br />
and botanical preparations. A guidance document focussing on botanicals and botanical preparations<br />
intended for use as food supplements was published after public consultation.<br />
<br />
<br />
A conceptual framework for safety assessment was advocated, in which botanicals or botanical<br />
preparations for which an adequate body of knowledge exists could benefit from a “presumption of<br />
safety” without any need for further testing (first level of the framework). Issues that should be<br />
carefully considered in order to reach such a conclusion were discussed in detail in the guidance<br />
document. Botanicals and botanical preparations for which a presumption of safety is not possible<br />
would be subject to a more extensive safety assessment, based on additional data to be provided in<br />
accordance with the methodology described in the second level of the proposed framework.<br />
<br />
<br />
As a follow up, it was decided to test the adequacy of the above-mentioned approach described in the<br />
guidance document for safety assessment with a selected number of examples including botanicals<br />
known to contain toxic substances or having a reported toxic effect, botanicals with an established<br />
history of food use, and botanicals that are known to contain potentially genotoxic/carcinogenic<br />
substances. To this end, an EFSA Scientific Cooperation (ESCO) Working Group, composed of<br />
experts identified by the members of the Advisory Forum and by the Scientific Committee EFSA was<br />
established in April 2008. This working group was also given the task to finalise the Compendium of<br />
botanicals reported to contain toxic, addictive, psychotropic, or other substances of concern. The resulting ESCO report and Compendium9 were provided to the EFSA Executive Director in May<br />
2009.<br />
<br />
<br />
''TERMS OF REFERENCE AS PROVIDED BY EFSA''<br />
<br />
The Scientific Committee has been requested in May 2009 by the European Food Safety Authority<br />
to consider the recommendations made in the ESCO report for updating the guidance document for<br />
the safety assessment of botanicals and botanical preparations intended for use as ingredients in food<br />
supplements.<br />
<br />
<br />
''ACKNOWLEDGEMENTS''<br />
<br />
The European Food Safety Authority wishes to thank the members of the EFSA Scientific<br />
Cooperation (ESCO) Working Group on Botanicals and Botanical Preparations for the preparation of<br />
the ESCO Report, which was used by the Scientific Committee to update this guidance document.<br />
The European Food Safety Authority would also like to thank the members of the former Scientific<br />
Committee for their contributions to the present guidance document.<br />
<br />
<br />
''ASSESSMENT''<br />
<br />
1. '''Introduction'''<br />
The Scientific Committee decided to focus its work first on the safety assessment of botanicals and<br />
botanical preparations used as ingredients in food supplements (hereafter referred to, as botanical<br />
ingredients), although the approach chosen is, in principle, applicable also to other uses of botanicals<br />
and botanical preparations in the food and feed areas. It is not in the scope of the present guidance to<br />
address issues related to quality assurance and good hygienic practices currently regulated by the EU<br />
Food Legislation, nor to assess the safety of food supplements as end products. The present guidance<br />
does not therefore address hazards linked to the presence of contaminants and foodborne pathogens in<br />
the botanicals and botanicals preparations.<br />
<br />
<br />
A two-level tiered conceptual framework for safety assessment consisting of a safety assessment<br />
based on available knowledge and a subsequent level in which further testing and/or data are required<br />
is proposed by the Scientific Committee. Botanicals or botanical preparations for which an adequate<br />
body of knowledge exists, can benefit from a “presumption of safety” without any need for further<br />
testing. Based on reasonable evidence, they can then be assumed to be safe, sometimes under certain<br />
restrictions. The Scientific Committee used as an example the Qualified Presumption of Safety (QPS)<br />
approach developed for microorganisms in food and feed (EFSA, 2007a) to propose criteria for<br />
presuming a botanical or a botanical preparation safe. Botanicals and botanical preparations for which<br />
a presumption of safety is not possible should be subject to a more extensive safety assessment, based<br />
on additional data to be provided according to the methodology described by EFSA. By proposing a<br />
first safety assessment level based on available knowledge, the approach proposed by the Scientific<br />
Committee for the safety assessment of botanicals and botanical preparations is in line with EFSA’s<br />
policy to stimulate food and feed risk assessment approaches that minimise the number of<br />
experimental animals and any suffering (EFSA, 2009).<br />
<br />
<br />
In order to facilitate the implementation of the above-mentioned approach, EFSA has also compiled a<br />
Compendium of botanicals and botanical preparations that have been reported to contain toxic,<br />
addictive, psychotropic or other substances that may be of concern. This Compendium should be seen<br />
as a tool to gather relevant information and define priorities for safety assessment. The inclusion of a<br />
botanical in this Compendium does not imply that it is not safe for use in food supplements. Without<br />
prejudice to the existing legal framework, such Compendium has no legal status and may not be used<br />
as support or evidence in any disagreement or dispute pertaining to the legal classification of products<br />
or substances.<br />
<br />
<br />
Safety assessment of botanicals and botanical preparations<br />
EFSA Journal 2009; 7(9):1249 7<br />
2. '''Safety assessment of botanicals and botanical preparations intended for use as<br />
ingredients in food supplements'''<br />
<br />
It should be noted that Regulation 258/97/EC concerning novel foods and novel food ingredients<br />
applies to all foods, including food supplements, containing substances which have not been used for<br />
human consumption to a significant degree within the Community before 15 May 1997 and which fall<br />
under certain categories specified in the above-mentioned Regulation. In the case of a proposed use as<br />
a novel food, botanicals or botanical preparations should be assessed following the guidelines of the<br />
Commission Recommendation 97/618/EC of 29 July 1997 concerning the scientific aspects and the<br />
presentation of information necessary to support applications for the placing on the market of novel<br />
foods and novel food ingredients.<br />
<br />
<br />
Moreover, Regulation 1829/2003/EC on genetically modified food and feed would apply to any GMO<br />
ingredients used in food supplements. In the case of botanicals or botanical preparations derived from<br />
genetically modified plants, information should be provided in line with the guidance document of the<br />
EFSA Scientific Panel on Genetically Modified Organisms for the risk assessment of genetically<br />
modified plants and derived food (EFSA, 2006a).<br />
When the botanical or botanical preparation is intended for use as a food intended for particular<br />
nutritional uses (PARNUTS – Directive 89/398/EEC), the guidance document from the Scientific<br />
Committee on Food on submissions for safety evaluation of sources of nutrients or of other<br />
ingredients proposed for use in the manufacture of foods (SCF, 2001a) should also be consulted.<br />
<br />
<br />
It should also be underlined that this report only deals with guidance on safety assessment, whereas<br />
the scientific substantiation of any claims made on food supplements, as required by the Regulation<br />
on Nutrition and Health Claims, will be dealt with in separate EFSA documents, such as the<br />
“Scientific and technical guidance for the preparation and presentation of the application for<br />
authorisation of a health claim” (EFSA, 2007b).<br />
It is not the objective of this report to produce a list of safe botanicals and botanical preparations<br />
intended for food supplement use, but only to provide guidance on how to assess safety of botanical<br />
ingredients. Moreover, priority criteria are proposed, and a Compendium has been compiled to serve<br />
as a preliminary tool for risk assessors (see section 3).<br />
<br />
<br />
2.1. '''Proposed data requirements for safety assessment of botanicals and botanical<br />
preparations used as ingredients in food supplements'''<br />
<br />
It is understood that the use of botanicals and botanical preparations as ingredients in food<br />
supplements will have to be in compliance with the existing EU Food Legislation. This would<br />
include maximum permissible levels of chemical and biological contaminants (e.g. pesticides,<br />
mycotoxins, heavy metals and foodborne pathogens), modalities for ensuring quality, and application<br />
of good hygienic practice, including HACCP methodologies. The issues of controls needed to ensure<br />
constancy over time of the composition of botanical food supplements on the market and batch-tobatch<br />
variation are not addressed in this document as these are risk management aspects and therefore<br />
outside the scope of EFSA.<br />
<br />
The following sections aim at identifying data and information considered as necessary to assess the<br />
safety of botanical ingredients. These data are of: (i) technical; (ii) exposure and (iii) toxicological<br />
nature. The lists below are meant to give guidance on data requirements. They have been made as<br />
exhaustive as possible and should be adapted on a case-by-case basis, depending on the nature of the<br />
botanical or botanical preparation. This implies that not all the information listed below would be<br />
needed in all cases and that the amount of information available for a given botanical or botanical<br />
preparation may in some cases be sufficient without further testing (see section 2.2.1).<br />
<br />
<br />
'''2.1.1. Technical data'''<br />
<br />
<br />
2.1.1.1. Identity and nature of the source material<br />
<br />
It is recognized that identification of the botanical source and botanical preparation may in some cases<br />
be complicated. It is recommended to follow as much as possible the nomenclature of the European<br />
Pharmacopeia. Additional nomenclature sources are as follows:<br />
<br />
World Checklist of Selected Plant Families (Royal Botanic Garden, Kew); the books by Hanelt<br />
(2001) also available on the Internet as Mansfeld’s World Database of Agricultural and Horticultural<br />
Crops; and the database by United States Department of Agriculture. If a scientific name is not found<br />
in any of the above-named references, its existence may be checked in The International Plant Names<br />
Index.<br />
<br />
<br />
Since there have been many instances where species have been reclassified or renamed, a same<br />
species may be known by different scientific names. Common (vernacular) names may also be<br />
provided, but it should be noted that a common name used in one region to refer to a particular plant<br />
may be used elsewhere to refer to another quite unrelated species. Hence common names may not<br />
uniquely identify a species and are not as reliable as the scientific names.<br />
<br />
<br />
The following scheme summarizes the requirements for description of the identity of the botanical:<br />
<br />
<br />
;Scientific (Latin) name:<br />
:full systematic species name incl. botanical family, genus,<br />
species, variety, subspecies, author’s name, and chemotype if<br />
applicable<br />
<br />
;Synonyms: <br />
:botanical name(s) that may be used interchangeably with the<br />
preferred scientific name<br />
;Common names: <br />
:vernacular name(s)<br />
;Part used: <br />
;e.g. root, leaf, seed …<br />
;Geographical origin: <br />
:continent, country, region<br />
;Growth and harvesting conditions: <br />
:wild or cultivated, cultivation practices, time of harvest in relation<br />
to both season and stage of the plant growth.<br />
<br />
2.1.1.2. Manufacturing process<br />
<br />
The following information is considered necessary for assessing the safety of botanicals and botanical<br />
preparations:<br />
i):Information on the method(s) of manufacture (e.g. the process by which the raw material is<br />
converted into a preparation, such as extraction or other procedure(s), and plant extract ratio)<br />
<br />
ii):Information on substances entering the manufacturing process, e.g. identity of the extraction<br />
solvent, reagents, special precautions (light and temperature).<br />
<br />
iii):Standardization criteria (e.g. see European Pharmacopoeia).<br />
<br />
Botanicals or botanical preparations might become hazardous as a result of deviations in the<br />
production process (e.g. misclassification, switching of species). Therefore the safety of botanicals<br />
and botanical preparations should be ensured by following a Hazard Analysis and Critical Control<br />
Point (HACCP) approach (Codex Alimentarius 1997). The whole production chain, from primary<br />
production of botanicals to the storage and commercialisation of the botanical preparations should be<br />
taken into consideration. The HACCP system must be applied with the necessary flexibility and<br />
adapted to each botanical preparation on a case-by-case basis.<br />
<br />
<br />
2.1.1.3. Chemical composition<br />
<br />
Data on the chemical composition of the botanical ingredient should be provided with emphasis on<br />
the concentrations of constituent of relevance for the safety assessment; this includes the<br />
concentrations of:<br />
:*Compounds should be classified according to their chemical structure (e.g. flavonoids,<br />
terpenoids, alkaloids, etc.). Levels at which the constituents are present in the respective part<br />
of the botanical or botanical preparation should be given where available.<br />
:*Constituents to characterise the quality, chemical fingerprint, production process and/or<br />
biological activity of the preparation (markers).<br />
:*Constituents that provide reasons for concern due to their chemical, physiological or<br />
toxicological properties.<br />
In some cases, it may be difficult to identify the active principle responsible for an effect. Therefore<br />
the strength of the evidence underlying the concerns over a compound being reason for concern<br />
should also be given.<br />
<br />
<br />
2.1.1.4. Specifications<br />
<br />
Specifications of the botanicals or botanical preparations are required. They may be based on<br />
nutritional or biologically active components or, when these are not known, on selected chemical<br />
markers. Limits for or absence of specific undesirable / toxic substances should be specified. The<br />
proposed specifications should be modelled on recent European or other internationally accepted<br />
specifications (e.g. pharmacopoeia or the guidelines of the EMEA Committee on Herbal Medicinal<br />
Safety assessment of botanicals and botanical preparations<br />
<br />
Products (HMPC)). Where the proposed specifications differ from internationally recognised<br />
specifications, the latter specifications should be set out alongside the proposed new specifications,<br />
and any differences pointed out. Validated and well-established methods should be preferably used<br />
for the analysis of compounds considered in specifications.<br />
<br />
The specifications should include concentrations of major groups of constituents present in the<br />
botanical preparation including for example: amino acids, lipids, polysaccharides, volatile oil,<br />
inorganic ions, polyphenols, alkaloids, terpenes, alkenylbenzenes, lignin, saponins etc. as well as the<br />
major constituents within these classes.<br />
<br />
In addition, information on maximum levels for possible contaminants including e.g. heavy metals,<br />
mycotoxins, pesticide residues, and polycyclic aromatic hydrocarbon (PAH) residues should be<br />
provided.<br />
<br />
<br />
2.1.1.5. Stability of the botanical or botanical preparation used as ingredient in food supplement<br />
<br />
The stability of the botanical ingredient should be demonstrated over the shelf-life time. Any<br />
information concerning possible degradation should also be provided.<br />
<br />
<br />
2.1.1.6. Proposed uses and use levels<br />
<br />
Information on intended uses and recommended intakes for a product should specifically mention<br />
uses and use levels for the following categories:<br />
:* Common foods<br />
:* Food supplements<br />
:* Medicinal products<br />
<br />
Special attention should be given to population groups with specific uses like for example young<br />
children. Information on the duration of the proposed uses and use levels should also be provided<br />
<br />
<br />
2.1.1.7. Information on existing assessments<br />
<br />
Information on any existing assessments by international bodies or national competent authorities<br />
should be provided.<br />
<br />
<br />
2.1.2. Exposure: extent and duration<br />
<br />
Data and information should be provided on:<br />
:i) Anticipated human exposure to the botanical ingredient, including amount (e.g. maximum and<br />
average daily intake or exposure), frequency and duration. It is important to characterize as much as<br />
possible the expected human exposure to the botanical ingredient according to the recommended<br />
modalities of use in terms of extent and duration. Clear distinction should be made between intake of<br />
a botanical itself, intake of its essential oil and other preparations made of it.<br />
:ii) Possibility of additional / combined human exposure to the botanical or botanical preparation<br />
through different categories of food, food supplements and/or medicinal products that can be<br />
consumed together.<br />
:ii) Modality of use of the ingredient.<br />
:iv) Information on historical (food, food supplement and medicinal) use of the ingredient in<br />
human population groups in relation to the modalities of use and resulting exposure levels if known.<br />
Data derived from use outside of the European Union should also be considered.<br />
<br />
<br />
All data should be representative of the ingredient to be used for the European market. In this context,<br />
food use includes, in principle, the consumption of raw and cooked vegetables, spices, flavours, food<br />
supplements already in use for a long time16 and any other related food items.<br />
<br />
<br />
Estimates of average exposure ranges associated with the use of the botanical ingredient in the EU<br />
Member States should also be provided. Uncertainties associated with the food consumption data<br />
considered and anticipated exposure ranges should be clearly described (EFSA, 2006b).<br />
<br />
A matter to be specifically addressed in the evaluation is whether the proposed use and use levels will<br />
significantly increase already existing human exposure.<br />
<br />
<br />
'''2.1.3. Toxicological data'''<br />
<br />
Studies on toxicity and toxicokinetics including metabolism of botanicals and botanical preparations<br />
should be conducted using internationally agreed protocols. Test methods described by OECD or in<br />
European Commission Directives 87/432/EEC and 67/548/EC – Annex 5 are recommended. It is<br />
advisable to ensure that the most up-to-date version of any test guideline is followed. Use of any<br />
methods differing from internationally agreed protocols should be justified. Protocols for special<br />
studies differing from standard tests should be developed on a case-by-case basis.<br />
<br />
To ensure general acceptance of the data submitted, studies should be carried out according to the<br />
principles of Good Laboratory Practice (GLP) described in Council Directive 87/18/EEC and<br />
accompanied by a statement of GLP compliance. Adequate explanation should be provided for<br />
divergence from these principles.<br />
<br />
Council Directive 86/609/EEC, on the protection of animals used for experimental and other scientific<br />
purposes, requires that care is taken to avoid unnecessary use of animals. Studies carried out should<br />
be those necessary to demonstrate the safety of a botanical or botanical preparation and planned in<br />
accordance with the principles of reduction, refinement and replacement. However, where adequate<br />
data are not available for the safety assessment (see section 3.2.1), in vivo studies using experimental<br />
animals may be needed in order to assess possible risks to humans from the ingestion of botanicals or<br />
botanical preparations. Alternative validated methods involving fewer or no animals for toxicity<br />
endpoints may in the future be developed and should be considered on a case-by-case basis.<br />
<br />
If available, data on possible interactions (e.g. herbal-drug) should also be provided.<br />
<br />
<br />
'''2.2. Proposed general framework for assessing the safety of botanicals and botanical<br />
preparations used as ingredients in food supplement'''<br />
<br />
Several guidance documents (AFSSA, 2003; Council of Europe, 2005; Schilter et al., 2003) have been<br />
published on the principles for assessment of botanicals and botanical preparations in the food and<br />
feed area. The present guidance document is not intended to reiterate these, but to outline a<br />
framework that could be used by risk assessors when assessing the safety of a botanical or a botanical<br />
preparation. It also proposes a scientific approach to the assessment of available data.<br />
<br />
The aim of the assessment is to ensure that botanicals or botanical preparations, when used in food<br />
supplements in the manner, quantities and time period of intake proposed, would not pose a risk to the<br />
health of consumers. Data should provide not only information relevant to the healthy adult consumer,<br />
but also relevant to those population groups potentially vulnerable due to their pattern of food<br />
consumption or their physiological or health status, e.g. young age, elderly, pregnancy,<br />
immunocompromised etc.<br />
<br />
A general framework for assessing the safety with core tests and other tests is given, which should<br />
enable determination of what information is required to establish the safety-in-use of the botanical or<br />
botanical preparation. The application of this guidance to specific cases will depend on the nature of<br />
the botanical or botanical preparation, its intended uses and levels of use in food supplements and on<br />
whether the botanical or botanical preparation has a long term history of food use17, showing that, at<br />
proposed exposure levels, no adverse effect on human health has been reported. In addition to<br />
laboratory tests, it may be possible to use human data derived from medical use, epidemiology, or<br />
specific studies on volunteers (e.g. on absorption and metabolism), or any other data reporting<br />
possible adverse health effects, either anecdotal or on the basis of case reports of intoxication, e.g data<br />
related to toxicity on livestock animals, or on botanicals that closely resemble botanicals which are<br />
known to have caused toxic effects.<br />
<br />
However, it is recognized that for botanical ingredients lacking a history of food use, or for botanicals<br />
whose intended use levels will significantly exceed historical intake levels, an assessment of safety<br />
generally relies on experimental toxicity data largely derived from investigations in laboratory<br />
animals.<br />
<br />
The approach herein proposed for the safety assessment of botanicals and botanical preparations not<br />
regulated in the framework of specific regulations such as the one on novel foods, and illustrated by<br />
Figure 1, consists of the two following levels:<br />
:*Level A: Safety assessment based on available knowledge.<br />
:*Level B: Safety assessment including newly generated data.<br />
<br />
Figure 1: Proposed tiered approach for the safety assessment of botanicals and botanical<br />
preparations.<br />
<br />
<br />
'''.2.1. Level A: Safety assessment based on available knowledge'''<br />
<br />
Depending on the botanical ingredient and its uses, there are circumstances under which no additional<br />
data are judged necessary for the safety evaluation, i.e. a presumption of safety would be applied.<br />
This would be the case whenever available data would allow to conclude that exposure to known<br />
levels of the botanical ingredient has occurred in large population groups for many years without<br />
reported adverse effects.<br />
<br />
Therefore, an important requirement is that the data as outlined in chapter 2.1 are provided and that<br />
no significant increase of intake compared to historical levels is to be expected due to the intended<br />
levels of use in food supplements. This implies that not only use levels but also chemotypes of<br />
botanicals and the chemical composition of the botanical preparations should be in line with<br />
historically used ones. This approach can only be applied when intakes due to the intended levels of<br />
use are within the range of intake levels derived from the European Member States’ average diets or<br />
from studies on specific subgroups. It is recognized that the acceptability of such an approach relies<br />
mainly on the objective of not significantly increasing exposures beyond the levels linked to the safe<br />
history of use.<br />
<br />
If compounds of concern can be well defined, evaluations can focus on these specific compounds. In<br />
some cases, it may be difficult to identify the active principle responsible for an effect. In such cases<br />
the strength of the evidence underlying the concerns over a compound taken as the reference<br />
compound for the safety evaluation should also be given.<br />
<br />
For botanicals and botanical preparations with a potential to contain toxic, addictive, psychotropic or<br />
other substances that may be of concern (see also the Compendium and section 3), presumption of<br />
safety can be applied only if there is convincing evidence that these undesirable substances in the<br />
specific plant parts or preparations are either absent in the source material, or significantly reduced if<br />
not excluded, or inactivated during processing.<br />
<br />
In cases where the above-mentioned substances are known to be present in the botanical ingredient<br />
under evaluation (see attached Compendium), additional consideration should be given to support the<br />
presumption of safety of the botanical preparation. The significance of overall exposure to such<br />
substances should be assessed and compared with existing health-based guidance values such as the<br />
acceptable / tolerable daily intake (ADI/TDI). Consideration of exposure to the substance of concern<br />
in relation to the Threshold of Toxicological Concern (TTC) values may also be helpful.<br />
<br />
In cases where no health-based guidance values are available or where the botanical ingredient<br />
contains substances that are both genotoxic and carcinogenic, the “Margin of Exposure” (MOE)<br />
approach (EFSA, 2005) could be applied covering the botanical(s) under examination and any other<br />
dietary sources of exposure. The MOE approach compares toxic effect levels with human exposure<br />
levels. Alternatively, it could be evaluated whether the expected exposure to the genotoxic and<br />
carcinogenic ingredient is likely to be increased, compared to the intake from other sources.<br />
<br />
It is plausible that the kinetics as well as the expression of the inherent toxicity of a naturally<br />
occurring substance could be modified by the matrix in which it is present. Depending on the<br />
mechanism of action, this could result in the toxicity being unchanged, reduced or even increased.<br />
Research on individual substance/matrix interactions or botanical preparations cannot be used to draw<br />
general conclusions about intact botanicals, herbs and spices under all conditions of use, ingestion and<br />
metabolism. Where a matrix effect is advocated to support the safety of specific levels of substances<br />
(e.g. that data from a pure substance may overestimate effects of the substance in the botanical<br />
matrix), testing and/or other data should be provided to demonstrate the occurrence of the matrix<br />
effect of the preparation and its magnitude. A matrix effect should be judged on a case-by-case basis.<br />
<br />
Extrapolating from one preparation to another and/or from one botanical to another with respect to the<br />
same substance of toxicological concern can only been considered when accompanied by evidence of<br />
their composition with respect to the substance of concern and pattern of consumption.<br />
<br />
For food supplements consisting of complex mixtures of different botanicals, the above-mentioned<br />
assessment could be carried out on the levels of individual substances of concern known to be present<br />
(see also the Compendium), with the understanding of the limitation that such an approach does not<br />
generally allow the assessment of possible synergistic or antagonistic effects.Any data on possible<br />
herb-drug interaction should be carefully considered.<br />
<br />
In the case of a botanical ingredient whose anticipated intake is significantly higher than the estimated<br />
historical intake level, or for which the historical intake level cannot be assessed, additional data<br />
should be provided for the safety assessment, as described in the following sections.<br />
<br />
'''2.2.2. Additional data required for the level B assessment'''<br />
<br />
The reasons for carrying out toxicological studies should be stated, as should the reasons for not<br />
submitting a study that might be expected. The studies that might be expected can be seen from the<br />
“Guidance on submissions for food additive evaluations by the Scientific Committee on Food” (SCF<br />
2001b). All the important results should be presented and discussed and the original study reports<br />
should be submitted in order to allow independent, critical appraisal.<br />
<br />
The toxicology section of the dossier should start with a section describing in detail the specifications<br />
and identity criteria for the botanical preparation(s) used for the toxicity studies and their relationship<br />
to the final product to be used in the food supplement. It should be demonstrated unambiguously that<br />
these characteristics are in compliance with the technical details specified for the botanical<br />
preparation in this report.<br />
<br />
The toxicological tests should, as far as possible, follow the recommendations for data reporting given<br />
in the relevant guidelines (e.g. OECD, 1998). The material to be tested, with lot or batch number,<br />
should be well identified, characterized and standardized. It is important that for each study performed<br />
it is stated whether the test material conforms to the proposed specifications. If it does not conform,<br />
then the specifications of the test material should be given together with a rationale for using these<br />
data in the safety assessment of the product intended for the market.<br />
<br />
<br />
*''Toxicokinetics including metabolism''<br />
<br />
Information on toxicokinetics of relevant biologically active constituents present in the botanical or<br />
botanical preparation should be provided whenever available from the literature. Not all aspects need<br />
to be investigated in every case. Additional issues that may deserve consideration are:<br />
:*The possibility of interactions among constituents of the botanical or botanical<br />
preparation that can alter bioavailability, metabolism, and toxicity.<br />
:*The possibility of interactions with medicinal products.<br />
*''Genotoxicity testing''<br />
For the genotoxicity testing of botanicals and botanical preparations, in vitro tests covering effects<br />
both at gene and chromosome levels are required19. Specific tests are likely to include the Ames test<br />
(OECD guideline 471) and an in vitro test for the detection of chromosomal aberrations (OECD<br />
guideline 473) or an in vitro micronucleus assay (draft OECD guideline 487), and possibly the mouse<br />
lymphoma tk assay (OECD 476). The particular test strategy may depend upon the test material<br />
considered.<br />
<br />
There may be circumstances under which it may be justified to deviate from the above-mentioned<br />
core set. In such cases a scientific justification should be provided and additional types of<br />
considerations or mechanistic studies may be needed.<br />
<br />
A positive in vitro test normally requires follow-up by in vivo testing, unless it can be adequately<br />
demonstrated that the positive in vitro findings are not relevant for the in vivo situation. The choice of the appropriate in vivo test is critical, due to different sensitivities, different endpoints and other<br />
variables. It requires expert judgement based on all available information, to be applied case-by-case.<br />
For this reason, a flexible approach is preferable to a fixed decision tree.<br />
<br />
<br />
*''Subchronic toxicity testing''<br />
<br />
A 90-day study in the rat with the test material administered via the diet is the minimum requirement<br />
to establish a no-observed-adverse-effect level. Subchronic toxicity testing should be carried out<br />
independently of the results of the in vitro and in vivo genotoxicity testing.<br />
<br />
*''Other studies''<br />
<br />
Depending on the outcome of the genotoxicity and subchronic toxicity studies, or other specific<br />
relevant information, further studies may be required (e.g. reproductive toxicity, developmental<br />
toxicity, neurotoxicity, immunotoxicity, chronic toxicity/carcinogenicity).<br />
<br />
<br />
''3. Establishing a Compendium of botanicals and prioritising them to be considered for a<br />
safety assessment.''<br />
<br />
A Compendium of botanicals reported to contain toxic, addictive, psychotropic or other substances<br />
that may be of concern has been produced to complement the present guidance document.<br />
<br />
The Compendium contains the following information:<br />
:*The botanical (binomial) denomination of the plant (genus, species and in some cases variety or<br />
subspecies when relevant), with synonyms in use.<br />
:*The plant parts and substances of possible toxicological concern<br />
:*Additional specific information of relevance for the risk assessment, e.g. adulterations<br />
:*References, either to existing international / national list of plants that were used to populate the<br />
Compendium, or to published literature when specific information has been added.<br />
<br />
The Compendium aims at flagging plants or part of plants or substances of possible concern for<br />
human heath naturally present in the listed botanicals and that, therefore, require specific attention<br />
while assessing the safety of the product(s) containing such botanical(s). For some botanicals in the<br />
Compendium, adverse (toxic) effect(s) are mentioned although sometimes based on anecdotal reports<br />
and even though the constituent(s) of concern are not elucidated in the literature. In some cases the<br />
whole genus was flagged because of the likely presence of substances of concern characteristic for the<br />
toxicity of that genus.<br />
<br />
The presence of a substance of concern in a given botanical does not mean that this substance will<br />
also be present in the botanical preparation. This depends largely on the plant part used, as well as the<br />
preparation method.<br />
<br />
The Compendium contains also an “insufficient information” list regrouping botanicals that appear in<br />
one of the sources of information, but for which sufficient information could not be found on possible<br />
substances of concern, or for which the information available could not be verified.<br />
<br />
Without prejudice to the existing legal framework, it should be noted that this Compendium has no<br />
legal status and should not be used as support or evidence in any disagreement or dispute pertaining to<br />
the legal classification of products or substances.<br />
<br />
The Compendium is a living document which should be periodically updated by EFSA. As a<br />
consequence, the absence of a given species in this Compendium cannot be interpreted as meaning<br />
that the species is devoid of substances hazardous for human health. In the same way, not mentioning<br />
a specific part of plant, does not imply absence of substance(s) of concern in this part. Botanicals that<br />
have not been reported as having been considered for food or food supplement use in the European<br />
countries or botanicals classified as novel foods or GMOs will not appear in the Compendium.<br />
<br />
''Priority setting for safety assessment:''<br />
The botanicals in the above-mentioned Compendium should be assessed according to the following<br />
recommendations:<br />
<br />
Priority should be given to botanicals and botanical preparations:<br />
:*known to have an established history of food use and that have been identified to contain<br />
significant levels of substances of concern.<br />
:*that are not allowed/recommended for food use in some European countries, but which are<br />
still in use in some other EU countries, particularly when the intended use levels in food are<br />
known or expected to be high.<br />
:*for which some adverse health effects have been reported, either anecdotally, or on the basis<br />
of case reports of intoxication, epidemiological data or any toxicity data from livestock<br />
animals or experimental animals, or for botanicals that closely resemble botanicals which are<br />
known to have caused toxic effects.<br />
:*for which consumption has significantly increased during recent years in Member States.<br />
:*for which there are both limited history of use and toxicity data available, and for which the<br />
intended use levels are expected to be relatively high (e.g. high interest to the food industry).<br />
<br />
Botanical ingredients that are reported to have a low toxic potential, and for which the intended<br />
intake/exposure levels are within the range of intake levels resulting from the European Member<br />
States average diet would be given a low priority.<br />
<br />
'''''CONCLUSIONS AND RECOMMENDATIONS'''''<br />
<br />
A two-level tiered approach for the safety assessment of botanical ingredients intended for use in food<br />
supplements is proposed. This approach consists of a safety assessment based on available knowledge<br />
and a subsequent level in which further testing and/or data are required. It allows the recognition of<br />
presumption of safety without further testing, based on long-term history of use with no reported<br />
adverse effect and with no significant increased exposure. For those botanical ingredients for which a<br />
presumption of safety based on available data cannot be established, it introduces a framework for<br />
assessing their safety, including the types of testing that would be most useful. Recommendations for<br />
prioritising botanicals for safety assessment are also made.<br />
<br />
The Compendium of botanicals reported to contain toxic, addictive, psychotropic or other substances<br />
that may be of concern, is considered to facilitate the assessment by flagging possible safety issues,<br />
and should therefore be considered as an essential part of this guidance document. The Scientific<br />
Committee recommends to maintain it up-to-date, making use of relevant available national lists of<br />
plants and of any other relevant data available, as well as of updated assessments carried out on<br />
botanicals by qualified bodies. The Scientific Committee also recommends to further expand the<br />
Compendium with botanicals not having any market history in Europe in order to prepare the<br />
implementation of the new Novel Food Regulation, which foresees a notification process for<br />
botanicals and botanical preparations having a history of safe use in the third country of origin.<br />
<br />
<br />
'''European Food Safety Authority'''<br />
<br />
''SCIENTIFIC COMMITTEE''<br />
Discussion Paper on “Botanicals and Botanical Preparations widely used<br />
as food supplements and related products: Coherent and Comprehensive<br />
Risk Assessment and Consumer Information Approaches”<br />
<br />
(adopted by written procedure on 23 June 2004)<br />
<br />
1. In view of the fact that botanicals and botanical preparations intended for human<br />
consumption as food supplements and related products are very widely marketed<br />
with a variety of claims, the present discussion paper aims at increasing awareness<br />
of some key issues to improve comprehensiveness and coherence of current<br />
approaches to risk assessment and consumer information on these products.<br />
<br />
2. A large number of botanical materials (e.g. whole, fragmented or cut plants, algae,<br />
fungi, lichens), and botanical preparations obtained from these materials by various<br />
processes (e.g. extraction, distillation, purification, concentration and fermentation)<br />
readily find their way onto the food supplements market. These materials are also<br />
often labelled as natural foods, largely organic, and foods specifically intended to<br />
support sport activities. Personal care products and the so-called “traditional herbal<br />
medicinal products” represent additional sources of exposure of consumers to<br />
botanical products. New products are also emerging, consisting of substances that<br />
commonly occur at low levels in botanical components of the diet, which are then<br />
extracted and re-introduced at much higher levels in specific products.<br />
<br />
3. Botanicals and botanical preparations are widely available to consumers through<br />
several distribution channels in the E.U. and elsewhere. In particular, they are sold<br />
over the counter in pharmacies and can be bought in supermarkets, herbalist’s<br />
shops and other shops, or via the Internet. They are currently available and used in<br />
such a way that they are almost becoming part of the common diet, thus providing<br />
for a significant human exposure from a public health point of view.<br />
<br />
4. There are some general concerns with respect to botanicals and botanical<br />
preparations mainly relating to quality and safety issues:<br />
:*Contamination (both chemical and microbiological) is a documented problem.<br />
It has been associated, for example, with botanical products originating from<br />
Asia. Deaths through poisoning following consumption of such products have<br />
been reported in Europe and the US arising from contamination with heavy<br />
metals, synthetic drugs and other undesirable substances (Ernst, 2002).<br />
Misidentification of plants harvested from the wild is also a continuing<br />
problem. When sales of traditional herbal products remained restricted to<br />
particular ethnic groups, which are familiar with the products and able to exert a<br />
local control on quality, problems were more rarely encountered. The growing<br />
volume of sales in the European Union with products obtained from suppliers<br />
based in Asia or elsewhere and the move towards widespread outlets for the<br />
products of traditional medicine call for more formal pre-marketing assessment<br />
and more stringent controls than the occasional random checks and analyses<br />
often carried out by individual national or local authorities on what is already<br />
out in the market.<br />
:*There is world-wide recognition of potential problems associated with<br />
botanicals and botanical products, not only in terms of safety, but also in terms<br />
of the claimed amounts and stability of the active ingredients. For example, the<br />
US Pharmacopeia, which considers the safety of food supplements as well as<br />
medicines, announced in December 2002 the establishment of an advisory<br />
panel specifically to advice on improving the quality of botanical products.<br />
:*Any efficacy shown by botanical products is usually a product of one or more<br />
plant secondary metabolites. Secondary metabolism responds to stress imposed<br />
by biotic and abiotic factors and, as a consequence, patterns and concentrations<br />
of metabolites can show considerable variation among plants belonging to the<br />
same species and variety. For instance, it is not unusual for metabolites<br />
produced in response to pathogen attack to vary in concentration one thousandfold<br />
over short time periods. While consistency of product is more easily<br />
controlled in cultivated plants, particularly those grown in containment,<br />
collections from the wild make it difficult to ensure that concentrations of<br />
bioactive agents meet specifications and are within safe limits.<br />
:*A very large literature exists on toxic substances naturally-occurring in plants.<br />
Of particular concern are plant products consumed in concentrated forms.<br />
Concerns can relate directly to the toxicological profile of the active agent(s). It<br />
has been the case with kava-kava (Piper methysticum), its withdrawal from the<br />
market being advised recently because of the association of its consumption with acute liver failure (Kraft et al., 2001). In June 2001, the US FDA,<br />
following action by the UK and Australia, advised manufacturers of dietary<br />
supplements to avoid the use of the various types of comfrey (Symphytum spp.)<br />
because of the health concerns associated with the presence of pyrrolizidine<br />
alkaloids. Moreover, since 1993, cases of nephrotoxicity and carcinogenicity<br />
have been reported in Belgium, France and United Kingdom as a result of<br />
inadvertent exposure to Aristolochia species in unlicensed herbal medicines<br />
(EMEA, 2000).<br />
:*Interactions of herbal products with prescription products are well recognised,<br />
although widely under-reported (Ernst, 2000; Sorensen, 2002). In the past,<br />
when such products were usually obtained from outlets run by knowledgeable<br />
individuals, advice on use and contra-indications was often available. Currently,<br />
contra-indications do not usually appear on the labels or any associated<br />
documentation when herbal products are sold through supermarkets and other<br />
retail outlets. Yet, a survey of the available information on interactions with<br />
medicinal compounds of the more commonly purchased botanical products<br />
(e.g. ginkgo, garlic, St. John’s Wort and ginseng) found recorded adverse<br />
interactions for all but Echinacea and saw palmetto (Izzo and Ernst, 2001).<br />
Incidence and severity of effects associated with prescription drug-dietary<br />
supplement interactions in a small group of primary care patients have also<br />
been investigated by Peng et al. (2004); the most common botanical products<br />
included garlic, ginkgo biloba, saw palmetto and ginseng. While most<br />
interactions were judged not to be serious, an incidence of 6% of potentially<br />
severe health consequences was recorded among patients taking at the same<br />
time specific drugs and specific botanical products.<br />
<br />
5. This heterogeneous group of commodities includes products which, mainly<br />
depending on their intended uses and presentations, fall under different Community<br />
regulatory frameworks and for some types of products legal provisions for a<br />
preliminary risk assessment do not exist yet. The main legislations to be considered<br />
in this context are Directive 2002/46/EC on food supplements and Directive<br />
2004/27/EC on traditional herbal medicinal products:<br />
<br />
:*Directive 2002/46/EC foresees the use as food supplements of vitamins and<br />
minerals listed in the Annexes to the Directive. It also allows the use for the<br />
same purpose of still undetermined substances with a nutritional or<br />
physiological effect, but definition of such effects is not provided for.<br />
According to Art. 4, para 8, the European Commission shall produce, not later<br />
than 12 July 2007, a report on the advisability of establishing specific rules,<br />
including, where appropriate, categories of additional vitamins and minerals or<br />
of substances with a nutritional or physiological effect, accompanied by any proposals for amendments to Directive 2002/46/EC**. Thus a regulatory<br />
framework for further developments in this area already exists.<br />
:*Directive 2004/27/EC on “traditional herbal medicinal products” provides for<br />
definitions of (i) traditional herbal medicinal products, (ii) herbal medicinal<br />
products, (iii) herbal preparations and (iv) herbal substances. The directive<br />
introduces a simplified registration procedure, based on “traditional use”, but<br />
ensuring quality and safety as for any other medicinal product. Community lists<br />
will have to be prepared of traditional herbal medicinal products, herbal<br />
preparations and herbal products. On the other hand, traditional herbal<br />
materials, which are authorised for use in medicinal products, will continue to<br />
contribute to the dietary intake of bioactive agents as long as they comply with<br />
the general food regulations and make no medicinal claim.<br />
<br />
6. Also relevant in this context are the Directives 1989/398/EEC and 96/84/EC on<br />
“Food for special purposes” and the Regulation 1997/258/CE on “novel foods” that<br />
provide additional channels for some botanicals and botanical preparations to enter<br />
the food market, and the proposed Directives on “nutritional and health claims” and<br />
“food fortification” at present under consideration by the European Parliament and<br />
Council.<br />
<br />
7. As the market volume expands, so does the need for a better characterisation of<br />
botanicals and botanical preparations, and for harmonising the scientific assessment<br />
of risks from exposure of consumers to these products.<br />
<br />
8. It is important, therefore, from a public health point of view, to achieve a<br />
comprehensive and coherent approach to risk assessment and consumer<br />
information on botanicals and botanical preparations widely present in different<br />
categories of commodities. Such an approach would, in time, overcome the existing<br />
information gaps on many of these products and bring together the fragmentary<br />
provisions for risk assessment on botanicals and botanical preparations in the<br />
current relevant regulations. To this end, the present paper aims at increasing<br />
awareness on these issues and at facilitating a critical analysis of the present<br />
situation. It is intended to lead to a stronger partnership and collaboration among all<br />
the stakeholders who have a role in this important sector.<br />
<br />
9. Although it is not the objective of this discussion paper to provide a detailed<br />
analysis of the way forward, the following reflections address some issues in order<br />
to facilitate an open discussion particularly in the frame of future developments of<br />
the above-mentioned Directive 2002/46/EC:<br />
<br />
:*As systematic information about the range of botanicals and botanical products<br />
present on the market is lacking, consideration could be given, to carrying out a<br />
survey to identify the main product categories currently marketed and a study to<br />
clarify the potential health-related issues that may need to be addressed.<br />
:*In view of the difficulty of compiling a full inventory of botanicals and<br />
botanical products, the possibility could also be considered of adopting and<br />
regularly updating a list of plants or parts of plants which should not be used or<br />
could be put under scrutiny because of the presence of undesirable substances,<br />
especially if effective reduction or removal of such substances can not be<br />
ensured.<br />
:*As purity specifications for all botanicals and botanical preparations are very<br />
difficult to define, the development of ad hoc manufacturing guidelines, could<br />
be considered in order to improve their characterisation and safety. Experience<br />
already existing in the pharmaceutical sector could be helpful to this end.<br />
:*Considering the importance of providing to consumers adequate information to<br />
allow the safe use of botanicals and botanical preparations, the possibility of<br />
establishing accredited information sources easily accessible to consumers on<br />
these products also deserves attention. A complicating issue in this respect is<br />
the diffusion of misleading claims which are very difficult to counterbalance by<br />
means of reliable consumer information. However, in this respect, the situation<br />
is likely to improve when the proposal for a Community Directive providing for<br />
a clear evaluation procedure of “Nutritional and Health Claims” will be<br />
adopted.<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
http://www.efsa.europa.eu/de/scdocs/doc/1249.pdf</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=EFSA_guidance_on_safety_assessment_of_botanicals&diff=21993
EFSA guidance on safety assessment of botanicals
2011-07-07T10:09:14Z
<p>Minttu: </p>
<hr />
<div>{{nugget<br />
|authors= <br />
|reference= <br />
|urn= <br />
|ethics= <br />
|journal=<br />
|moderator=Minttu<br />
|stub=Yes}}<br />
<br />
<ref>[http://www.efsa.europa.eu/de/scdocs/doc/1249.pdf]: EFSA Journal 2009; 7(9):1249<br />
For citation purposes: EFSA Scientific Committee; Guidance on safety assessment of botanicals and botanical preparations<br />
intended for use as ingredients in food supplements, on request of EFSA. EFSA Journal 2009; 7(9):1249. [19 pp.].<br />
doi:10.2093/j.efsa.2009.1249. Available online: www.efsa.europa.eu<br />
© European Food Safety Authority, 2009 1 </ref><br />
<br />
<br />
'''''SCIENTIFIC OPINION'''''<br />
<br />
<br />
''Guidance on Safety assessment of botanicals and botanical preparations intended for use as ingredients in food supplements''<br />
<br />
<br />
'''EFSA Scientific Committee'''<br />
<br />
<br />
European Food Safety Authority (EFSA), Parma, Italy<br />
<br />
<br />
This guidance document published on 9 September 2009, replaces the earlier version published on 20<br />
June 2008 with the Question Number: EFSA-Q-2005-233.<br />
<br />
<br />
''ABSTRACT''<br />
<br />
In this opinion, EFSA’s Scientific Committee provides guidance on the scientific data needed to carry out a safety assessments of a botanical or a botanical preparation. It also proposes a two-tiered scientific approach for the safety assessment depending on the available knowledge on a given botanical and the substance(s) it contains. The guidance also provides a set of criteria to help prioritise the safety assessment of botanical ingredients which<br />
are in use. EFSA has also compiled the available information on a large number of botanicals which have been reported to contain substances that may be of health concern when used in food or food supplements. The resulting compendium, which will be regularly updated, should be considered as part of this guidance document<br />
and is intended to assist manufacturers and food safety authorities by highlighting possible safety issues which may require further consideration.<br />
<br />
<br />
''KEY WORDS''<br />
<br />
Botanicals, botanical preparations, safety assessment, food supplements, toxicological properties, medicinal<br />
properties.<br />
<br />
<br />
''SUMMARY''<br />
<br />
Following the discussion paper of the Scientific Committee on botanicals and botanical preparations<br />
adopted on 23 June 2004, The European Food Safety Authority (EFSA) asked in August 2005 the<br />
Scientific Committee to develop a two-level tiered approach for the safety assessment of botanicals<br />
and botanical preparations. This approach consists of a first safety assessment level based on<br />
available knowledge and a subsequent level in which the safety assessment includes newly generated<br />
data.<br />
<br />
<br />
The present guidance document is focussed on botanicals and botanical preparations intended for use<br />
in food supplements, although the approach chosen is, in principle, applicable also to other uses of<br />
botanicals and botanical preparations in the food and feed areas.<br />
<br />
<br />
A general framework for safety assessment is proposed by the Scientific Committee, in which<br />
botanicals or botanical preparations for which an adequate body of knowledge exists could benefit<br />
from a “presumption of safety” without any need for further testing. Issues that should be carefully<br />
considered in order to reach such a conclusion are discussed in detail in the present guidance<br />
document. Botanicals and botanical preparations for which a presumption of safety is not possible<br />
based on available knowledge would be subject to a more extensive safety assessment, requiring<br />
additional data to be provided.<br />
<br />
<br />
It is not the objective of this opinion to produce a list of safe botanicals and botanical preparations<br />
intended for food supplement use, but only to provide guidance on how to assess safety of botanical<br />
ingredients.<br />
<br />
<br />
The Scientific Committee developed criteria for prioritising botanicals for safety assessment and has<br />
compiled a Compendium of botanicals that are reported to contain toxic, addictive, psychotropic or<br />
other substances that may be of concern. The main purpose of the Compendium, which should be<br />
considered as part of this guidance document, is to draw attention to issues that would need to be<br />
taken into account when assessing the safety of botanicals used as ingredients in food supplements,<br />
and to facilitate the establishment of priorities for safety assessment.<br />
<br />
<br />
The Scientific Committee recommends maintaining the Compendium up-to-date, making use of<br />
relevant available national lists of plants and of any other relevant data available, as well as of<br />
updated assessments carried out on botanicals by qualified bodies. The Scientific Committee also<br />
recommends to further expand the Compendium with botanicals not having any market history in<br />
Europe but having a documented history of use in their third country of origin.<br />
<br />
<br />
TABLE OF CONTENTS<br />
:*Abstract <br />
:*Summary <br />
:*Table of contents <br />
:*Background as provided by EFSA <br />
:*Terms of reference as provided by EFSA <br />
:*Acknowledgements <br />
:*Assessment <br />
:1.Introduction <br />
:2.Safety assessment of botanicals and botanical preparations intended for use as ingredients in<br />
food supplements <br />
:2.1Proposed data requirements for safety assessment of botanicals and botanical preparations<br />
used as ingredients in food supplements <br />
:2.1.1.Technical data<br />
::2.1.1.1. Identity and nature of the source material <br />
::2.1.1.2. Manufacturing process<br />
::2.1.1.3. Chemical composition <br />
::2.1.1.4. Specifications <br />
::2.1.1.5. Stability of the botanical or botanical preparation used as ingredient in food supplement <br />
::2.1.1.6. Proposed uses and use levels <br />
::2.1.1.7. Information on existing assessments <br />
:2.1.2. Exposure: extent and duration <br />
:2.1.3. Toxicological data <br />
2.2. Proposed general framework for assessing the safety of botanicals and botanical<br />
preparations used as ingredients in food supplement <br />
:2.2.1. Level A: Safety assessment based on available knowledge <br />
:2.2.2. Additional data required for the level B assessment <br />
3. Establishing a Compendium of botanicals and prioritising them to be considered for a safety<br />
assessment. <br />
:*Conclusions and recommendations <br />
:*References <br />
<br />
<br />
''BACKGROUND AS PROVIDED BY EFSA''<br />
A discussion paper by the Scientific Committee on botanicals and botanical preparations widely used<br />
in food supplements and related products was adopted on 23 June 2004 (SC document EFSA/SC/26<br />
Final3). In this paper, the Committee expressed concerns about quality and safety issues of botanicals<br />
and botanical preparations that have become widely available to consumers through several<br />
distribution channels in the EU. The use of botanicals and botanical preparations in food is regulated<br />
under the General Food Law (178/2002/EC), which attributes the primary legal responsibility for the<br />
safety of the products placed on the market to business operators. The Regulation however does not<br />
provide any guidance on how the safety of these products should be assessed. As the market volume<br />
and the variety of products expand, so does the need for a better characterisation of the range of<br />
botanicals and botanical preparations on the market, and for harmonising the risk assessment and<br />
consumer information approaches for these products. The paper aimed at increasing awareness of<br />
EFSA’s Advisory Forum on potential public health aspects associated with these products.<br />
<br />
<br />
The Secretariat brought the discussion paper to the attention of the Advisory Forum at its meeting of<br />
the 1st of October, 2004. Simultaneously, an invitation was sent to the members of the Advisory Forum to take note of the concerns<br />
raised by the Scientific Committee and to complete a questionnaire to provide a better understanding of the issue in Europe.<br />
<br />
<br />
By the end of January 2005, replies were received from twenty five countries, comprising twenty two<br />
EU Member States and three EFTA Countries. The members of the Advisory Forum underlined the<br />
importance of this issue for their countries and asked EFSA to initiate a self-task in order to develop<br />
some guidance on how to assess the safety of botanical ingredients.<br />
<br />
<br />
Following the mandate received by the Scientific Committee in August 2005 from EFSA, the<br />
Scientific Committee developed a two-level tiered approach for the safety assessment of botanicals<br />
and botanical preparations. A guidance document focussing on botanicals and botanical preparations<br />
intended for use as food supplements was published after public consultation.<br />
<br />
<br />
A conceptual framework for safety assessment was advocated, in which botanicals or botanical<br />
preparations for which an adequate body of knowledge exists could benefit from a “presumption of<br />
safety” without any need for further testing (first level of the framework). Issues that should be<br />
carefully considered in order to reach such a conclusion were discussed in detail in the guidance<br />
document. Botanicals and botanical preparations for which a presumption of safety is not possible<br />
would be subject to a more extensive safety assessment, based on additional data to be provided in<br />
accordance with the methodology described in the second level of the proposed framework.<br />
<br />
<br />
As a follow up, it was decided to test the adequacy of the above-mentioned approach described in the<br />
guidance document for safety assessment with a selected number of examples including botanicals<br />
known to contain toxic substances or having a reported toxic effect, botanicals with an established<br />
history of food use, and botanicals that are known to contain potentially genotoxic/carcinogenic<br />
substances. To this end, an EFSA Scientific Cooperation (ESCO) Working Group, composed of<br />
experts identified by the members of the Advisory Forum and by the Scientific Committee EFSA was<br />
established in April 2008. This working group was also given the task to finalise the Compendium of<br />
botanicals reported to contain toxic, addictive, psychotropic, or other substances of concern. The resulting ESCO report and Compendium9 were provided to the EFSA Executive Director in May<br />
2009.<br />
<br />
<br />
''TERMS OF REFERENCE AS PROVIDED BY EFSA''<br />
<br />
The Scientific Committee has been requested in May 2009 by the European Food Safety Authority<br />
to consider the recommendations made in the ESCO report for updating the guidance document for<br />
the safety assessment of botanicals and botanical preparations intended for use as ingredients in food<br />
supplements.<br />
<br />
<br />
''ACKNOWLEDGEMENTS''<br />
<br />
The European Food Safety Authority wishes to thank the members of the EFSA Scientific<br />
Cooperation (ESCO) Working Group on Botanicals and Botanical Preparations for the preparation of<br />
the ESCO Report, which was used by the Scientific Committee to update this guidance document.<br />
The European Food Safety Authority would also like to thank the members of the former Scientific<br />
Committee for their contributions to the present guidance document.<br />
<br />
<br />
''ASSESSMENT''<br />
<br />
1. '''Introduction'''<br />
The Scientific Committee decided to focus its work first on the safety assessment of botanicals and<br />
botanical preparations used as ingredients in food supplements (hereafter referred to, as botanical<br />
ingredients), although the approach chosen is, in principle, applicable also to other uses of botanicals<br />
and botanical preparations in the food and feed areas. It is not in the scope of the present guidance to<br />
address issues related to quality assurance and good hygienic practices currently regulated by the EU<br />
Food Legislation, nor to assess the safety of food supplements as end products. The present guidance<br />
does not therefore address hazards linked to the presence of contaminants and foodborne pathogens in<br />
the botanicals and botanicals preparations.<br />
<br />
<br />
A two-level tiered conceptual framework for safety assessment consisting of a safety assessment<br />
based on available knowledge and a subsequent level in which further testing and/or data are required<br />
is proposed by the Scientific Committee. Botanicals or botanical preparations for which an adequate<br />
body of knowledge exists, can benefit from a “presumption of safety” without any need for further<br />
testing. Based on reasonable evidence, they can then be assumed to be safe, sometimes under certain<br />
restrictions. The Scientific Committee used as an example the Qualified Presumption of Safety (QPS)<br />
approach developed for microorganisms in food and feed (EFSA, 2007a) to propose criteria for<br />
presuming a botanical or a botanical preparation safe. Botanicals and botanical preparations for which<br />
a presumption of safety is not possible should be subject to a more extensive safety assessment, based<br />
on additional data to be provided according to the methodology described by EFSA. By proposing a<br />
first safety assessment level based on available knowledge, the approach proposed by the Scientific<br />
Committee for the safety assessment of botanicals and botanical preparations is in line with EFSA’s<br />
policy to stimulate food and feed risk assessment approaches that minimise the number of<br />
experimental animals and any suffering (EFSA, 2009).<br />
<br />
<br />
In order to facilitate the implementation of the above-mentioned approach, EFSA has also compiled a<br />
Compendium of botanicals and botanical preparations that have been reported to contain toxic,<br />
addictive, psychotropic or other substances that may be of concern. This Compendium should be seen<br />
as a tool to gather relevant information and define priorities for safety assessment. The inclusion of a<br />
botanical in this Compendium does not imply that it is not safe for use in food supplements. Without<br />
prejudice to the existing legal framework, such Compendium has no legal status and may not be used<br />
as support or evidence in any disagreement or dispute pertaining to the legal classification of products<br />
or substances.<br />
<br />
<br />
Safety assessment of botanicals and botanical preparations<br />
EFSA Journal 2009; 7(9):1249 7<br />
2. '''Safety assessment of botanicals and botanical preparations intended for use as<br />
ingredients in food supplements'''<br />
<br />
It should be noted that Regulation 258/97/EC concerning novel foods and novel food ingredients<br />
applies to all foods, including food supplements, containing substances which have not been used for<br />
human consumption to a significant degree within the Community before 15 May 1997 and which fall<br />
under certain categories specified in the above-mentioned Regulation. In the case of a proposed use as<br />
a novel food, botanicals or botanical preparations should be assessed following the guidelines of the<br />
Commission Recommendation 97/618/EC of 29 July 1997 concerning the scientific aspects and the<br />
presentation of information necessary to support applications for the placing on the market of novel<br />
foods and novel food ingredients.<br />
<br />
<br />
Moreover, Regulation 1829/2003/EC on genetically modified food and feed would apply to any GMO<br />
ingredients used in food supplements. In the case of botanicals or botanical preparations derived from<br />
genetically modified plants, information should be provided in line with the guidance document of the<br />
EFSA Scientific Panel on Genetically Modified Organisms for the risk assessment of genetically<br />
modified plants and derived food (EFSA, 2006a).<br />
When the botanical or botanical preparation is intended for use as a food intended for particular<br />
nutritional uses (PARNUTS – Directive 89/398/EEC), the guidance document from the Scientific<br />
Committee on Food on submissions for safety evaluation of sources of nutrients or of other<br />
ingredients proposed for use in the manufacture of foods (SCF, 2001a) should also be consulted.<br />
<br />
<br />
It should also be underlined that this report only deals with guidance on safety assessment, whereas<br />
the scientific substantiation of any claims made on food supplements, as required by the Regulation<br />
on Nutrition and Health Claims, will be dealt with in separate EFSA documents, such as the<br />
“Scientific and technical guidance for the preparation and presentation of the application for<br />
authorisation of a health claim” (EFSA, 2007b).<br />
It is not the objective of this report to produce a list of safe botanicals and botanical preparations<br />
intended for food supplement use, but only to provide guidance on how to assess safety of botanical<br />
ingredients. Moreover, priority criteria are proposed, and a Compendium has been compiled to serve<br />
as a preliminary tool for risk assessors (see section 3).<br />
<br />
<br />
2.1. '''Proposed data requirements for safety assessment of botanicals and botanical<br />
preparations used as ingredients in food supplements'''<br />
<br />
It is understood that the use of botanicals and botanical preparations as ingredients in food<br />
supplements will have to be in compliance with the existing EU Food Legislation. This would<br />
include maximum permissible levels of chemical and biological contaminants (e.g. pesticides,<br />
mycotoxins, heavy metals and foodborne pathogens), modalities for ensuring quality, and application<br />
of good hygienic practice, including HACCP methodologies. The issues of controls needed to ensure<br />
constancy over time of the composition of botanical food supplements on the market and batch-tobatch<br />
variation are not addressed in this document as these are risk management aspects and therefore<br />
outside the scope of EFSA.<br />
<br />
The following sections aim at identifying data and information considered as necessary to assess the<br />
safety of botanical ingredients. These data are of: (i) technical; (ii) exposure and (iii) toxicological<br />
nature. The lists below are meant to give guidance on data requirements. They have been made as<br />
exhaustive as possible and should be adapted on a case-by-case basis, depending on the nature of the<br />
botanical or botanical preparation. This implies that not all the information listed below would be<br />
needed in all cases and that the amount of information available for a given botanical or botanical<br />
preparation may in some cases be sufficient without further testing (see section 2.2.1).<br />
<br />
<br />
'''2.1.1. Technical data'''<br />
<br />
<br />
2.1.1.1. Identity and nature of the source material<br />
<br />
It is recognized that identification of the botanical source and botanical preparation may in some cases<br />
be complicated. It is recommended to follow as much as possible the nomenclature of the European<br />
Pharmacopeia. Additional nomenclature sources are as follows:<br />
<br />
World Checklist of Selected Plant Families (Royal Botanic Garden, Kew); the books by Hanelt<br />
(2001) also available on the Internet as Mansfeld’s World Database of Agricultural and Horticultural<br />
Crops; and the database by United States Department of Agriculture. If a scientific name is not found<br />
in any of the above-named references, its existence may be checked in The International Plant Names<br />
Index.<br />
<br />
<br />
Since there have been many instances where species have been reclassified or renamed, a same<br />
species may be known by different scientific names. Common (vernacular) names may also be<br />
provided, but it should be noted that a common name used in one region to refer to a particular plant<br />
may be used elsewhere to refer to another quite unrelated species. Hence common names may not<br />
uniquely identify a species and are not as reliable as the scientific names.<br />
<br />
<br />
The following scheme summarizes the requirements for description of the identity of the botanical:<br />
<br />
<br />
;Scientific (Latin) name:<br />
:full systematic species name incl. botanical family, genus,<br />
species, variety, subspecies, author’s name, and chemotype if<br />
applicable<br />
<br />
;Synonyms: <br />
:botanical name(s) that may be used interchangeably with the<br />
preferred scientific name<br />
;Common names: <br />
:vernacular name(s)<br />
;Part used: <br />
;e.g. root, leaf, seed …<br />
;Geographical origin: <br />
:continent, country, region<br />
;Growth and harvesting conditions: <br />
:wild or cultivated, cultivation practices, time of harvest in relation<br />
to both season and stage of the plant growth.<br />
<br />
2.1.1.2. Manufacturing process<br />
<br />
The following information is considered necessary for assessing the safety of botanicals and botanical<br />
preparations:<br />
i):Information on the method(s) of manufacture (e.g. the process by which the raw material is<br />
converted into a preparation, such as extraction or other procedure(s), and plant extract ratio)<br />
<br />
ii):Information on substances entering the manufacturing process, e.g. identity of the extraction<br />
solvent, reagents, special precautions (light and temperature).<br />
<br />
iii):Standardization criteria (e.g. see European Pharmacopoeia).<br />
<br />
Botanicals or botanical preparations might become hazardous as a result of deviations in the<br />
production process (e.g. misclassification, switching of species). Therefore the safety of botanicals<br />
and botanical preparations should be ensured by following a Hazard Analysis and Critical Control<br />
Point (HACCP) approach (Codex Alimentarius 1997). The whole production chain, from primary<br />
production of botanicals to the storage and commercialisation of the botanical preparations should be<br />
taken into consideration. The HACCP system must be applied with the necessary flexibility and<br />
adapted to each botanical preparation on a case-by-case basis.<br />
<br />
<br />
2.1.1.3. Chemical composition<br />
<br />
Data on the chemical composition of the botanical ingredient should be provided with emphasis on<br />
the concentrations of constituent of relevance for the safety assessment; this includes the<br />
concentrations of:<br />
:*Compounds should be classified according to their chemical structure (e.g. flavonoids,<br />
terpenoids, alkaloids, etc.). Levels at which the constituents are present in the respective part<br />
of the botanical or botanical preparation should be given where available.<br />
:*Constituents to characterise the quality, chemical fingerprint, production process and/or<br />
biological activity of the preparation (markers).<br />
:*Constituents that provide reasons for concern due to their chemical, physiological or<br />
toxicological properties.<br />
In some cases, it may be difficult to identify the active principle responsible for an effect. Therefore<br />
the strength of the evidence underlying the concerns over a compound being reason for concern<br />
should also be given.<br />
<br />
<br />
2.1.1.4. Specifications<br />
<br />
Specifications of the botanicals or botanical preparations are required. They may be based on<br />
nutritional or biologically active components or, when these are not known, on selected chemical<br />
markers. Limits for or absence of specific undesirable / toxic substances should be specified. The<br />
proposed specifications should be modelled on recent European or other internationally accepted<br />
specifications (e.g. pharmacopoeia or the guidelines of the EMEA Committee on Herbal Medicinal<br />
Safety assessment of botanicals and botanical preparations<br />
<br />
Products (HMPC)). Where the proposed specifications differ from internationally recognised<br />
specifications, the latter specifications should be set out alongside the proposed new specifications,<br />
and any differences pointed out. Validated and well-established methods should be preferably used<br />
for the analysis of compounds considered in specifications.<br />
<br />
The specifications should include concentrations of major groups of constituents present in the<br />
botanical preparation including for example: amino acids, lipids, polysaccharides, volatile oil,<br />
inorganic ions, polyphenols, alkaloids, terpenes, alkenylbenzenes, lignin, saponins etc. as well as the<br />
major constituents within these classes.<br />
<br />
In addition, information on maximum levels for possible contaminants including e.g. heavy metals,<br />
mycotoxins, pesticide residues, and polycyclic aromatic hydrocarbon (PAH) residues should be<br />
provided.<br />
<br />
<br />
2.1.1.5. Stability of the botanical or botanical preparation used as ingredient in food supplement<br />
<br />
The stability of the botanical ingredient should be demonstrated over the shelf-life time. Any<br />
information concerning possible degradation should also be provided.<br />
<br />
<br />
2.1.1.6. Proposed uses and use levels<br />
<br />
Information on intended uses and recommended intakes for a product should specifically mention<br />
uses and use levels for the following categories:<br />
:* Common foods<br />
:* Food supplements<br />
:* Medicinal products<br />
<br />
Special attention should be given to population groups with specific uses like for example young<br />
children. Information on the duration of the proposed uses and use levels should also be provided<br />
<br />
<br />
2.1.1.7. Information on existing assessments<br />
<br />
Information on any existing assessments by international bodies or national competent authorities<br />
should be provided.<br />
<br />
<br />
2.1.2. Exposure: extent and duration<br />
<br />
Data and information should be provided on:<br />
:i) Anticipated human exposure to the botanical ingredient, including amount (e.g. maximum and<br />
average daily intake or exposure), frequency and duration. It is important to characterize as much as<br />
possible the expected human exposure to the botanical ingredient according to the recommended<br />
modalities of use in terms of extent and duration. Clear distinction should be made between intake of<br />
a botanical itself, intake of its essential oil and other preparations made of it.<br />
:ii) Possibility of additional / combined human exposure to the botanical or botanical preparation<br />
through different categories of food, food supplements and/or medicinal products that can be<br />
consumed together.<br />
:ii) Modality of use of the ingredient.<br />
:iv) Information on historical (food, food supplement and medicinal) use of the ingredient in<br />
human population groups in relation to the modalities of use and resulting exposure levels if known.<br />
Data derived from use outside of the European Union should also be considered.<br />
<br />
<br />
All data should be representative of the ingredient to be used for the European market. In this context,<br />
food use includes, in principle, the consumption of raw and cooked vegetables, spices, flavours, food<br />
supplements already in use for a long time16 and any other related food items.<br />
<br />
<br />
Estimates of average exposure ranges associated with the use of the botanical ingredient in the EU<br />
Member States should also be provided. Uncertainties associated with the food consumption data<br />
considered and anticipated exposure ranges should be clearly described (EFSA, 2006b).<br />
<br />
A matter to be specifically addressed in the evaluation is whether the proposed use and use levels will<br />
significantly increase already existing human exposure.<br />
<br />
<br />
'''2.1.3. Toxicological data'''<br />
<br />
Studies on toxicity and toxicokinetics including metabolism of botanicals and botanical preparations<br />
should be conducted using internationally agreed protocols. Test methods described by OECD or in<br />
European Commission Directives 87/432/EEC and 67/548/EC – Annex 5 are recommended. It is<br />
advisable to ensure that the most up-to-date version of any test guideline is followed. Use of any<br />
methods differing from internationally agreed protocols should be justified. Protocols for special<br />
studies differing from standard tests should be developed on a case-by-case basis.<br />
<br />
To ensure general acceptance of the data submitted, studies should be carried out according to the<br />
principles of Good Laboratory Practice (GLP) described in Council Directive 87/18/EEC and<br />
accompanied by a statement of GLP compliance. Adequate explanation should be provided for<br />
divergence from these principles.<br />
<br />
Council Directive 86/609/EEC, on the protection of animals used for experimental and other scientific<br />
purposes, requires that care is taken to avoid unnecessary use of animals. Studies carried out should<br />
be those necessary to demonstrate the safety of a botanical or botanical preparation and planned in<br />
accordance with the principles of reduction, refinement and replacement. However, where adequate<br />
data are not available for the safety assessment (see section 3.2.1), in vivo studies using experimental<br />
animals may be needed in order to assess possible risks to humans from the ingestion of botanicals or<br />
botanical preparations. Alternative validated methods involving fewer or no animals for toxicity<br />
endpoints may in the future be developed and should be considered on a case-by-case basis.<br />
<br />
If available, data on possible interactions (e.g. herbal-drug) should also be provided.<br />
<br />
<br />
'''2.2. Proposed general framework for assessing the safety of botanicals and botanical<br />
preparations used as ingredients in food supplement'''<br />
<br />
Several guidance documents (AFSSA, 2003; Council of Europe, 2005; Schilter et al., 2003) have been<br />
published on the principles for assessment of botanicals and botanical preparations in the food and<br />
feed area. The present guidance document is not intended to reiterate these, but to outline a<br />
framework that could be used by risk assessors when assessing the safety of a botanical or a botanical<br />
preparation. It also proposes a scientific approach to the assessment of available data.<br />
<br />
The aim of the assessment is to ensure that botanicals or botanical preparations, when used in food<br />
supplements in the manner, quantities and time period of intake proposed, would not pose a risk to the<br />
health of consumers. Data should provide not only information relevant to the healthy adult consumer,<br />
but also relevant to those population groups potentially vulnerable due to their pattern of food<br />
consumption or their physiological or health status, e.g. young age, elderly, pregnancy,<br />
immunocompromised etc.<br />
<br />
A general framework for assessing the safety with core tests and other tests is given, which should<br />
enable determination of what information is required to establish the safety-in-use of the botanical or<br />
botanical preparation. The application of this guidance to specific cases will depend on the nature of<br />
the botanical or botanical preparation, its intended uses and levels of use in food supplements and on<br />
whether the botanical or botanical preparation has a long term history of food use17, showing that, at<br />
proposed exposure levels, no adverse effect on human health has been reported. In addition to<br />
laboratory tests, it may be possible to use human data derived from medical use, epidemiology, or<br />
specific studies on volunteers (e.g. on absorption and metabolism), or any other data reporting<br />
possible adverse health effects, either anecdotal or on the basis of case reports of intoxication, e.g data<br />
related to toxicity on livestock animals, or on botanicals that closely resemble botanicals which are<br />
known to have caused toxic effects.<br />
<br />
However, it is recognized that for botanical ingredients lacking a history of food use, or for botanicals<br />
whose intended use levels will significantly exceed historical intake levels, an assessment of safety<br />
generally relies on experimental toxicity data largely derived from investigations in laboratory<br />
animals.<br />
<br />
The approach herein proposed for the safety assessment of botanicals and botanical preparations not<br />
regulated in the framework of specific regulations such as the one on novel foods, and illustrated by<br />
Figure 1, consists of the two following levels:<br />
:*Level A: Safety assessment based on available knowledge.<br />
:*Level B: Safety assessment including newly generated data.<br />
<br />
Figure 1: Proposed tiered approach for the safety assessment of botanicals and botanical<br />
preparations.<br />
<br />
<br />
'''.2.1. Level A: Safety assessment based on available knowledge'''<br />
<br />
Depending on the botanical ingredient and its uses, there are circumstances under which no additional<br />
data are judged necessary for the safety evaluation, i.e. a presumption of safety would be applied.<br />
This would be the case whenever available data would allow to conclude that exposure to known<br />
levels of the botanical ingredient has occurred in large population groups for many years without<br />
reported adverse effects.<br />
<br />
Therefore, an important requirement is that the data as outlined in chapter 2.1 are provided and that<br />
no significant increase of intake compared to historical levels is to be expected due to the intended<br />
levels of use in food supplements. This implies that not only use levels but also chemotypes of<br />
botanicals and the chemical composition of the botanical preparations should be in line with<br />
historically used ones. This approach can only be applied when intakes due to the intended levels of<br />
use are within the range of intake levels derived from the European Member States’ average diets or<br />
from studies on specific subgroups. It is recognized that the acceptability of such an approach relies<br />
mainly on the objective of not significantly increasing exposures beyond the levels linked to the safe<br />
history of use.<br />
<br />
If compounds of concern can be well defined, evaluations can focus on these specific compounds. In<br />
some cases, it may be difficult to identify the active principle responsible for an effect. In such cases<br />
the strength of the evidence underlying the concerns over a compound taken as the reference<br />
compound for the safety evaluation should also be given.<br />
<br />
For botanicals and botanical preparations with a potential to contain toxic, addictive, psychotropic or<br />
other substances that may be of concern (see also the Compendium and section 3), presumption of<br />
safety can be applied only if there is convincing evidence that these undesirable substances in the<br />
specific plant parts or preparations are either absent in the source material, or significantly reduced if<br />
not excluded, or inactivated during processing.<br />
<br />
In cases where the above-mentioned substances are known to be present in the botanical ingredient<br />
under evaluation (see attached Compendium), additional consideration should be given to support the<br />
presumption of safety of the botanical preparation. The significance of overall exposure to such<br />
substances should be assessed and compared with existing health-based guidance values such as the<br />
acceptable / tolerable daily intake (ADI/TDI). Consideration of exposure to the substance of concern<br />
in relation to the Threshold of Toxicological Concern (TTC) values may also be helpful.<br />
<br />
In cases where no health-based guidance values are available or where the botanical ingredient<br />
contains substances that are both genotoxic and carcinogenic, the “Margin of Exposure” (MOE)<br />
approach (EFSA, 2005) could be applied covering the botanical(s) under examination and any other<br />
dietary sources of exposure. The MOE approach compares toxic effect levels with human exposure<br />
levels. Alternatively, it could be evaluated whether the expected exposure to the genotoxic and<br />
carcinogenic ingredient is likely to be increased, compared to the intake from other sources.<br />
<br />
It is plausible that the kinetics as well as the expression of the inherent toxicity of a naturally<br />
occurring substance could be modified by the matrix in which it is present. Depending on the<br />
mechanism of action, this could result in the toxicity being unchanged, reduced or even increased.<br />
Research on individual substance/matrix interactions or botanical preparations cannot be used to draw<br />
general conclusions about intact botanicals, herbs and spices under all conditions of use, ingestion and<br />
metabolism. Where a matrix effect is advocated to support the safety of specific levels of substances<br />
(e.g. that data from a pure substance may overestimate effects of the substance in the botanical<br />
matrix), testing and/or other data should be provided to demonstrate the occurrence of the matrix<br />
effect of the preparation and its magnitude. A matrix effect should be judged on a case-by-case basis.<br />
<br />
Extrapolating from one preparation to another and/or from one botanical to another with respect to the<br />
same substance of toxicological concern can only been considered when accompanied by evidence of<br />
their composition with respect to the substance of concern and pattern of consumption.<br />
<br />
For food supplements consisting of complex mixtures of different botanicals, the above-mentioned<br />
assessment could be carried out on the levels of individual substances of concern known to be present<br />
(see also the Compendium), with the understanding of the limitation that such an approach does not<br />
generally allow the assessment of possible synergistic or antagonistic effects.Any data on possible<br />
herb-drug interaction should be carefully considered.<br />
<br />
In the case of a botanical ingredient whose anticipated intake is significantly higher than the estimated<br />
historical intake level, or for which the historical intake level cannot be assessed, additional data<br />
should be provided for the safety assessment, as described in the following sections.<br />
<br />
'''2.2.2. Additional data required for the level B assessment'''<br />
<br />
The reasons for carrying out toxicological studies should be stated, as should the reasons for not<br />
submitting a study that might be expected. The studies that might be expected can be seen from the<br />
“Guidance on submissions for food additive evaluations by the Scientific Committee on Food” (SCF<br />
2001b). All the important results should be presented and discussed and the original study reports<br />
should be submitted in order to allow independent, critical appraisal.<br />
<br />
The toxicology section of the dossier should start with a section describing in detail the specifications<br />
and identity criteria for the botanical preparation(s) used for the toxicity studies and their relationship<br />
to the final product to be used in the food supplement. It should be demonstrated unambiguously that<br />
these characteristics are in compliance with the technical details specified for the botanical<br />
preparation in this report.<br />
<br />
The toxicological tests should, as far as possible, follow the recommendations for data reporting given<br />
in the relevant guidelines (e.g. OECD, 1998). The material to be tested, with lot or batch number,<br />
should be well identified, characterized and standardized. It is important that for each study performed<br />
it is stated whether the test material conforms to the proposed specifications. If it does not conform,<br />
then the specifications of the test material should be given together with a rationale for using these<br />
data in the safety assessment of the product intended for the market.<br />
<br />
<br />
*''Toxicokinetics including metabolism''<br />
<br />
Information on toxicokinetics of relevant biologically active constituents present in the botanical or<br />
botanical preparation should be provided whenever available from the literature. Not all aspects need<br />
to be investigated in every case. Additional issues that may deserve consideration are:<br />
:*The possibility of interactions among constituents of the botanical or botanical<br />
preparation that can alter bioavailability, metabolism, and toxicity.<br />
:*The possibility of interactions with medicinal products.<br />
*''Genotoxicity testing''<br />
For the genotoxicity testing of botanicals and botanical preparations, in vitro tests covering effects<br />
both at gene and chromosome levels are required19. Specific tests are likely to include the Ames test<br />
(OECD guideline 471) and an in vitro test for the detection of chromosomal aberrations (OECD<br />
guideline 473) or an in vitro micronucleus assay (draft OECD guideline 487), and possibly the mouse<br />
lymphoma tk assay (OECD 476). The particular test strategy may depend upon the test material<br />
considered.<br />
<br />
There may be circumstances under which it may be justified to deviate from the above-mentioned<br />
core set. In such cases a scientific justification should be provided and additional types of<br />
considerations or mechanistic studies may be needed.<br />
<br />
A positive in vitro test normally requires follow-up by in vivo testing, unless it can be adequately<br />
demonstrated that the positive in vitro findings are not relevant for the in vivo situation. The choice of the appropriate in vivo test is critical, due to different sensitivities, different endpoints and other<br />
variables. It requires expert judgement based on all available information, to be applied case-by-case.<br />
For this reason, a flexible approach is preferable to a fixed decision tree.<br />
<br />
<br />
*''Subchronic toxicity testing''<br />
<br />
A 90-day study in the rat with the test material administered via the diet is the minimum requirement<br />
to establish a no-observed-adverse-effect level. Subchronic toxicity testing should be carried out<br />
independently of the results of the in vitro and in vivo genotoxicity testing.<br />
<br />
*''Other studies''<br />
<br />
Depending on the outcome of the genotoxicity and subchronic toxicity studies, or other specific<br />
relevant information, further studies may be required (e.g. reproductive toxicity, developmental<br />
toxicity, neurotoxicity, immunotoxicity, chronic toxicity/carcinogenicity).<br />
<br />
<br />
''3. Establishing a Compendium of botanicals and prioritising them to be considered for a<br />
safety assessment.''<br />
<br />
A Compendium of botanicals reported to contain toxic, addictive, psychotropic or other substances<br />
that may be of concern has been produced to complement the present guidance document.<br />
<br />
The Compendium contains the following information:<br />
:*The botanical (binomial) denomination of the plant (genus, species and in some cases variety or<br />
subspecies when relevant), with synonyms in use.<br />
:*The plant parts and substances of possible toxicological concern<br />
:*Additional specific information of relevance for the risk assessment, e.g. adulterations<br />
:*References, either to existing international / national list of plants that were used to populate the<br />
Compendium, or to published literature when specific information has been added.<br />
<br />
The Compendium aims at flagging plants or part of plants or substances of possible concern for<br />
human heath naturally present in the listed botanicals and that, therefore, require specific attention<br />
while assessing the safety of the product(s) containing such botanical(s). For some botanicals in the<br />
Compendium, adverse (toxic) effect(s) are mentioned although sometimes based on anecdotal reports<br />
and even though the constituent(s) of concern are not elucidated in the literature. In some cases the<br />
whole genus was flagged because of the likely presence of substances of concern characteristic for the<br />
toxicity of that genus.<br />
<br />
The presence of a substance of concern in a given botanical does not mean that this substance will<br />
also be present in the botanical preparation. This depends largely on the plant part used, as well as the<br />
preparation method.<br />
<br />
The Compendium contains also an “insufficient information” list regrouping botanicals that appear in<br />
one of the sources of information, but for which sufficient information could not be found on possible<br />
substances of concern, or for which the information available could not be verified.<br />
<br />
Without prejudice to the existing legal framework, it should be noted that this Compendium has no<br />
legal status and should not be used as support or evidence in any disagreement or dispute pertaining to<br />
the legal classification of products or substances.<br />
<br />
The Compendium is a living document which should be periodically updated by EFSA. As a<br />
consequence, the absence of a given species in this Compendium cannot be interpreted as meaning<br />
that the species is devoid of substances hazardous for human health. In the same way, not mentioning<br />
a specific part of plant, does not imply absence of substance(s) of concern in this part. Botanicals that<br />
have not been reported as having been considered for food or food supplement use in the European<br />
countries or botanicals classified as novel foods or GMOs will not appear in the Compendium.<br />
<br />
''Priority setting for safety assessment:''<br />
The botanicals in the above-mentioned Compendium should be assessed according to the following<br />
recommendations:<br />
<br />
Priority should be given to botanicals and botanical preparations:<br />
:*known to have an established history of food use and that have been identified to contain<br />
significant levels of substances of concern.<br />
:*that are not allowed/recommended for food use in some European countries, but which are<br />
still in use in some other EU countries, particularly when the intended use levels in food are<br />
known or expected to be high.<br />
:*for which some adverse health effects have been reported, either anecdotally, or on the basis<br />
of case reports of intoxication, epidemiological data or any toxicity data from livestock<br />
animals or experimental animals, or for botanicals that closely resemble botanicals which are<br />
known to have caused toxic effects.<br />
:*for which consumption has significantly increased during recent years in Member States.<br />
:*for which there are both limited history of use and toxicity data available, and for which the<br />
intended use levels are expected to be relatively high (e.g. high interest to the food industry).<br />
<br />
Botanical ingredients that are reported to have a low toxic potential, and for which the intended<br />
intake/exposure levels are within the range of intake levels resulting from the European Member<br />
States average diet would be given a low priority.<br />
<br />
'''''CONCLUSIONS AND RECOMMENDATIONS'''''<br />
<br />
A two-level tiered approach for the safety assessment of botanical ingredients intended for use in food<br />
supplements is proposed. This approach consists of a safety assessment based on available knowledge<br />
and a subsequent level in which further testing and/or data are required. It allows the recognition of<br />
presumption of safety without further testing, based on long-term history of use with no reported<br />
adverse effect and with no significant increased exposure. For those botanical ingredients for which a<br />
presumption of safety based on available data cannot be established, it introduces a framework for<br />
assessing their safety, including the types of testing that would be most useful. Recommendations for<br />
prioritising botanicals for safety assessment are also made.<br />
<br />
The Compendium of botanicals reported to contain toxic, addictive, psychotropic or other substances<br />
that may be of concern, is considered to facilitate the assessment by flagging possible safety issues,<br />
and should therefore be considered as an essential part of this guidance document. The Scientific<br />
Committee recommends to maintain it up-to-date, making use of relevant available national lists of<br />
plants and of any other relevant data available, as well as of updated assessments carried out on<br />
botanicals by qualified bodies. The Scientific Committee also recommends to further expand the<br />
Compendium with botanicals not having any market history in Europe in order to prepare the<br />
implementation of the new Novel Food Regulation, which foresees a notification process for<br />
botanicals and botanical preparations having a history of safe use in the third country of origin.<br />
<br />
<br />
'''European Food Safety Authority'''<br />
<br />
''SCIENTIFIC COMMITTEE''<br />
Discussion Paper on “Botanicals and Botanical Preparations widely used<br />
as food supplements and related products: Coherent and Comprehensive<br />
Risk Assessment and Consumer Information Approaches”<br />
<br />
(adopted by written procedure on 23 June 2004)<br />
<br />
1. In view of the fact that botanicals and botanical preparations intended for human<br />
consumption as food supplements and related products are very widely marketed<br />
with a variety of claims, the present discussion paper aims at increasing awareness<br />
of some key issues to improve comprehensiveness and coherence of current<br />
approaches to risk assessment and consumer information on these products.<br />
<br />
2. A large number of botanical materials (e.g. whole, fragmented or cut plants, algae,<br />
fungi, lichens), and botanical preparations obtained from these materials by various<br />
processes (e.g. extraction, distillation, purification, concentration and fermentation)<br />
readily find their way onto the food supplements market. These materials are also<br />
often labelled as natural foods, largely organic, and foods specifically intended to<br />
support sport activities. Personal care products and the so-called “traditional herbal<br />
medicinal products” represent additional sources of exposure of consumers to<br />
botanical products. New products are also emerging, consisting of substances that<br />
commonly occur at low levels in botanical components of the diet, which are then<br />
extracted and re-introduced at much higher levels in specific products.<br />
<br />
3. Botanicals and botanical preparations are widely available to consumers through<br />
several distribution channels in the E.U. and elsewhere. In particular, they are sold<br />
over the counter in pharmacies and can be bought in supermarkets, herbalist’s<br />
shops and other shops, or via the Internet. They are currently available and used in<br />
such a way that they are almost becoming part of the common diet, thus providing<br />
for a significant human exposure from a public health point of view.<br />
<br />
4. There are some general concerns with respect to botanicals and botanical<br />
preparations mainly relating to quality and safety issues:<br />
:*Contamination (both chemical and microbiological) is a documented problem.<br />
It has been associated, for example, with botanical products originating from<br />
Asia. Deaths through poisoning following consumption of such products have<br />
been reported in Europe and the US arising from contamination with heavy<br />
metals, synthetic drugs and other undesirable substances (Ernst, 2002).<br />
Misidentification of plants harvested from the wild is also a continuing<br />
problem. When sales of traditional herbal products remained restricted to<br />
particular ethnic groups, which are familiar with the products and able to exert a<br />
local control on quality, problems were more rarely encountered. The growing<br />
volume of sales in the European Union with products obtained from suppliers<br />
based in Asia or elsewhere and the move towards widespread outlets for the<br />
products of traditional medicine call for more formal pre-marketing assessment<br />
and more stringent controls than the occasional random checks and analyses<br />
often carried out by individual national or local authorities on what is already<br />
out in the market.<br />
:*There is world-wide recognition of potential problems associated with<br />
botanicals and botanical products, not only in terms of safety, but also in terms<br />
of the claimed amounts and stability of the active ingredients. For example, the<br />
US Pharmacopeia, which considers the safety of food supplements as well as<br />
medicines, announced in December 2002 the establishment of an advisory<br />
panel specifically to advice on improving the quality of botanical products.<br />
:*Any efficacy shown by botanical products is usually a product of one or more<br />
plant secondary metabolites. Secondary metabolism responds to stress imposed<br />
by biotic and abiotic factors and, as a consequence, patterns and concentrations<br />
of metabolites can show considerable variation among plants belonging to the<br />
same species and variety. For instance, it is not unusual for metabolites<br />
produced in response to pathogen attack to vary in concentration one thousandfold<br />
over short time periods. While consistency of product is more easily<br />
controlled in cultivated plants, particularly those grown in containment,<br />
collections from the wild make it difficult to ensure that concentrations of<br />
bioactive agents meet specifications and are within safe limits.<br />
:*A very large literature exists on toxic substances naturally-occurring in plants.<br />
Of particular concern are plant products consumed in concentrated forms.<br />
Concerns can relate directly to the toxicological profile of the active agent(s). It<br />
has been the case with kava-kava (Piper methysticum), its withdrawal from the<br />
market being advised recently because of the association of its consumption with acute liver failure (Kraft et al., 2001). In June 2001, the US FDA,<br />
following action by the UK and Australia, advised manufacturers of dietary<br />
supplements to avoid the use of the various types of comfrey (Symphytum spp.)<br />
because of the health concerns associated with the presence of pyrrolizidine<br />
alkaloids. Moreover, since 1993, cases of nephrotoxicity and carcinogenicity<br />
have been reported in Belgium, France and United Kingdom as a result of<br />
inadvertent exposure to Aristolochia species in unlicensed herbal medicines<br />
(EMEA, 2000).<br />
:*Interactions of herbal products with prescription products are well recognised,<br />
although widely under-reported (Ernst, 2000; Sorensen, 2002). In the past,<br />
when such products were usually obtained from outlets run by knowledgeable<br />
individuals, advice on use and contra-indications was often available. Currently,<br />
contra-indications do not usually appear on the labels or any associated<br />
documentation when herbal products are sold through supermarkets and other<br />
retail outlets. Yet, a survey of the available information on interactions with<br />
medicinal compounds of the more commonly purchased botanical products<br />
(e.g. ginkgo, garlic, St. John’s Wort and ginseng) found recorded adverse<br />
interactions for all but Echinacea and saw palmetto (Izzo and Ernst, 2001).<br />
Incidence and severity of effects associated with prescription drug-dietary<br />
supplement interactions in a small group of primary care patients have also<br />
been investigated by Peng et al. (2004); the most common botanical products<br />
included garlic, ginkgo biloba, saw palmetto and ginseng. While most<br />
interactions were judged not to be serious, an incidence of 6% of potentially<br />
severe health consequences was recorded among patients taking at the same<br />
time specific drugs and specific botanical products.<br />
<br />
5. This heterogeneous group of commodities includes products which, mainly<br />
depending on their intended uses and presentations, fall under different Community<br />
regulatory frameworks and for some types of products legal provisions for a<br />
preliminary risk assessment do not exist yet. The main legislations to be considered<br />
in this context are Directive 2002/46/EC on food supplements and Directive<br />
2004/27/EC on traditional herbal medicinal products:<br />
<br />
:*Directive 2002/46/EC foresees the use as food supplements of vitamins and<br />
minerals listed in the Annexes to the Directive. It also allows the use for the<br />
same purpose of still undetermined substances with a nutritional or<br />
physiological effect, but definition of such effects is not provided for.<br />
According to Art. 4, para 8, the European Commission shall produce, not later<br />
than 12 July 2007, a report on the advisability of establishing specific rules,<br />
including, where appropriate, categories of additional vitamins and minerals or<br />
of substances with a nutritional or physiological effect, accompanied by any proposals for amendments to Directive 2002/46/EC**. Thus a regulatory<br />
framework for further developments in this area already exists.<br />
:*Directive 2004/27/EC on “traditional herbal medicinal products” provides for<br />
definitions of (i) traditional herbal medicinal products, (ii) herbal medicinal<br />
products, (iii) herbal preparations and (iv) herbal substances. The directive<br />
introduces a simplified registration procedure, based on “traditional use”, but<br />
ensuring quality and safety as for any other medicinal product. Community lists<br />
will have to be prepared of traditional herbal medicinal products, herbal<br />
preparations and herbal products. On the other hand, traditional herbal<br />
materials, which are authorised for use in medicinal products, will continue to<br />
contribute to the dietary intake of bioactive agents as long as they comply with<br />
the general food regulations and make no medicinal claim.<br />
<br />
6. Also relevant in this context are the Directives 1989/398/EEC and 96/84/EC on<br />
“Food for special purposes” and the Regulation 1997/258/CE on “novel foods” that<br />
provide additional channels for some botanicals and botanical preparations to enter<br />
the food market, and the proposed Directives on “nutritional and health claims” and<br />
“food fortification” at present under consideration by the European Parliament and<br />
Council.<br />
<br />
7. As the market volume expands, so does the need for a better characterisation of<br />
botanicals and botanical preparations, and for harmonising the scientific assessment<br />
of risks from exposure of consumers to these products.<br />
<br />
8. It is important, therefore, from a public health point of view, to achieve a<br />
comprehensive and coherent approach to risk assessment and consumer<br />
information on botanicals and botanical preparations widely present in different<br />
categories of commodities. Such an approach would, in time, overcome the existing<br />
information gaps on many of these products and bring together the fragmentary<br />
provisions for risk assessment on botanicals and botanical preparations in the<br />
current relevant regulations. To this end, the present paper aims at increasing<br />
awareness on these issues and at facilitating a critical analysis of the present<br />
situation. It is intended to lead to a stronger partnership and collaboration among all<br />
the stakeholders who have a role in this important sector.<br />
<br />
9. Although it is not the objective of this discussion paper to provide a detailed<br />
analysis of the way forward, the following reflections address some issues in order<br />
to facilitate an open discussion particularly in the frame of future developments of<br />
the above-mentioned Directive 2002/46/EC:<br />
<br />
:*As systematic information about the range of botanicals and botanical products<br />
present on the market is lacking, consideration could be given, to carrying out a<br />
survey to identify the main product categories currently marketed and a study to<br />
clarify the potential health-related issues that may need to be addressed.<br />
:*In view of the difficulty of compiling a full inventory of botanicals and<br />
botanical products, the possibility could also be considered of adopting and<br />
regularly updating a list of plants or parts of plants which should not be used or<br />
could be put under scrutiny because of the presence of undesirable substances,<br />
especially if effective reduction or removal of such substances can not be<br />
ensured.<br />
:*As purity specifications for all botanicals and botanical preparations are very<br />
difficult to define, the development of ad hoc manufacturing guidelines, could<br />
be considered in order to improve their characterisation and safety. Experience<br />
already existing in the pharmaceutical sector could be helpful to this end.<br />
:*Considering the importance of providing to consumers adequate information to<br />
allow the safe use of botanicals and botanical preparations, the possibility of<br />
establishing accredited information sources easily accessible to consumers on<br />
these products also deserves attention. A complicating issue in this respect is<br />
the diffusion of misleading claims which are very difficult to counterbalance by<br />
means of reliable consumer information. However, in this respect, the situation<br />
is likely to improve when the proposal for a Community Directive providing for<br />
a clear evaluation procedure of “Nutritional and Health Claims” will be<br />
adopted.<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
http://www.efsa.europa.eu/de/scdocs/doc/1249.pdf</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=EFSA_guidance_on_safety_assessment_of_botanicals&diff=21992
EFSA guidance on safety assessment of botanicals
2011-07-07T09:56:30Z
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EFSA Journal 2009; 7(9):1249<br />
For citation purposes: EFSA Scientific Committee; Guidance on safety assessment of botanicals and botanical preparations<br />
intended for use as ingredients in food supplements, on request of EFSA. EFSA Journal 2009; 7(9):1249. [19 pp.].<br />
doi:10.2093/j.efsa.2009.1249. Available online: www.efsa.europa.eu<br />
© European Food Safety Authority, 2009 1<br />
<br />
<br />
'''''SCIENTIFIC OPINION'''''<br />
<br />
<br />
''Guidance on Safety assessment of botanicals and botanical preparations intended for use as ingredients in food supplements''<br />
<br />
<br />
'''EFSA Scientific Committee'''<br />
<br />
<br />
European Food Safety Authority (EFSA), Parma, Italy<br />
<br />
<br />
This guidance document published on 9 September 2009, replaces the earlier version published on 20<br />
June 2008 with the Question Number: EFSA-Q-2005-233.<br />
<br />
<br />
''ABSTRACT''<br />
<br />
In this opinion, EFSA’s Scientific Committee provides guidance on the scientific data needed to carry out a safety assessments of a botanical or a botanical preparation. It also proposes a two-tiered scientific approach for the safety assessment depending on the available knowledge on a given botanical and the substance(s) it contains. The guidance also provides a set of criteria to help prioritise the safety assessment of botanical ingredients which<br />
are in use. EFSA has also compiled the available information on a large number of botanicals which have been reported to contain substances that may be of health concern when used in food or food supplements. The resulting compendium, which will be regularly updated, should be considered as part of this guidance document<br />
and is intended to assist manufacturers and food safety authorities by highlighting possible safety issues which may require further consideration.<br />
<br />
<br />
''KEY WORDS''<br />
<br />
Botanicals, botanical preparations, safety assessment, food supplements, toxicological properties, medicinal<br />
properties.<br />
<br />
<br />
''SUMMARY''<br />
<br />
Following the discussion paper of the Scientific Committee on botanicals and botanical preparations<br />
adopted on 23 June 2004, The European Food Safety Authority (EFSA) asked in August 2005 the<br />
Scientific Committee to develop a two-level tiered approach for the safety assessment of botanicals<br />
and botanical preparations. This approach consists of a first safety assessment level based on<br />
available knowledge and a subsequent level in which the safety assessment includes newly generated<br />
data.<br />
<br />
<br />
The present guidance document is focussed on botanicals and botanical preparations intended for use<br />
in food supplements, although the approach chosen is, in principle, applicable also to other uses of<br />
botanicals and botanical preparations in the food and feed areas.<br />
<br />
<br />
A general framework for safety assessment is proposed by the Scientific Committee, in which<br />
botanicals or botanical preparations for which an adequate body of knowledge exists could benefit<br />
from a “presumption of safety” without any need for further testing. Issues that should be carefully<br />
considered in order to reach such a conclusion are discussed in detail in the present guidance<br />
document. Botanicals and botanical preparations for which a presumption of safety is not possible<br />
based on available knowledge would be subject to a more extensive safety assessment, requiring<br />
additional data to be provided.<br />
<br />
<br />
It is not the objective of this opinion to produce a list of safe botanicals and botanical preparations<br />
intended for food supplement use, but only to provide guidance on how to assess safety of botanical<br />
ingredients.<br />
<br />
<br />
The Scientific Committee developed criteria for prioritising botanicals for safety assessment and has<br />
compiled a Compendium of botanicals that are reported to contain toxic, addictive, psychotropic or<br />
other substances that may be of concern. The main purpose of the Compendium, which should be<br />
considered as part of this guidance document, is to draw attention to issues that would need to be<br />
taken into account when assessing the safety of botanicals used as ingredients in food supplements,<br />
and to facilitate the establishment of priorities for safety assessment.<br />
<br />
<br />
The Scientific Committee recommends maintaining the Compendium up-to-date, making use of<br />
relevant available national lists of plants and of any other relevant data available, as well as of<br />
updated assessments carried out on botanicals by qualified bodies. The Scientific Committee also<br />
recommends to further expand the Compendium with botanicals not having any market history in<br />
Europe but having a documented history of use in their third country of origin.<br />
<br />
<br />
TABLE OF CONTENTS<br />
:*Abstract <br />
:*Summary <br />
:*Table of contents <br />
:*Background as provided by EFSA <br />
:*Terms of reference as provided by EFSA <br />
:*Acknowledgements <br />
:*Assessment <br />
* Introduction <br />
* Safety assessment of botanicals and botanical preparations intended for use as ingredients in<br />
food supplements <br />
:*Proposed data requirements for safety assessment of botanicals and botanical preparations<br />
used as ingredients in food supplements <br />
:*Technical data<br />
::* Identity and nature of the source material <br />
::* Manufacturing process<br />
::* Chemical composition <br />
::* Specifications <br />
::* Stability of the botanical or botanical preparation used as ingredient in food supplement <br />
::* Proposed uses and use levels <br />
::* Information on existing assessments <br />
:* Exposure: extent and duration <br />
:* Toxicological data <br />
* Proposed general framework for assessing the safety of botanicals and botanical<br />
preparations used as ingredients in food supplement <br />
:* Level A: Safety assessment based on available knowledge <br />
:* Additional data required for the level B assessment <br />
* Establishing a Compendium of botanicals and prioritising them to be considered for a safety<br />
assessment. <br />
:*Conclusions and recommendations <br />
:*References <br />
<br />
<br />
''BACKGROUND AS PROVIDED BY EFSA''<br />
A discussion paper by the Scientific Committee on botanicals and botanical preparations widely used<br />
in food supplements and related products was adopted on 23 June 2004 (SC document EFSA/SC/26<br />
Final3). In this paper, the Committee expressed concerns about quality and safety issues of botanicals<br />
and botanical preparations that have become widely available to consumers through several<br />
distribution channels in the EU. The use of botanicals and botanical preparations in food is regulated<br />
under the General Food Law (178/2002/EC), which attributes the primary legal responsibility for the<br />
safety of the products placed on the market to business operators. The Regulation however does not<br />
provide any guidance on how the safety of these products should be assessed. As the market volume<br />
and the variety of products expand, so does the need for a better characterisation of the range of<br />
botanicals and botanical preparations on the market, and for harmonising the risk assessment and<br />
consumer information approaches for these products. The paper aimed at increasing awareness of<br />
EFSA’s Advisory Forum on potential public health aspects associated with these products.<br />
<br />
<br />
The Secretariat brought the discussion paper to the attention of the Advisory Forum at its meeting of<br />
the 1st of October, 2004. Simultaneously, an invitation was sent to the members of the Advisory Forum to take note of the concerns<br />
raised by the Scientific Committee and to complete a questionnaire to provide a better understanding of the issue in Europe.<br />
<br />
<br />
By the end of January 2005, replies were received from twenty five countries, comprising twenty two<br />
EU Member States and three EFTA Countries. The members of the Advisory Forum underlined the<br />
importance of this issue for their countries and asked EFSA to initiate a self-task in order to develop<br />
some guidance on how to assess the safety of botanical ingredients.<br />
<br />
<br />
Following the mandate received by the Scientific Committee in August 2005 from EFSA, the<br />
Scientific Committee developed a two-level tiered approach for the safety assessment of botanicals<br />
and botanical preparations. A guidance document focussing on botanicals and botanical preparations<br />
intended for use as food supplements was published after public consultation.<br />
<br />
<br />
A conceptual framework for safety assessment was advocated, in which botanicals or botanical<br />
preparations for which an adequate body of knowledge exists could benefit from a “presumption of<br />
safety” without any need for further testing (first level of the framework). Issues that should be<br />
carefully considered in order to reach such a conclusion were discussed in detail in the guidance<br />
document. Botanicals and botanical preparations for which a presumption of safety is not possible<br />
would be subject to a more extensive safety assessment, based on additional data to be provided in<br />
accordance with the methodology described in the second level of the proposed framework.<br />
<br />
<br />
As a follow up, it was decided to test the adequacy of the above-mentioned approach described in the<br />
guidance document for safety assessment with a selected number of examples including botanicals<br />
known to contain toxic substances or having a reported toxic effect, botanicals with an established<br />
history of food use, and botanicals that are known to contain potentially genotoxic/carcinogenic<br />
substances. To this end, an EFSA Scientific Cooperation (ESCO) Working Group, composed of<br />
experts identified by the members of the Advisory Forum and by the Scientific Committee EFSA was<br />
established in April 2008. This working group was also given the task to finalise the Compendium of<br />
botanicals reported to contain toxic, addictive, psychotropic, or other substances of concern. The resulting ESCO report and Compendium9 were provided to the EFSA Executive Director in May<br />
2009.<br />
<br />
<br />
''TERMS OF REFERENCE AS PROVIDED BY EFSA''<br />
<br />
The Scientific Committee has been requested in May 2009 by the European Food Safety Authority<br />
to consider the recommendations made in the ESCO report for updating the guidance document for<br />
the safety assessment of botanicals and botanical preparations intended for use as ingredients in food<br />
supplements.<br />
<br />
<br />
''ACKNOWLEDGEMENTS''<br />
<br />
The European Food Safety Authority wishes to thank the members of the EFSA Scientific<br />
Cooperation (ESCO) Working Group on Botanicals and Botanical Preparations for the preparation of<br />
the ESCO Report, which was used by the Scientific Committee to update this guidance document.<br />
The European Food Safety Authority would also like to thank the members of the former Scientific<br />
Committee for their contributions to the present guidance document.<br />
<br />
<br />
''ASSESSMENT''<br />
<br />
1. '''Introduction'''<br />
The Scientific Committee decided to focus its work first on the safety assessment of botanicals and<br />
botanical preparations used as ingredients in food supplements (hereafter referred to, as botanical<br />
ingredients), although the approach chosen is, in principle, applicable also to other uses of botanicals<br />
and botanical preparations in the food and feed areas. It is not in the scope of the present guidance to<br />
address issues related to quality assurance and good hygienic practices currently regulated by the EU<br />
Food Legislation, nor to assess the safety of food supplements as end products. The present guidance<br />
does not therefore address hazards linked to the presence of contaminants and foodborne pathogens in<br />
the botanicals and botanicals preparations.<br />
<br />
<br />
A two-level tiered conceptual framework for safety assessment consisting of a safety assessment<br />
based on available knowledge and a subsequent level in which further testing and/or data are required<br />
is proposed by the Scientific Committee. Botanicals or botanical preparations for which an adequate<br />
body of knowledge exists, can benefit from a “presumption of safety” without any need for further<br />
testing. Based on reasonable evidence, they can then be assumed to be safe, sometimes under certain<br />
restrictions. The Scientific Committee used as an example the Qualified Presumption of Safety (QPS)<br />
approach developed for microorganisms in food and feed (EFSA, 2007a) to propose criteria for<br />
presuming a botanical or a botanical preparation safe. Botanicals and botanical preparations for which<br />
a presumption of safety is not possible should be subject to a more extensive safety assessment, based<br />
on additional data to be provided according to the methodology described by EFSA. By proposing a<br />
first safety assessment level based on available knowledge, the approach proposed by the Scientific<br />
Committee for the safety assessment of botanicals and botanical preparations is in line with EFSA’s<br />
policy to stimulate food and feed risk assessment approaches that minimise the number of<br />
experimental animals and any suffering (EFSA, 2009).<br />
<br />
<br />
In order to facilitate the implementation of the above-mentioned approach, EFSA has also compiled a<br />
Compendium of botanicals and botanical preparations that have been reported to contain toxic,<br />
addictive, psychotropic or other substances that may be of concern. This Compendium should be seen<br />
as a tool to gather relevant information and define priorities for safety assessment. The inclusion of a<br />
botanical in this Compendium does not imply that it is not safe for use in food supplements. Without<br />
prejudice to the existing legal framework, such Compendium has no legal status and may not be used<br />
as support or evidence in any disagreement or dispute pertaining to the legal classification of products<br />
or substances.<br />
<br />
<br />
Safety assessment of botanicals and botanical preparations<br />
EFSA Journal 2009; 7(9):1249 7<br />
2. '''Safety assessment of botanicals and botanical preparations intended for use as<br />
ingredients in food supplements'''<br />
<br />
It should be noted that Regulation 258/97/EC concerning novel foods and novel food ingredients<br />
applies to all foods, including food supplements, containing substances which have not been used for<br />
human consumption to a significant degree within the Community before 15 May 1997 and which fall<br />
under certain categories specified in the above-mentioned Regulation. In the case of a proposed use as<br />
a novel food, botanicals or botanical preparations should be assessed following the guidelines of the<br />
Commission Recommendation 97/618/EC of 29 July 1997 concerning the scientific aspects and the<br />
presentation of information necessary to support applications for the placing on the market of novel<br />
foods and novel food ingredients.<br />
<br />
<br />
Moreover, Regulation 1829/2003/EC on genetically modified food and feed would apply to any GMO<br />
ingredients used in food supplements. In the case of botanicals or botanical preparations derived from<br />
genetically modified plants, information should be provided in line with the guidance document of the<br />
EFSA Scientific Panel on Genetically Modified Organisms for the risk assessment of genetically<br />
modified plants and derived food (EFSA, 2006a).<br />
When the botanical or botanical preparation is intended for use as a food intended for particular<br />
nutritional uses (PARNUTS – Directive 89/398/EEC), the guidance document from the Scientific<br />
Committee on Food on submissions for safety evaluation of sources of nutrients or of other<br />
ingredients proposed for use in the manufacture of foods (SCF, 2001a) should also be consulted.<br />
<br />
<br />
It should also be underlined that this report only deals with guidance on safety assessment, whereas<br />
the scientific substantiation of any claims made on food supplements, as required by the Regulation<br />
on Nutrition and Health Claims, will be dealt with in separate EFSA documents, such as the<br />
“Scientific and technical guidance for the preparation and presentation of the application for<br />
authorisation of a health claim” (EFSA, 2007b).<br />
It is not the objective of this report to produce a list of safe botanicals and botanical preparations<br />
intended for food supplement use, but only to provide guidance on how to assess safety of botanical<br />
ingredients. Moreover, priority criteria are proposed, and a Compendium has been compiled to serve<br />
as a preliminary tool for risk assessors (see section 3).<br />
<br />
<br />
2.1. '''Proposed data requirements for safety assessment of botanicals and botanical<br />
preparations used as ingredients in food supplements'''<br />
<br />
It is understood that the use of botanicals and botanical preparations as ingredients in food<br />
supplements will have to be in compliance with the existing EU Food Legislation. This would<br />
include maximum permissible levels of chemical and biological contaminants (e.g. pesticides,<br />
mycotoxins, heavy metals and foodborne pathogens), modalities for ensuring quality, and application<br />
of good hygienic practice, including HACCP methodologies. The issues of controls needed to ensure<br />
constancy over time of the composition of botanical food supplements on the market and batch-tobatch<br />
variation are not addressed in this document as these are risk management aspects and therefore<br />
outside the scope of EFSA.<br />
<br />
The following sections aim at identifying data and information considered as necessary to assess the<br />
safety of botanical ingredients. These data are of: (i) technical; (ii) exposure and (iii) toxicological<br />
nature. The lists below are meant to give guidance on data requirements. They have been made as<br />
exhaustive as possible and should be adapted on a case-by-case basis, depending on the nature of the<br />
botanical or botanical preparation. This implies that not all the information listed below would be<br />
needed in all cases and that the amount of information available for a given botanical or botanical<br />
preparation may in some cases be sufficient without further testing (see section 2.2.1).<br />
<br />
<br />
'''2.1.1. Technical data'''<br />
<br />
<br />
2.1.1.1. Identity and nature of the source material<br />
<br />
It is recognized that identification of the botanical source and botanical preparation may in some cases<br />
be complicated. It is recommended to follow as much as possible the nomenclature of the European<br />
Pharmacopeia. Additional nomenclature sources are as follows:<br />
<br />
World Checklist of Selected Plant Families (Royal Botanic Garden, Kew); the books by Hanelt<br />
(2001) also available on the Internet as Mansfeld’s World Database of Agricultural and Horticultural<br />
Crops; and the database by United States Department of Agriculture. If a scientific name is not found<br />
in any of the above-named references, its existence may be checked in The International Plant Names<br />
Index.<br />
<br />
<br />
Since there have been many instances where species have been reclassified or renamed, a same<br />
species may be known by different scientific names. Common (vernacular) names may also be<br />
provided, but it should be noted that a common name used in one region to refer to a particular plant<br />
may be used elsewhere to refer to another quite unrelated species. Hence common names may not<br />
uniquely identify a species and are not as reliable as the scientific names.<br />
<br />
<br />
The following scheme summarizes the requirements for description of the identity of the botanical:<br />
<br />
<br />
;Scientific (Latin) name:<br />
:full systematic species name incl. botanical family, genus,<br />
species, variety, subspecies, author’s name, and chemotype if<br />
applicable<br />
<br />
;Synonyms: <br />
:botanical name(s) that may be used interchangeably with the<br />
preferred scientific name<br />
;Common names: <br />
:vernacular name(s)<br />
;Part used: <br />
;e.g. root, leaf, seed …<br />
;Geographical origin: <br />
:continent, country, region<br />
;Growth and harvesting conditions: <br />
:wild or cultivated, cultivation practices, time of harvest in relation<br />
to both season and stage of the plant growth.<br />
<br />
2.1.1.2. Manufacturing process<br />
<br />
The following information is considered necessary for assessing the safety of botanicals and botanical<br />
preparations:<br />
i):Information on the method(s) of manufacture (e.g. the process by which the raw material is<br />
converted into a preparation, such as extraction or other procedure(s), and plant extract ratio)<br />
<br />
ii):Information on substances entering the manufacturing process, e.g. identity of the extraction<br />
solvent, reagents, special precautions (light and temperature).<br />
<br />
iii):Standardization criteria (e.g. see European Pharmacopoeia).<br />
<br />
Botanicals or botanical preparations might become hazardous as a result of deviations in the<br />
production process (e.g. misclassification, switching of species). Therefore the safety of botanicals<br />
and botanical preparations should be ensured by following a Hazard Analysis and Critical Control<br />
Point (HACCP) approach (Codex Alimentarius 1997). The whole production chain, from primary<br />
production of botanicals to the storage and commercialisation of the botanical preparations should be<br />
taken into consideration. The HACCP system must be applied with the necessary flexibility and<br />
adapted to each botanical preparation on a case-by-case basis.<br />
<br />
<br />
2.1.1.3. Chemical composition<br />
<br />
Data on the chemical composition of the botanical ingredient should be provided with emphasis on<br />
the concentrations of constituent of relevance for the safety assessment; this includes the<br />
concentrations of:<br />
:*Compounds should be classified according to their chemical structure (e.g. flavonoids,<br />
terpenoids, alkaloids, etc.). Levels at which the constituents are present in the respective part<br />
of the botanical or botanical preparation should be given where available.<br />
:*Constituents to characterise the quality, chemical fingerprint, production process and/or<br />
biological activity of the preparation (markers).<br />
:*Constituents that provide reasons for concern due to their chemical, physiological or<br />
toxicological properties.<br />
In some cases, it may be difficult to identify the active principle responsible for an effect. Therefore<br />
the strength of the evidence underlying the concerns over a compound being reason for concern<br />
should also be given.<br />
<br />
<br />
2.1.1.4. Specifications<br />
<br />
Specifications of the botanicals or botanical preparations are required. They may be based on<br />
nutritional or biologically active components or, when these are not known, on selected chemical<br />
markers. Limits for or absence of specific undesirable / toxic substances should be specified. The<br />
proposed specifications should be modelled on recent European or other internationally accepted<br />
specifications (e.g. pharmacopoeia or the guidelines of the EMEA Committee on Herbal Medicinal<br />
Safety assessment of botanicals and botanical preparations<br />
<br />
Products (HMPC)). Where the proposed specifications differ from internationally recognised<br />
specifications, the latter specifications should be set out alongside the proposed new specifications,<br />
and any differences pointed out. Validated and well-established methods should be preferably used<br />
for the analysis of compounds considered in specifications.<br />
<br />
The specifications should include concentrations of major groups of constituents present in the<br />
botanical preparation including for example: amino acids, lipids, polysaccharides, volatile oil,<br />
inorganic ions, polyphenols, alkaloids, terpenes, alkenylbenzenes, lignin, saponins etc. as well as the<br />
major constituents within these classes.<br />
<br />
In addition, information on maximum levels for possible contaminants including e.g. heavy metals,<br />
mycotoxins, pesticide residues, and polycyclic aromatic hydrocarbon (PAH) residues should be<br />
provided.<br />
<br />
<br />
2.1.1.5. Stability of the botanical or botanical preparation used as ingredient in food supplement<br />
<br />
The stability of the botanical ingredient should be demonstrated over the shelf-life time. Any<br />
information concerning possible degradation should also be provided.<br />
<br />
<br />
2.1.1.6. Proposed uses and use levels<br />
<br />
Information on intended uses and recommended intakes for a product should specifically mention<br />
uses and use levels for the following categories:<br />
:* Common foods<br />
:* Food supplements<br />
:* Medicinal products<br />
<br />
Special attention should be given to population groups with specific uses like for example young<br />
children. Information on the duration of the proposed uses and use levels should also be provided<br />
<br />
<br />
2.1.1.7. Information on existing assessments<br />
<br />
Information on any existing assessments by international bodies or national competent authorities<br />
should be provided.<br />
<br />
<br />
2.1.2. Exposure: extent and duration<br />
<br />
Data and information should be provided on:<br />
:i) Anticipated human exposure to the botanical ingredient, including amount (e.g. maximum and<br />
average daily intake or exposure), frequency and duration. It is important to characterize as much as<br />
possible the expected human exposure to the botanical ingredient according to the recommended<br />
modalities of use in terms of extent and duration. Clear distinction should be made between intake of<br />
a botanical itself, intake of its essential oil and other preparations made of it.<br />
:ii) Possibility of additional / combined human exposure to the botanical or botanical preparation<br />
through different categories of food, food supplements and/or medicinal products that can be<br />
consumed together.<br />
:ii) Modality of use of the ingredient.<br />
:iv) Information on historical (food, food supplement and medicinal) use of the ingredient in<br />
human population groups in relation to the modalities of use and resulting exposure levels if known.<br />
Data derived from use outside of the European Union should also be considered.<br />
<br />
<br />
All data should be representative of the ingredient to be used for the European market. In this context,<br />
food use includes, in principle, the consumption of raw and cooked vegetables, spices, flavours, food<br />
supplements already in use for a long time16 and any other related food items.<br />
<br />
<br />
Estimates of average exposure ranges associated with the use of the botanical ingredient in the EU<br />
Member States should also be provided. Uncertainties associated with the food consumption data<br />
considered and anticipated exposure ranges should be clearly described (EFSA, 2006b).<br />
<br />
A matter to be specifically addressed in the evaluation is whether the proposed use and use levels will<br />
significantly increase already existing human exposure.<br />
<br />
<br />
'''2.1.3. Toxicological data'''<br />
<br />
Studies on toxicity and toxicokinetics including metabolism of botanicals and botanical preparations<br />
should be conducted using internationally agreed protocols. Test methods described by OECD or in<br />
European Commission Directives 87/432/EEC and 67/548/EC – Annex 5 are recommended. It is<br />
advisable to ensure that the most up-to-date version of any test guideline is followed. Use of any<br />
methods differing from internationally agreed protocols should be justified. Protocols for special<br />
studies differing from standard tests should be developed on a case-by-case basis.<br />
<br />
To ensure general acceptance of the data submitted, studies should be carried out according to the<br />
principles of Good Laboratory Practice (GLP) described in Council Directive 87/18/EEC and<br />
accompanied by a statement of GLP compliance. Adequate explanation should be provided for<br />
divergence from these principles.<br />
<br />
Council Directive 86/609/EEC, on the protection of animals used for experimental and other scientific<br />
purposes, requires that care is taken to avoid unnecessary use of animals. Studies carried out should<br />
be those necessary to demonstrate the safety of a botanical or botanical preparation and planned in<br />
accordance with the principles of reduction, refinement and replacement. However, where adequate<br />
data are not available for the safety assessment (see section 3.2.1), in vivo studies using experimental<br />
animals may be needed in order to assess possible risks to humans from the ingestion of botanicals or<br />
botanical preparations. Alternative validated methods involving fewer or no animals for toxicity<br />
endpoints may in the future be developed and should be considered on a case-by-case basis.<br />
<br />
If available, data on possible interactions (e.g. herbal-drug) should also be provided.<br />
<br />
<br />
'''2.2. Proposed general framework for assessing the safety of botanicals and botanical<br />
preparations used as ingredients in food supplement'''<br />
<br />
Several guidance documents (AFSSA, 2003; Council of Europe, 2005; Schilter et al., 2003) have been<br />
published on the principles for assessment of botanicals and botanical preparations in the food and<br />
feed area. The present guidance document is not intended to reiterate these, but to outline a<br />
framework that could be used by risk assessors when assessing the safety of a botanical or a botanical<br />
preparation. It also proposes a scientific approach to the assessment of available data.<br />
<br />
The aim of the assessment is to ensure that botanicals or botanical preparations, when used in food<br />
supplements in the manner, quantities and time period of intake proposed, would not pose a risk to the<br />
health of consumers. Data should provide not only information relevant to the healthy adult consumer,<br />
but also relevant to those population groups potentially vulnerable due to their pattern of food<br />
consumption or their physiological or health status, e.g. young age, elderly, pregnancy,<br />
immunocompromised etc.<br />
<br />
A general framework for assessing the safety with core tests and other tests is given, which should<br />
enable determination of what information is required to establish the safety-in-use of the botanical or<br />
botanical preparation. The application of this guidance to specific cases will depend on the nature of<br />
the botanical or botanical preparation, its intended uses and levels of use in food supplements and on<br />
whether the botanical or botanical preparation has a long term history of food use17, showing that, at<br />
proposed exposure levels, no adverse effect on human health has been reported. In addition to<br />
laboratory tests, it may be possible to use human data derived from medical use, epidemiology, or<br />
specific studies on volunteers (e.g. on absorption and metabolism), or any other data reporting<br />
possible adverse health effects, either anecdotal or on the basis of case reports of intoxication, e.g data<br />
related to toxicity on livestock animals, or on botanicals that closely resemble botanicals which are<br />
known to have caused toxic effects.<br />
<br />
However, it is recognized that for botanical ingredients lacking a history of food use, or for botanicals<br />
whose intended use levels will significantly exceed historical intake levels, an assessment of safety<br />
generally relies on experimental toxicity data largely derived from investigations in laboratory<br />
animals.<br />
<br />
The approach herein proposed for the safety assessment of botanicals and botanical preparations not<br />
regulated in the framework of specific regulations such as the one on novel foods, and illustrated by<br />
Figure 1, consists of the two following levels:<br />
:*Level A: Safety assessment based on available knowledge.<br />
:*Level B: Safety assessment including newly generated data.<br />
<br />
Figure 1: Proposed tiered approach for the safety assessment of botanicals and botanical<br />
preparations.<br />
<br />
<br />
'''.2.1. Level A: Safety assessment based on available knowledge'''<br />
<br />
Depending on the botanical ingredient and its uses, there are circumstances under which no additional<br />
data are judged necessary for the safety evaluation, i.e. a presumption of safety would be applied.<br />
This would be the case whenever available data would allow to conclude that exposure to known<br />
levels of the botanical ingredient has occurred in large population groups for many years without<br />
reported adverse effects.<br />
<br />
Therefore, an important requirement is that the data as outlined in chapter 2.1 are provided and that<br />
no significant increase of intake compared to historical levels is to be expected due to the intended<br />
levels of use in food supplements. This implies that not only use levels but also chemotypes of<br />
botanicals and the chemical composition of the botanical preparations should be in line with<br />
historically used ones. This approach can only be applied when intakes due to the intended levels of<br />
use are within the range of intake levels derived from the European Member States’ average diets or<br />
from studies on specific subgroups. It is recognized that the acceptability of such an approach relies<br />
mainly on the objective of not significantly increasing exposures beyond the levels linked to the safe<br />
history of use.<br />
<br />
If compounds of concern can be well defined, evaluations can focus on these specific compounds. In<br />
some cases, it may be difficult to identify the active principle responsible for an effect. In such cases<br />
the strength of the evidence underlying the concerns over a compound taken as the reference<br />
compound for the safety evaluation should also be given.<br />
<br />
For botanicals and botanical preparations with a potential to contain toxic, addictive, psychotropic or<br />
other substances that may be of concern (see also the Compendium and section 3), presumption of<br />
safety can be applied only if there is convincing evidence that these undesirable substances in the<br />
specific plant parts or preparations are either absent in the source material, or significantly reduced if<br />
not excluded, or inactivated during processing.<br />
<br />
In cases where the above-mentioned substances are known to be present in the botanical ingredient<br />
under evaluation (see attached Compendium), additional consideration should be given to support the<br />
presumption of safety of the botanical preparation. The significance of overall exposure to such<br />
substances should be assessed and compared with existing health-based guidance values such as the<br />
acceptable / tolerable daily intake (ADI/TDI). Consideration of exposure to the substance of concern<br />
in relation to the Threshold of Toxicological Concern (TTC) values may also be helpful.<br />
<br />
In cases where no health-based guidance values are available or where the botanical ingredient<br />
contains substances that are both genotoxic and carcinogenic, the “Margin of Exposure” (MOE)<br />
approach (EFSA, 2005) could be applied covering the botanical(s) under examination and any other<br />
dietary sources of exposure. The MOE approach compares toxic effect levels with human exposure<br />
levels. Alternatively, it could be evaluated whether the expected exposure to the genotoxic and<br />
carcinogenic ingredient is likely to be increased, compared to the intake from other sources.<br />
<br />
It is plausible that the kinetics as well as the expression of the inherent toxicity of a naturally<br />
occurring substance could be modified by the matrix in which it is present. Depending on the<br />
mechanism of action, this could result in the toxicity being unchanged, reduced or even increased.<br />
Research on individual substance/matrix interactions or botanical preparations cannot be used to draw<br />
general conclusions about intact botanicals, herbs and spices under all conditions of use, ingestion and<br />
metabolism. Where a matrix effect is advocated to support the safety of specific levels of substances<br />
(e.g. that data from a pure substance may overestimate effects of the substance in the botanical<br />
matrix), testing and/or other data should be provided to demonstrate the occurrence of the matrix<br />
effect of the preparation and its magnitude. A matrix effect should be judged on a case-by-case basis.<br />
<br />
Extrapolating from one preparation to another and/or from one botanical to another with respect to the<br />
same substance of toxicological concern can only been considered when accompanied by evidence of<br />
their composition with respect to the substance of concern and pattern of consumption.<br />
<br />
For food supplements consisting of complex mixtures of different botanicals, the above-mentioned<br />
assessment could be carried out on the levels of individual substances of concern known to be present<br />
(see also the Compendium), with the understanding of the limitation that such an approach does not<br />
generally allow the assessment of possible synergistic or antagonistic effects.Any data on possible<br />
herb-drug interaction should be carefully considered.<br />
<br />
In the case of a botanical ingredient whose anticipated intake is significantly higher than the estimated<br />
historical intake level, or for which the historical intake level cannot be assessed, additional data<br />
should be provided for the safety assessment, as described in the following sections.<br />
<br />
'''2.2.2. Additional data required for the level B assessment'''<br />
<br />
The reasons for carrying out toxicological studies should be stated, as should the reasons for not<br />
submitting a study that might be expected. The studies that might be expected can be seen from the<br />
“Guidance on submissions for food additive evaluations by the Scientific Committee on Food” (SCF<br />
2001b). All the important results should be presented and discussed and the original study reports<br />
should be submitted in order to allow independent, critical appraisal.<br />
<br />
The toxicology section of the dossier should start with a section describing in detail the specifications<br />
and identity criteria for the botanical preparation(s) used for the toxicity studies and their relationship<br />
to the final product to be used in the food supplement. It should be demonstrated unambiguously that<br />
these characteristics are in compliance with the technical details specified for the botanical<br />
preparation in this report.<br />
<br />
The toxicological tests should, as far as possible, follow the recommendations for data reporting given<br />
in the relevant guidelines (e.g. OECD, 1998). The material to be tested, with lot or batch number,<br />
should be well identified, characterized and standardized. It is important that for each study performed<br />
it is stated whether the test material conforms to the proposed specifications. If it does not conform,<br />
then the specifications of the test material should be given together with a rationale for using these<br />
data in the safety assessment of the product intended for the market.<br />
<br />
<br />
*''Toxicokinetics including metabolism''<br />
<br />
Information on toxicokinetics of relevant biologically active constituents present in the botanical or<br />
botanical preparation should be provided whenever available from the literature. Not all aspects need<br />
to be investigated in every case. Additional issues that may deserve consideration are:<br />
:*The possibility of interactions among constituents of the botanical or botanical<br />
preparation that can alter bioavailability, metabolism, and toxicity.<br />
:*The possibility of interactions with medicinal products.<br />
*''Genotoxicity testing''<br />
For the genotoxicity testing of botanicals and botanical preparations, in vitro tests covering effects<br />
both at gene and chromosome levels are required19. Specific tests are likely to include the Ames test<br />
(OECD guideline 471) and an in vitro test for the detection of chromosomal aberrations (OECD<br />
guideline 473) or an in vitro micronucleus assay (draft OECD guideline 487), and possibly the mouse<br />
lymphoma tk assay (OECD 476). The particular test strategy may depend upon the test material<br />
considered.<br />
<br />
There may be circumstances under which it may be justified to deviate from the above-mentioned<br />
core set. In such cases a scientific justification should be provided and additional types of<br />
considerations or mechanistic studies may be needed.<br />
<br />
A positive in vitro test normally requires follow-up by in vivo testing, unless it can be adequately<br />
demonstrated that the positive in vitro findings are not relevant for the in vivo situation. The choice of the appropriate in vivo test is critical, due to different sensitivities, different endpoints and other<br />
variables. It requires expert judgement based on all available information, to be applied case-by-case.<br />
For this reason, a flexible approach is preferable to a fixed decision tree.<br />
<br />
<br />
*''Subchronic toxicity testing''<br />
<br />
A 90-day study in the rat with the test material administered via the diet is the minimum requirement<br />
to establish a no-observed-adverse-effect level. Subchronic toxicity testing should be carried out<br />
independently of the results of the in vitro and in vivo genotoxicity testing.<br />
<br />
*''Other studies''<br />
<br />
Depending on the outcome of the genotoxicity and subchronic toxicity studies, or other specific<br />
relevant information, further studies may be required (e.g. reproductive toxicity, developmental<br />
toxicity, neurotoxicity, immunotoxicity, chronic toxicity/carcinogenicity).<br />
<br />
<br />
''3. Establishing a Compendium of botanicals and prioritising them to be considered for a<br />
safety assessment.''<br />
<br />
A Compendium of botanicals reported to contain toxic, addictive, psychotropic or other substances<br />
that may be of concern has been produced to complement the present guidance document.<br />
<br />
The Compendium contains the following information:<br />
:*The botanical (binomial) denomination of the plant (genus, species and in some cases variety or<br />
subspecies when relevant), with synonyms in use.<br />
:*The plant parts and substances of possible toxicological concern<br />
:*Additional specific information of relevance for the risk assessment, e.g. adulterations<br />
:*References, either to existing international / national list of plants that were used to populate the<br />
Compendium, or to published literature when specific information has been added.<br />
<br />
The Compendium aims at flagging plants or part of plants or substances of possible concern for<br />
human heath naturally present in the listed botanicals and that, therefore, require specific attention<br />
while assessing the safety of the product(s) containing such botanical(s). For some botanicals in the<br />
Compendium, adverse (toxic) effect(s) are mentioned although sometimes based on anecdotal reports<br />
and even though the constituent(s) of concern are not elucidated in the literature. In some cases the<br />
whole genus was flagged because of the likely presence of substances of concern characteristic for the<br />
toxicity of that genus.<br />
<br />
The presence of a substance of concern in a given botanical does not mean that this substance will<br />
also be present in the botanical preparation. This depends largely on the plant part used, as well as the<br />
preparation method.<br />
<br />
The Compendium contains also an “insufficient information” list regrouping botanicals that appear in<br />
one of the sources of information, but for which sufficient information could not be found on possible<br />
substances of concern, or for which the information available could not be verified.<br />
<br />
Without prejudice to the existing legal framework, it should be noted that this Compendium has no<br />
legal status and should not be used as support or evidence in any disagreement or dispute pertaining to<br />
the legal classification of products or substances.<br />
<br />
The Compendium is a living document which should be periodically updated by EFSA. As a<br />
consequence, the absence of a given species in this Compendium cannot be interpreted as meaning<br />
that the species is devoid of substances hazardous for human health. In the same way, not mentioning<br />
a specific part of plant, does not imply absence of substance(s) of concern in this part. Botanicals that<br />
have not been reported as having been considered for food or food supplement use in the European<br />
countries or botanicals classified as novel foods or GMOs will not appear in the Compendium.<br />
<br />
''Priority setting for safety assessment:''<br />
The botanicals in the above-mentioned Compendium should be assessed according to the following<br />
recommendations:<br />
<br />
Priority should be given to botanicals and botanical preparations:<br />
:*known to have an established history of food use and that have been identified to contain<br />
significant levels of substances of concern.<br />
:*that are not allowed/recommended for food use in some European countries, but which are<br />
still in use in some other EU countries, particularly when the intended use levels in food are<br />
known or expected to be high.<br />
:*for which some adverse health effects have been reported, either anecdotally, or on the basis<br />
of case reports of intoxication, epidemiological data or any toxicity data from livestock<br />
animals or experimental animals, or for botanicals that closely resemble botanicals which are<br />
known to have caused toxic effects.<br />
:*for which consumption has significantly increased during recent years in Member States.<br />
:*for which there are both limited history of use and toxicity data available, and for which the<br />
intended use levels are expected to be relatively high (e.g. high interest to the food industry).<br />
<br />
Botanical ingredients that are reported to have a low toxic potential, and for which the intended<br />
intake/exposure levels are within the range of intake levels resulting from the European Member<br />
States average diet would be given a low priority.<br />
<br />
'''''CONCLUSIONS AND RECOMMENDATIONS'''''<br />
<br />
A two-level tiered approach for the safety assessment of botanical ingredients intended for use in food<br />
supplements is proposed. This approach consists of a safety assessment based on available knowledge<br />
and a subsequent level in which further testing and/or data are required. It allows the recognition of<br />
presumption of safety without further testing, based on long-term history of use with no reported<br />
adverse effect and with no significant increased exposure. For those botanical ingredients for which a<br />
presumption of safety based on available data cannot be established, it introduces a framework for<br />
assessing their safety, including the types of testing that would be most useful. Recommendations for<br />
prioritising botanicals for safety assessment are also made.<br />
<br />
The Compendium of botanicals reported to contain toxic, addictive, psychotropic or other substances<br />
that may be of concern, is considered to facilitate the assessment by flagging possible safety issues,<br />
and should therefore be considered as an essential part of this guidance document. The Scientific<br />
Committee recommends to maintain it up-to-date, making use of relevant available national lists of<br />
plants and of any other relevant data available, as well as of updated assessments carried out on<br />
botanicals by qualified bodies. The Scientific Committee also recommends to further expand the<br />
Compendium with botanicals not having any market history in Europe in order to prepare the<br />
implementation of the new Novel Food Regulation, which foresees a notification process for<br />
botanicals and botanical preparations having a history of safe use in the third country of origin.<br />
<br />
<br />
'''European Food Safety Authority'''<br />
<br />
''SCIENTIFIC COMMITTEE''<br />
Discussion Paper on “Botanicals and Botanical Preparations widely used<br />
as food supplements and related products: Coherent and Comprehensive<br />
Risk Assessment and Consumer Information Approaches”<br />
<br />
(adopted by written procedure on 23 June 2004)<br />
<br />
1. In view of the fact that botanicals and botanical preparations intended for human<br />
consumption as food supplements and related products are very widely marketed<br />
with a variety of claims, the present discussion paper aims at increasing awareness<br />
of some key issues to improve comprehensiveness and coherence of current<br />
approaches to risk assessment and consumer information on these products.<br />
<br />
2. A large number of botanical materials (e.g. whole, fragmented or cut plants, algae,<br />
fungi, lichens), and botanical preparations obtained from these materials by various<br />
processes (e.g. extraction, distillation, purification, concentration and fermentation)<br />
readily find their way onto the food supplements market. These materials are also<br />
often labelled as natural foods, largely organic, and foods specifically intended to<br />
support sport activities. Personal care products and the so-called “traditional herbal<br />
medicinal products” represent additional sources of exposure of consumers to<br />
botanical products. New products are also emerging, consisting of substances that<br />
commonly occur at low levels in botanical components of the diet, which are then<br />
extracted and re-introduced at much higher levels in specific products.<br />
<br />
3. Botanicals and botanical preparations are widely available to consumers through<br />
several distribution channels in the E.U. and elsewhere. In particular, they are sold<br />
over the counter in pharmacies and can be bought in supermarkets, herbalist’s<br />
shops and other shops, or via the Internet. They are currently available and used in<br />
such a way that they are almost becoming part of the common diet, thus providing<br />
for a significant human exposure from a public health point of view.<br />
<br />
4. There are some general concerns with respect to botanicals and botanical<br />
preparations mainly relating to quality and safety issues:<br />
:*Contamination (both chemical and microbiological) is a documented problem.<br />
It has been associated, for example, with botanical products originating from<br />
Asia. Deaths through poisoning following consumption of such products have<br />
been reported in Europe and the US arising from contamination with heavy<br />
metals, synthetic drugs and other undesirable substances (Ernst, 2002).<br />
Misidentification of plants harvested from the wild is also a continuing<br />
problem. When sales of traditional herbal products remained restricted to<br />
particular ethnic groups, which are familiar with the products and able to exert a<br />
local control on quality, problems were more rarely encountered. The growing<br />
volume of sales in the European Union with products obtained from suppliers<br />
based in Asia or elsewhere and the move towards widespread outlets for the<br />
products of traditional medicine call for more formal pre-marketing assessment<br />
and more stringent controls than the occasional random checks and analyses<br />
often carried out by individual national or local authorities on what is already<br />
out in the market.<br />
:*There is world-wide recognition of potential problems associated with<br />
botanicals and botanical products, not only in terms of safety, but also in terms<br />
of the claimed amounts and stability of the active ingredients. For example, the<br />
US Pharmacopeia, which considers the safety of food supplements as well as<br />
medicines, announced in December 2002 the establishment of an advisory<br />
panel specifically to advice on improving the quality of botanical products.<br />
:*Any efficacy shown by botanical products is usually a product of one or more<br />
plant secondary metabolites. Secondary metabolism responds to stress imposed<br />
by biotic and abiotic factors and, as a consequence, patterns and concentrations<br />
of metabolites can show considerable variation among plants belonging to the<br />
same species and variety. For instance, it is not unusual for metabolites<br />
produced in response to pathogen attack to vary in concentration one thousandfold<br />
over short time periods. While consistency of product is more easily<br />
controlled in cultivated plants, particularly those grown in containment,<br />
collections from the wild make it difficult to ensure that concentrations of<br />
bioactive agents meet specifications and are within safe limits.<br />
:*A very large literature exists on toxic substances naturally-occurring in plants.<br />
Of particular concern are plant products consumed in concentrated forms.<br />
Concerns can relate directly to the toxicological profile of the active agent(s). It<br />
has been the case with kava-kava (Piper methysticum), its withdrawal from the<br />
market being advised recently because of the association of its consumption with acute liver failure (Kraft et al., 2001). In June 2001, the US FDA,<br />
following action by the UK and Australia, advised manufacturers of dietary<br />
supplements to avoid the use of the various types of comfrey (Symphytum spp.)<br />
because of the health concerns associated with the presence of pyrrolizidine<br />
alkaloids. Moreover, since 1993, cases of nephrotoxicity and carcinogenicity<br />
have been reported in Belgium, France and United Kingdom as a result of<br />
inadvertent exposure to Aristolochia species in unlicensed herbal medicines<br />
(EMEA, 2000).<br />
:*Interactions of herbal products with prescription products are well recognised,<br />
although widely under-reported (Ernst, 2000; Sorensen, 2002). In the past,<br />
when such products were usually obtained from outlets run by knowledgeable<br />
individuals, advice on use and contra-indications was often available. Currently,<br />
contra-indications do not usually appear on the labels or any associated<br />
documentation when herbal products are sold through supermarkets and other<br />
retail outlets. Yet, a survey of the available information on interactions with<br />
medicinal compounds of the more commonly purchased botanical products<br />
(e.g. ginkgo, garlic, St. John’s Wort and ginseng) found recorded adverse<br />
interactions for all but Echinacea and saw palmetto (Izzo and Ernst, 2001).<br />
Incidence and severity of effects associated with prescription drug-dietary<br />
supplement interactions in a small group of primary care patients have also<br />
been investigated by Peng et al. (2004); the most common botanical products<br />
included garlic, ginkgo biloba, saw palmetto and ginseng. While most<br />
interactions were judged not to be serious, an incidence of 6% of potentially<br />
severe health consequences was recorded among patients taking at the same<br />
time specific drugs and specific botanical products.<br />
<br />
5. This heterogeneous group of commodities includes products which, mainly<br />
depending on their intended uses and presentations, fall under different Community<br />
regulatory frameworks and for some types of products legal provisions for a<br />
preliminary risk assessment do not exist yet. The main legislations to be considered<br />
in this context are Directive 2002/46/EC on food supplements and Directive<br />
2004/27/EC on traditional herbal medicinal products:<br />
<br />
:*Directive 2002/46/EC foresees the use as food supplements of vitamins and<br />
minerals listed in the Annexes to the Directive. It also allows the use for the<br />
same purpose of still undetermined substances with a nutritional or<br />
physiological effect, but definition of such effects is not provided for.<br />
According to Art. 4, para 8, the European Commission shall produce, not later<br />
than 12 July 2007, a report on the advisability of establishing specific rules,<br />
including, where appropriate, categories of additional vitamins and minerals or<br />
of substances with a nutritional or physiological effect, accompanied by any proposals for amendments to Directive 2002/46/EC**. Thus a regulatory<br />
framework for further developments in this area already exists.<br />
:*Directive 2004/27/EC on “traditional herbal medicinal products” provides for<br />
definitions of (i) traditional herbal medicinal products, (ii) herbal medicinal<br />
products, (iii) herbal preparations and (iv) herbal substances. The directive<br />
introduces a simplified registration procedure, based on “traditional use”, but<br />
ensuring quality and safety as for any other medicinal product. Community lists<br />
will have to be prepared of traditional herbal medicinal products, herbal<br />
preparations and herbal products. On the other hand, traditional herbal<br />
materials, which are authorised for use in medicinal products, will continue to<br />
contribute to the dietary intake of bioactive agents as long as they comply with<br />
the general food regulations and make no medicinal claim.<br />
<br />
6. Also relevant in this context are the Directives 1989/398/EEC and 96/84/EC on<br />
“Food for special purposes” and the Regulation 1997/258/CE on “novel foods” that<br />
provide additional channels for some botanicals and botanical preparations to enter<br />
the food market, and the proposed Directives on “nutritional and health claims” and<br />
“food fortification” at present under consideration by the European Parliament and<br />
Council.<br />
<br />
7. As the market volume expands, so does the need for a better characterisation of<br />
botanicals and botanical preparations, and for harmonising the scientific assessment<br />
of risks from exposure of consumers to these products.<br />
<br />
8. It is important, therefore, from a public health point of view, to achieve a<br />
comprehensive and coherent approach to risk assessment and consumer<br />
information on botanicals and botanical preparations widely present in different<br />
categories of commodities. Such an approach would, in time, overcome the existing<br />
information gaps on many of these products and bring together the fragmentary<br />
provisions for risk assessment on botanicals and botanical preparations in the<br />
current relevant regulations. To this end, the present paper aims at increasing<br />
awareness on these issues and at facilitating a critical analysis of the present<br />
situation. It is intended to lead to a stronger partnership and collaboration among all<br />
the stakeholders who have a role in this important sector.<br />
<br />
9. Although it is not the objective of this discussion paper to provide a detailed<br />
analysis of the way forward, the following reflections address some issues in order<br />
to facilitate an open discussion particularly in the frame of future developments of<br />
the above-mentioned Directive 2002/46/EC:<br />
<br />
:*As systematic information about the range of botanicals and botanical products<br />
present on the market is lacking, consideration could be given, to carrying out a<br />
survey to identify the main product categories currently marketed and a study to<br />
clarify the potential health-related issues that may need to be addressed.<br />
:*In view of the difficulty of compiling a full inventory of botanicals and<br />
botanical products, the possibility could also be considered of adopting and<br />
regularly updating a list of plants or parts of plants which should not be used or<br />
could be put under scrutiny because of the presence of undesirable substances,<br />
especially if effective reduction or removal of such substances can not be<br />
ensured.<br />
:*As purity specifications for all botanicals and botanical preparations are very<br />
difficult to define, the development of ad hoc manufacturing guidelines, could<br />
be considered in order to improve their characterisation and safety. Experience<br />
already existing in the pharmaceutical sector could be helpful to this end.<br />
:*Considering the importance of providing to consumers adequate information to<br />
allow the safe use of botanicals and botanical preparations, the possibility of<br />
establishing accredited information sources easily accessible to consumers on<br />
these products also deserves attention. A complicating issue in this respect is<br />
the diffusion of misleading claims which are very difficult to counterbalance by<br />
means of reliable consumer information. However, in this respect, the situation<br />
is likely to improve when the proposal for a Community Directive providing for<br />
a clear evaluation procedure of “Nutritional and Health Claims” will be<br />
adopted.</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Usability_of_Mediawiki_as_a_collaborative_workspace_for_knowledge_creation&diff=20628
Usability of Mediawiki as a collaborative workspace for knowledge creation
2011-04-19T08:09:23Z
<p>Minttu: </p>
<hr />
<div>{{study|moderator = Tekerane}}<br />
[[op_fi:Mediawikin käytettävyys yhteisenä työympäristönä tiedon keräämiseen]]<br />
<br />
{{summary box|question = <br />
How do the various collaborative elements of Opasnet wiki support knowledge creation?<br />
|answer = <br />
}}<br />
<br />
==Tasks==<br />
<br />
* Refactor the current [[Peer rating]] extension. The new extension system should have two rating bars: scientific quality and usefulness.<br />
<br />
==Methods==<br />
<br />
* Questionnaire to OpasNet users<br />
** Roles of OpasNet users (administrator, researcher, reader, ...)<br />
* Personal research diary<br />
* Interviews, personal communications?<br />
<br />
==Thoughts on scope==<br />
<br />
===Possible issues with the rating system===<br />
<br />
* Do users know how to rate pages? How do they understand the scale of rating?<br />
** Possibility of a "[http://en.wikipedia.org/wiki/Office_Assistant paperclip assistant]" to help users understand the rating system, or encourage them to use it? ("First time here? Learn more about rating bar!")<br />
* Do users bother rating pages? Do users need to be encouraged to rate, do the users notice the rating tools?<br />
* Usability: are the rating tools easy to use and clear?<br />
* What are the benefits of the ratings to the author(s) of the page?<br />
* What are the benefits of the ratings to other users?<br />
<br />
===Discussion tools===<br />
<br />
* The [[Discussion]] tools should be included in the study.<br />
<br />
===Other===<br />
<br />
* Wiki editing conflicts (multiple users editing a page)<br />
* MediaWiki citing markup for sources (if it is somehow relevant)</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Benefit-risk_assessment_of_methyl_mercury_and_omega-3_fatty_acids_in_fish&diff=20566
Benefit-risk assessment of methyl mercury and omega-3 fatty acids in fish
2011-04-14T11:22:22Z
<p>Minttu: </p>
<hr />
<div>[[Category:Fish]]<br />
[[Category:Heavy metals]]<br />
[[Category:Benefit-risk assessment]]<br />
{{assessment|moderator=Olli<br />
| reference = {{publication<br />
| authors = Jouni T. Tuomisto, Olli Leino<br />
| page = Benefit-risk assessment of methyl mercury and omega-3 fatty acids in fish<br />
| explanation = <br />
| publishingyear = 2010<br />
| urn = <br />
| elsewhere = <br />
}}<br />
}} <br />
[[op_fi:Hyöty-riskiarviointi metyylielohopeasta ja omega-3 rasvahapoista kalassa]]<br />
<br />
{{summary box<br />
| question = What are the effects of methyl mercury and omega-3 fatty acids on development of intelligence quotient (IQ) in children? The source of exposure is Finnish fish consumption. <br />
| answer = <br />
* The consumption of oily fish can be increased without a fear of detrimental effects of methyl mercury in the children. In contrast, the consumption of predator fish, especially pike, should be avoided during pregnancy.<br />
* The case seems to be fairly well established, as the total value of additional information is fairly low.<br />
}}<br />
<br />
[[Image:Benefit-risk assessment of methyl mercury and omega-3 fatty acids in fish diagram.png]]<br />
<br />
The [[:Image:Mercury vs omega-3.ANA|Analytica model file]] contains the actual calculations for this assessment.<br />
<br />
This project is planned to serve as a case study to represent the utilization of the [[open assessment]] method. <br />
<br />
== Scope ==<br />
<br />
=== Purpose ===<br />
<br />
What are the effects of methyl mercury and omega-3 fatty acids on development of intelligence quotient (IQ) in children? The source of exposure is Finnish fish consumption. <br />
<br />
=== Boundaries ===<br />
<br />
*Population of Finland <br />
*Current situation<br />
<br />
=== Scenarios ===<br />
<br />
* Business as usual (the current situation).<br />
* Total fish consumption is above the median.<br />
* Total fish consumption is below the median.<br />
* No fish consumption. {{reslink|Potential scenarios}} <br />
<br />
=== Intended users ===<br />
<br />
* Authorities giving food recommendations.<br />
* Anyone interested.<br />
<br />
=== Participants ===<br />
<br />
* [[Beneris]] researchers, especially [[User:Olli|Olli]] and [[User:Patrycja Gradowska|Patrycja Gradowska]].<br />
<br />
== Definition ==<br />
<br />
[[Image:Benefit-risk assessment of methyl mercury and omega-3 fatty acids in fish diagram.png]]<br />
<br />
=== Decision variables ===<br />
<br />
* Fish intake of pregnant mothers in Finland [[:beneris:File:Beneris Food consumption pregnant women FINLAND 300507 th.xls|Unpublished data, requires a password]].<br />
<br />
=== Indicators ===<br />
<br />
*[[Intelligence quotient change in children in Beneris|Intelligence quotient change in children in Beneris]]<br />
<br />
=== Other variables ===<br />
<br />
'''Environmental variables''' <br />
<br />
*[[Concentrations of beneficial nutrients in fish]] <br />
*[[Mercury and methyl mercury concentrations in fish]]<br />
<br />
'''Exposure variables''' <br />
<br />
*[[Domestic fish consumption of the pregnant women in Finland]] (unpublished data, requires a password)<br />
*[[Fish oil intake in Beneris]] <br />
*[[Methyl mercury intake from fish in Beneris]]<br />
<br />
'''Population characteristics''' <br />
<br />
* [[Body weight in Finland]]<br />
* [[Baseline intelligence quotient (IQ) score in children]]<br />
* [[Intelligence quotient (IQ) in children in Beneris]]<br />
<br />
'''Exposure-response functions''' <br />
<br />
*[[ERF of methyl mercury on intelligence quotient]] <br />
*[[ERF of omega-3 fatty acids on intelligence quotient]]<br />
<br />
=== Indices ===<br />
<br />
* Fish (species): Herring, Vendace, Whitefish, Pike, Perch, Salmon, Pike-pearch<br />
* Water (from which the fish comes from): Baltic Sea, Inland lake<br />
* '''NOTE!''' <br />
** Herring is only from the Baltic Sea.<br />
** All pike-pearch is shown as "Inland lake" although a part comes from the Baltic Sea.<br />
** All salmon is shown as "Inland lake" although most of it comes from the Atlantic Ocean from Norway.<br />
<br />
=== Analyses ===<br />
<br />
* What should be done to the total fish intake to keep the net effect of fish on the child's IQ positive?<br />
* For the scenarios "total fish above median" and "total fish below median", what is the [[VOI]] for different [[variable]]s?<br />
<br />
== Result ==<br />
<br />
=== Results ===<br />
<br />
NOTE! Average DHA and methylmercury exposure leads to zero impact compared with the background IQ.<br />
<br />
[[image:Benefit-risk assessment of methyl mercury and omega-3 fatty acids in fish.png]]<br />
<br />
The top graph shows the distribution of changed IQ in the child due to fish consumption of the pregnant mother in Finland (compared with the situation without any fish consumption). The lower graph shows the result of the first analysis: what should the fish intakes be to ensure that the IQ of the child does not decrease? The lower panel of the lower graph lists each species (leftmost column), the central column shows the intake of that species in the current situation, and the rightmost column shows the intake in the hypothetical situation where no IQ loss may occur. From the graph, it can be seen that to reach the objective, <br />
* Atlantic salmon could be eaten more,<br />
* there is no need to change the intake of Baltic herring,<br />
* vendace, whitefish, and perch intakes could be slightly reduced during pregnancy,<br />
* pike intake should be clearly reduced during pregnancy,<br />
* there is not enough information to conclude anything about pike-perch.<br />
<br />
[[Image:Benefit-risk assessment of methyl mercury and omega-3 fatty acids in fish VOI.png]]<br />
<br />
The [[value of information]] analysis shows that for the decision "increase the total fish intake above the current median versus reduce it below the median", there is theoretically 0.02 IQ points per child to be gained if more information would be available. The further information needs are mainly about the most consumed fish species, namely herring and salmon. More should be known about both DHA and methyl mercury.<br />
<br />
===Conclusions===<br />
<br />
* The consumption of oily fish can be increased without a fear of detrimental effects of methyl mercury in the children. In contrast, the consumption of predator fish, especially pike, should be avoided during pregnancy.<br />
* The case seems to be fairly well established, as the total value of additional information is fairly low.<br />
<br />
==See also==<br />
<br />
Fish-related assessments:<br />
* [[Benefit-risk assessment of fish consumption for Beneris]]<br />
* [[Benefit-risk assessment of methyl mercury and omega-3 fatty acids in fish]]<br />
* [[Benefit-risk assessment on farmed salmon]]<br />
<br />
==References==<br />
<br />
<references/><br />
[[Category:Beneris]]<br />
[[Category:THL publications 2010]]</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Assessment_of_building_policies%27_effect_on_dampness_and_asthma_in_Europe&diff=20555
Assessment of building policies' effect on dampness and asthma in Europe
2011-04-14T09:33:29Z
<p>Minttu: </p>
<hr />
<div>[[Category:Indoor air]]<br />
[[Category:Intarese]]<br />
[[Category:Mega case study]]<br />
[[Category:THL publications 2011]]<br />
{{assessment|moderator=Teemu R<br />
| reference = {{publication<br />
| authors = Teemu Rintala, Jouni T. Tuomisto<br />
| page = Dampness and asthma<br />
| explanation = An assessment of building policies' effect on dampness and asthma in Europe<br />
| publishingyear = 2011<br />
| urn = <br />
| elsewhere = <br />
}}<br />
}}<br />
[[op_fi:Arviointi rakennuspolitiikan vaikutuksista kosteusvaurioihin ja astmaan Euroopassa]]<br />
{{summary box<br />
|question = Dampness and mould in homes is a major environmental health hazard causing asthma and allergic or respiratory symptoms. Good building policies can reduce dampness in homes. What are the effects of different plausible building policies on dampness in homes and consequently on asthma prevalence in Europe between 2010 and 2050?<br />
|answer = There are currently 1.7 million (95 % CI 0.8 - 2.9 million) cases of asthma due to indoor dampness in Europe. This number is likely to increase in the future due to decreased ventilation in aim to reduce energy consumption, if other measures are not taken. It is important to maintain good air exchange and humidity conditions even when energy saving measures are taken. More should be known about determinants of dampness-related health problems to be able to design climate-friendly building policies that also reduce dampness in homes.}}<br />
<br />
==Scope==<br />
<br />
In this study, the research question was the following: What are the effects of different building policies on dampness and mould in residential buildings, and consequently on asthma prevalence in Europe? The building policies considered aim at reducing greenhouse gas emissions and thus mitigate climate change. We looked specifically at years 2010, 2020, 2030, and 2050 in the European Union. The study was performed as an [[open assessment]] in the internet as a part of the so called Common Case Study of INTARESE and HEIMTSA projects. A technical objective was to test feasibility of web workspace and on-line modelling tools developed in the projects.<br />
<br />
===Boundaries===<br />
<br />
'''Boundaries, scenarios, intended users, and participants''' are the same as in the [[Mega case study|Common Case Study]]. In brief, the situation is assessed in [[EU-30]] (the current 27 EU member states plus Norway, Iceland, and Switzerland) for the next forty years. Four scenarios are considered: 1) '''BAU''': business as usual contains the implementation of already made decisions but no further actions; 2) '''ALL''': all such policies are implemented that are required to reduce the total greenhouse gas emissions by 70 % by 2050; 3) '''INSULATION''': only building insulation policies from ALL are implemented (ALL also contains policies to increase biomass use, but these are not implemented here); 4) '''RENOVATION''': same as ALL except that ventilation is not improved in 50 % of those buildings that are insulated up to tighter standards (in other scenarios, insulation is always combined with improved ventilation).<br />
<br />
==Rationale==<br />
<br />
[[image:HIA of dampness in Europe.png|thumb|400 px|A causal diagram of health effects of dampness in Europe.]]<br />
The assessment is based on a causal model presented in the figure. Each node in the graph (also called a variable in the model) are described in more detail elsewhere; only a summary of the model is presented here.<br />
<br />
'''Building policies'''<br />
<br />
[[Building policies in Europe|European building policies]] described above are considered. The aim of the policies is to mitigate climate change by reducing greenhouse gas emissions from heating and cooling of buildings. In this sub-assessment, we do not consider greenhouse gas emissions or climate impacts, but only health impacts occurring as collateral damages or benefits. The purpose of the assessment is to estimate the impacts of each building policy and identify those policies that produce the best health outcomes. <br />
<br />
'''Exposure estimation'''<br />
<br />
The logic of the assessment is that the climate change mitigation policies considered affect [[:heande:HI:Air exchange rate for European residences|air exchange rates in buildings]]. It is expected that [[:heande:Moisture damage|moisture problems]] become more likely if the air exchange decreases. Nation-wide dampness estimates were obtained from several studies reviewed in this sub-assessment (http://heande.opasnet.org/wiki/Moisture_damage). However, several countries (Luxembourg, Netherlands, Switzerland, Ireland, Norway, United Kingdom, Bulgaria, Hungary, Lithuania, Romania, Slovakia, Slovenia, Malta) were rejected due to lack of data. <br />
<br />
'''Health impact estimation<br />
<br />
[[Asthma prevalence due to building dampness in Europe|Asthma prevalence]] (number of asthma cases) attributable to indoor problems due to residential mould or dampness was chosen as the outcome of interest for two reasons. First, there are plausible information about the causal association between dampness and asthma; second, asthma is a fairly common and severe disease, and therefore it is likely that focusing on this single endpoint can produce a reasonable estimate about the total magnitude of the problem. <br />
<br />
The current scientific epidemiological literature contains plausible exposure-response functions for the [[ERF of indoor dampness on respiratory health effects|association of moisture problems and asthma]]. In this assessment, number of current asthma cases (i.e., prevalence) is used as the outcome indicator. The current exposure-response estimate is 1.56 (odds ratio OR) for current asthma risk (prevalence) due to existing dampness problem (Fisk et al., 2007).<br />
<ref>W. J. Fisk, Q. Lei-Gomez, M. J. Mendell. Meta-analyses of the associations of respiratory health effects with dampness and mold in homes. Indoor Air 2007; 17: 284–296. {{doi|10.1111/j.1600-0668.2007.00475.x}}</ref><br />
Linear no-threshold exposure-response function was assumed for the whole population in each country.<br />
<br />
The prevalence of dampness-induced asthma depends also on the [[Asthma prevalence|background prevalence of asthma]] and the [[Population of Europe by Country|population size]]. Asthma and population size differ by country and the population also changes in time. However, the determinants of asthma are not known well enough to predict time trends into the future and so the asthma background is assumed constant in time in this assessment.<br />
<br />
'''Policy evaluation<br />
<br />
Finally, the asthma prevalence under each policy scenario are compared and optimum scenario found. It should be noted, however, that this sub-assessment only has a very narrow view on all impacts of the policies and therefore it cannot be used as an ultimate guidance for policy selection. Instead, this sub-assessment gives important information for the [[Mega case study|Common Case Study]] as a whole, which may produce such overall conclusions.<br />
<br />
'''Impacts<br />
<br />
For overall conclusions, it is crucial that the impacts observed in a sub-assessment can be compared with other impacts observed in other sub-assessment. To this aim, we expressed the outcome using two alternative summary indicators: disability-adjusted life years (DALY) and euros (€). DALYs are computed by multiplying the number of cases of a disease with a respective [[Disability weights|disability or severity weight]] and the duration of the disease. The idea is to measure the overall healthy years that are lost due to several diseases. The disability weight (estimated by WHO) for a treated asthma case is 0.059.<br />
<br />
'''Monetary valuation<br />
<br />
The costs of diseases include direct costs of treatment, indirect costs due to loss of productivity (absence from work), and willingness of a person to pay extra to avoid the disease. Because the monetary estimation of impacts was not the main objective in this sub-assessment, we did not go through this laborious path. Instead, we simply assumed that the DALY estimate also provides a reasonable indicator of all monetary costs of the asthma cases. Thus, we multiplied the DALY estimate with an estimate of [[DALY to money conversion|willingness to pay to avoid a loss of one healthy life year]]. This has typically been in the order of 30000 - 60000 euros per saved life year. This results in a preliminary estimate of monetary impact, which can be used in comparisons in other parts of the [[Mega case study|Common Case Study]] and the value of information analysis (see below).<br />
<br />
A methodological objective was a proof of concept for running assessment models via open internet interface. Therefore, the model development, data storage, and model runs were all performed in Opasnet using R software and Opasnet Base. The main page of the sub-assessment is http://en.opasnet.org/w/Dampness_and_asthma . <br />
<br />
===Analyses===<br />
<br />
Two analyses were performed in the sub-assessment. First, the main analysis was the optimisation of the health impact across different policy options as described before. Second, a value of information analysis was performed based on the monetary impact estimates.<br />
<br />
[[Value of information]] is a statistical method that estimates the largest sum of money a decision maker should be willing to pay to be able to reduce uncertainty in the decision before actually making the decision. The analysis is based on the idea that even if one of the options looked the best based on the expected value of impact, it is possible that, due to uncertainties described in the decision model, in some cases some other option could actually be the best. The decision maker would be better off, if she could do more research, reduce the uncertainty and actually find out whether the alternative indeed turns out to be better. The beauty of [[value of information analysis]] is that it can be performed before the decision, but more importantly, before any further research is done. If the value of information analysis shows low value, the decision maker can decide now with only a low probability of regret afterwards. On the other hand, if it shows high value, the decision-maker would be better off if she postponed the actual decision and put effort in further research and analysis (assuming that such work is feasible).<br />
<br />
==Result==<br />
<br />
===Results===<br />
<br />
[[Asthma prevalence due to building dampness in Europe]]: {{#opasnet_base_link:Op_en4723}}<br />
<ref>Results for the Biomass scenario [[:heande:Air exchange rate for European residences#Definition|are wrong]] and the scenario is perhaps irrelevant in this sub-assessment, because biomass usage does not affect air exchange rates. So, it is ignored in the results although it was a part of the [[Mega case study|Common Case Study]]. </ref><br />
<br />
[[Image:European_building_policy_impact_on_asthma.png|thumb|The impacts of European building policies on asthma attributable to residential building dampness.]]<br />
<br />
[[Image:E.b.p. impact on asthma distributions.png|thumb|Result distributions.]]<br />
<br />
[[Image:E.b.p. impact on asthma EVPI.png|thumb|[[Value of information]] analysis result (EVPI).]]<br />
<br />
{|{{prettytable}}<br />
|+'''Asthma cases (prevalence) in Europe due to residential building dampness (mean and 95% confidence interval).'''<br />
! !!colspan="4"|Year<br />
|----<br />
!Policy!!2010!!2020!!2030!!2050<br />
|----<br />
|BAU || 1715846 (794208-2918407) || 2069089 (929518-3645690) || 2300513 (1007103-4193891) || 2417413 (1016202-4559645)<br />
|----<br />
|All || NA || 2071501 (940391-3650210) || 2634778 (1139578-4745158) || 3009693 (1251020-5519308)<br />
|----<br />
|Insulation || NA || NA || NA || 3002498 (1239186-5524389)<br />
|----<br />
|Renovation || NA || NA || NA || 3416010 (1443227-6233562)<br />
|----<br />
|}<br />
<br />
{|{{prettytable}}<br />
|+'''Asthma DALYs in Europe due to residential building dampness (mean and 95% confidence interval).'''<br />
! !!colspan="4"|Year<br />
|----<br />
!Policy!!2010!!2020!!2030!!2050<br />
|----<br />
|BAU || 101235 (46858-172186) || 122076 (54842-215096) || 135730 (59419-247440) || 142627 (59956-269019)<br />
|----<br />
|All || NA || 122219 (55483-215362) || 155452 (67235-279964) || 177572 (73810-325639)<br />
|----<br />
|Insulation || NA || NA || NA || 177147 (73112-325939)<br />
|----<br />
|Renovation || NA || NA || NA || 201545 (85150-367780)<br />
|----<br />
|}<br />
<br />
{|{{prettytable}}<br />
|+'''Asthma monetary impact (based on DALYs) in Europe due to residential building dampness (mean and 95% confidence interval). Unit: M€'''<br />
! !!colspan="4"|Year<br />
|----<br />
!Policy!!2010!!2020!!2030!!2050<br />
|----<br />
|BAU || 4552 (2065-7861) || 5478 (2464-9800) || 6105 (2617-11307) || 6404 (2622-12279)<br />
|----<br />
|All || NA || 5491 (2434-9869) || 7012 (2981-13005) || 7989 (3285-14872)<br />
|----<br />
|Insulation || NA || NA || NA || 7995 (3244-15283)<br />
|----<br />
|Renovation || NA || NA || NA || 9059 (3827-16881)<br />
|----<br />
|}<br />
<br />
{| {{prettytable}}<br />
|+ '''Asthma cases (prevalence) attributable to residential building dampness in Europe in 2010.<br />
! Country of observation!! Mean!! SD<br />
|----<br />
|| Austria|| 23958|| 19818<br />
|----<br />
|| Belgium|| 46983|| 24769<br />
|----<br />
|| Cyprus|| 3010|| 706<br />
|----<br />
|| Czech Republic|| 65640|| 31215<br />
|----<br />
|| Denmark|| 9088|| 6502<br />
|----<br />
|| Estonia|| 8188|| 2735<br />
|----<br />
|| Finland|| 10881|| 17198<br />
|----<br />
|| France|| 303354|| 161230<br />
|----<br />
|| Germany|| 379346|| 221077<br />
|----<br />
|| Greece|| 20517|| 7842<br />
|----<br />
|| Italy|| 279127|| 99106<br />
|----<br />
|| Latvia|| 11991|| 3158<br />
|----<br />
|| Poland|| 270064|| 49342<br />
|----<br />
|| Portugal|| 48477|| 18082<br />
|----<br />
|| Spain|| 226670|| 93709<br />
|----<br />
|| Sweden|| 20039|| 24323<br />
|----<br />
! Total!! 1715846|| <br />
|----<br />
|}<br />
<br />
===Conclusions===<br />
<br />
There are currently 1.7 million (95 % CI 0.8 - 2.9 million) cases of asthma due to indoor dampness in Europe. This number is likely to increase in the future due to decreased ventilation in aim to reduce energy consumption, if other measures are not taken. It is important to maintain good air exchange and humidity conditions even when energy saving measures are taken. It is important to maintain good air exchange and humidity conditions even when energy saving measures are taken. <br />
<br />
The value of information analysis showed that further information is worth about 500 to 1000 million euros. In this assessment, all of the value goes into the most critical issue, namely the impacts of policy on dampness prevalence, which in this assessment was modelled by using air exchange rate. Of course, some dampness problems are not related to air exchange at all, so focussing on that specific topic will not be the optimal solution. Instead, wide and robust understanding is needed about why harmful dampness occurs and what can be done to repair such problems and especially to prevent them in advance. A thorough examination of current knowledge was not done in this assessment. It seems obvious that collecting and organising existing information is a cost-effective way to reduce uncertainty in this issue, because that would cost only a small fraction of the value of that information according to this assessment.<br />
<br />
In theory, the reasons for hazardous microbial growth and mould in building structures are simple: if there is constant moisture, microbes start growing. Therefore, buildings should be built and repaired to avoid moisture. However, the issue is much more complex in practice. <br />
<br />
Even if there is moisture and microbial growth, it is sometimes very harmful to health but sometimes less harmful; determinants of this are poorly understood. In many cases, dampness is invisible and the building owner is unaware of the problem. Also, many owners are unaware of risks of dampness and ignore the problem. Even if the problems is acknowledged, there may be insufficient expertise or resources to repair the problem. Further on, the building industry has varying expertise and capability to build such buildings where typical dampness risks are managed beforehand. Especially, there are limited knowledge and expertice on moisture control of highly energy efficient buildings. And finally, the changing climate is likely to cause problems that were not anticipated at the time when buildings were built.<br />
<br />
In conclusion, more should be known about determinants of dampness-related health problems and moisture control of highly energy efficient buildings to be able to design climate-friendly building policies that also reduce dampness in homes.<br />
<br />
==R code for detailed analysis==<br />
<br />
*This code features [[R]] functions described on [[Opasnet Base Connection for R]] and [[Operating intelligently with multidimensional arrays in R]]. <br />
<br />
<nowiki>library(ggplot2)<br />
asthma <- op_baseGetData("opasnet_base", "Op_en4723", exclude = 48823)<br />
array <- DataframeToArray(asthma)<br />
array <- array[,,,c(2,1,3,4),,]<br />
##### Cases #####<br />
means <- apply(array, c(2,3,4), mean, na.rm=TRUE)<br />
means <- apply(means, c(2,3), sum, na.rm=TRUE)<br />
plot1 <- as.data.frame(as.table(means))<br />
plot1 <- ggplot(plot1[plot1[,"Freq"]!=0,], aes(Year, weight=Freq, fill=Policy)) + geom_bar(position="dodge") + <br />
scale_x_discrete("Year") + scale_y_continuous("Cases")<br />
plot1<br />
ci <- apply(apply(array, c(1,3,4), sum, na.rm=TRUE), c(2,3), quantile, probs=c(0.025,0.975))<br />
final1 <- means<br />
final1[,] <- paste(round(means), " (", round(ci[1,,]), "-", round(ci[2,,]), ")", sep="")<br />
final1[c(2:4,7:8,11:12)] <- NA<br />
final1<br />
##### DALYs #####<br />
DALY <- array*0.059<br />
means <- apply(DALY, c(2,3,4), mean, na.rm=TRUE)<br />
means <- apply(means, c(2,3), sum, na.rm=TRUE)<br />
plot2 <- as.data.frame(as.table(means))<br />
plot2 <- ggplot(plot2[plot2[,"Freq"]!=0,], aes(Year, weight=Freq, fill=Policy)) + geom_bar(position="dodge") + <br />
scale_x_discrete("Year") + scale_y_continuous("DALYs")<br />
plot2<br />
ci <- apply(apply(DALY, c(1,3,4), sum, na.rm=TRUE), c(2,3), quantile, probs=c(0.025,0.975))<br />
final2 <- means<br />
final2[,] <- paste(round(means), " (", round(ci[1,,]), "-", round(ci[2,,]), ")", sep="")<br />
final2[c(2:4,7:8,11:12)] <- NA<br />
final2<br />
##### Cost #####<br />
mpdaly <- op_baseGetData("opasnet_base", "Op_en4858")<br />
cost <- IntArray(mpdaly, DALY, "DALYs")<br />
cost <- data.frame(cost[,c("obs","Country","Policy","Year")], Result=cost[,"Result"]*cost[,"DALYs"])<br />
cost <- DataframeToArray(cost)<br />
cost <- cost[,,c(2,1,3,4),]<br />
means <- apply(cost, c(2,3,4), mean, na.rm=TRUE)<br />
means <- apply(means, c(2,3), sum, na.rm=TRUE)/10^6<br />
plot3 <- as.data.frame(as.table(means))<br />
plot3 <- ggplot(plot3[plot3[,"Freq"]!=0,], aes(Year, weight=Freq, fill=Policy)) + geom_bar(position="dodge") + <br />
scale_x_discrete("Year") + scale_y_continuous("Cost (M€)")<br />
plot3<br />
ci <- apply(apply(cost, c(1,3,4), sum, na.rm=TRUE), c(2,3), quantile, probs=c(0.025,0.975))/10^6<br />
final3 <- means<br />
final3[,] <- paste(round(means), " (", round(ci[1,,]), "-", round(ci[2,,]), ")", sep="")<br />
final3[c(2:4,7:8,11:12)] <- NA<br />
final3<br />
##### Probability density plot #####<br />
costdf <- as.data.frame(as.table(apply(cost, c(1,3,4), sum)/1e9))<br />
costdf <- costdf[is.na(costdf[,"Freq"])==FALSE,]<br />
plot4 <- ggplot(costdf, aes(x=Freq, y=..density.., fill=Policy)) + geom_density(alpha=0.2, adjust=4) + <br />
scale_x_continuous(expression("Cost ("*10^9*"€)")) + scale_y_continuous("Density") + facet_wrap(~Year)<br />
plot4<br />
##### Expected Value of Perfect Information #####<br />
evpi <- (apply(apply(cost, c(2,3,4), mean, na.rm=TRUE), c(1,3), min, na.rm=TRUE) - apply(apply(cost, c(1,2,4), min, <br />
na.rm=TRUE), c(2,3), mean, na.rm=TRUE))/1e6<br />
plot5 <- as.data.frame(as.table(apply(evpi, 2, sum)))<br />
plot5 <- ggplot(plot5, aes(Var1, weight=Freq)) + geom_bar(position="dodge") + <br />
scale_x_discrete("Year") + scale_y_continuous("Value of perfect information (M€)")<br />
plot5<br />
##### Expected Value of Partial Perfect Information #####<br />
#Same as that of perfect information, because of only one decision variable <br />
#and one intermediate variable that could make a difference.<br />
ae <- op_baseGetData("opasnet_base", "Erac2499")<br />
aer <- DataframeToArray(ae)<br />
aer <- aer[,,c(2,1,4,5),]<br />
dropnonmax <- function(x) {<br />
x[x<max(x, na.rm = TRUE)] <- NA<br />
return(x)<br />
}<br />
aer <- apply(aer, c(1,2,4), dropnonmax)<br />
aer <- as.data.frame(as.table(aer))<br />
aer <- aer[,c(2,3,1,4,5)]<br />
colnames(aer)[3] <- "Policy"<br />
aer <- aer[is.na(aer[,"Freq"])==FALSE,]<br />
aer <- IntArray(aer, cost, "Cost")<br />
aer <- DataframeToArray(aer[,c("obs","Country","Year","Cost")],"Cost")<br />
test2 <- (apply(apply(cost, c(2,3,4), mean, na.rm=TRUE), c(1,3), min, na.rm=TRUE) - apply(aer, c(2,3), mean))/1e6<br />
plot6 <- as.data.frame(as.table(apply(test2, 2, sum)))<br />
plot6 <- ggplot(plot6, aes(Var1, weight=Freq)) + geom_bar(position="dodge") + <br />
scale_x_discrete("Year") + scale_y_continuous("Value of perfect information (M€)")<br />
plot6<br />
test2==evpi #test whether the values are the same</nowiki><br />
<br />
==See also==<br />
<br />
The parts of the sub-assessment model about dampness and asthma.<br />
;Decision variables<br />
*[[Building policies in Europe]]<br />
<br />
;Other variables<br />
*[[Population of Europe by Country]]<br />
*[[Asthma prevalence]]<br />
*[[:heande:HI:Air exchange rate for European residences]]<br />
*[[:heande:Moisture damage]]<br />
*[[ERF of indoor dampness on respiratory health effects]]<br />
*[[Disability weights]]<br />
*[[DALY to money conversion]]<br />
<br />
;Indicators<br />
*[[Asthma prevalence due to building dampness in Europe]]<br />
<br />
You can also click the nodes on the graph to go to pages with more detailed description about that topic.<br />
<br />
<imagemap><br />
Image:HIA of dampness in Europe.png|<br />
<br />
rect 22 25 215 149 [[Building policies in Europe]]<br />
rect 23 169 214 289 [[heande:HI:Air exchange rate for European residences]]<br />
rect 24 317 215 440 [[ERF of indoor dampness on respiratory health effects]]<br />
rect 245 168 436 291 [[heande:Moisture damage]]<br />
rect 247 318 428 434 [[Asthma prevalence due to building dampness in Europe]]<br />
rect 472 172 662 290 [[Population of Europe by Country]]<br />
rect 472 319 661 439 [[Asthma prevalence]]<br />
<br />
desc bottom-left<br />
</imagemap><br />
<br />
==Keywords==<br />
<br />
Dampness, indoor air, asthma, Europe<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
==Related files==<br />
<br />
{{mfiles}}</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Benefit-risk_assessment_on_farmed_salmon&diff=20378
Benefit-risk assessment on farmed salmon
2011-04-11T08:46:39Z
<p>Minttu: </p>
<hr />
<div>[[Category:Fish]]<br />
[[Category:Benefit-risk assessment]]<br />
[[Category:Persistent organic pollutants]]<br />
[[Category:Cancer]]<br />
[[Category:Cardiovascular disease]]<br />
{{assessment|moderator=Jouni}}<br />
[[op_fi:Hyöty-riskiarviointi viljellystä lohesta]]<br />
<br />
{{summary box|question = <br />
Is the recommendation about not to eat farmed salmon because of its persistent pollutants justifiable based on public health considerations?<br />
|answer = <br />
* Pollutant risk is much smaller than the net health benefit of farmed salmon<br />
* Scientific uncertainties related to recommendations are unimportant<br />
* Some scientific and political uncertainties related to feed limits are important<br />
}}<br />
<br />
[[image:Farmed salmon assessment.PNG|thumb|center|400px|Causal diagram of the farmed salmon assessment.]]<br />
<br />
==Scope==<br />
<br />
===Purpose===<br />
<br />
'''The purpose''' of the assessment is to evaluate the recommendation given by Hites et al <ref name=hites>R. A. Hites et al. Global assessment of organic contaminants in farmed salmon. Science, 9 Jan. 2004, p. 226</ref> that people should not eat farmed salmon too often because of the pollutant concentrations. <br />
<br />
Is the recommendation about not to eat farmed salmon because of its persistent pollutants justifiable based on public health considerations?<br />
<br />
===Boundaries===<br />
<br />
* Pollutants: Toxaphene, dieldrin, PCB<br />
* Nutrients: Omega-3 fatty acids<br />
* Health impacts: <br />
** Total cancer caused by pollutants<br />
** Cardiovascular deaths and the impact of omega-3 fatty acids<br />
* Population: the population of Western Europe (European Economic Area as of beginning of 2004)<br />
* Current situation (year 2004)<br />
<br />
===Scenarios===<br />
<br />
* Recommendation for not to eat farmed salmon too often (yes/no)<br />
* Setting up new stricter regulations about pollutants in fish feed (yes/no)<br />
<br />
===Intended users===<br />
<br />
* The primary users are public health authorities and decision-makers involved in giving food recommendations.<br />
* The secondary user group is the general public. Quantitative estimates are offered to increase understanding of the magnitudes of the related issues.<br />
<br />
===Participants===<br />
<br />
The assessment is restricted to a group of environmental health researchers. See participant list in [[Farmed salmon (project)]].<br />
<br />
==Definition==<br />
<br />
<imagemap><br />
image:Farmed salmon assessment.PNG|<br />
<br />
rect 348 120 501 186 [[Variable:Recommendation for consumption of farmed salmon]]<br />
rect 232 120 329 185 [[Variable:Pollutant concentration limits for fish feed]]<br />
rect 117 129 217 177 [[Variable:Persistent pollutant concentrations in fish feed]]<br />
rect 119 190 218 242 [[Variable:Persistent pollutant concentrations in salmon]]<br />
rect 271 191 371 244 [[Variable:Salmon intake in the population of the Western Europe]]<br />
rect 416 186 512 251 [[Variable:Omega-3 content in salmon]]<br />
rect 206 257 305 305 [[Variable:Exposure to persistent pollutants due to salmon in the population of the Western Europe]]<br />
rect 335 256 433 305 [[Variable:Omega-3 intake due to salmon in the population of the Western Europe]]<br />
rect 87 292 185 393 [[Variable:Dose-response function of persistent pollutants]]<br />
rect 208 320 306 369 [[Variable:Pollutant health risk due to the consumption of salmon]]<br />
rect 337 319 433 368 [[Variable:Cardiovascular effects of omega-3 in salmon in the Western Europe]]<br />
rect 454 301 552 387 [[Variable:Dose-response function of cardiovascular effects of omega-3 fatty acids]]<br />
rect 86 394 186 457 [[Variable:Total mortality in the Western Europe]]<br />
rect 271 391 371 441 [[Variable:Net health effects due to the consumption of salmon]]<br />
rect 455 392 553 458 [[Variable:Cardiovascular mortality in the Western Europe]]<br />
<br />
desc bottom-left<br />
</imagemap><br />
{{Farmed salmon assessment}}<br />
<br />
===Analyses===<br />
<br />
* Value of information analyses<br />
** Outcome: Net health effect; Decision: Recommend restricted farmed salmon consumption?; Variables tested: all<br />
** Outcome: Net health effect; Decision: Lower limits for pollutants in fish feed?; Variables tested: all<br />
* Importance analyses<br />
** Outcome: Mortality by recommendation; Variables tested: all<br />
** Outcome: Mortality by feed regulation; Variables tested: all<br />
<br />
==Result==<br />
<br />
===Results===<br />
<br />
The main results and conclusions have been published by Tuomisto et al.<ref>Tuomisto JT, Tuomisto J, Tainio M, Niittynen M, Verkasalo P, Vartiainen T, Kiviranta H, Pekkanen J. Risk-benefit analysis of eating farmed salmon. Science. 2004 Jul 23;305(5683):476-7 [http://www.sciencemag.org/cgi/content/full/305/5683/476 Read the article]</ref><br />
<br />
Figure. Benefits and risks (number of avoided deaths per year) of eating farmed salmon in Western Europe.<br />
<br />
[[Image:Benefit-risk diagram for farmed salmon.PNG]]<br />
<br />
Table: Net health impacts (avoided deaths per year) of eating farmed salmon in Western Europe. The results include the health impacts of the total health impact of omega-3 intake from salmon.<br />
<br />
{| {{prettytable}}<br />
|Statistics or fractile<br />
|Business as usual<br />
|Recommend restrictions<br />
|Stricker rules for feed<br />
|Both<br />
|----<br />
|Mean<br />
|31062<br />
|22929<br />
|31428<br />
|23296<br />
|----<br />
|SD<br />
|22650<br />
|17105<br />
|22842<br />
|17317<br />
|----<br />
|0.01<br />
|576<br />
|404<br />
|653<br />
|460<br />
|----<br />
|0.025<br />
|1782<br />
|1286<br />
|1847<br />
|1356<br />
|----<br />
|0.05<br />
|3632<br />
|2697<br />
|3766<br />
|2803<br />
|----<br />
|0.25<br />
|14547<br />
|10590<br />
|14780<br />
|10793<br />
|----<br />
|0.5 (Median)<br />
|25187<br />
|18504<br />
|25479<br />
|18829<br />
|----<br />
|0.75<br />
|43064<br />
|31526<br />
|43628<br />
|32091<br />
|----<br />
|0.95<br />
|76141<br />
|56697<br />
|77010<br />
|57393<br />
|----<br />
|0.975<br />
|88267<br />
|66397<br />
|89040<br />
|67249<br />
|----<br />
|0.99<br />
|101832<br />
|79328<br />
|102202<br />
|80143<br />
|----<br />
|}<br />
<br />
Table: Net health impacts (avoided deaths per year) of eating farmed salmon in Western Europe, compared with the business-as-usual scenario. The results include the health impacts of the total health impact of omega-3 intake from salmon. <br />
<br />
{| {{prettytable}}<br />
|Statistics or fractile<br />
|Business as usual<br />
|Recommend restrictions<br />
|Stricter rules for feed<br />
|Both<br />
|----<br />
|Mean<br />
|0<br />
| -8133<br />
|366<br />
| -7766<br />
|----<br />
|SD<br />
|0<br />
|9703<br />
|982<br />
|9637<br />
|----<br />
|0.01<br />
|0<br />
| -45895<br />
| -2335<br />
| -45557<br />
|----<br />
|0.025<br />
|0<br />
| -35624<br />
| -1662<br />
| -35171<br />
|----<br />
|0.05<br />
|0<br />
| -27745<br />
| -1155<br />
| -27041<br />
|----<br />
|0.25<br />
|0<br />
| -10929<br />
| -60<br />
| -10553<br />
|----<br />
|0.5 (Median)<br />
|0<br />
| -4876<br />
|264<br />
| -4560<br />
|----<br />
|0.75<br />
|0<br />
| -1567<br />
|820<br />
| -1307<br />
|----<br />
|0.95<br />
|0<br />
| -112<br />
|2117<br />
|147<br />
|----<br />
|0.975<br />
|0<br />
| -10<br />
|2635<br />
|459<br />
|----<br />
|0.99<br />
|0<br />
|14<br />
|3180<br />
|995<br />
|----<br />
|}<br />
<br />
Figure. Value of information (VOI) calculated as avoided deaths per year in Western Europe. The first two bars are for the decision about recommending restrictions to salmon consumption. No single variable was important enough to gain any VOI; therefore, only the uncertain variable emphasized by Hites<ref name=hites>R. A. Hites et al. Global assessment of organic contaminants in farmed salmon. Science, 9 Jan. 2004, p. 226</ref> is shown. The other bars are for the decision about setting stricter limits for fish feed.<br />
<br />
[[Image:VOI analysis for farmed salmon.PNG]]<br />
<br />
===Conclusions===<br />
<br />
* Pollutant risk is much smaller than the net health benefit of farmed salmon<br />
* Scientific uncertainties related to recommendations are unimportant<br />
* Some scientific and political uncertainties related to feed limits are important<br />
<br />
==See also==<br />
<br />
Fish-related assessments:<br />
* [[Benefit-risk assessment of fish consumption for Beneris]]<br />
* [[Benefit-risk assessment of methyl mercury and omega-3 fatty acids in fish]]<br />
* [[Benefit-risk assessment on farmed salmon]]<br />
* [http://fairquestions.typepad.com/fishfarmfuss/2010/02/letter-to-the-aaas.html?utm_source=Aquafeed+English+Newsletter&utm_campaign=f0479b3a1a-Aquafeed_Newsletter_03-11-10&utm_medium=email On open letter by Vivian Krause]: "It does not appear to me that [http://www.ncbi.nlm.nih.gov/pubmed/14716013 Hites et al. (2004)] and [http://www.ncbi.nlm.nih.gov/pubmed/18079401 Krkosek et al. (2007)] were published in SCIENCE on the basis of scientific merit."<br />
<br />
==References==<br />
<br />
<references/><br />
[[Category:Dioxins]]</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Health_impact_of_radon_in_Europe&diff=20179
Health impact of radon in Europe
2011-04-08T12:44:53Z
<p>Minttu: </p>
<hr />
<div>[[heande:Radon]] <br />
[[Category:Radon]] <br />
[[Category:Indoor air]]<br />
[[Category:Intarese]]<br />
[[Category:Mega case study]]<br />
[[Category:THL publications 2011]]<br />
{{assessment|moderator=Teemu R<br />
| reference = {{publication<br />
| authors = Teemu Rintala, Jouni T. Tuomisto<br />
| page = Health impact of radon in Europe<br />
| explanation = <br />
| publishingyear = 2011<br />
| urn = <br />
| elsewhere = <br />
}}<br />
}}<br />
[[op_fi:Radonin terveysvaikutukset Euroopassa]]<br />
{{summary box<br />
|question = Radon gas in homes is a major environmental health hazard causing lung cancer. Good building policies can reduce radon concentrations in indoor air in homes. What are the effects of different plausible building policies on radon in homes and consequently on lung cancer mortality in Europe between 2010 and 2050?<br />
|answer = There are currently 43000 (95 % CI 7186-104660) lung cancer deaths due to indoor radon in Europe. This number is likely to increase in the future due to decreased ventilation in aim to reduce energy consumption, if other measures are not taken. It is important to maintain good air exchange conditions and proper building insulation even when energy saving measures are taken. More should be known about practical conditions and potential to radon reduction, as well as about the knowledge level, preparedness, and practical hindrances to take such actions by building owners. Value of information analysis shows that this information is so valuable that putting resources in this research is clearly cost-effective. The ultimate aim should be to reduce energy consumption, greenhouse gas emissions, and indoor radon in a cost-effective and synergistic way.}}<br />
<br />
==Scope==<br />
<br />
In this study, the research question is the following: What are the effects of different building policies on radon in residential buildings, and consequently on lung cancer incidence in Europe? The building policies considered aim at reducing greenhouse gas emissions and thus mitigate climate change. We look specifically at years 2010, 2020, 2030, and 2050 in the European Union. The study is performed as an open assessment in the internet as a part of the so called [[Common Case Study]] of [[INTARESE]] and [[HEIMTSA]] projects. A technical objective was to test feasibility of web workspace and on-line modelling tools developed in the projects.<br />
<br />
===Boundaries===<br />
<br />
Boundaries, scenarios, intended users, and participants are the same as in the [[Common Case Study]]. In brief, the situation is assessed in [[EU-30]] (the current 27 EU member states plus Norway, Iceland, and Switzerland) for the next forty years. [[Building policies in Europe|Four scenarios]] are considered: <br />
# '''BAU''': business as usual contains the implementation of already made decisions but no further actions; <br />
# '''ALL''': all such policies are implemented that are required to reduce the total greenhouse gas emissions by 70 % by 2050; <br />
# '''INSULATION''': only building insulation policies from ALL are implemented (ALL also contains policies to increase biomass use, but these are not implemented here); <br />
# '''RENOVATION''': same as ALL except that ventilation is not improved in 50 % of those buildings that are insulated up to tighter standards (in other scenarios, insulation is always combined with improved ventilation).<br />
<br />
==Rationale==<br />
<br />
The assessment is based on a causal model presented in the figure. Each node in the graph (also called a variable in the model) are described in more detail elsewhere; only a summary of the model is presented here.<br />
<br />
'''Policy estimation'''<br />
<br />
[[Building policies in Europe|European building policies]] described above are considered. The aim of the policies is to mitigate climate change by reducing greenhouse gas emissions from heating and cooling of buildings. In this sub-assessment, we do not consider greenhouse gas emissions or climate impacts, but only health impacts (specifically lung cancer) occurring as collateral damages or benefits. The purpose of the assessment is to estimate the impacts of each building policy and identify those policies that produce the best health outcomes.<br />
<br />
'''Exposure estimation'''<br />
<br />
The logic of the assessment is that the climate change mitigation policies considered affect [[:heande:HI:Air exchange rate for European residences|air exchange rates]] in buildings. There is a simple negative association between air exchange and radon: air exchange removes radon from indoor air. However, there are many complicating factors which are not considered in this assessment. Radon comes to indoor air mainly from soil via gas leakages in the building ground floor. The most important omission in the assessment is that there are effective methods to prevent radon leakages into the building in the first place. Although these are typically cheap to implement during construction, they can be very costly if implemented in an existing building. Therefore, this first pass assessment simply assumes that such measures are not taken more in the future than what they have been taken so far, i.e. the radon emissions from soil into indoor air will remain at the current levels. Although this is a somewhat pessimistic assumption, the knowledge about radon and its mitigation have been around for decades, and the current situation is the result of radon policies that societies have been willing to implement in practice. [[Radon concentrations in European residences|Nation-wide radon estimates]] were obtained from EnVIE project and UNSCEAR 2000 report reviewed in this sub-assessment (http://en.opasnet.org/w/Radon_concentrations_in_European_residences). However, United Kingdom, Czech Republic, and Slovenia were rejected due to lack of data.<br />
<br />
'''Health effect estimation'''<br />
<br />
[[Lung cancer cases due to radon in Europe|Lung cancer mortality]] (number of deaths due to lung cancer) attributable to [[Radon concentrations in European residences|indoor radon concentrations]] was chosen as the outcome of interest for two reasons. First, there is clear evidence about the causal association between indoor radon and lung cancer; second, lung cancer is the only known endpoint of radon exposure, and as a deathly disease, focusing on mortality can produce a reasonable estimate about the total magnitude of the problem.<br />
<br />
The current epidemiological literature contains plausible exposure-response functions for the [[ERF for long-term indoor exposure to radon and lung cancer|association of indoor radon and lung cancer]]. The current exposure-response estimate is 1.16 (risk ratio RR) for lung cancer mortality per 100 Bq/m<sup>3</sup> radon concentration increase (Darby 2004 and 2005).<br />
<ref>Darby S, Hill D, Auvinen A, Barros-Dios JM, Baysson H, Bochicchio F, Deo H, Falk R, Forastiere F, Hakama M, Heid I, Kreienbrock L, Kreutzer M, Lagarde F, Mäkeläinen I, Muirhead C, Obereigner W, Pershagen G, Ruano-Ravina A, Ruosteenoja E, Schaffrath-Rosario A, Tirmarche M, Tomasek L, Whitley E, Wichmann H-E, Doll R. Radon in homes and lung cancer risk: collaborative analysis of individual data from 13 European case-control studies. British Medical Journal 2005; 330: 223–226.</ref><br />
<ref name="darby2006">Darby S, Hill D, Deo H, Auvinen A, Barros-Dios JM, Baysson H, Bochicchio F, Falk R, Farchi S, Figueiras A, Hakama M, Heid I, Hunter N, Kreienbrock L, Kreuzer M, Lagarde FC, Mäkeläinen I, Muirhead C, Oberaigner W, Pershagen G, Ruosteenoja E, Schaffrath Rosario A, Tirmarche M, Tomášek L, Whitley E, Wichmann H-E, Doll R. Residential radon and lung cancer – detailed results of a collaborative analysis of individual data on 7148 persons with lung cancer and 14 208 persons without lung cancer from 13 epidemiologic studies in Europe. Scandinavian Journal of Work, Environment Health 2006; 32 Suppl 1: 1–84. </ref><br />
Linear no-threshold exposure-response function was assumed for the whole population in each country.<br />
<br />
Lung cancer mortality due to radon depends also on the [[WHO mortality data|background mortality of lung cancer]] and the [[Population of Europe by Country|population size]]. [[Population of Europe by Country|Population size]] differs by country and also in time; data from the [[Common Case Study]] was used also in this sub-assessment. The same [[WHO mortality data|lung cancer background mortality]] is assumed for the whole Europe: 58.2 cases/100000 person-years (Globocan 2008). The main exposures causing lung cancer are known fairly well: smoking, asbestos, radon, and smoke from any source. Many of these exposures are decreasing at some rate in Europe. However, for simplicity we assume no change in the background risk of lung cancer, and this somewhat overestimates the impacts of radon and also the impacts of policies on lung cancer in the future.<br />
<br />
'''Policy evaluation'''<br />
<br />
Finally, the lung cancer mortalities under each policy scenario are compared and the optimum scenario is found. It should be noted, however, that this sub-assessment only has a very narrow view on all impacts of the policies and therefore it cannot be used as an ultimate guidance for policy selection. Instead, this sub-assessment gives important information for the [[Common Case Study]] as a whole, which may produce such overall conclusions.<br />
<br />
'''Impact estimation'''<br />
<br />
For overall conclusions, it is crucial that the impacts observed in a sub-assessment can be compared with other impacts observed in other sub-assessment. To this aim, we expressed the outcome using two alternative summary indicators: disability-adjusted life years (DALY) and euros (€). [[DALY]]s are computed by multiplying the number of cases of a disease with a respective [[Disability weights|disability or severity weight]] and the duration of the disease. The idea is to measure the overall healthy years that are lost due to several diseases. The disability weight (estimated by WHO) for lung cancer is 0.146. We assume that each case of lung cancer causes a period of 2 to 36 months under disease, and a life expectancy loss of 1 to 15 years. <br />
<br />
Lung cancer is a rather deadly disease and few patient that get a lung cancer diagnosis will actually be cured. Therefore, lung cancer mortality covers most DALYs involved, especially when the years with disease before death are included. However, there is also a fraction of patients that eventually die from something else, and their DALYs are not included in an assessment about mortality cases only. Therefore, we used slightly higher estimates for life expectancy loss to compensate for the non-mortality cases. We thought this was more reliable than trying to count lung cancer morbidity separately and then end up with double counting problems.<br />
<br />
The costs of diseases include direct costs of treatment, indirect costs due to loss of productivity (absence from work), and willingness of a person to pay extra to avoid the disease. Because the monetary estimation of impacts is not the main objective in this sub-assessment, we do not go through this laborious path. Instead, we simply assume that the DALY estimate also provides a reasonable indicator of all monetary costs of the asthma cases. Thus, we multiply the DALY estimate with an estimate of [[DALY to money conversion|willingness to pay]] to avoid a loss of one healthy life year. This has typically been in the order of 30000 - 60000 euros per saved life year. This results in a preliminary estimate of monetary impact, which can be used in comparisons in other parts of the [[Common Case Study]] and the [[value of information analysis]] (see below).<br />
<br />
A methodological objective was a proof of concept for running assessment models via open internet interface. Therefore, the model development, data storage, and model runs were all performed in [[Opasnet]] using [[R]] software and [[Opasnet Base]]. The main page of the sub-assessment is http://en.opasnet.org/w/Health_impact_of_radon_in_Europe .<br />
<br />
===Analyses===<br />
<br />
Two analyses were performed in the sub-assessment. First, the main analysis was the optimisation of the health impact across different policy options as described before. Second, a [[value of information analysis]] was performed based on the monetary impact estimates.<br />
<br />
[[Value of information]] is a statistical method that estimates the largest sum of money a decision maker should be willing to pay to be able to reduce uncertainty in the decision before actually making the decision. The analysis is based on the idea that even if one of the options seemed to be the best based on the expected value of impact, it is possible that, due to uncertainties described in the decision model, some other option could actually be the best. The decision maker would be better off, if she could do more research, reduce the uncertainty and actually find out whether an alternative indeed turns out to be better. The beauty of value of information analysis is that it can be performed before the decision, but more importantly, before any further research is done. If the value of information analysis shows low value, the decision maker can decide now with only a low probability of regret afterwards. On the other hand, if it shows high value, the decision-maker would be better off if she postponed the actual decision and put effort in further research and analysis (assuming that such research is feasible).<br />
<br />
==Result==<br />
<br />
===Results===<br />
<br />
[[Lung cancer cases due to radon in Europe]]: {{#opasnet_base_link:Op_en4715}}<br />
<br />
*Results for the Biomass scenario [[:heande:Air exchange rate for European residences#Definition|are wrong]] and the scenario is perhaps irrelevant because biomass usage does not affect air exchange rates which this assessment is concerned with, so it should be ignored. <br />
<br/><br />
<br />
[[Image:Health impact of radon.png|thumb|The impacts of European building policies on lung cancer due to indoor radon.]]<br />
<br />
[[Image:Health impact of radon distribution.png|thumb|Result distributions]]<br />
<br />
[[Image:Health impact of radon EVPI.png|thumb|[[Value of information]] analysis results]]<br />
<br />
{|{{prettytable}}<br />
|+'''Lung cancer cases in Europe due to indoor radon in residences (mean and 95% confidence interval).'''<br />
! !!colspan="4"|Year<br />
|----<br />
!Policy!!2010!!2020!!2030!!2050<br />
|----<br />
|BAU || 43074 (7186-104660) || 51801 (8934-129303) || 58716 (9427-155621) || 63718 (10407-178566)<br />
|----<br />
|All || NA || 52660 (8892-130780) || 68086 (10544-180827) || 81022 (11983-235695)<br />
|----<br />
|Insulation || NA || NA || NA || 80149 (11898-228747)<br />
|----<br />
|Renovation || NA || NA || NA || 92783 (13365-275851)<br />
|----<br />
|}<br />
<br />
{|{{prettytable}}<br />
|+'''Lung cancer DALYs in Europe due to indoor radon in residences (mean and 95% confidence interval).'''<br />
! !!colspan="4"|Year<br />
|----<br />
!Policy!!2010!!2020!!2030!!2050<br />
|----<br />
|BAU || 358244 (54193-940205) || 427824 (65203-1156026) || 483005 (70921-1335438) || 524154 (80215-1545369)<br />
|----<br />
|All || NA || 433106 (65625-1140190) || 562607 (78874-1614252) || 663170 (89720-2045648)<br />
|----<br />
|Insulation || NA || NA || NA || 664141 (88638-2108941)<br />
|----<br />
|Renovation || NA || NA || NA || 773105 (107764-2392599)<br />
|----<br />
|}<br />
<br />
{|{{prettytable}}<br />
|+'''Lung cancer monetary impact (based on DALYs) in Europe due to indoor radon in residences (mean and 95% confidence interval). Unit: M€'''<br />
! !!colspan="4"|Year<br />
|----<br />
!Policy!!2010!!2020!!2030!!2050<br />
|----<br />
|BAU || 16147 (2519-42699) || 19250 (3039-53378) || 21770 (3121-60868) || 23585 (3590-70455)<br />
|----<br />
|All || NA || 19464 (3009-53226) || 25219 (3682-71977) || 29715 (3973-94741)<br />
|----<br />
|Insulation || NA || NA || NA || 29877 (4049-93146)<br />
|----<br />
|Renovation || NA || NA || NA || 34810 (4748-106804)<br />
|----<br />
|}<br />
<br />
{| {{prettytable}}<br />
|+ '''Lung cancer cases attributable to indoor radon in residences in Europe, year 2010.<br />
! Country of observation!! Mean!! SD<br />
|----<br />
| Austria<br />
| 1071<br />
| 1202<br />
|----<br />
| Belgium<br />
| 885<br />
| 872<br />
|----<br />
| Bulgaria<br />
| 297<br />
| 338<br />
|----<br />
| Switzerland<br />
| 1540<br />
| 2764<br />
|----<br />
| Cyprus<br />
| 9<br />
| 12<br />
|----<br />
| Germany<br />
| 4843<br />
| 4207<br />
|----<br />
| Denmark<br />
| 373<br />
| 400<br />
|----<br />
| Estonia<br />
| 218<br />
| 245<br />
|----<br />
| Spain<br />
| 8460<br />
| 18071<br />
|----<br />
| Finland<br />
| 812<br />
| 802<br />
|----<br />
| France<br />
| 8320<br />
| 12045<br />
|----<br />
| Greece<br />
| 813<br />
| 880<br />
|----<br />
| Hungary<br />
| 1617<br />
| 2161<br />
|----<br />
| Ireland<br />
| 552<br />
| 636<br />
|----<br />
| Italy<br />
| 4952<br />
| 4444<br />
|----<br />
| Lithuania<br />
| 236<br />
| 277<br />
|----<br />
| Luxembourg<br />
| 69<br />
| 64<br />
|----<br />
| Latvia<br />
| 226<br />
| 294<br />
|----<br />
| Malta<br />
| 43<br />
| 50<br />
|----<br />
| Netherlands<br />
| 523<br />
| 350<br />
|----<br />
| Norway<br />
| 575<br />
| 673<br />
|----<br />
| Poland<br />
| 2264<br />
| 2151<br />
|----<br />
| Portugal<br />
| 1140<br />
| 1214<br />
|----<br />
| Romania<br />
| 1236<br />
| 1313<br />
|----<br />
| Sweden<br />
| 1375<br />
| 1600<br />
|----<br />
| Slovakia<br />
| 626<br />
| 678<br />
|----<br />
|| '''Total'''|| '''43074'''|| <br />
|----<br />
|}<br />
<br />
===Conclusions===<br />
<br />
There are currently 43000 (95 % CI 7200 - 105000) lung cancer deaths per year due to indoor radon in Europe. This number is likely to increase in the future due to decreased ventilation in aim to reduce energy consumption, if other measures are not taken. It is important to maintain good air exchange even when energy saving measures are taken.<br />
<br />
The value of information analysis shows that further information is worth about 5 to 10 billion euros. This is ten times higher than with dampness and asthma. In this assessment, all of the value goes into the most critical issue, namely the impacts of air exchange rate. However, in many cases the main problem is air leakage through the ground floor structures and lack of preventive measures (such as sub-floor ventilation), which contributes to radon entering indoor air in the first place. Therefore, focussing on air exchange only may not be the optimal solution. Instead, understanding is needed about why buildings are still often constructed in an unoptimal way and how high radon levels could be cost-effectively reduced in existing buildings. <br />
<br />
A thorough examination of current knowledge was not done in this assessment. It seems obvious that collecting and organising existing information is a cost-effective way to reduce uncertainty in this issue, because that would cost only a small fraction of the value of that information according to this assessment.<br />
<br />
Radon is invisible and odourless gas and impossible to detect with senses. It is technically easy to measure and it could therefore be routinely measured in all apartments. However, the building owners are typically unaware of the problem and may therefore ignore it. For example, in Finland, where radon concentrations are relatively high, majority of residents are unaware of the radon levels of their place of residence (Turunen et al. 2010 http://www.ehjournal.net/content/9/1/69). Even if the problem is acknowledged, there may be insufficient expertise or resources to repair the problem. Further on, the building industry has varying expertise to build radon-effective buildings.<br />
<br />
In conclusion, more should be known about reasons why and how radon-effective building construction and maintenance practices are or are not implemented. Radon is an important environmental health issue that should be considered when climate-friendly building policies (especially those that affect indoor air conditions) are implemnented.<br />
<br />
==R code for detailed analysis==<br />
<br />
*This code features [[R]] functions described on [[Opasnet Base Connection for R]] and [[Operating intelligently with multidimensional arrays in R]].<br />
<br />
<rcode graphics="1"><br />
library(OpasnetBaseUtils)<br />
library(ggplot2)<br />
cancer <- op_baseGetData("opasnet_base", "Op_en4715", exclude = 48823)<br />
array <- DataframeToArray(cancer)<br />
array <- array[,,,c(2,1,3,4),,]<br />
##### Cases #####<br />
means <- apply(array, c(2,3,4), mean, na.rm=TRUE)<br />
means <- apply(means, c(2,3), sum, na.rm=TRUE)<br />
plot1 <- as.data.frame(as.table(means))<br />
plot1 <- ggplot(plot1[plot1[,"Freq"]!=0,], aes(Year, weight=Freq, fill=Policy)) + geom_bar(position="dodge") + <br />
scale_x_discrete("Year") + scale_y_continuous("Cases")<br />
plot1<br />
ci <- apply(apply(array, c(1,3,4), sum, na.rm=TRUE), c(2,3), quantile, probs=c(0.025,0.975))<br />
final1 <- means<br />
final1[,] <- paste(round(means), " (", round(ci[1,,]), "-", round(ci[2,,]), ")", sep="")<br />
final1[c(2:4,7:8,11:12)] <- NA<br />
final1<br />
##### DALYs #####<br />
DALY <- array(NA, dim = c(dim(array), 3), dimnames = dimnames(array))<br />
DALY[,,,,1] <- array<br />
DALY[,,,,2] <- runif(dim(array)[1],2,36)/12<br />
DALY[,,,,3] <- runif(dim(array)[1],1,15)<br />
DALY <- DALY[,,,,1]*0.146*DALY[,,,,2]+DALY[,,,,1]*DALY[,,,,3]<br />
means <- apply(DALY, c(2,3,4), mean, na.rm=TRUE)<br />
means <- apply(means, c(2,3), sum, na.rm=TRUE)<br />
plot2 <- as.data.frame(as.table(means))<br />
plot2 <- ggplot(plot2[plot2[,"Freq"]!=0,], aes(Year, weight=Freq, fill=Policy)) + geom_bar(position="dodge") + <br />
scale_x_discrete("Year") + scale_y_continuous("DALYs")<br />
plot2<br />
ci <- apply(apply(DALY, c(1,3,4), sum, na.rm=TRUE), c(2,3), quantile, probs=c(0.025,0.975))<br />
final2 <- means<br />
final2[,] <- paste(round(means), " (", round(ci[1,,]), "-", round(ci[2,,]), ")", sep="")<br />
final2[c(2:4,7:8,11:12)] <- NA<br />
final2<br />
##### Cost #####<br />
mpdaly <- op_baseGetData("opasnet_base", "Op_en4858")<br />
cost <- IntArray(mpdaly, DALY, "DALYs")<br />
cost <- data.frame(cost[,c("obs","Country","Policy","Year")], Result=cost[,"Result"]*cost[,"DALYs"])<br />
cost <- DataframeToArray(cost)<br />
cost <- cost[,,c(2,1,3,4),]<br />
means <- apply(cost, c(2,3,4), mean, na.rm=TRUE)<br />
means <- apply(means, c(2,3), sum, na.rm=TRUE)/10^6<br />
plot3 <- as.data.frame(as.table(means))<br />
plot3 <- ggplot(plot3[plot3[,"Freq"]!=0,], aes(Year, weight=Freq, fill=Policy)) + geom_bar(position="dodge") + <br />
scale_x_discrete("Year") + scale_y_continuous("Cost (M€)")<br />
plot3<br />
ci <- apply(apply(cost, c(1,3,4), sum, na.rm=TRUE), c(2,3), quantile, probs=c(0.025,0.975))/10^6<br />
final3 <- means<br />
final3[,] <- paste(round(means), " (", round(ci[1,,]), "-", round(ci[2,,]), ")", sep="")<br />
final3[c(2:4,7:8,11:12)] <- NA<br />
final3<br />
##### Probability density plot #####<br />
costdf <- as.data.frame(as.table(apply(cost, c(1,3,4), sum)/1e9))<br />
costdf <- costdf[is.na(costdf[,"Freq"])==FALSE,]<br />
plot4 <- ggplot(costdf, aes(x=Freq, y=..density.., fill=Policy)) + geom_density(alpha=0.2, adjust=4) + <br />
scale_x_continuous(expression("Cost ("*10^9*"€)"), limits = c(-50,300)) + scale_y_continuous("Density") + facet_wrap(~Year)<br />
plot4<br />
##### Expected Value of Perfect Information #####<br />
evpi <- (apply(apply(cost, c(2,3,4), mean, na.rm=TRUE), c(1,3), min, na.rm=TRUE) - apply(apply(cost, c(1,2,4), min, <br />
na.rm=TRUE), c(2,3), mean, na.rm=TRUE))/1e6<br />
plot5 <- as.data.frame(as.table(apply(evpi, 2, sum)))<br />
plot5 <- ggplot(plot5, aes(Var1, weight=Freq)) + geom_bar(position="dodge") + <br />
scale_x_discrete("Year") + scale_y_continuous("Value of perfect information (M€)")<br />
plot5<br />
##### Expected Value of Partial Perfect Information #####<br />
#Same as that of perfect information, because of only one decision-dependent uncertain variable<br />
ae <- op_baseGetData("opasnet_base", "Erac2499")<br />
aer <- DataframeToArray(ae)<br />
aer <- aer[,,c(2,1,4,5),]<br />
dropnonmax <- function(x) {<br />
x[x<max(x, na.rm = TRUE)] <- NA<br />
return(x)<br />
}<br />
aer <- apply(aer, c(1,2,4), dropnonmax)<br />
aer <- as.data.frame(as.table(aer))<br />
aer <- aer[,c(2,3,1,4,5)]<br />
colnames(aer)[3] <- "Policy"<br />
aer <- aer[is.na(aer[,"Freq"])==FALSE,]<br />
aer <- IntArray(aer, cost, "Cost")<br />
aer <- DataframeToArray(aer[,c("obs","Country","Year","Cost")],"Cost")<br />
test2 <- (apply(apply(cost, c(2,3,4), mean, na.rm=TRUE), c(1,3), min, na.rm=TRUE) - apply(aer, c(2,3), mean))/1e6<br />
plot6 <- as.data.frame(as.table(apply(test2, 2, sum)))<br />
plot6 <- ggplot(plot6, aes(Var1, weight=Freq)) + geom_bar(position="dodge") + <br />
scale_x_discrete("Year") + scale_y_continuous("Value of perfect information (M€)")<br />
plot6<br />
test2==evpi #Test if the values are the same<br />
test2-evpi <br />
# It seems that for some reason aer evppi is slightly smaller than evpi, <br />
# although it should be the only variable that varies in the "Policy" dimension<br />
</rcode><br />
<br />
==See also==<br />
<br />
*[[Radon]]<br />
* [[ERF for long-term indoor exposure to radon and lung cancer]]<br />
* [http://rem.jrc.ec.europa.eu/RemWeb/Publications/EUR_RADON.pdf An Overview of Radon Surveys in Europe]. Joint Research Centre, 2005. ISBN 92-79-01066-2 <br />
* In [[Heande]] (password-protected)<br />
*[[:heande:HI:Radon Indoor Air Case]]<br />
** [[:heande:Indoor air quality & its impact on man|Indoor air quality & its impact on man]]<br />
** [[:heande:Radon|Radon]]<br />
** [[:heande:Indoor air|Indoor air]]<br />
** [[:heande:Radon sisäilma annos-vaste|Radon sisäilma annos-vaste]]<br />
** [[:heande:Radon sisäilma altistus Suomi|Radon sisäilma altistus Suomi]]<br />
** [[:heande:Radon ja pitkäikäiset nuklidit porakaivo, kokonaissyöpäkuolemat annos-vaste|Radon ja pitkäikäiset nuklidit porakaivo]]<br />
** [[:heande:Radon ja pitkäikäiset nuklidit porakaivo, efektiivinen annos|Radon ja pitkäikäiset nuklidit porakaivo]]<br />
** [[:heande:Radon ja pitkäikäiset nuklidit porakaivovedessä|Radon ja pitkäikäiset nuklidit porakaivovedessä]]<br />
<br />
==Keywords==<br />
<br />
Radon, indoor air, lung cancer, Europe<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
==Related files==<br />
<br />
{{mfiles}}</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Should_I_take_iodine_tablets%3F&diff=20154
Should I take iodine tablets?
2011-04-08T10:06:36Z
<p>Minttu: </p>
<hr />
<div>[[Category:Radioactivity]]<br />
{{variable|moderator=Jouni<br />
|reference = {{publication<br />
| authors = <br />
| title = <br />
| explanation = <br />
| publishingyear = <br />
| urn = <br />
| reference = <br />
}}<br />
}}<br />
[[op_fi:Pitäisikö minun ottaa joditabletteja?]]<br />
<br />
{{summary box<br />
|question = Should I take iodine tablets because of radioactive emissions from the Fukushima nuclear accident?<br />
|answer = Most likely you should not take iodine. It is recommended only to a part of those people who have been within 20 km from Fukushima since the accident. For all others, there is no benefit from iodine tablets.}}<br />
<br />
== Scope ==<br />
<br />
Should I take iodine tablets?<br />
<br />
== Result ==<br />
<br />
If you are not in Japan, you should NOT take iodine because of Fukushima nuclear accident. Your own doctor will advice you if you need to take iodine due to some other reason. If you are in Japan, see more details below.<br />
<br />
You should take iodine tablets (for dose, see table below) because of the Fukushima nuclear accident if and ONLY if all of these apply (you may have other reasons for iodine therapy, but we are not talking about that):<br />
* You are 40 years of age or younger.<br />
* You are living in the alert level 1 area (purple area, see map) of you have stayed or will stay there for more than a day between March 16 and March 31, 2011.<br />
** If you are near that area but not inside, you should not take iodine, but if possible, buy them from a pharmacy or get them from your local evalucation centre so that you have them readily at hand if the situation changes.<br />
* You are reading this between March 23 and March 31, 2011.<br />
* You have not taken iodine tablets within the previous three months.<br />
* You have consulted your doctor if you have a thyroid disease (e.g. goitre, hyperthyroidism).<br />
<br />
<googlemap lat="37.319444" lon="141.021111" type="map" zoom="9"><br />
37.319444, 141.021111 Fukushima power plants<br />
#C142D0 (#CE5FAB)<br />
37.508019, 141.023254, Alert area 1<br />
37.500175, 141.15509<br />
37.454402, 141.218262<br />
37.382416, 141.240234<br />
37.319099, 141.240234<br />
37.277586, 141.212769<br />
37.240424, 141.141357<br />
37.206269, 141.064453<br />
37.208457, 140.982056<br />
37.245635, 140.894165<br />
37.324305, 140.85022<br />
37.406419, 140.839233<br />
37.478382, 140.880432<br />
37.504533, 140.93811<br />
37.513248, 141.020508<br />
</googlemap><br />
<br />
== Definition ==<br />
<br />
=== Data ===<br />
<br />
On 16 March, Japan's Nuclear Safety Commission recommended local authorities to instruct evacuees leaving the 20-kilometre area to ingest stable (not radioactive) iodine. The pills and syrup (for children) had been prepositioned at evacuation centers. The order recommended taking a single dose, with an amount dependent on age: <ref>[http://www.iaea.org/newscenter/news/tsunamiupdate01.html IAEA]: Fukushima Nuclear Accident Update (20 March 2011, 21:00 UTC), accessed 23 March 2011. </ref><br />
<br />
{| {{prettytable}}<br />
|+ '''Amount of iodine that should be taken if the criteria apply.<br />
|----<br />
!Age<br />
!Dose of iodine<br />
|----<br />
|Baby || 12.5 mg<br />
|----<br />
|1 mo.-3 yrs. || 25 mg<br />
|----<br />
|3-13 yrs. || 38 mg<br />
|----<br />
|13-40 yrs. || 76 mg<br />
|----<br />
|40+ yrs. || Not necessary<br />
|}<br />
<br />
=== Dependencies ===<br />
<br />
Whether you should take iodine depends on several things.<br />
* Your location.<br />
* The time when you are reading these instructions.<br />
* Your previous diseases and treatments.<br />
<br />
==See also==<br />
<br />
* [[Fukushima nuclear accident]]<br />
<br />
==Keywords==<br />
<br />
Nuclear energy, nuclear accident, Fukushima, radioactivity, iodine<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
==Related files==<br />
<br />
{{mfiles}}</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Assessment_of_the_health_impacts_of_H1N1_vaccination&diff=20151
Assessment of the health impacts of H1N1 vaccination
2011-04-08T09:36:51Z
<p>Minttu: </p>
<hr />
<div>[[Category:DARM exercise]]<br />
{{assessment|moderator=Teemu R}}<br />
[[op_fi:Sikainfluenssarokotteen terveyshaitat]]<br />
<br />
{{summary box<br />
|question = What was the overall health impact of the H1N1 (swine flu) vaccination in Finland in 2009-2010? Given current knowledge, which was the better decision between vaccinating as happened versus vaccinating no-one?<br />
|answer = Given current knowledge, the decision to vaccinate the whole population was better than not vaccinating anyone even when narcolepsy is included in the assessment. Results of the [[Value of information]] analysis suggest that further knowledge about the uncertain variables considered would not have changed the decision.}}<br />
<br />
{{participants needed}}<br />
<br />
This assessment is about the total health effects the 2009 swine flu pandemic. It utilizes data from the Infectious disease registry (TTR) maintained by THL, the National narcolepsy task force report from 31.1.2011 and WHO. The current model is a simplification with no time dimension.<br />
<br />
==Scope==<br />
<br />
*What was the overall health impact of the H1N1 vaccination in Finland in 2009-2010?<br />
*Given current knowledge, which was the better decision between vaccinating as happened versus vaccinating no-one?<br />
*Monetary impact is not considered.<br />
<br />
===Participants===<br />
<br />
* THL: [[User:Virpi Kollanus|Virpi Kollanus]], [[User:Marko|Marko]], [[User:Mikko Pohjola|Mikko Pohjola]], [[User:Jouni|Jouni]], [[User:Teemu R|Teemu R]]<br />
* This is an [[open assessment]]. Anyone can participate.<br />
<br />
==Result==<br />
<br />
{{resultlink}}<br />
<br />
===Results===<br />
<br />
[[File:Swinefluxnarc prob.dens.png|thumb|500px|Distributions of the results for the different scenarios/decisions.]]<br />
<br />
*From initial results it would appear like swine flu is more significant than narcolepsy in terms of DALYs.<br />
**Vaccinating as planned would result in approximately 1850 DALYs due to swine flu and narcolepsy combined.<br />
**Vaccinating no-one would result in approximately 4400 DALYs due to swine flu.<br />
<br />
*Probability of swine flu variable is revealed by both the sensitivity- and [[Value of information]]-analyses to have the most impact on the outcome. <br />
**The VOI analysis also reveals that further knowledge about the uncertain variables in the model is only worth up to ~80 DALYs, when considering the decision by age group, and less than 1 DALY when considering the decision as on/off as defined in the decision variable above. Which is only a small fraction of the total DALYs.<br />
<br />
*Suggested statement: Pandemrix should not be used any more anywhere because its narcolepsy risk is too high.<br />
**Resolution: '''Not accepted'''. Pandemrix is still an effective and safe vaccine. However, due to precautionary reasons, other alternatives should be used when available, because the occurrence of narcolepsy is not understood. {{reslink|Pandemrix should not be used because of narcolepsy risk}}<br />
<br />
===Conclusions===<br />
<br />
Given current knowledge, the decision to vaccinate the whole population was better than not vaccinating anyone. Results of the [[Value of information]] analysis suggest that further knowledge about the uncertain variables considered would not have changed the decision. The total impact of the swine flu pandemic and related narcolepsy cases in Finland in terms of DALYs is slightly smaller than that of [[Health impact of radon in Europe|radon]] (~6700 DALYs yearly) and slightly larger than that of [[Assessment of building policies' effect on dampness and asthma in Europe|moisture damage]] (~650 DALYs yearly) for instance.<br />
<br />
==Rationale==<br />
<br />
[[File:H1N1 vaccination health impact.png|thumb|500px|Causal diagram.]]<br />
<br />
;Decisions<br />
*Vaccination decision<br />
**Vaccinate everyone (observed vaccination coverage)<br />
**Vaccinate no-one (0 vaccination coverage)<br />
<br />
;Variables<br />
*[[H1N1 vaccination coverage in Finland]]<br />
*[[ERF of H1N1 vaccination on Narcolepsy]]<br />
**Assumed lognormally distributed<br />
*[[A(H1N1)v immunity in the Finnish population]]<br />
**P(immune) = 1 - P(not vaccinated) * P(no base immunity)<br />
*[[Population of Finland]]<br />
*[[Disability weights]]<br />
**DALY weight of narcolepsy equals roughly that of epilepsy (0.065)<br />
**DALY weight of having swine flu assumed ~0.5<br />
*Life expectancy by age groups in Finland<ref>[http://www.who.int/healthinfo/statistics/mortality_life_tables/en/ WHO life table estimates for 2008, Finland]</ref><br />
*Probability of catching swine flu given subject is not immune<br />
**Estimated from data available (population, total immunity, number of cases) by fitting the number of cases to a poisson distribution and calculating probability from the mean estimate by dividing by the non-immune population<br />
*Fraction of all cases represented by lab confirmed cases (which we have data on)<br />
**Estimated as beta-distributed with mean of 0.2 and some sd<br />
*Probability of death due to swine flu given a subject has swine flu and belongs to a risk group<br />
**Estimated from data available<br />
**Assumed all deaths will be lab confirmed cases<br />
**Assumed that all deaths belonged to a risk group (had some base condition)<br />
*Fraction of population belonging to a risk group<br />
**Arbitrary values; trying to account for kids of age <1 and old folks with heart conditions etc.<br />
*Length of swine flu<br />
**Assumed to be flat 5 days (mildly incapacitated for this duration)<br />
*[[Narcolepsy in Finland]]<br />
*[[AH1N1 cases in Finland]]<br />
<br />
;Indicators<br />
*DALYs from narcolepsy caused by vaccination<br />
*DALYs from having swine flu<br />
*DALYs from deaths caused by swine flu<br />
<br />
== R code ==<br />
<br />
*Basic model<br />
**Uncertainties of ERF of vaccine on narcolepsy, fraction of all cases represented by lab confirmed cases and probability of catching swine flu are implemented. <br />
<br />
<rcode graphics="1"><br />
# Model; original data inputs are disability weights (isfw, inarcw), population (ipop/dpop), (atm) ERF of vaccine on narcolepsy (NERF), <br />
# vaccination coverage (ivac_cov), base immunity in the population (ibimm) and observed number of sf cases (dsf)<br />
<br />
# Function for aggregating indicators into DALYs<br />
# Narcolepsy DALY weight taken as 0.065 (that of treated epilepsy)<br />
# iEl is expectation of remaining life in an age group, value for "All" is arbitrary for now<br />
# ilsf is the length of swine flu (e.g. how long was the subject absent frow work) in years<br />
# ifrg is the fraction of population belonging to a risk group of dying from swine flu, default values are arbitrary<br />
# iElrgc is the expected life correction for the risk group (people with heart conditions etc are likely to die earlier)<br />
<br />
outcome <- function(inarc = narc(), isf = sf(), inarcw = data.frame(Result=0.065),#op_baseGetData("opasnet_base", "Op_en2307")[,-c(1,2)], <br />
isfw = data.frame(Result=0.5), iEl = data.frame(Age=c("0-4 ","5-9","10-14","15-19","20-24","25-29","30-34","35-39","40-44","45-49",<br />
"50-54","55-59","60-64","65-69","70-74","75-79","80+","All"), Result = c(79,75.1,70.1,65.1,60.3,55.5,50.7,45.9,41.1,36.5,31.9,27.6,<br />
23.5,19.5,15.7,12.1,9,50)), ilsf = data.frame(Result=5/365), isfpd = sfpd(), ifrg = data.frame(Age = c("0-4 ","5-9","10-14","15-19",<br />
"20-24","25-29","30-34","35-39","40-44","45-49","50-54","55-59","60-64","65-69","70-74","75-79","80+"), Result = c(0.1, rep(0.001,<br />
11), rep(0.5,5))), iElrgc = data.frame(Age = c("0-4 ","5-9","10-14","15-19","20-24","25-29","30-34","35-39","40-44","45-49","50-54",<br />
"55-59","60-64","65-69","70-74","75-79","80+"), Result = c(rep(1,12), rep(0.5,5))), ...) {<br />
<br />
names(inarc)[names(inarc)=="Result"] <- "inarc"<br />
names(inarcw)[names(inarcw)=="Result"] <- "inarcw"<br />
names(isf)[names(isf)=="Result"] <- "isf"<br />
names(isfw)[names(isfw)=="Result"] <- "isfw"<br />
names(iEl)[names(iEl)=="Result"] <- "iEl"<br />
names(ilsf)[names(ilsf)=="Result"] <- "ilsf"<br />
names(isfpd)[names(isfpd)=="Result"] <- "isfpd"<br />
names(ifrg)[names(ifrg)=="Result"] <- "ifrg"<br />
names(iElrgc)[names(iElrgc)=="Result"] <- "iElrgc"<br />
<br />
# Calculating narcolepsy DALYs<br />
onarc <- merge(inarc, inarcw)<br />
onarc <- merge(onarc, iEl)<br />
onarc <- model.frame(I(inarc * inarcw * iEl) ~., data = onarc)<br />
colnames(onarc)[1] <- "onarc"<br />
<br />
# Calculating swine flu DALYs from missing work<br />
osf <- merge(isf, isfw)<br />
osf <- merge(osf, ilsf)<br />
osf <- model.frame(I(isf * isfw * ilsf) ~., data = osf)<br />
colnames(osf)[1] <- "osf"<br />
<br />
#Calculating swine flu DALYs from deaths<br />
osfm <- merge(isf, isfpd)<br />
osfm <- merge(osfm, iEl)<br />
osfm <- merge(osfm, ifrg)<br />
osfm <- merge(osfm, iElrgc)<br />
osfm <- model.frame(I(isf * isfpd * iEl * ifrg * iElrgc) ~., data = osfm)<br />
colnames(osfm)[1] <- "osfm"<br />
<br />
# Aggregate (it is crucial that both variables are distinguished by the same age groups and other indices so that values<br />
# are not replicated to fill empty cells)<br />
out <- merge(onarc, osf)<br />
out <- merge(out, osfm)<br />
out <- reshape(out, idvar = names(out)[(names(out)%in%c("onarc","osf","osfm"))==FALSE], times = c("onarc","osf","osfm"), <br />
timevar = "Outcome", varying = list(c("onarc","osf","osfm")), direction = "long")<br />
colnames(out)[ncol(out)] <- "Result"<br />
rownames(out) <- 1:nrow(out)<br />
<br />
return(out)<br />
}<br />
<br />
# Function for calculating narcolepsy cases, depends on erf of vac on narc, pop, vac_cov and background incidence (fraction)<br />
<br />
narc <- function(iNERF = op_baseGetData("opasnet_base", "Op_en4923")[,-c(1)], ipop = op_baseGetData("opasnet_base", "Op_en2949")[,-c(1,2)], <br />
ivac_cov = op_baseGetData("opasnet_base", "Op_en4925")[,-c(1,2)], ibgi = data.frame(Result=1.4e-5), ...) {<br />
names(iNERF)[names(iNERF)=="Result"] <- "iNERF"<br />
names(ipop)[names(ipop)=="Result"] <- "ipop" <br />
names(ivac_cov)[names(ivac_cov)=="Result"] <- "ivac_cov"<br />
names(ibgi)[names(ibgi)=="Result"] <- "ibgi"<br />
out <- merge(iNERF, ipop)<br />
out <- merge(out, ivac_cov)<br />
out <- merge(out, ibgi)<br />
out <- model.frame(I((iNERF - 1) * ipop * ivac_cov * ibgi) ~., data = out)<br />
colnames(out)[1] <- "Result"<br />
return(out)<br />
}<br />
<br />
# A function for calculating iNERF might be added later<br />
<br />
# Function for calculating swine flu cases<br />
# ilcf is the fraction of actual swine flu cases represented by the lab confirmed cases<br />
# assumed binomially distributed, if uncertainty of probability of getting swine flu is not <br />
# present, the point estimate will be used as such and n samples sampled from the same distribution;<br />
# however if the probability has an uncertainty, only 1 sample from each distribution is sampled where<br />
# samples of the probability will be used as inputs; disabled sampling here since it would make different scenarios incomparable<br />
<br />
sf <- function(isfp = sfp(), ipop = op_baseGetData("opasnet_base", "Op_en2949")[,-c(1,2)], iimm = imm(), n = 1000, <br />
ilcf = tlcf, ...) {<br />
names(isfp)[names(isfp)=="Result"] <- "isfp"<br />
names(ipop)[names(ipop)=="Result"] <- "ipop" <br />
names(iimm)[names(iimm)=="Result"] <- "iimm"<br />
names(ilcf)[names(ilcf)=="Result"] <- "ilcf"<br />
out <- merge(isfp, ipop)<br />
out <- merge(out, iimm)<br />
out <- merge(out, ilcf)<br />
#Result <- NA<br />
#for (i in 1:nrow(out)) {<br />
# if (sum(as.numeric(colnames(isfp)=="obs"))>0){<br />
# Result[i] <- rbinom(1, round(out$ipop[i]*(1-out$iimm[i])), out$isfp[i]) / out$ilcf[i]<br />
# } else {<br />
# Result[((i-1)*n + 1):(i*n)] <- rbinom(n, round(out$ipop[i]*(1-out$iimm[i])), out$isfp[i]) / out$ilcf[i]<br />
# }<br />
#}<br />
#out <- data.frame(out[,(colnames(out)%in%c("isfp","ipop","iimm","ilcf"))==FALSE], Result)<br />
out <- model.frame(I(isfp * ipop * (1 - iimm) / ilcf) ~., data = out)<br />
colnames(out)[1] <- "Result"<br />
return(out)<br />
}<br />
<br />
# Function for calculating probability of getting swine flu given subject is not vaccinated (simplified model)<br />
# dsf, dpop and dimm are the actual data we have<br />
# uncertainty: number of cases is binomially distributed, number of trials (n) is the number of people who were not immune to swine-flu<br />
# outcome (x) is known, p is unknown. P can be easily calculated from x = p*n, when we assume that x is the expected value of the <br />
# distribution. But we're interested in the uncertainty of the estimate... When n is suitably large a poisson distribution becomes <br />
# an excellent approximation of the binomial distribution. So we can fit the poisson distribution using an R function (I didn't find<br />
# one for binomial) from just one observation -> acquire value of x with standard error -> use as uncertainty of estimate; which produces<br />
# rubbish because we only have a single observation, sd of the mean estimate of the poisson distribution appears to be (n*p)^0.5, so the <br />
# variance of the parameter is n * p, which divided by n gives p ... so the expected value is p and the variance is p, which causes problems<br />
# with the beta distribution (shape parameters become negative), hence variance is assumed to be variance^2 arbitrarily<br />
<br />
sfp <- function(dsf = op_baseGetData("opasnet_base", "Op_en4933")[,-c(1,2)], dpop = op_baseGetData("opasnet_base", "Op_en2949", <br />
series_id = 970)[,-c(1,2)], dimm = imm(), n = 1000, ...) {<br />
names(dsf)[names(dsf)=="Result"] <- "dsf"<br />
names(dpop)[names(dpop)=="Result"] <- "dpop"<br />
names(dimm)[names(dimm)=="Result"] <- "dimm"<br />
temp1 <- merge(dimm, dpop)<br />
temp1 <- model.frame(I(dpop * (1 - dimm)) ~., data = temp1)<br />
colnames(temp1)[1] <- "popnonimm"<br />
out <- merge(temp1, dsf)<br />
temp2 <- data.frame(obs=NA, Age=NA, fitp=NA)<br />
out2 <- data.frame()<br />
for (i in 1:nrow(out)) {<br />
temp2 <- data.frame(obs=1:n, Age=out$Age[i], fitp=rbeta(n, paralpha(fitdistr(round(out$dsf[i]), "poisson")[[1]] / <br />
out$popnonimm[i], (fitdistr(round(out$dsf[i]), "poisson")[[2]]^2 / out$popnonimm[i])^2), <br />
parbeta(fitdistr(round(out$dsf[i]), "poisson")[[1]] / out$popnonimm[i], (fitdistr(round(out$dsf[i]), <br />
"poisson")[[2]]^2 / out$popnonimm[i])^2)))<br />
out2 <- rbind(out2, merge(out[i,], temp2, all.x = TRUE, all.y = FALSE))<br />
}<br />
out2 <- out2[,(colnames(out2)%in%c("dsf", "popnonimm"))==FALSE]<br />
colnames(out2)[ncol(out2)] <- "Result"<br />
return(out2)<br />
}<br />
<br />
# Function for calculating probability of mortality after catching swine flu given that a subject belongs to a risk group<br />
# children of age < 1 and adults of 60+ afflicted by heart conditions etc are considered to belong to a risk group<br />
# ifrg is the fraction belonging to the risk group in a given age group<br />
# p(death|sf&rg)) assumed constant in all age groups<br />
<br />
sfpd <- function(dsf = op_baseGetData("opasnet_base", "Op_en4933")[,-c(1,2)], dmsf = data.frame(Result=44), <br />
dfrg = data.frame(Age = c("0-4 ","5-9","10-14","15-19","20-24","25-29","30-34","35-39","40-44","45-49",<br />
"50-54","55-59","60-64","65-69","70-74","75-79","80+"), Result = c(0.1, rep(0.001,11), rep(0.5,5))), ilcf = tlcf, ...) {<br />
names(dsf)[names(dsf)=="Result"] <- "dsf"<br />
names(dmsf)[names(dmsf)=="Result"] <- "dmsf"<br />
names(dfrg)[names(dfrg)=="Result"] <- "dfrg"<br />
names(ilcf)[names(ilcf)=="Result"] <- "ilcf"<br />
out <- merge(dsf, dfrg)<br />
out <- merge(out, ilcf)<br />
#out <- merge(out, dmsf)<br />
out <- model.frame(I(dfrg * dsf / ilcf) ~., data = out)<br />
colnames(out)[1] <- "Result"<br />
if (sum(as.numeric(colnames(out)=="obs"))>0) {#out <- as.data.frame(as.table(tapply(out$)))<br />
out <- data.frame(obs = levels(factor(out$obs)), Result = dmsf$dmsf/tapply(out$Result, out$obs, sum))<br />
} else {out <- data.frame(Result=dmsf$dmsf/sum(out$Freq))}<br />
return(out)<br />
}<br />
<br />
# Function for calculating total immunity to swine flu in the whole population<br />
# P(imm) = P(vac or base_imm)<br />
<br />
imm <- function(ibimm = op_baseGetData("opasnet_base", "Op_en4943", series_id = 994)[,-c(1,2)], <br />
ivac_cov = op_baseGetData("opasnet_base", "Op_en4925")[,-c(1,2)], ...) {<br />
names(ibimm)[names(ibimm)=="Result"] <- "ibimm"<br />
names(ivac_cov)[names(ivac_cov)=="Result"] <- "ivac_cov"<br />
out <- merge(ibimm, ivac_cov)<br />
out <- model.frame(I(1 - (1 - ibimm) * (1 - ivac_cov)) ~., data = out)<br />
colnames(out)[1] <- "Result"<br />
return(out)<br />
}<br />
<br />
# Calculating the outcome with different scenarios<br />
<br />
paralpha <- function(imean, ivar) imean * (imean * (1 - imean) / ivar - 1)<br />
parbeta <- function(imean, ivar) (1 - imean) * (imean * (1 - imean) / ivar - 1)<br />
library(OpasnetBaseUtils)<br />
library(MASS)<br />
library(ggplot2)<br />
<br />
# Common variable generation<br />
<br />
n <- 1000<br />
tlcf <- data.frame(obs = 1:n, Result=rbeta(n, paralpha(0.2, 0.1^2), parbeta(0.2, 0.1^2)))<br />
#ggplot(tlcf, aes(x=Result)) + geom_density()<br />
#tlcf <- data.frame(Result = 0.1)<br />
<br />
tsfp <- sfp()<br />
<br />
#test2 <- data.frame(obs = 1:n, Result=rbeta(n, paralpha(0.2, 0.2^2+0.01), parbeta(0.2, 0.2^2+0.01)))<br />
#ggplot(test2, aes(x=Result)) + geom_density()<br />
<br />
# Default, model based on current knowledge<br />
<br />
# fast version below<br />
#vacscenario <- outcome(inarc = narc(iNERF = data.frame(Age = c("0-4 ","5-9","10-14","15-19","20-24","25-29","30-34","35-39","40-44","45-49",<br />
# "50-54","55-59","60-64","65-69","70-74","75-79","80+","All"), Result = c(1,rep(9.2, 3), rep(1, 13), 4))))<br />
#novacscenario <- outcome(inarc = narc(iNERF = data.frame(Age = c("0-4 ","5-9","10-14","15-19","20-24","25-29","30-34","35-39","40-44","45-49",<br />
# "50-54","55-59","60-64","65-69","70-74","75-79","80+","All"), Result = c(1,rep(9.2, 3), rep(1, 13), 4)), <br />
# ivac_cov=data.frame(Result=0)), sf(iimm=imm(ivac_cov=data.frame(Result=0))))<br />
#colnames(vacscenario)[ncol(vacscenario)] <- "vacscenario"<br />
#colnames(novacscenario)[ncol(novacscenario)] <- "novacscenario"<br />
#fout <- merge(vacscenario, novacscenario)<br />
#fout<br />
<br />
# slow ver below<br />
<br />
tvac_cov <- data.frame(op_baseGetData("opasnet_base", "Op_en4925")[,-c(1,2)], Scenario = "vacscenario")<br />
tvac_cov <- rbind(tvac_cov, data.frame(Age=tvac_cov[,"Age"], Result = 0, Scenario = "novacscenario"))<br />
<br />
test <- outcome(inarc = narc(ivac_cov = tvac_cov), sf(isfp = tsfp, iimm = imm(ivac_cov = tvac_cov)))<br />
temp <- as.data.frame(as.table(tapply(test$Result, test[,c("obs","Scenario")], sum)))<br />
ggplot(temp, aes(x = Freq, fill = Scenario)) + geom_density(alpha = 0.2)<br />
tapply(temp$Freq, temp[,c("Scenario")], mean)<br />
#op_baseWrite("opasnet_base", test)<br />
<br />
# Sensitivity and value of information analysis<br />
<br />
#test <- op_baseGetData("opasnet_base", "Op_en4926")<br />
temp2 <- as.data.frame(as.table(tapply(test$Result, test[,(colnames(test)%in%c("Result","Outcome"))==FALSE], sum)))<br />
tNERF <- op_baseGetData("opasnet_base", "Op_en4923")[,-c(1)]<br />
colnames(tNERF)[colnames(tNERF)=="Result"] <- "tNERF"<br />
colnames(tlcf)[colnames(tlcf)=="Result"] <- "tlcf"#tlcf from above<br />
colnames(tsfp)[colnames(tsfp)=="Result"] <- "tsfp"#tsfp from above<br />
temp2 <- merge(temp2, tNERF)<br />
temp2 <- merge(temp2, tlcf)<br />
temp2 <- merge(temp2, tsfp)<br />
<br />
temp2$NERFbin <- cut(temp2$tNERF, c(-Inf, 1, quantile(temp2$tNERF[temp2$tNERF>1], 1:9/10), Inf))<br />
temp2$lcfbin <- cut(temp2$tlcf, c(-Inf, quantile(temp2$tlcf, 1:9/10), Inf))<br />
temp2$sfpbin <- cut(temp2$tsfp, c(-Inf, quantile(temp2$tsfp, 1:9/10), Inf))<br />
<br />
temp3 <- as.data.frame(as.table(tapply(temp2$Freq, temp2[,(colnames(temp2)%in%c("Freq","obs","tNERF","tlcf","tsfp",<br />
"lcfbin","sfpbin"))==FALSE], mean)))<br />
colnames(temp3)[ncol(temp3)] <- "EogNERF"<br />
temp2 <- merge(temp2, temp3)<br />
<br />
temp3 <- as.data.frame(as.table(tapply(temp2$Freq, temp2[,(colnames(temp2)%in%c("Freq","obs","tNERF","tlcf","tsfp",<br />
"NERFbin","sfpbin","EogNERF"))==FALSE], mean)))<br />
colnames(temp3)[ncol(temp3)] <- "Eoglcf"<br />
temp2 <- merge(temp2, temp3)<br />
<br />
temp3 <- as.data.frame(as.table(tapply(temp2$Freq, temp2[,(colnames(temp2)%in%c("Freq","obs","tNERF","tlcf","tsfp",<br />
"lcfbin","NERFbin","EogNERF","Eoglcf"))==FALSE], mean)))<br />
colnames(temp3)[ncol(temp3)] <- "Eogsfp"<br />
temp2 <- merge(temp2, temp3)<br />
<br />
## Correlation<br />
<br />
cor(temp2$Freq, temp2[,c("tNERF", "tlcf", "tsfp")], method = "spearman")<br />
<br />
## EVPI<br />
<br />
mean(tapply(temp$Freq, temp$obs, min)) - min(tapply(temp$Freq, temp$Scenario, mean)) # not considering by age group<br />
mean(apply(tapply(temp2$Freq, temp2[,c("obs","Age")], min), 1, sum)) - sum(apply(tapply(temp2$Freq, temp2[,c("Scenario","Age")], mean), 2, min))<br />
<br />
## EVXPI for NERF, lcf and sfp<br />
<br />
mean(apply(tapply(temp2$EogNERF, temp2[,(colnames(temp2)%in%c("Freq","Scenario","tNERF","tlcf","tsfp","NERFbin","lcfbin","sfpbin",<br />
"EogNERF","Eoglcf","Eogsfp"))==FALSE], min), 2, sum)) - sum(apply(tapply(temp2$Freq, temp2[,c("Scenario","Age")], mean), 2, min))<br />
<br />
mean(apply(tapply(temp2$Eoglcf, temp2[,(colnames(temp2)%in%c("Freq","Scenario","tNERF","tlcf","tsfp","NERFbin","lcfbin","sfpbin",<br />
"EogNERF","Eoglcf","Eogsfp"))==FALSE], min), 2, sum)) - sum(apply(tapply(temp2$Freq, temp2[,c("Scenario","Age")], mean), 2, min))<br />
<br />
mean(apply(tapply(temp2$Eogsfp, temp2[,(colnames(temp2)%in%c("Freq","Scenario","tNERF","tlcf","tsfp","NERFbin","lcfbin","sfpbin",<br />
"EogNERF","Eoglcf","Eogsfp"))==FALSE], min), 2, sum)) - sum(apply(tapply(temp2$Freq, temp2[,c("Scenario","Age")], mean), 2, min))<br />
<br />
#vacscenario <- outcome()<br />
#novacscenario <- outcome(inarc = narc(ivac_cov=data.frame(Result=0)), sf(iimm=imm(ivac_cov=data.frame(Result=0))))<br />
#temp <- as.data.frame(as.table(tapply(vacscenario$Result, vacscenario[,c("obs","Outcome")], sum)))<br />
#tapply(vacscenario$Result, vacscenario[,c("Age","Outcome")], mean)<br />
#tapply(temp$Freq, temp$Outcome, mean)<br />
#ggplot(temp, aes(x=Freq, fill=Outcome)) + geom_density(alpha = 0.2)<br />
#colnames(vacscenario)[ncol(vacscenario)] <- "vacscenario"<br />
#colnames(novacscenario)[ncol(novacscenario)] <- "novacscenario"<br />
#fout <- merge(vacscenario, novacscenario)<br />
#fout <- reshape(fout, idvar = names(fout)[(names(fout)%in%c("vacscenario","novacscenario"))==FALSE], times = c("vacscenario","novacscenario"), <br />
# timevar = "Scenario", varying = list(c("vacscenario","novacscenario")), direction = "long")<br />
#colnames(fout)[ncol(fout)] <- "Result"<br />
#temp <- as.data.frame(as.table(tapply(fout$Result, fout[,c("obs","Scenario")], sum)))<br />
#ggplot(temp, aes(x = Freq, fill = Scenario)) + geom_density(alpha = 0.2)<br />
<br />
<br />
# What actually happened<br />
<br />
#defscenario <- outcome(inarc = op_baseGetData("opasnet_base", "Op_en4922")[,-1], isf = op_baseGetData("opasnet_base", "Op_en4933")[,-1])<br />
<br />
# Narcolepsy erf = 1<br />
<br />
#nerfscenario <- outcome(iNERF = data.frame(Result=1))<br />
<br />
# No one was vaccinated<br />
<br />
#novacscenario <- outcome(ivac_cov = 0)<br />
<br />
# Other<br />
</rcode><br />
<br />
==See also==<br />
<br />
==References==<br />
<br />
<references/></div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Personal_exposures_and_microenvironment_concentrations_of_PM2.5,_VOC,_NO2_and_CO_in_Oxford_in_1998-2000&diff=16100
Personal exposures and microenvironment concentrations of PM2.5, VOC, NO2 and CO in Oxford in 1998-2000
2010-06-23T12:29:38Z
<p>Minttu: Created page with 'category:Exposure assessment Category:Expoplatform Category:Concentration database {{study|moderator=minttu}} ==Scope== Personal exposures among 50 persons and micro…'</p>
<hr />
<div>[[category:Exposure assessment]]<br />
[[Category:Expoplatform]]<br />
[[Category:Concentration database]]<br />
{{study|moderator=minttu}}<br />
<br />
==Scope==<br />
Personal exposures among 50 persons and microenvironment concentrations of PM2.5, VOC, NO2 and CO in Oxford, UK in 1998-2000<br />
<ref>Lai et al., Atmospheric Environment 38 (2004), 6399-6410<br />
</ref><br />
<br />
==Definition==<br />
<br />
* id: study24<br />
* Abbreviation:<br />
<br />
===Data===<br />
<br />
{| {{prettytable}}<br />
| id<br />
| obj_type<br />
| obj_id<br />
| name<br />
| data_table<br />
| study_id<br />
| desc<br />
| add_info<br />
| location<br />
|----<br />
<br />
| 603<br />
| P<br />
| 110-54-3<br />
| hexane<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of hexane (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 604<br />
| P<br />
| 110-82-7<br />
| cyclohexane<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of cyclohexane (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 605<br />
| P<br />
| 111-84-2<br />
| n-nonane<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of nonane (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 606<br />
| P<br />
| 124-18-5<br />
| decane<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of decane (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 607<br />
| P<br />
| 1120-21-4<br />
| undecane<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of undecane (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 608<br />
| P<br />
| 71-43-2<br />
| benzene<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of benzene (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 609<br />
| P<br />
| 91-20-3<br />
| naphthalene<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of naphthalene (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 610<br />
| P<br />
| 95-47-6<br />
| o-xylene<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of o-xylene (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 611<br />
| P<br />
| 25551-13-7<br />
| trimethylbenzene<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of trimethylbenzene (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 612<br />
| P<br />
| 100-41-4<br />
| ethylbenzene<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of ethylbenzene (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 613<br />
| P<br />
| 100-42-5<br />
| styrene<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of styrene (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 614<br />
| P<br />
| 103-65-1<br />
| propylbenzene<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of propylbenzene (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 615<br />
| P<br />
| 108-88-3<br />
| toluene<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of toluene (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 616<br />
| P<br />
| 71-36-3<br />
| 1-butanol<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of 1-butanol (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 617<br />
| P<br />
| 78-83-1<br />
| 2-methyl-1-propanol<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of 2-methyl-1-propanol (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 618<br />
| P<br />
| 104-76-7<br />
| 2-ethyl-1-hexanol<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of 2-ethyl-1hexanol (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 619<br />
| P<br />
| 108-95-2<br />
| phenol<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of phenol (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 620<br />
| P<br />
| 111-87-5<br />
| 1-octanol<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of 1-octanol (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 621<br />
| P<br />
| 111-76-2<br />
| 2-butoxyethanol<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of 1-butoxy-ethanol (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 622<br />
| P<br />
| 66-25-1<br />
| hexanal<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of hexanal (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 623<br />
| P<br />
| 100-52-7<br />
| benzaldehyde<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of benzalhedyhe (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 624<br />
| P<br />
| 124-13-0<br />
| octanal<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of octanal (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 625<br />
| P<br />
| 79-00-5<br />
| 1,1,2-trichloroethane<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of 1,1,2-trichloroethane (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 626<br />
| P<br />
| 79-01-6<br />
| trichloroethene<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of trichloroethene (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 627<br />
| P<br />
| 127-18-4<br />
| tetrachloroethene<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of terachloroethene (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 628<br />
| P<br />
| 80-56-8<br />
| alpha-pinene<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of alpha-pinene (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 629<br />
| P<br />
| 5989-27-5<br />
| limonene<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of d-limonene (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 630<br />
| P<br />
| 872-50-4<br />
| 1-methyl-2-pyrrolidinone<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of 1-methyl-2-pyrrolidinone (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 631<br />
| P<br />
| 13466-78-9<br />
| 3-carene<br />
| VOC_P_24<br />
| study24<br />
| Summary statistics of 3-carene (µg/m3) for personal exposure levels.<br />
| <br />
| O<br />
|----<br />
| 632<br />
| I<br />
| 110-54-3<br />
| hexane<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of hexane (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 633<br />
| I<br />
| 110-82-7<br />
| cyclohexane<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of cyclohexane (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 634<br />
| I<br />
| 111-84-2<br />
| n-nonane<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of nonane (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 635<br />
| I<br />
| 124-18-5<br />
| decane<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of decane (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 636<br />
| I<br />
| 1120-21-4<br />
| undecane<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of undecane (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 637<br />
| I<br />
| 71-43-2<br />
| benzene<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of benzene (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 638<br />
| I<br />
| 91-20-3<br />
| naphthalene<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of naphthalene (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 639<br />
| I<br />
| 95-47-6<br />
| o-xylene<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of o-xylene (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 640<br />
| I<br />
| 25551-13-7<br />
| trimethylbenzene<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of trimethylbenzene (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 641<br />
| I<br />
| 100-41-4<br />
| ethylbenzene<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of ethylbenzene (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 642<br />
| I<br />
| 100-42-5<br />
| styrene<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of styrene (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 643<br />
| I<br />
| 103-65-1<br />
| propylbenzene<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of propylbenzene (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 644<br />
| I<br />
| 108-88-3<br />
| toluene<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of toluene (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 645<br />
| I<br />
| 71-36-3<br />
| 1-butanol<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of 1-butanol (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 646<br />
| I<br />
| 78-83-1<br />
| 2-methyl-1-propanol<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of 2-methyl-1-propanol (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 647<br />
| I<br />
| 104-76-7<br />
| 2-ethyl-1-hexanol<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of 2-ethyl-1-hexanol (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 648<br />
| I<br />
| 108-95-2<br />
| phenol<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of phenol (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 649<br />
| I<br />
| 111-87-5<br />
| 1-octanol<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of 1-octanol (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 650<br />
| I<br />
| 111-76-2<br />
| 2-butoxyethanol<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of 2-butoxy-ethanol (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 651<br />
| I<br />
| 66-25-1<br />
| hexanal<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of hexanal (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 652<br />
| I<br />
| 100-52-7<br />
| benzaldehyde<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of benzaldehyde (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 653<br />
| I<br />
| 124-13-0<br />
| octanal<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of ocatnal (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 654<br />
| I<br />
| 79-00-5<br />
| 1,1,2-trichloroethane<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of 1,1,2-trichloroethane (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 655<br />
| I<br />
| 79-01-6<br />
| trichloroethene<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of trichloroethene (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 656<br />
| I<br />
| 127-18-4<br />
| tetrachloroethene<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of tetrachloroethene (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 657<br />
| I<br />
| 80-56-8<br />
| alpha-pinene<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of alpha-pinene (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 658<br />
| I<br />
| 5989-27-5<br />
| limonene<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of d-limonene (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 659<br />
| I<br />
| 872-50-4<br />
| 1-methyl-2-pyrrolidinone<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of 1-methyl-2-pyrrolidinone (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 660<br />
| I<br />
| 13466-78-9<br />
| 3-carene<br />
| VOC_I_8<br />
| study24<br />
| Summary statistics of 3-carene (µg/m3) for residental indoor. <br />
| <br />
| O<br />
|----<br />
| 661<br />
| O<br />
| 110-54-3<br />
| hexane<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of hexane (µg/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 662<br />
| O<br />
| 110-82-7<br />
| cyclohexane<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of cyclohexane (µg/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 663<br />
| O<br />
| 111-84-2<br />
| n-nonane<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of nonane (µg/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 664<br />
| O<br />
| 124-18-5<br />
| decane<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of decane (µg/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 665<br />
| O<br />
| 1120-21-4<br />
| undecane<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of undecane (µg/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 666<br />
| O<br />
| 71-43-2<br />
| benzene<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of benzene (µg/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 667<br />
| O<br />
| 91-20-3<br />
| naphthalene<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of naphthalene (µg/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 668<br />
| O<br />
| 95-47-6<br />
| o-xylene<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of o-xylene (µg/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 669<br />
| O<br />
| 25551-13-7<br />
| trimethylbenzene<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of trimethylbenzene (µg/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 670<br />
| O<br />
| 100-41-4<br />
| ethylbenzene<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of ethylbenzene (µg/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 671<br />
| O<br />
| 100-42-5<br />
| styrene<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of styrene (µg/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 672<br />
| O<br />
| 103-65-1<br />
| propylbenzene<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of propylbenzene (µg/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 673<br />
| O<br />
| 108-88-3<br />
| toluene<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of toluene (ug/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 674<br />
| O<br />
| 71-36-3<br />
| 1-butanol<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of 1-butanol (ug/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 675<br />
| O<br />
| 78-83-1<br />
| 2-methyl-1-propanol<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of 2-methyl-1-propanol (ug/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 676<br />
| O<br />
| 104-76-7<br />
| 2-ethyl-1-hexanol<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of 2-ethyl-1-hexanol (ug/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 677<br />
| O<br />
| 108-95-2<br />
| phenol<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of phenol (ug/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 678<br />
| O<br />
| 111-87-5<br />
| 1-octanol<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of 1-octanol (ug/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 679<br />
| O<br />
| 111-76-2<br />
| 2-butoxyethanol<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of 2-butoxy-ethanol (ug/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 680<br />
| O<br />
| 66-25-1<br />
| hexanal<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of hexanal (ug/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 681<br />
| O<br />
| 100-52-7<br />
| benzaldehyde<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of benzaldehyde (ug/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 682<br />
| O<br />
| 124-13-0<br />
| octanal<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of ocatnal (ug/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 683<br />
| O<br />
| 79-00-5<br />
| 1,1,2-trichloroethane<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of 1,1,2-trichloroethane (ug/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 684<br />
| O<br />
| 79-01-6<br />
| trichloroethene<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of trichloroethene (ug/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 685<br />
| O<br />
| 127-18-4<br />
| tetrachloroethene<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of tetrachloroethene (ug/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 686<br />
| O<br />
| 80-56-8<br />
| alpha-pinene<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of alpha-pinene (ug/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 687<br />
| O<br />
| 5989-27-5<br />
| limonene<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of d-limonene (ug/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 688<br />
| O<br />
| 872-50-4<br />
| 1-methyl-2-pyrrolidinone<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of 1-methyl-2-pyrrolidinone (ug/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 689<br />
| O<br />
| 13466-78-9<br />
| 3-carene<br />
| VOC_O_6<br />
| study24<br />
| Summary statistics of 3-carene (ug/m3) for residental outdoor. <br />
| <br />
| O<br />
|----<br />
| 690<br />
| W<br />
| 110-54-3<br />
| hexane<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of hexane for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 691<br />
| W<br />
| 110-82-7<br />
| cyclohexane<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of cyclohexane for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 692<br />
| W<br />
| 111-84-2<br />
| n-nonane<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of nonane for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 693<br />
| W<br />
| 124-18-5<br />
| decane<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of decane for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 694<br />
| W<br />
| 1120-21-4<br />
| undecane<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of undecane for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 695<br />
| W<br />
| 71-43-2<br />
| benzene<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of benzene for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 696<br />
| W<br />
| 91-20-3<br />
| naphthalene<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of naphthalene for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 697<br />
| W<br />
| 95-47-6<br />
| o-xylene<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of o-xylene for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 698<br />
| W<br />
| 25551-13-7<br />
| trimethylbenzene<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of trimethylbenzene for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 699<br />
| W<br />
| 100-41-4<br />
| ethylbenzene<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of ethylbenzene for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 700<br />
| W<br />
| 100-42-5<br />
| styrene<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of styrene for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 701<br />
| W<br />
| 103-65-1<br />
| propylbenzene<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of propylbenzene for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 702<br />
| W<br />
| 108-88-3<br />
| toluene<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of toluene for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 703<br />
| W<br />
| 71-36-3<br />
| 1-butanol<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of 1-butanol for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 704<br />
| W<br />
| 78-83-1<br />
| 2-methyl-1-propanol<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of 2-methyl-1-propanol for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 705<br />
| W<br />
| 104-76-7<br />
| 2-ethyl-1-hexanol<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of 2-ethyl-1-hexanol for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 706<br />
| W<br />
| 108-95-2<br />
| phenol<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of phenol for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 707<br />
| W<br />
| 111-87-5<br />
| 1-octanol<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of 1-octanol for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 708<br />
| W<br />
| 111-76-2<br />
| 2-butoxyethanol<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of 2-butoxy-ethanol for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 709<br />
| W<br />
| 66-25-1<br />
| hexanal<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of hexanal for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 710<br />
| W<br />
| 100-52-7<br />
| benzaldehyde<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of benzaldehyde for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 711<br />
| W<br />
| 124-13-0<br />
| octanal<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of octanal for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 712<br />
| W<br />
| 79-00-5<br />
| 1,1,2-trichloroethane<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of 1,1,2-trichloroethane for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 713<br />
| W<br />
| 79-01-6<br />
| trichloroethene<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of trichloroethene for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 714<br />
| W<br />
| 127-18-4<br />
| tetrachloroethene<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of tetrachloroethene for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 715<br />
| W<br />
| 80-56-8<br />
| alpha-pinene<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of alpha-pinene for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 716<br />
| W<br />
| 5989-27-5<br />
| limonene<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of d-limonene for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 717<br />
| W<br />
| 872-50-4<br />
| 1-methyl-2-pyrrolidinone<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of 1-methyl-2-pyrrolidinone for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
| 718<br />
| W<br />
| 13466-78-9<br />
| 3-carene<br />
| VOC_W_1<br />
| study24<br />
| Summary statistics of 3-carene for workplace (ug/m3)<br />
| <br />
| O<br />
|----<br />
|}<br />
<br />
<br />
<br />
==Result==<br />
<br />
==See also==<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
==Related files==</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Volatile_organic_compounds_among_workers_in_Mexico_in_2002&diff=16098
Volatile organic compounds among workers in Mexico in 2002
2010-06-23T12:25:41Z
<p>Minttu: </p>
<hr />
<div>[[category:Exposure assessment]]<br />
[[Category:Expoplatform]]<br />
[[Category:Concentration database]]<br />
{{study|moderator=minttu}}<br />
<br />
==Scope==<br />
Personal exposures to volatile organic compounds among 68 outdoor and indoor workers in two mexican cities in 2002<br />
<ref>Tovalin-Ahumada et al.,The Science of The Total Environment 376 (2007), 60-71<br />
</ref><br />
<br />
==Definition==<br />
<br />
* id: study21<br />
* Abbreviation:<br />
<br />
===Data===<br />
<br />
{| {{prettytable}}<br />
| id<br />
| obj_type<br />
| obj_id<br />
| name<br />
| data_table<br />
| study_id<br />
| desc<br />
| add_info<br />
| location<br />
|----<br />
<br />
| 373<br />
| P<br />
| 71-43-2<br />
| benzene<br />
| VOC_P_13<br />
| study11<br />
| Personal benzene exposures (ug/m3) in six periods<br />
| Measurements took place every 2 months and lasted from Monday to Friday.<br />
| A<br />
|----<br />
| 374<br />
| I<br />
| 71-43-2<br />
| benzene<br />
| VOC_I_3<br />
| study11<br />
| Concentration of benzene in home indoor (ug/m3) in six periods<br />
| Measurements took place every 2 months and lasted from Monday to Friday.<br />
| A<br />
|----<br />
|}<br />
<br />
<br />
==Result==<br />
<br />
==See also==<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
==Related files==</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Volatile_organic_compounds_among_workers_in_Mexico_in_2002&diff=16096
Volatile organic compounds among workers in Mexico in 2002
2010-06-23T12:22:32Z
<p>Minttu: </p>
<hr />
<div>[[category:Exposure assessment]]<br />
[[Category:Expoplatform]]<br />
[[Category:Concentration database]]<br />
{{study|moderator=minttu}}<br />
<br />
==Scope==<br />
Indoor air and personal exposure to benzene in Athens, Greece in 1997-1998 with 50 non-smoking persons<br />
<ref>Chatzis et al., Sci. Total Environ. 349 (2005), 72-80<br />
</ref><br />
<br />
==Definition==<br />
<br />
* id: study21<br />
* Abbreviation:<br />
<br />
===Data===<br />
<br />
{| {{prettytable}}<br />
| id<br />
| obj_type<br />
| obj_id<br />
| name<br />
| data_table<br />
| study_id<br />
| desc<br />
| add_info<br />
| location<br />
|----<br />
<br />
| 373<br />
| P<br />
| 71-43-2<br />
| benzene<br />
| VOC_P_13<br />
| study11<br />
| Personal benzene exposures (ug/m3) in six periods<br />
| Measurements took place every 2 months and lasted from Monday to Friday.<br />
| A<br />
|----<br />
| 374<br />
| I<br />
| 71-43-2<br />
| benzene<br />
| VOC_I_3<br />
| study11<br />
| Concentration of benzene in home indoor (ug/m3) in six periods<br />
| Measurements took place every 2 months and lasted from Monday to Friday.<br />
| A<br />
|----<br />
|}<br />
<br />
<br />
==Result==<br />
<br />
==See also==<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
==Related files==</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Volatile_organic_compounds_among_workers_in_Mexico_in_2002&diff=16094
Volatile organic compounds among workers in Mexico in 2002
2010-06-23T12:17:42Z
<p>Minttu: Created page with 'category:Exposure assessment Category:Expoplatform Category:Concentration database {{study|moderator=minttu}} ==Scope== Indoor air and personal exposure to benzene i…'</p>
<hr />
<div>[[category:Exposure assessment]]<br />
[[Category:Expoplatform]]<br />
[[Category:Concentration database]]<br />
{{study|moderator=minttu}}<br />
<br />
==Scope==<br />
Indoor air and personal exposure to benzene in Athens, Greece in 1997-1998 with 50 non-smoking persons<br />
<ref>Chatzis et al., Sci. Total Environ. 349 (2005), 72-80<br />
</ref><br />
<br />
==Definition==<br />
<br />
* id: study11<br />
* Abbreviation:<br />
<br />
===Data===<br />
<br />
{| {{prettytable}}<br />
| id<br />
| abbrev<br />
| desc<br />
| ref<br />
|----<br />
<br />
| 373<br />
| P<br />
| 71-43-2<br />
| benzene<br />
| VOC_P_13<br />
| study11<br />
| Personal benzene exposures (ug/m3) in six periods<br />
| Measurements took place every 2 months and lasted from Monday to Friday.<br />
| A<br />
|----<br />
| 374<br />
| I<br />
| 71-43-2<br />
| benzene<br />
| VOC_I_3<br />
| study11<br />
| Concentration of benzene in home indoor (ug/m3) in six periods<br />
| Measurements took place every 2 months and lasted from Monday to Friday.<br />
| A<br />
|----<br />
|}<br />
<br />
<br />
==Result==<br />
<br />
==See also==<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
==Related files==</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Aromatic_hydrocarbons_in_persons_blood_in_Northern_Germany_in_1995-1997&diff=16092
Aromatic hydrocarbons in persons blood in Northern Germany in 1995-1997
2010-06-23T12:09:55Z
<p>Minttu: Created page with 'category:Exposure assessment Category:Expoplatform Category:Concentration database {{study|moderator=minttu}} ==Scope== Aromatic hydrocarbons in indoor and outdoor a…'</p>
<hr />
<div>[[category:Exposure assessment]]<br />
[[Category:Expoplatform]]<br />
[[Category:Concentration database]]<br />
{{study|moderator=minttu}}<br />
<br />
==Scope==<br />
Aromatic hydrocarbons in indoor and outdoor air and in non-smoking persons blood in Northern Germany in 1995-1997<br />
<ref>Ilgen et al., Atmospheric Environment 35 (2001), 1235-1252<br />
</ref><br />
<br />
==Definition==<br />
<br />
* id: study19<br />
* Abbreviation:<br />
<br />
===Data===<br />
<br />
{| {{prettytable}}<br />
| id<br />
| obj_type<br />
| obj_id<br />
| name<br />
| data_table<br />
| study_id<br />
| desc<br />
| add_info<br />
| location<br />
|----<br />
<br />
| 510<br />
| O<br />
| 71-43-2<br />
| benzene<br />
| VOC_O_5<br />
| study19<br />
| Outdoor air concentrations of benzene (µg/m3) in a rural and an urban area<br />
| <br />
| HA<br />
|----<br />
| 511<br />
| O<br />
| 108-88-3<br />
| toluene<br />
| VOC_O_5<br />
| study19<br />
| Outdoor air concentrations of toluene (µg/m3) in a rural and an urban area<br />
| <br />
| HA<br />
|----<br />
| 512<br />
| I<br />
| 71-43-2<br />
| benzene<br />
| VOC_I_6<br />
| study19<br />
| Average indoor concentrations (µg/m3) (passive sampling 14 d) in rural and urban area.<br />
| <br />
| HA<br />
|----<br />
| 513<br />
| I<br />
| 108-88-3<br />
| toluene<br />
| VOC_I_6<br />
| study19<br />
| Average indoor concentrations (µg/m3) (passive sampling 14 d) in rural and urban area.<br />
| <br />
| HA<br />
|----<br />
| 514<br />
| I<br />
| 100-41-4<br />
| ethylbenzene<br />
| VOC_I_6<br />
| study19<br />
| Average indoor concentrations (µg/m3) (passive sampling 14 d) in rural and urban area.<br />
| <br />
| HA<br />
|----<br />
| 515<br />
| I<br />
| 95-47-6<br />
| o-xylene<br />
| VOC_I_6<br />
| study19<br />
| Average indoor concentrations (µg/m3) (passive sampling 14 d) in rural and urban area.<br />
| <br />
| HA<br />
|----<br />
| 516<br />
| H<br />
| 71-43-2<br />
| benzene<br />
| VOC_H_4<br />
| study19<br />
| Concentrations in blood (ng/l) in rural and urban area<br />
| <br />
| HA<br />
|----<br />
| 517<br />
| H<br />
| 100-41-4<br />
| ethylbenzene<br />
| VOC_H_4<br />
| study19<br />
| Concentrations in blood (ng/l) in rural and urban area<br />
| <br />
| HA<br />
|----<br />
| 518<br />
| H<br />
| 95-47-6<br />
| o-xylene<br />
| VOC_H_4<br />
| study19<br />
| Concentrations in blood (ng/l) in rural and urban area<br />
| <br />
| HA<br />
|----<br />
|}<br />
<br />
<br />
==Result==<br />
<br />
==See also==<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
==Related files==</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Exposure_to_benzene_in_Athens,_Greece_in_1997-1998&diff=16090
Exposure to benzene in Athens, Greece in 1997-1998
2010-06-23T12:05:23Z
<p>Minttu: </p>
<hr />
<div>[[category:Exposure assessment]]<br />
[[Category:Expoplatform]]<br />
[[Category:Concentration database]]<br />
{{study|moderator=minttu}}<br />
<br />
==Scope==<br />
Indoor air and personal exposure to benzene in Athens, Greece in 1997-1998 with 50 non-smoking persons<br />
<ref>Chatzis et al., Sci. Total Environ. 349 (2005), 72-80<br />
</ref><br />
<br />
==Definition==<br />
<br />
* id: study11<br />
* Abbreviation:<br />
<br />
===Data===<br />
<br />
{| {{prettytable}}<br />
| id<br />
| obj_type<br />
| obj_id<br />
| name<br />
| data_table<br />
| study_id<br />
| desc<br />
| add_info<br />
| location<br />
|----<br />
<br />
| 373<br />
| P<br />
| 71-43-2<br />
| benzene<br />
| VOC_P_13<br />
| study11<br />
| Personal benzene exposures (ug/m3) in six periods<br />
| Measurements took place every 2 months and lasted from Monday to Friday.<br />
| A<br />
|----<br />
| 374<br />
| I<br />
| 71-43-2<br />
| benzene<br />
| VOC_I_3<br />
| study11<br />
| Concentration of benzene in home indoor (ug/m3) in six periods<br />
| Measurements took place every 2 months and lasted from Monday to Friday.<br />
| A<br />
|----<br />
|}<br />
<br />
<br />
==Result==<br />
<br />
==See also==<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
==Related files==</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Blood_cadmium_concentrations_in_Central_Italy&diff=16088
Blood cadmium concentrations in Central Italy
2010-06-23T12:02:20Z
<p>Minttu: Created page with 'category:Exposure assessment Category:Expoplatform Category:Concentration database {{study|moderator=minttu}} ==Scope== Blood cadmium concentrations in 334 persons i…'</p>
<hr />
<div>[[category:Exposure assessment]]<br />
[[Category:Expoplatform]]<br />
[[Category:Concentration database]]<br />
{{study|moderator=minttu}}<br />
<br />
==Scope==<br />
Blood cadmium concentrations in 334 persons in the general population of Umbria, Central Italy<br />
<ref>dell`Omo et al., The Science of The Total Environment 226 (1999), 57-64<br />
</ref><br />
<br />
==Definition==<br />
<br />
* id: study16<br />
* Abbreviation:<br />
<br />
===Data===<br />
<br />
{| {{prettytable}}<br />
| id<br />
| obj_type<br />
| obj_id<br />
| name<br />
| data_table<br />
| study_id<br />
| desc<br />
| add_info<br />
| location<br />
|----<br />
<br />
| 447<br />
| H<br />
| 7440-43-9<br />
| cadmium<br />
| MET_H_7<br />
| study16<br />
| Blood cadmium levels (µg/l) in relation to smoking habit, gender and residental area<br />
| <br />
| UMB<br />
|----<br />
|}<br />
<br />
<br />
==Result==<br />
<br />
==See also==<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
==Related files==</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Category:Concentration_database&diff=16087
Category:Concentration database
2010-06-23T11:55:35Z
<p>Minttu: </p>
<hr />
<div>[[Category:Expoplatform]]<br />
List of pages that belong to the '''Concentration database''' of [[ExpoPlatform]].<br />
<br />
*[[EXPOLIS]]<br />
*[[Shield]]<br />
*[[Exposure to toxic air contaminants in ETS]]<br />
*[[VOC exposures with children age of 3 to 12 years in 1997]]<br />
*[[Volatile organic compounds in Mexico City]]<br />
*[[NHEXAS]]<br />
*[[Aromatic hydrocarbons with 55 non-smoking persons in Germany]]<br />
*[[MACBETH]]<br />
*[[TEAM]]<br />
*[[GerES]]<br />
*[[Exposure to benzene in Athens, Greece in 1997-1998]]<br />
*[[Blood cadmium concentrations in Central Italy]]<br />
*[[Internal exposure to acrylamide in smoking and non-smoking adults from Germany]]<br />
*[[Aromatic hydrocarbons in persons blood in Northern Germany in 1995-1997]]<br />
*[[NHANES]]<br />
*[[Volatile organic compounds among workers in Mexico in 2002]]<br />
*[[Fine particulate matter and VOCs between trasport microenvironments in Dublin]]<br />
*[[Volatile organic compounds in smoking and non-smoking homes in 1991 in Columbus]]<br />
*[[Personal exposures and microenvironment concentrations of PM2.5, VOC, NO2 and CO in Oxford in 1998-2000]]<br />
*[[Personal exposure of children and adults to airborne benzene in France in 2001-2003]]<br />
*[[Pollutants measured in blood and urine]]<br />
*[[Volatile organic compounds among workers in Mexico.]]<br />
*[[Benzene exposure in non-smoking people residing in Italy]]<br />
*[[Ambient Air Levels and the Personal Exposure of Children to Benzene, Toluene, and Xylenes in Denmark]]<br />
*[[Personal exposure to elements in Mexico City air]]<br />
*[[Personal daily exposures to benzo(a)pyrene of taxi drivers in Italy]]<br />
*[[Personal carbon monoxide exposures of preschool children in Finland]]</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Exposure_to_benzene_in_Athens,_Greece_in_1997-1998&diff=16086
Exposure to benzene in Athens, Greece in 1997-1998
2010-06-23T11:52:58Z
<p>Minttu: Created page with 'category:Exposure assessment Category:Expoplatform Category:Concentration database {{study|moderator=minttu}} ==Scope== Indoor air and personal exposure to benzene i…'</p>
<hr />
<div>[[category:Exposure assessment]]<br />
[[Category:Expoplatform]]<br />
[[Category:Concentration database]]<br />
{{study|moderator=minttu}}<br />
<br />
==Scope==<br />
Indoor air and personal exposure to benzene in Athens, Greece in 1997-1998 with 50 non-smoking persons<br />
<ref>Chatzis et al., Sci. Total Environ. 349 (2005), 72-80<br />
</ref><br />
<br />
==Definition==<br />
<br />
* id: study11<br />
* Abbreviation:<br />
<br />
===Data===<br />
<br />
{| {{prettytable}}<br />
| 373<br />
| P<br />
| 71-43-2<br />
| benzene<br />
| VOC_P_13<br />
| study11<br />
| Personal benzene exposures (ug/m3) in six periods<br />
| Measurements took place every 2 months and lasted from Monday to Friday.<br />
| A<br />
|----<br />
| 374<br />
| I<br />
| 71-43-2<br />
| benzene<br />
| VOC_I_3<br />
| study11<br />
| Concentration of benzene in home indoor (ug/m3) in six periods<br />
| Measurements took place every 2 months and lasted from Monday to Friday.<br />
| A<br />
|----<br />
|}<br />
<br />
<br />
==Result==<br />
<br />
==See also==<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
==Related files==</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=TEAM&diff=16084
TEAM
2010-06-23T11:49:14Z
<p>Minttu: </p>
<hr />
<div>[[category:Exposure assessment]]<br />
[[Category:Expoplatform]]<br />
[[Category:Concentration database]]<br />
{{study|moderator=minttu}}<br />
<br />
==Scope==<br />
<br />
TEAM study: Variability of environmental exposures to volatile organic compounds in years 1981-1987 <ref>Rappaport and Kupper, J. Exposure. Analysis & Environ. Epidemiology 14 (2004), 92-107<br />
</ref><br />
<br />
==Definition==<br />
<br />
* id: study9<br />
* Abbreviation:<br />
<br />
===Data===<br />
<br />
{| {{prettytable}}<br />
| 321<br />
| P<br />
| 71-43-2<br />
| benzene<br />
| VOC_P_11<br />
| study9<br />
| Personal 24h benzene concentrations (ug/m3) in 1981-1987<br />
| Parameters estimated using logged air concentrations; see study for more information. NM - not measured.<br />
| BAY, ELI, GRB, LA, DLA<br />
|----<br />
| 322<br />
| P<br />
| 67-66-3<br />
| chloroform<br />
| VOC_P_11<br />
| study9<br />
| Personal 24h chloroform concentrations (ug/m3) in 1981-1987<br />
| Parameters estimated using logged air concentrations; see study for more information. NM - not measured.<br />
| BAY, ELI, GRB, LA, DLA<br />
|----<br />
| 323<br />
| P<br />
| 100-41-4<br />
| ethylbenzene<br />
| VOC_P_11<br />
| study9<br />
| Personal 24h ethylbenzene concentrations (ug/m3) in 1981-1987<br />
| Parameters estimated using logged air concentrations; see study for more information. NM - not measured.<br />
| BAY, ELI, GRB, LA, DLA<br />
|----<br />
| 324<br />
| P<br />
| 71-55-6<br />
| 1,1,1-trichloroethane<br />
| VOC_P_11<br />
| study9<br />
| Personal 24h methylchloroform concentrations (ug/m3) in 1981-1987<br />
| Parameters estimated using logged air concentrations; see study for more information. NM - not measured.<br />
| BAY, ELI, GRB, LA, DLA<br />
|----<br />
| 325<br />
| P<br />
| 106-46-7<br />
| p-dichlorobenzene<br />
| VOC_P_11<br />
| study9<br />
| Personal 24h p-dichlorobenzene concentrations (ug/m3) in 1981-1987<br />
| Parameters estimated using logged air concentrations; see study for more information. NM - not measured.<br />
| BAY, ELI, GRB, LA, DLA<br />
|----<br />
| 326<br />
| P<br />
| 127-18-4<br />
| tetrachloroethene<br />
| VOC_P_11<br />
| study9<br />
| Personal 24h perchloroethylene concentrations (ug/m3) in 1981-1987<br />
| Parameters estimated using logged air concentrations; see study for more information. NM - not measured.<br />
| BAY, ELI, GRB, LA, DLA<br />
|----<br />
| 327<br />
| P<br />
| 100-42-5<br />
| styrene<br />
| VOC_P_11<br />
| study9<br />
| Personal 24h styrene concentrations (ug/m3) in 1981-1987<br />
| Parameters estimated using logged air concentrations; see study for more information. NM - not measured.<br />
| BAY, ELI, GRB, LA, DLA<br />
|----<br />
| 328<br />
| P<br />
| 79-01-6<br />
| trichloroethene<br />
| VOC_P_11<br />
| study9<br />
| Personal 24h trichloroethylene concentrations (ug/m3) in 1981-1987<br />
| Parameters estimated using logged air concentrations; see study for more information. NM - not measured.<br />
| BAY, ELI, GRB, LA, DLA<br />
|----<br />
| 329<br />
| P<br />
| 95-47-6<br />
| o-xylene<br />
| VOC_P_11<br />
| study9<br />
| Personal 24h o-xylene concentrations (ug/m3) in 1981-1987<br />
| Parameters estimated using logged air concentrations; see study for more information. NM - not measured.<br />
| BAY, ELI, GRB, LA, DLA<br />
|----<br />
|}<br />
<br />
<br />
==Result==<br />
<br />
<br />
<br />
==See also==<br />
<br />
<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
==Related files==<br />
<br />
{{mfiles}}</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=TEAM&diff=16080
TEAM
2010-06-23T11:44:11Z
<p>Minttu: Created page with 'category:Exposure assessment Category:Expoplatform Category:Concentration database {{study|moderator=Jouni}} ==Scope== Exposure to toxic air contaminants in ETS: An…'</p>
<hr />
<div>[[category:Exposure assessment]]<br />
[[Category:Expoplatform]]<br />
[[Category:Concentration database]]<br />
{{study|moderator=Jouni}}<br />
<br />
==Scope==<br />
<br />
Exposure to toxic air contaminants in ETS: An assessment for California based on personal monitoring data in years 1984 to 1990.<ref>Miller et al., J. Exposure. Analysis & Environ. Epidemiology 8 (1998), 287-311<br />
</ref><br />
<br />
==Definition==<br />
<br />
* id: study2<br />
* Abbreviation:<br />
<br />
===Data===<br />
<br />
{| {{prettytable}}<br />
| id<br />
| obj_type<br />
| obj_id<br />
| name<br />
| data_table<br />
| study_id<br />
| desc<br />
| add_info<br />
| location<br />
|----<br />
| 138<br />
| P<br />
| 71-43-2<br />
| benzene<br />
| VOC_P_2<br />
| study2<br />
| 24h Personal benzene exposure (ug/m3) in Californian population &lt;sup&gt;1&lt;/sup&gt;<br />
| &lt;sup&gt;1&lt;/sup&gt; ETS-only + unexposed and ETS only exposure categories indicate distribution constructed by the authors; the other distributions are derived from the Calfornia Exposures Database (see more detailes from the study) &lt;sup&gt;2&lt;/sup&gt; Number of observations. These observations were sampled 10 000 times using a weighting scheme designed to approximate Californian population exposures (see study for details).<br />
| CA<br />
|----<br />
| 139<br />
| P<br />
| 100-42-5<br />
| styrene<br />
| VOC_P_2<br />
| study2<br />
| 24h Personal styrene exposure (ug/m3) in Californian population &lt;sup&gt;1&lt;/sup&gt;<br />
| &lt;sup&gt;1&lt;/sup&gt; ETS-only + unexposed and ETS only exposure categories indicate distribution constructed by the authors; the other distributions are derived from the Calfornia Exposures Database (see more detailes from the study) &lt;sup&gt;2&lt;/sup&gt; Number of observations. These observations were sampled 10 000 times using a weighting scheme designed to approximate Californian population exposures (see study for details).<br />
| CA<br />
|----<br />
| 140<br />
| P<br />
| 95-47-6<br />
| o-xylene<br />
| VOC_P_2<br />
| study2<br />
| 24h Personal o-xylene exposure (ug/m3) in Californian population &lt;sup&gt;1&lt;/sup&gt;<br />
| &lt;sup&gt;1&lt;/sup&gt; ETS-only + unexposed and ETS only exposure categories indicate distribution constructed by the authors; the other distributions are derived from the Calfornia Exposures Database (see more detailes from the study) &lt;sup&gt;2&lt;/sup&gt; Number of observations. These observations were sampled 10 000 times using a weighting scheme designed to approximate Californian population exposures (see study for details).<br />
| CA<br />
|----<br />
|}<br />
<br />
==Result==<br />
<br />
{{resultlink}}<br />
<br />
<br />
<br />
==See also==<br />
<br />
<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
==Related files==<br />
<br />
{{mfiles}}</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Volatile_organic_compounds_in_Mexico_City&diff=16079
Volatile organic compounds in Mexico City
2010-06-23T11:42:37Z
<p>Minttu: </p>
<hr />
<div>[[category:Exposure assessment]]<br />
[[Category:Expoplatform]]<br />
[[Category:Concentration database]]<br />
{{study|moderator=minttu}}<br />
<br />
==Scope==<br />
Ambient, indoor and personal exposure relationships of volatile organic compounds in Mexico City Metropolitan Area<br />
<ref>Serrano-Trespalacios et al., J. Exposure Analysis & Environ. Epidemiology 14, Suppl 1 (2004), s118-s132<br />
</ref><br />
<br />
==Definition==<br />
<br />
* id: study4<br />
* Abbreviation:<br />
<br />
===Data===<br />
{| {{prettytable}}<br />
| id<br />
| obj_type<br />
| obj_id<br />
| name<br />
| data_table<br />
| study_id<br />
| desc<br />
| add_info<br />
| location<br />
|----<br />
<br />
| 171<br />
| P<br />
| 67-66-3<br />
| chloroform<br />
| VOC_P_4<br />
| study4<br />
| Personal chloroform concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 172<br />
| P<br />
| 71-43-2<br />
| benzene<br />
| VOC_P_4<br />
| study4<br />
| Personal benzene concentrations (ug/m3) <br />
| <br />
| MXC<br />
|----<br />
| 173<br />
| P<br />
| 100-41-4<br />
| ethylbenzene<br />
| VOC_P_4<br />
| study4<br />
| Personal ethylbenzene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 174<br />
| P<br />
| 100-42-5<br />
| styrene<br />
| VOC_P_4<br />
| study4<br />
| Personal styrene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 175<br />
| P<br />
| 106-46-7<br />
| 1,4-dichlorobenzene<br />
| VOC_P_4<br />
| study4<br />
| Personal 1,4-dichlorobenzene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 176<br />
| P<br />
| 106-99-0<br />
| 1,3-butadiene<br />
| VOC_P_4<br />
| study4<br />
| Personal 1,3-butadiene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 177<br />
| P<br />
| 108-88-3<br />
| toluene<br />
| VOC_P_4<br />
| study4<br />
| Personal toluene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 178<br />
| P<br />
| 127-18-4<br />
| tetrachloroethene<br />
| VOC_P_4<br />
| study4<br />
| Personal tetrachloroethylene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 179<br />
| P<br />
| 1634-04-4<br />
| methyl t-butyl ether<br />
| VOC_P_4<br />
| study4<br />
| Personal MTBE concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 180<br />
| P<br />
| 95-47-6<br />
| o-xylene<br />
| VOC_P_4<br />
| study4<br />
| Personal o-xylene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 181<br />
| P<br />
| 590-86-3<br />
| isovaleraldehyde<br />
| VOC_P_4<br />
| study4<br />
| Personal isovaleraldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 182<br />
| P<br />
| 123-38-6<br />
| propionaldehyde<br />
| VOC_P_4<br />
| study4<br />
| Personal propionaldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 183<br />
| P<br />
| 123-72-8<br />
| n-butyraldehyde<br />
| VOC_P_4<br />
| study4<br />
| Personal n-butyraldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 184<br />
| P<br />
| 75-07-0<br />
| acetaldehyde<br />
| VOC_P_4<br />
| study4<br />
| Personal acetaldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 185<br />
| P<br />
| 66-25-1<br />
| hexanal<br />
| VOC_P_4<br />
| study4<br />
| Personal hexanaldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 186<br />
| P<br />
| 50-00-0<br />
| formaldehyde<br />
| VOC_P_4<br />
| study4<br />
| Personal formaldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 187<br />
| P<br />
| 110-62-3<br />
| valeraldehyde<br />
| VOC_P_4<br />
| study4<br />
| Personal valeraldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 188<br />
| P<br />
| 71-55-6<br />
| 1,1,1-trichloroethane<br />
| VOC_P_4<br />
| study4<br />
| Personal 1,1,1-trichloroethane concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 189<br />
| P<br />
| 56-23-5<br />
| carbon tetrachloride<br />
| VOC_P_4<br />
| study4<br />
| Personal carbon tetrachloride concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 190<br />
| P<br />
| 4170-30-3<br />
| crotonaldehyde<br />
| VOC_P_4<br />
| study4<br />
| Personal crotonaldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 191<br />
| I<br />
| 67-66-3<br />
| chloroform<br />
| VOC_I_5<br />
| study4<br />
| Indoor chloroform concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 192<br />
| I<br />
| 71-43-2<br />
| benzene<br />
| VOC_I_5<br />
| study4<br />
| Indoor benzene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 193<br />
| I<br />
| 100-41-4<br />
| ethylbenzene<br />
| VOC_I_5<br />
| study4<br />
| Indoor ethylbenzene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 194<br />
| I<br />
| 100-42-5<br />
| styrene<br />
| VOC_I_5<br />
| study4<br />
| Indoor styrene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 195<br />
| I<br />
| 106-46-7<br />
| 1,4-dichlorobenzene<br />
| VOC_I_5<br />
| study4<br />
| Indoor 1,4-dichlorobenzene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 196<br />
| I<br />
| 106-99-0<br />
| 1,3-butadiene<br />
| VOC_I_5<br />
| study4<br />
| Indoor 1,3-butadiene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 197<br />
| I<br />
| 108-88-3<br />
| toluene<br />
| VOC_I_5<br />
| study4<br />
| Indoor toluene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 198<br />
| I<br />
| 127-18-4<br />
| tetrachloroethene<br />
| VOC_I_5<br />
| study4<br />
| Indoor tetrachloroethylene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 199<br />
| I<br />
| 1634-04-4<br />
| methyl t-butyl ether<br />
| VOC_I_5<br />
| study4<br />
| Indoor MTBE concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 200<br />
| I<br />
| 95-47-6<br />
| o-xylene<br />
| VOC_I_5<br />
| study4<br />
| Indoor o-xylene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 201<br />
| I<br />
| 590-86-3<br />
| isovaleraldehyde<br />
| VOC_I_5<br />
| study4<br />
| Indoor isovaleraldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 202<br />
| I<br />
| 123-38-6<br />
| propionaldehyde<br />
| VOC_I_5<br />
| study4<br />
| Indoor propionaldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 203<br />
| I<br />
| 123-72-8<br />
| n-butyraldehyde<br />
| VOC_I_5<br />
| study4<br />
| Indoor n-butyraldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 204<br />
| I<br />
| 75-07-0<br />
| acetaldehyde<br />
| VOC_I_5<br />
| study4<br />
| Indoor acetaldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 205<br />
| I<br />
| 66-25-1<br />
| hexanal<br />
| VOC_I_5<br />
| study4<br />
| Indoor hexanaldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 206<br />
| I<br />
| 50-00-0<br />
| formaldehyde<br />
| VOC_I_5<br />
| study4<br />
| Indoor formaldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 207<br />
| I<br />
| 110-62-3<br />
| valeraldehyde<br />
| VOC_I_5<br />
| study4<br />
| Indoor valeraldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 208<br />
| I<br />
| 71-55-6<br />
| 1,1,1-trichloroethane<br />
| VOC_I_5<br />
| study4<br />
| Indoor 1,1,1-trichloroethane concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 209<br />
| I<br />
| 56-23-5<br />
| carbon tetrachloride<br />
| VOC_I_5<br />
| study4<br />
| Indoor carbon tetrachloride concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 210<br />
| I<br />
| 4170-30-3<br />
| crotonaldehyde<br />
| VOC_I_5<br />
| study4<br />
| Indoor crotonaldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 211<br />
| O<br />
| 67-66-3<br />
| chloroform<br />
| VOC_O_4<br />
| study4<br />
| Outdoor (home) chloroform concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 212<br />
| O<br />
| 71-43-2<br />
| benzene<br />
| VOC_O_4<br />
| study4<br />
| Outdoor (home) benzene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 213<br />
| O<br />
| 100-41-4<br />
| ethylbenzene<br />
| VOC_O_4<br />
| study4<br />
| Outdoor (home) ethylbenzene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 214<br />
| O<br />
| 100-42-5<br />
| styrene<br />
| VOC_O_4<br />
| study4<br />
| Outdoor (home) styrene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 215<br />
| O<br />
| 106-46-7<br />
| 1,4-dichlorobenzene<br />
| VOC_O_4<br />
| study4<br />
| Outdoor (home) 1,4-dichlorobenzene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 216<br />
| O<br />
| 106-99-0<br />
| 1,3-butadiene<br />
| VOC_O_4<br />
| study4<br />
| Outdoor (home) 1,3-butadiene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 217<br />
| O<br />
| 108-88-3<br />
| toluene<br />
| VOC_O_4<br />
| study4<br />
| Outdoor (home) toluene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 218<br />
| O<br />
| 127-18-4<br />
| tetrachloroethene<br />
| VOC_O_4<br />
| study4<br />
| Outdoor (home) tetrachloroethylene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 219<br />
| O<br />
| 1634-04-4<br />
| methyl t-butyl ether<br />
| VOC_O_4<br />
| study4<br />
| Outdoor (home) MTBE concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 220<br />
| O<br />
| 95-47-6<br />
| o-xylene<br />
| VOC_O_4<br />
| study4<br />
| Outdoor (home) o-xylene concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 221<br />
| O<br />
| 590-86-3<br />
| isovaleraldehyde<br />
| VOC_O_4<br />
| study4<br />
| Outdoor (home) isovaleraldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 222<br />
| O<br />
| 123-38-6<br />
| propionaldehyde<br />
| VOC_O_4<br />
| study4<br />
| Outdoor (home) propionaldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 223<br />
| O<br />
| 123-72-8<br />
| n-butyraldehyde<br />
| VOC_O_4<br />
| study4<br />
| Outdoor (home) n-butyraldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 224<br />
| O<br />
| 75-07-0<br />
| acetaldehyde<br />
| VOC_O_4<br />
| study4<br />
| Outdoor (home) acetaldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 225<br />
| O<br />
| 66-25-1<br />
| hexanal<br />
| VOC_O_4<br />
| study4<br />
| Outdoor (home) hexanaldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 226<br />
| O<br />
| 50-00-0<br />
| formaldehyde<br />
| VOC_O_4<br />
| study4<br />
| Outdoor (home) formaldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 227<br />
| O<br />
| 110-62-3<br />
| valeraldehyde<br />
| VOC_O_4<br />
| study4<br />
| Outdoor (home) valeraldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 228<br />
| O<br />
| 71-55-6<br />
| 1,1,1-trichloroethane<br />
| VOC_O_4<br />
| study4<br />
| Outdoor (home) 1,1,1-trichloroethane concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 229<br />
| O<br />
| 56-23-5<br />
| carbon tetrachloride<br />
| VOC_O_4<br />
| study4<br />
| Outdoor (home) carbon tetrachloride concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
| 230<br />
| O<br />
| 4170-30-3<br />
| crotonaldehyde<br />
| VOC_O_4<br />
| study4<br />
| Outdoor (home) crotonaldehyde concentrations (ug/m3)<br />
| <br />
| MXC<br />
|----<br />
|}<br />
<br />
<br />
==Result==<br />
<br />
==See also==<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
==Related files==</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Volatile_organic_compounds_in_Mexico_City&diff=16074
Volatile organic compounds in Mexico City
2010-06-23T10:49:53Z
<p>Minttu: Created page with 'category:Exposure assessment Category:Expoplatform Category:Concentration database {{study|moderator=heta}} ==Scope== '''EXPOLIS''' study: A monitoring study that m…'</p>
<hr />
<div>[[category:Exposure assessment]]<br />
[[Category:Expoplatform]]<br />
[[Category:Concentration database]]<br />
{{study|moderator=heta}}<br />
<br />
==Scope==<br />
<br />
'''EXPOLIS''' study: A monitoring study that measured the population exposures to key air pollutants in six European cities. Concentrations were measured in home indoor, home outdoor and work indoor environments and in addition personal exposure were measured for 48hr with carry-on samplers. Measurements took place in 1996-1997.<ref>http://www.ktl.fi/expolis</ref><br />
<br />
<br />
==Definition==<br />
<br />
* id: expolis/study7<br />
* Abbreviation: EXPOLIS <br />
<br />
===Data===<br />
<br />
<br />
==Result==<br />
<br />
{{resultlink}}<br />
<br />
==See also==<br />
<br />
==References==<br />
<br />
<references/><br />
<br />
==Related files==<br />
<br />
{{mfiles}}</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Blind_drunk_%E2%80%93_or_dead_drunk%3F&diff=15763
Blind drunk – or dead drunk?
2010-06-21T09:44:42Z
<p>Minttu: Created page with 'Methanol, methyl alcohol or wood alcohol (CH3OH) is one of the chemicals well known by lay people. Its risks in poorly distilled moonshine whiskies and similar products of regula…'</p>
<hr />
<div>Methanol, methyl alcohol or wood alcohol (CH3OH) is one of the chemicals well known by lay people. Its risks in poorly distilled moonshine whiskies and similar products of regular alcohol or ethanol have become quite clear over decades. Methanol is added in many countries into technical alcohols on purpose: to denature alcohol to make it unfit for human consumption. This practice may also be criticized. My pharmacology professor Armas Vartiainen once stated that this practice should be subject to similar legislative process as the death penalty, because in fact it is a death penalty issued to anybody drinking these technical alcohols.<br />
<br />
Methanol poisoning is an example of the unexpected consequences caused by unification of standards between countries with different cultures and traditions. Free trade throughout Europe was interpreted to suffer from restrictions on methanol use, and methanol was reintroduced into markets in countries where it had not been used for decades. It is used in windshield washers, where its main advantage is its lower price compared with competing products; it is also quite effective at removing dirt. The proposal to add ethanol/methanol to petrol or to design automobile motors using these products as the sole fuel will cause an even more massive increase in methanol use.<br />
<br />
'''Health effects'''<br />
<br />
The hazards of methanol include both acute poisonings and long term adverse effects. Acute poisoning is usually caused by intentional or inadvertent consumption of technical products in place of alcohol. For example in Finland, acute deaths from methanol poisoning reached epidemic proportions after 1995 when the windshield washer products were introduced to the market due to the European Union ruling, and they started to decrease only after the year 2000 when warning labels with skull and crossbones were placed on the products to emphasize the deadly nature of these products. The problem still exists although at a somewhat lower level.<br />
<br />
The fatal dose is 80–150 ml of 40% methanol, but occasionally even 15 ml dose has caused death. Even 5 ml (a teaspoonful) can cause blindness. The blindness is caused by the metabolism of methanol in the body to formaldehyde and formic acid. Formaldehyde is so rapidly metabolised further to formic acid that it is usually not detected in the body, but formic acid concentrations may be high enough to evoke metabolic acidosis , and this causes damage to the eyes and brain. Permanent blindness can develop in 48 hours.<br />
<br />
'''Exposure via respiratory tract'''<br />
<br />
Part of the washer liquid components can also evaporate and enter the car interior via the ventilation system. Long-term exposure to methanol can then lead to a variety of central nervous system symptoms, headache, visual disturbances, tiredness and decreased vigilance. These can cause traffic safety problems. Exposure levels will depend on the ventilation system of the car. The risks of methanol fumes in cars require clarification, but it is already apparent that in some conditions they represent a serious hazard. In particular, any use leading to exposure of pregnant women and small children should be restricted.<br />
<br />
<br />
''Methanol is a good example of double standards in the attitudes toward chemicals. The introduction of a clearly hazardous chemical for everyday use has been justified because of economic arguments, even though there are many safer chemicals. One could claim that the most common victims (skid-row alcoholics) do not arouse the sympathy of the public.''</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Fluoride_%E2%80%93_friend_or_foe%3F&diff=15762
Fluoride – friend or foe?
2010-06-21T09:42:31Z
<p>Minttu: Created page with 'Fluoride is a source of great confusion, because on one hand it is added to tap water in hundreds of towns around the world, but on the other hand people are concerned about its …'</p>
<hr />
<div>Fluoride is a source of great confusion, because on one hand it is added to tap water in hundreds of towns around the world, but on the other hand people are concerned about its adverse effects. One example on this confusion is the discontinuation of fluoridation of water in Kuopio, Finland. Fluoride was added for thirty years (1959-1990) to prevent dental caries which was very prevalent in the region since the water naturally had a very low fluoride content. But a vocal local opposition movement finally succeeded in turning the general opinion on this issue, and the city fathers decided to discontinue fluoridation against expert advice, as they said that even beneficial interventions cannot be done without popular support. After this discontinuation of fluoride supplementation, the incidence of dental caries increased again.<br />
<br />
'''Benefit and risk'''<br />
<br />
Fluoride hardens the outer layer of tooth enamel and protects children's teeth from caries. This is because the fluoroapatite mineral in enamel is denser than the hydroxyapatite formed in the absence of fluoride. It may have beneficial effects also on the heart in decreasing the risk of heart attack. The beneficial concentration in water is about 1 mg/l. It is most effective in children before permanent teeth erupt, but there may be some limited benefits in children of older ages. <br />
<br />
We are dealing with a typical benefit-risk assessment. Low (1 mg/l) concentrations of fluoride are beneficial to the body, high concentrations (over 2 mg/l) cause harm. Exactly the same situation holds true for most vitamins and minerals. Additional confusion is caused by the inappropriate use of the word fluorine, which is a highly irritant and caustic vapour. The difference between fluorine and fluoride is as remarkable as between chlorine gas and table salt, sodium chloride.<br />
<br />
The safe range of fluoride concentrations in the drinking water is relatively narrow. To some extent, fluoride concentrations leading to useful and adverse effects also overlap and therefore it is best not to strive for maximal benefit. On the other hand, the allegations that fluoride causes cancer or increase mortality commonly argued by grass-root campaigners have not been substantiated in well-executed studies.<br />
<br />
Local application of fluoride solutions by dental personnel appears to be effective if dabbed on newly erupted teeth. The results of adding fluoride to toothpastes are conflicting. Dietary fluoride supplements can be used for children whose drinking water contains less than 0.7 mg/l fluoride. If one uses fluoride tablets, then care is required to ensure that children do not take extra tablets, because harmful effects are then possible.<br />
<br />
'''High natural concentrations'''<br />
<br />
It is well known that the natural fluoride concentrations in some geographical areas in many countries are too high. Often the limit value for fluoride in drinking water is 1.5 mg/l, but concentrations of 2–3 mg/l fluoride may already cause some mottling or irregular colouring of tooth enamel, a condition called dental fluorosis, and at 4–6 mg/l the mottling incidence approaches 100%. After chronic exposure to high concentrations of fluoride, also the bones become harder and brittle, at still higher exposures there may be structural changes in bones.<br />
<br />
The results on the association of excessive fluoride with fractures are equivocal. Some studies do suggest that hip fractures are increased in elderly women living in high-fluoride regions. In contrast, other studies have suggested fluoride at suitable levels may increase bone mineral density and decrease fractures. It seems to be clear that excessive fluoride intake does more harm than good. <br />
<br />
<br />
''Fluoride is a beneficial trace mineral for tooth development, but the problem is the relatively narrow range of the safe intake level. Excessively high concentrations cause adverse effects in both teeth and bones.''</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Are_we_starting_to_glow_from_the_uranium_in_our_environment%3F&diff=15761
Are we starting to glow from the uranium in our environment?
2010-06-21T09:41:45Z
<p>Minttu: Created page with 'Uranium in drinking water is a relatively recent concern, and Finland and Canada have been active in attempts to shed light on the risks of uranium exposure. The World Health Org…'</p>
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<div>Uranium in drinking water is a relatively recent concern, and Finland and Canada have been active in attempts to shed light on the risks of uranium exposure. The World Health Organisation has raised international awareness of this issue. The old limit values were based on radioactivity, but it is now appreciated that chemical toxicity is more important as a health risk.<br />
<br />
The World Health Organisation re-evaluated uranium recently. Now the basis was its chemical toxicity, and the new recommendation for the limit value is 0.015 mg/l, while the previous value based on radioactivity was 0.1 mg/l. The radiation risk is not considered so high. The same applies for so called depleted uranium, whose radioactivity is lower than that of natural uranium. Its main problem is also chemical toxicity, not radioactivity.<br />
<br />
The most important adverse effect of natural uranium is kidney toxicity, and this is the present basis for the health risk assessment. Some physiological changes have been detected in the users of tube wells in regions where there are uranium rich bedrocks. For example, increased excretion of calcium and phosphate to urine has been detected. The real implications for health are not yet known, and these continue to be studied.<br />
<br />
There may be other adverse effects. An association with increased blood pressure has been observed. Uranium is concentrated in the bones and may cause structural changes in bone. It is not known if natural uranium can cause cancer. There is enough information already to limit exposure to uranium as much as possible. It does seem to be a problem in drinking waters in many parts of Europe.<br />
<br />
<br />
''Uranium in drinking water was revealed as a problem only recently when it was realized that its chemical toxicity is more important than its radioactive properties.''</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Arsenic_in_the_drinking_water_%E2%80%93_reminiscent_of_the_movie_%E2%80%9CLavender_and_old_lace%E2%80%9D%3F&diff=15760
Arsenic in the drinking water – reminiscent of the movie “Lavender and old lace”?
2010-06-21T09:41:15Z
<p>Minttu: Created page with 'From the times of antiquity arsenic has been a substance recognized by toxicologists. The best known form is arsenic trioxide (usually known as “arsenic”). Large doses (i.e. …'</p>
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<div>From the times of antiquity arsenic has been a substance recognized by toxicologists. The best known form is arsenic trioxide (usually known as “arsenic”). Large doses (i.e. about one tenth of a gram) cause acute poisoning, including diarrhoea and other gastrointestinal symptoms, but also symptoms from a number of the internal organs, because arsenic has effects on critical metabolic functions in all cells. Death usually ensues from cardiovascular failure. Arsenic has been used over the years for political murders, because it is relatively tasteless. Nowadays long-term effects are more important than acute toxicity.<br />
<br />
The health effects of arsenic from drinking water are both very well known and widely studied, because the problem is world wide, with cancer being considered as the most critical adverse outcome. Very high concentrations in drinking water have also evoked a variety of vascular diseases even leading to gangrene of the lower extremities (so called black-foot disease). Other consequences are characteristic changes of the skin, peripheral neuropathies and liver injury. All these have been seen in high-exposure areas in Taiwan and Chile, recently also in Bangladesh after the introduction of deep tube wells.<br />
<br />
'''Possible effects of low concentrations'''<br />
<br />
Recent Finnish studies have suggested that there may be a slightly increased risk of bladder cancer in populations consuming water from tube wells (drilled wells) in arsenic rich areas. Blood cells demonstrate changes that may predict increased risk of cancer. The association could be detected even at arsenic concentrations lower than the present limit values of arsenic (0.01 mg/l). Therefore people living in those areas where the bedrock contains arsenic, and tube wells are used, need to be given good advice. One typical characteristic of arsenic concentrations is that they may be quite different in two wells very close to each other. Therefore individual analyses are needed to ensure that arsenic contaminated water should be avoided if at all possible.<br />
<br />
<br />
''Arsenic may be a problem, especially with deep tube wells in Europe or North America, but it is usually restricted in geographical terms. In risk areas it is advisable to analyse the arsenic concentrations. In arsenic rich areas of the world, the story is very different – there the risks are very high.''</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Does_aluminium_cause_dementia%3F&diff=15759
Does aluminium cause dementia?
2010-06-21T09:40:30Z
<p>Minttu: Created page with 'Housewives using aluminium kitchenware for cooking or making berry juices have switched to stainless steel products. The concern arose from information that aluminium was accumul…'</p>
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<div>Housewives using aluminium kitchenware for cooking or making berry juices have switched to stainless steel products. The concern arose from information that aluminium was accumulating in patients during dialysis treatment when non-distilled water was used for making dialysis solutions. Furthermore it has been shown that aluminium in the brain was associated with the plaque-like changes seen in Alzheimer’s disease. Subsequently some studies appeared to suggest that there was an association between aluminium in drinking water and dementia.<br />
<br />
'''Aluminium is ubiquitous'''<br />
<br />
Aluminium is one of the most common elements on earth. It dissolves into ground water to a very limited extent. Acidity of the water can promote dissolution, and rather high concentrations have been detected in some areas (over 1 mg/l). In areas with certain types of bedrock, well water may contain high concentrations of aluminium, and deep tube wells usually have even higher levels, but the variation in levels is very great.<br />
<br />
In tap water produced by well-equipped waterworks, the concentrations of aluminium are not usually high. Much of the aluminium originates from processing chemicals, because aluminium hydroxide is used as an adsorbent to remove the impurities present in raw water. It is more uncertain how much aluminium is in the tap water distributed by very small waterworks.<br />
<br />
'''Health effects'''<br />
<br />
It is not known exactly how to classify the health effects of aluminium in drinking water. It has been considered as completely innocuous, because aluminium hydroxide has been used at high doses in drug preparations as an antacid for over a hundred years, and also food contains large amounts of aluminium. Aluminium is absorbed very poorly. Some, so far unsubstantiated, findings in epidemiological studies have suggested an association between neurological diseases and long-term exposure to aluminium via drinking water.<br />
<br />
Therefore there is some indication of harmful effects of aluminium to the nervous system, but exposure to aluminium from drinking water or food has not been proven, contrary to the situations with dialysis treatment which allows aluminium to gain direct access to the organism. There is no health-based limit value recommendation by the World Health Organisation for aluminium in drinking water, but there is a technical quality recommendation of 0.2 mg/l. There is no evidence that aluminium kitchenware would cause any adverse effects.<br />
<br />
<br />
''Aluminium is one of the most common elements in the earth, and is generally regarded as safe. Since there is some uncertainty, it is unwise to drink water clearly exceeding the recommendations.''</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Are_the_risks_of_the_domestic_and_the_workplace_environments_different%3F&diff=15758
Are the risks of the domestic and the workplace environments different?
2010-06-21T09:38:28Z
<p>Minttu: </p>
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<div>This book deals with the risks of the general environment rather than the work environment. Those include the state of natural and man-made environment, chemicals, food and drinking water, and the possible risks involved with using them. The difference between the general environment and work environment is not always qualitative. The difference may only be in the level of exposure. A good example is hairdressing. Hairdressers seem to have a risk of cancer because of their occupation. This is probably due to the chemicals used in their work such as hair dyes. The customer is obviously exposed to exactly the same chemicals, but his/her exposure is only occasional whereas hairdressers are exposed every day, and thus the risk is only apparent in hairdressers.<br />
<br />
'''Exposure'''<br />
<br />
Exposure routes in the general environment are the gastrointestinal tract, airways and skin in this rank order. In the working environment, eating and drinking are not major routes and may even be forbidden, so they are not very important. It is worth remembering that poor hygiene may lead to exposure of heavy metals, carcinogenic chemicals or microbes during the lunch hour or at home after the working day. Some poisonings have been described even in children, when lead or other toxic compounds were carried home from the workplace in their father’s clothes.<br />
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In many occupations, the respiratory tract is the crucial route of absorption of chemicals as it is also for microbes and organic dusts. Even exposure through the skin may be important, not only causing contact allergies, but also as an exposure route evoking general toxicity. A good example is pesticide use in greenhouses. Workers may be exposed to orders of magnitude higher amounts of pesticides through their skin as compared with the residues to which consumers are exposed by eating the products in their food.<br />
<br />
'''Exposure levels'''<br />
<br />
Exposures in the workplace are often much higher than those in the living environment. In the factory, solvent concentrations are much higher than outside the factory. Moreover the exposure may be continuous while it is only occasional outside. In a bakery, the baker is exposed to flour dust continuously while at home the housewife may bake once a week. A welder may be exposed to a multitude of metal fumes, and the clothes of a car mechanic may be soiled with old lubricants. Cattle herdsmen work within the clouds of dust of animal hair and scurf. Consequently quite a lot information has been collected about the occupational environment, and this can be useful in estimating the effects in the general environment even though exposures may be ten or even a hundred times lower.<br />
<br />
'''Risk groups'''<br />
<br />
The work environment does not provide data about everything. Usually children are excluded, except for schools and day-care centres that are workplaces for teachers but the general environment for children. The work environment means there are no elderly people, and in some occupations there are no women. If these are the risk groups for a certain exposure, then the information is not available from this source.<br />
<br />
'''Risk levels'''<br />
<br />
Somewhat higher risk levels are usually accepted in the work environment than in the general environment. Increasing standard of living and improved occupational hygiene have decreased the difference. In the developed countries, one cannot imagine the risks that existed even a few decades ago in the coal mines. However, these terrible conditions are still with us, especially in the rapidly industrializing countries such as China. <br />
<br />
Asbestos is a good example of changes in attitudes in most countries. The very high risk of pulmonary cancers was due to extremely high exposures in the past. The indoor air in a factory was sometimes misty because of the asbestos fibres. It is not reasonable to imagine that the present low numbers of asbestos fibres in the air would be a significant cause of cancer.<br />
<br />
It is not always true that occupational risks are higher than environmental risks. Radiation control is presently so strict that occupational risks associated with radiation are minimal. In houses situated in uranium-rich regions, indoor radon may cause radiation exposure levels that would not be permitted in any occupation. No laboratory workers would be allowed to use benzene as carelessly as car drivers use it at a petrol station.1 Lately occupational regulation has been adopted in some countries to limit customer smoking in restaurants on the basis of preserving the workers’ health, even though the exposure of the person smoking the cigarette is of course far higher than that of the waiter.<br />
<br />
<br />
''There are both qualitative and quantitative differences between the work environment and living environment. Occupational risks are not dealt with in this book.''</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Is_it_more_dangerous_for_us_than_for_our_ancestors%3F&diff=15757
Is it more dangerous for us than for our ancestors?
2010-06-21T09:38:00Z
<p>Minttu: </p>
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<div>The shortest possible answer is: look at the differences between developing and industrialised countries. Isn’t the different life expectancy quite revealing? The comparison is not quite fair, however, because also in developing countries many risks of modern society are present, in some cases they are even worse than in highly developed and controlled industrial countries. Tony McMichael has written in his book Human frontiers, environments and disease that the turning point was in fact the introduction of agriculture and pastorialism about 10,000 years ago. It guaranteed food for more people, but at the expense of an unbalanced diet as compared with the hunter-gatherer societies collecting their food from a number of different sources.<br />
<br />
'''Food availability as the limiting factor'''<br />
<br />
During the early Stone Age, the population of the world was 5 to 8 million people, i.e. about one thousandth of the present number. Because of the long distances between tribal groups, infectious diseases were rare, and illnesses such as measles or tuberculosis had no chance of developing. Food shortages at the most difficult periods of the year limited the increase of populations. In the north, the limiting period was winter, in many warm areas it was the dry period. In addition, hunting, especially big game hunting, was dangerous. Therefore the average life expectancy was a mere 20 to 25 years.<br />
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The conditions changed dramatically when pastorialism developed in the Middle East (goats and sheep were tamed about 10,000 years ago), and very soon also agriculture started to develop.<br />
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Wheat was created via a genetic recombination in the Middle East, and people started actively to cultivate the new productive plant. In fact, the plant needed human help, because its heavy seeds had no way of spreading naturally.1 Agriculture was able to provide food for many more people in the same area than could be provided by hunting and gathering natural plant seeds. Continuous agriculture lead to permanent settlements, villages and small towns started to develop, and population increased. Since it was possible to store wheat, the difficult bottlenecks of the year could be overcome, and as we see in the advice of Joseph to the Egyptian Pharaoh, it was even possible to overcome occasional droughts lasting more than one year.2 It became also possible to support non-productive members of the society, e.g. the elderly. So for the first time in history, the Bible stated:3 “The days of our years are threescore years and ten.” This 70 years was possible for very few, and the normal life expectancy was still only about 30 years.<br />
<br />
'''Microbes attack'''<br />
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Living together with domestic animals as well as the dense population created many hygienic problems. The availability of food attracted mice, rats and flies, and they also spread microbes causing diseases. Many domesticated animals were herd animals that carried species-specific infectious diseases, and many of the animal microbes adapted themselves to infect humans. This was the beginning of many human infectious diseases. Influenza virus from birds and pigs infected also human beings. Ancestors of smallpox and tuberculosis in cattle adapted themselves into human forms of these deadly diseases. Whooping cough originated from pigs or dogs.<br />
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Even now, there are animal diseases that are also infective to humans. Such diseases are called zoonoses, and they include salmonellosis (e.g. murine typhus), listeriosis from cattle or milk, and diarrhoea caused by campylobacteria in drinking water contaminated with animal faeces. Psittacosis of birds can also easily infect humans, as can many infections of monkeys. Therefore tropical pets can be very dangerous unless they are professionally bred and pass strict health inspections. Rabies may be acquired from dog bites. Yersinia bacteria causing plague can take advantage of another kind of route; they are spread to humans from mice and rats by lice.<br />
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Man has adapted himself to these new pests over the millennia to some extent. Many of them are now known as children’s diseases (e.g. measles, rubella). After suffering a reasonably mild disease, the individual often gains life-long immunity. These diseases were, however, life-threatening in naïve populations. This was dramatically seen when Europeans brought these diseases to the Americas after the “discovery” of that continent. American Indians were totally susceptible to the diseases, and as much as 90% of the population in some areas died from “children’s diseases” such as smallpox and measles. This was one major reason why Europeans were able to conquer an entire continent with rather limited military might.<br />
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Europeans had met this same challenge much earlier. Many contagious diseases resided in India for millennia, because the population density was already high there. The old slow caravans could not bring these diseases to Europe, because individuals who became ill on the voyage either recovered or died before getting back home, and could not infect others. <br />
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During the Roman Empire, faster routes were discovered to India, the so-called Silk Road, a shorter caravan route to India and China, and shipping routes became faster. The consequence was the Antonine plague in the years 165 to 180, and other epidemics. The plague in A.D. 165 was in fact smallpox rather than bubonic plague, and some of the epidemics may have been measles. The Roman Empire never fully recovered from these catastrophes. These diseases have changed the history of mankind perhaps more than generally realised. After the times of antiquity, the next deadly wave was the Black Death of the 14th century which probably killed more than a third of the population in Europe.<br />
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Only during the nineteenth century were environmental aspects taken into consideration. Drinking water was realized to be crucial in the spread of cholera. Queen Victoria’s physician John Snow proved that by closing certain wells in London it was possible to prevent new cholera cases in their supply region. It was shown that the wells were being contaminated by the water from the River Thames, because sewage was fed into the river upstream of the wells. At that time, bacteria had not yet been proven to be responsible for diseases. Only after the discoveries of Louis Pasteur, Robert Koch and many others was it understood why hygiene was so important. It has been said that one of the greatest achievements in environmental health has been disinfection of drinking water that virtually brought to an end the spread of diseases such as cholera in Europe in the beginning of the twentieth century. It has also prevented many other infections transmitted by water.<br />
<br />
'''Introducing chemicals'''<br />
<br />
Rapid industrialization starting in the 18th century brought with it chemical pollutants. On the other hand, it should be remembered that the writer and philosopher Seneca complained already in A.D. 61 that urban air in Rome was so filthy from the smoke from the many chimneys that he could not breathe, and had to leave for his countryside retreat. Even in the Stone Age, open fires in the caves must have produced a lot of dangerous smoke even though promoting health by heating the immediate surroundings and scaring off potential predators.<br />
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The introduction of coal to replenish largely depleted fuel resources of firewood for heating, and for energy production for the newly started industries, soon caused massive problems for urban air. Depending on the area and conditions also other sources of problems emerged: heavy metals, carbon monoxide, and carcinogenic chemicals. Later, motorized traffic became more common – and with that came oxides of nitrogen and ozone. Water pollution also worsened due to the sewage produced by industries and cities.<br />
<br />
Crowded conditions, especially of workers housed next to factories, caused also risks of accidents, and many chemical accidents have occurred. Some of the best known are the explosion of a liquid gas tank in Mexico City (1984), and the leak of methyl isocyanate chemical in Bhopal (1984). These accidents killed thousands of people as well as causing tens of thousands of serious injuries.<br />
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In other words, problems have gone hand in hand with development. There is probably no new innovation that has not been followed by adverse effects of some sort. However, when the average life expectancy in Western Europe has increased to 80 years, there is no reason to look back with nostalgia to the previous centuries or millennia as being “more healthy than the present time.”<br />
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<br />
''The major risks to humans during history have been food shortage, microbes, and pollutants. Increasing life expectancy is the most unequivocal measure of a decrease in the total risk level.''</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=What_is_a_%E2%80%9Cchemical%E2%80%9D_after_all%3F&diff=15755
What is a “chemical” after all?
2010-06-21T09:37:35Z
<p>Minttu: </p>
<hr />
<div>My toxicology professor John Doull from Kansas City, KS, once wrote: "Even Rachel Carson was made of chemicals." He was clearly sick and tired of the view held by the media that chemicals are strange artificial substances jeopardizing our health. One example of such thinking was demonstrated by an organization measuring environmental chemicals in commissioners of the European Union and ministers of member countries. Several newspapers publicized how 38 chemicals were in this Commissioner or as many as 55 chemicals had been detected in some European politicians.<br />
<br />
There are two different misunderstandings in that sort of news. A more sensitive analysis would have revealed all studied 103 chemicals in all of the participants. In other words, the number of chemicals is totally useless information, because it only reveals the detection capability of the laboratory used. Professor Jaakko Paasivirta from Jyväskylä, Finland, used to say in his lectures that he could easily tell the brand of mosquito repellent used by the person who had picked the berries he was analysing. This kind of sensitivity is in fact not yet even close to the sensitivity needed in analysing dioxins in normal people or mother’s milk.<br />
<br />
Another mistake is that there are not a hundred or even ten thousand "chemicals" or any other fixed number of substances. As John Doull stated, everything is chemicals and there is nothing but chemicals in the world. You cannot escape chemicals, you yourself are made of chemicals. The entire world is a mixture of chemicals, and only a small proportion of chemicals in our environment are man-made.<br />
<br />
'''Pure chemicals'''<br />
<br />
The chemicals of our environment are rarely pure, but human activities may produce large amounts of pure chemicals. Water or hydrogen oxide is a pure chemical we use in the largest amounts. Nature keeps distilling water all the time, when it evaporates and falls back as rain. Regular tap water is 99.9 per cent pure water. Mineral waters contain more than 0.1 percent of salts and much of the time also carbonic acid. Therefore they are less than 99.9 percent pure water. Sugar is 99.9 percent pure sucrose, it is a purer chemical than many laboratory chemicals, to say nothing of technical chemicals. In fact, sugar is one of the chemicals produced in the largest volumes in pure form. There are some other pure chemicals known to us – salt, soda, acetone and ether. Many medicines are chemicals isolated and purified from nature such as digitalis, penicillin, atropine, morphine, and levodopa. Many of them can also be made by chemical synthetic processes.<br />
<br />
'''Mixtures'''<br />
<br />
Most substances in nature around us are mixtures of chemicals. The fats, proteins and carbohydrates in our food are not often thought of as mixtures of chemicals, but that is what they in fact are, and there is no difference in principle between substances naturally in the environment and those made by humans.<br />
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There are, however, some differences in practice between chemicals made by nature and those made by man. Life produces chemicals from elementary units following several relatively simple rules. Plants synthesize sugars by using two substrates, carbon dioxide from the atmosphere and water. Green chlorophyll of plants utilizes the energy of sunlight for photosynthesis, and helps enzymes1 to synthesize first low-molecular weight intermediates such as organic acids. These are then used to construct more complex organic molecules such as sugars, fatty acids, and also amino acids by adding nitrogen from soil nitrates. <br />
<br />
These building blocks are then used to construct large macromolecules, carbohydrates such as starch or cellulose from sugars, proteins from amino acids, and fats and waxes from fatty acids and alcohols like glycerol. In addition, different small and medium size molecules are constructed; these are sometimes very poisonous.2 A common feature of the natural chemicals is that they can usually be broken down to small-molecular forms, often all the way back to carbon dioxide. In other words, they can be "burned" or oxidized. Organisms have the enzymatic machinery both to build and to break down organic compounds.<br />
<br />
'''Problems of synthetic substances'''<br />
<br />
Many of the early synthetic products were like natural organic products in that the enzymatic machinery of our body could handle them in the same way as the natural compounds. Often they were in fact "semisynthetic" compounds, being synthesized from natural starting materials. Examples are tar, ether, methyl alcohol or ammonia. They can be easily handled by biological mechanisms, because their parts are familiar to the body’s machinery.<br />
<br />
With the advances in chemistry, man learned to make artificial substances with no counterparts in nature. Many of them contained a halogen such as chlorine, often also fluorine. It is often typical of these chemicals that microbes,3 animals or humans cannot break them down with their enzymes. An extreme example is dioxin (TCDD),4 the half-life of which is almost ten years in human beings, because it is neither broken down nor excreted. It is a very resistant and poorly water-soluble substance, and even soil bacteria succeed in breaking it down extremely slowly. Therefore it resembles some persistent metal elements such as cadmium which once they gain access to the body, are almost impossible to remove.<br />
<br />
'''The difference is not toxicity but sometimes persistence'''<br />
<br />
Both natural compounds and man-made substances include very poisonous and quite harmless chemicals. Natural chemicals can usually be broken down, while some synthetic compounds are very persistent. This was initially thought of as an advantage. PCB oils seemed to be very good for heavy duty use in difficult conditions. They are heat-resistant, not flammable, insulate electricity, and resist heavy pressure. Therefore they were used in hydraulic pumps and electrical equipment, until it was realized that the apparent advantage was, in fact, a disadvantage. These chemicals are not broken down, and therefore they gradually accumulate in the environment.<br />
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<br />
''The whole world is built of chemicals. There is no reason to be afraid of chemicals, but it would be very useful to understand them and the rules of their behaviour.''</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=What_is_the_wisdom_in_%E2%80%9CIt%E2%80%99s_the_dose_that_determines_that_a_thing_is_not_a_poison%E2%80%9D%3F&diff=15754
What is the wisdom in “It’s the dose that determines that a thing is not a poison”?
2010-06-21T09:37:09Z
<p>Minttu: </p>
<hr />
<div>One of the most famous expressions in toxicology is “It’s the dose that determines that a thing is not a poison.” It was uttered in self-defence by a Swiss physician known as Paracelsus, actually Philippus Aureolus Theobrastus Bombastus von Hohenheim in the sixteenth century. He had used mercury salts to treat syphilis, for which they have a modest effect. He was accused of poisoning his patients, and he wrote as his defence: "Was ist das nit gifft ist, alle ding sind gifft, und nichts ohn gifft. Allein die dosis macht das ein ding kein gift ist" (What is not a poison? Everything is poisonous. It’s the dose that determines that a thing is not a poison).<br />
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Experimental toxicology has proven how right Paracelsus was over four hundred years ago. In animal experiments, every single chemical can be shown to be toxic, even life-threatening, if the dose is high enough. An American scientist Bruce Ames surveyed many carcinogenicity studies, and found that about half of chemicals could be said to cause cancer, if given to animals in long-term experiments at the maximal doses tolerated. The likelihood of cancer for natural compounds was not very different from that of synthetic chemicals. Thus also long-term effects such as cancer-causing properties depend on the dose and not on the name or origin of the chemical.<br />
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Different chemicals have very different potencies. Aflatoxin or dioxin may be dangerous already at doses of one millionth of a gram. On the other hand, there are some compounds, even pesticides, that are tolerated by experimental animals at levels of several grams per kilogram body weight. The statement that all chemicals are poisons does not mean that they are poisonous at the same dose. It only means that completely safe chemicals do not exist, neither synthetic chemicals nor natural substances. Therefore the risk must be viewed relative to their typical doses or exposures.<br />
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'''Safety margin'''<br />
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We have seen that it is not important if a substance is poisonous or not poisonous. It is not even important how poisonous it is. The important thing is, how large the exposure dose is relative to the poisonous dose. If the toxic dose of dioxin is one millionth of a gram, and the dose to which people are exposed is one thousand millionth of a gram, there is a thousand-fold difference between the toxic dose and the actual dose. We say that there is a thousand-fold safety margin.<br />
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However, if the safe dose of table salt is less than five grams per day, and we consume every day 15 grams, we should be worried. There is no safety margin. Or to take an even more mundane example, if the lethal dose of alcohol is 300 grams, and we drink 100 grams at a single session, we are frighteningly close to the lethal dose. This tiny safety margin, threefold, would be out of question if it was proposed for most chemicals. Thus the fact that alcohol has relatively low toxicity does not mean that it is not deadly dangerous stuff, if the dose is high.<br />
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''Knowing that a substance is poisonous does not help much. The crucial point is the dose compared with the toxic dose causing death or adverse effects. It is the distance between the toxic dose and the actual dose which determines the safety margin.''</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Is_expert_jargon_just_a_way_to_confuse_the_man_in_the_street%3F&diff=15753
Is expert jargon just a way to confuse the man in the street?
2010-06-21T09:36:39Z
<p>Minttu: </p>
<hr />
<div>The language of scientists is prone to cause confusion among lay people. It is intended to be accurate, but often causes misinterpretation. The most common complaint is that scientists never state anything in unambiguous terms, but rather "on one hand this but on the other hand that". This is due to different use of language. In fact, an ambiguous-looking statement may contain much more truth than something stated as a hard fact in newspapers.<br />
<br />
'''What is safe?'''<br />
<br />
In general language it may be stated that an expensive car is a safe car. To a scientist this is not true at all. Around 50,000 people die in traffic accidents in Europe every year, and all kinds of cars are involved. Moreover, the exhaust gases of even the best cars are dangerous for health, and therefore no present car is safe. But a good car may be safe in a relative sense, as compared with an old rusted hulk. To lay people then, safety means relative safety, in comparison with something else they know. Scientists would often see safety as absolute safety, which is not even theoretically possible.<br />
<br />
This difference is much more problematic with chemicals than with cars. As science would not deem any chemical as absolutely safe, many citizens will interpret all chemicals as being dangerous. The man in the street does not have any personal experience with which to base his comparison – and this is different from his knowledge of motor cars. Therefore the risk1 of chemicals appears to be such that a personal likelihood to get ill or die is very high. Whenever a child is born with developmental defect, or an adult is diagnosed to have cancer, a cause is often sought in the emissions of a nearby factory or energy plant. This happens even if the likelihood of disease would be relatively high in all populations, with or without industrial emissions. In such circumstances, the likelihood of there being one particular source is not very high.<br />
<br />
Serious developmental effects occur in more than one child out of a hundred, and up to every third person is likely to contract cancer without any apparent external cause. Legislation and authorities aim at much lower risk levels. Experience has shown that a risk of serious health consequences of more than one in ten thousand has always led to varying degrees of stringent regulations to minimise the risk.<br />
<br />
'''Safer than something else'''<br />
<br />
Perhaps the most effective way of telling people how dangerous something is, is to compare it with something else they know better. Fifty thousand deaths from traffic accidents in Europe means that calculated over the entire lifetime there is one in a hundred chance that you will die in a car crash. This is very high risk level indeed. Environmental tobacco smoke would cause a lifetime risk that is somewhere between one in a thousand and one in a hundred. Even this is a very high risk, and it is very good idea to discourage smoking indoors as much as possible. Without any control measures, this would mean tens of thousands of premature deaths per year in Europe.<br />
<br />
Carcinogenic chemicals are often regulated according to a principle that the risk may not exceed one in a million during the whole lifetime of a person. If five million people (e.g. the whole population of Finland or the state of Minnesota) would be exposed over their whole lifetime to the maximum allowed level of a chemical, there would be one extra cancer case in about 15–20 years. This is because in such a population somewhat over 50,000 babies are born per year, and it would take 15–20 years for one million babies to be born. In this population of one million babies, there would be one extra cancer case during their whole lifetime. In the same population there are some 25,000 cancers per year, most without any known reason.<br />
<br />
Voluntarily accepted risks are often very much higher. Smoking is believed to cause the premature death of every other smoker, in other words the risk is one in two. The risk from unhealthy diet may be about equal to that of smoking. Thus a smoker takes a risk that is 50,000 times higher than the risk accepted for him or her by health authorities e.g. when regulating levels of chemicals in drinking water.<br />
<br />
Many people do not realise that also the risks of smoking and risks of unhealthy diet are chemical risks in the broad sense. Tobacco smoke is a mixture of many chemicals, and food is nothing but chemicals: fats, proteins and carbohydrates – all are simply chemicals.<br />
<br />
<br />
''Assessment of risks is very tricky, but it seems to be even trickier to convey the message in a relevant form to the general public.''</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=Is_it_the_final_straw_that_breaks_the_camel%E2%80%99s_back%3F&diff=15752
Is it the final straw that breaks the camel’s back?
2010-06-21T09:36:09Z
<p>Minttu: </p>
<hr />
<div>There are many Finnish folk tales about the inhabitants of the village of Hölmölä (roughly translated as Moronsville). The stories revolve around the stubborn stupidity of the inhabitants and how their actions inevitably frustrate their intentions. One folk tale describes the actions of a farmer loading firewood onto a cart to be pulled by a horse. With every new log, the farmer mutters “Well, if it can manage so much, then it can manage one more log”. Ultimately, the poor horse is not able to pull the huge burden of wood even one step. The farmer then starts to remove the piles of firewood one at a time, saying now “Well if it can’t cope with this, then it can’t manage even this log”. Finally, all the firewood has returned to its original pile, and the farmer with his horse return home with an empty cart.<br />
<br />
This fable illustrates one major dilemma in trying to formulate a working environmental policy. It is always possible to claim that one more load on the environment will not matter; it’s only a drop in the ocean. Conversely, when attempts are being made to place restrictions on some environmental pollutant, then the arguments are made that the limits should be set even lower, the emissions reduced even further and the polluter should be penalized by paying even greater fines. <br />
<br />
One may get the impression that it is industry-supported interest groups who state that the environment will not be disturbed by one further burden, whereas it is activist organizations and individuals wishing to preserve the environment who are forever urging that the entire burden has to be eliminated. In fact such a clear, black-white distinction has not existed for many years.<br />
<br />
There is an inconsistency in the attitudes of all of us to the environment; we hold opinions which simultaneously exaggerate and minimize the risks to our environment. We vehemently oppose the construction of a waste-combustion facility in our neighbourhood, but happily burn garden (and other household) refuse in our own back yard. We are in favour of the creation of more and larger national parks but campaign in favour of better and wider highways to make it easier to drive to our country cottage. We support measures to limit air pollution at the same time as we purchase a new, heavier, poor fuel economy, turbo-charged SUV to transport us to the shops downtown. We demand that our food has to be safe and free of chemicals but are content to grab a bite to eat at a service station where we are surrounded by fumes and chemicals.<br />
<br />
The author, Jared Diamond, has described in his book “Collapse” how the Easter Islanders in a mere two hundred years were able to destroy the lush, paradise-like, environment of their island home and to condemn their descendants to a life of poverty, hunger and misery. Diamond traced the seeds of this tragedy to the destruction of the island’s forests. What makes the situation so tragic is that the trees were felled for the most inconsequential reasons. <br />
<br />
The village clans would compete to see who could build the biggest and greatest number of monumental statues and huge numbers of trees were cut down to roll the statues from the stone quarries to their sites on the coast. The huge funeral pyres, which burnt for days to commemorate the death of a clan chief, were another waste of timber. More and more forest was cleared to provide land for agriculture, but without the stabilizing influence of the trees, the soil was quickly eroded and thus more virgin forests had to be cleared. <br />
<br />
The ultimate irony is that Easter Island is surrounded by some of the best fishing stocks in the world, but when the last tree was cut down, the islanders could no longer build ocean-worthy fishing vessels and a large proportion of the population went hungry while surrounded by an abundance of food. This ignorance and stupidity when combined with senseless competition and vanity led to the total collapse of the civilization, cannibalism and the most extreme misery imaginable.<br />
<br />
We need to ask ourselves these questions. How can we avoid the fate of the Easter Islanders? What is the best and most sensible approach? How can we achieve a balance between exploitation and preservation of our planet’s resources? How great an emphasis should we place on health when we are debating environmental issues? How strict do we need to be in adhering to agreed policies? It is clear that decisions need to be backed by political consensus and widespread support from the general public. However, it seems today as if the greatest problem is ignorance and lack of understanding. This may seem a surprising statement; never before has so much information been available so widely. <br />
<br />
The problem is that there is a plethora of information, but much of it resembles the information on the Internet. One only has to google the term “dioxin” to be linked to millions of so-called facts. The problem is to find the few nuggets of wisdom in this mass of dross. Can we identify sites that are reliable, based on a comprehensive assessment of the available data? Instead, we are provided with a more and more fragmented perspective and a failure to view the larger picture. Even the so-called experts often are unable to take the wider view; they have their own specialities and their own territories, which they defend with terrier-like ferocity. The same can be said about the environmental activist organizations, they too can take a very blinkered view of the world. <br />
<br />
During the 1980s, a committee was created to draft proposals for incorporation into the Public Health Act. During the hearings, a junior civil servant whose job description included supervision of environmental issues in the greater Helsinki region expressed his opinions. The committee had not yet agreed on who should have overall responsibility for monitoring and enforcing environmental health issues, should it be the civil servants from the environmental agency or those from the health care system? The young man argued that whenever a problem arose about the health effects of some pollutant, it was the environmental agency which invariably demanded the strictest possible limits to be enforced. He believed that this “strictest possible” approach was the best way to achieve the desired public health goals. <br />
<br />
In fact, adoption of a “strictest possible” policy does not require any professional skills or expertise. The test of true professional expertise is being able to differentiate between those issues where it is essential to be strict from other cases where such stringency is harmful. An old fable tells of the boy who cried wolf so often that when the wolf did arrive no-one listened to his cries anymore. We need to keep our powder dry for the day when the wolf does appear at our door. <br />
<br />
''The simplistic approach of invariably calling for the strictest limits and controls in environmental and environmental health issues may be self-defeating. True professional expertise, often lacking today, is able to identify the cases when we need to be strict from those times when more flexibility should be applied. It often requires expert cooperation to gain a wider perspective of the problems.''</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=User:Minttu&diff=15577
User:Minttu
2010-06-08T11:51:19Z
<p>Minttu: </p>
<hr />
<div>{{encyclopedia|moderator=minttu}}<br />
==kengännumero 38==<br />
[[File:viikset.jpg|100px|right]]<br />
<br />
[[user:Aino|Aino's page]]<br />
<br />
[http://www.facebook.com naamakirjaan!!]<br />
<br />
[[:op_fi:etusivu]]<br />
<br />
[[op_fi:etusivu]]<br />
<br />
*plöö<br />
*plää<br />
**ölmölöplöö<br />
#grrr<br />
##grrrr<br />
###grrr<br />
*#moimoimoi<br />
:heimoi<br />
<br />
{{todo|mene kotiin ja nuku|Noora, Minttu|project=plantlibra}}<br />
<br />
{|{{prettytable}}<br />
! noora<br />
! pieta<br />
! heta<br />
|-----<br />
| '''aiinoo'''<br />
| ''heetaaa''<br />
| '''''nooraa'''''<br />
|-----<br />
| [http://www.facebook.com/home.php?#!/aino.paakkinen?ref=ts aino ;D]<br />
| element<br />
| element<br />
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[[Category:food]]<br />
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heimoi<ref name="nk">noora</ref><br />
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===viitteet===<br />
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joojoo<ref name="nk"/><br />
<br />
<references/></div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=User:Minttu&diff=15575
User:Minttu
2010-06-08T11:41:25Z
<p>Minttu: </p>
<hr />
<div>{{encyclopedia|moderator=minttu}}<br />
==kengännumero 38==<br />
[[File:viikset.jpg|100px|right]]<br />
<br />
[[user:Aino|Aino's page]]<br />
<br />
[http://www.facebook.com naamakirjaan!!]<br />
<br />
[[:op_fi:etusivu]]<br />
<br />
[[op_fi:etusivu]]<br />
<br />
*plöö<br />
*plää<br />
**ölmölöplöö<br />
#grrr<br />
##grrrr<br />
###grrr<br />
*#moimoimoi<br />
:heimoi<br />
<br />
{|{{prettytable}}<br />
! noora<br />
! pieta<br />
! heta<br />
|-----<br />
| '''aiinoo'''<br />
| ''heetaaa''<br />
| '''''nooraa'''''<br />
|-----<br />
| [http://www.facebook.com/home.php?#!/aino.paakkinen?ref=ts aino ;D]<br />
| element<br />
| element<br />
|-----<br />
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[[Category:food]]<br />
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heimoi<ref name="nk">noora</ref><br />
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===viitteet===<br />
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joojoo<ref name="nk"/><br />
<br />
<references/></div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=User:Minttu&diff=15573
User:Minttu
2010-06-08T11:36:32Z
<p>Minttu: </p>
<hr />
<div>{{encyclopedia|moderator=minttu}}<br />
==kengännumero 38==<br />
[[File:viikset.jpg|100px|right]]<br />
<br />
[[user:Aino|Aino's page]]<br />
<br />
[http://www.facebook.com naamakirjaan!!]<br />
<br />
[[:op_fi:etusivu]]<br />
<br />
[[op_fi:etusivu]]<br />
<br />
*plöö<br />
*plää<br />
**ölmölöplöö<br />
#grrr<br />
##grrrr<br />
###grrr<br />
*#moimoimoi<br />
:heimoi<br />
<br />
{|{{prettytable}}<br />
! noora<br />
! pieta<br />
! heta<br />
|-----<br />
| '''aiinoo'''<br />
| ''heetaaa''<br />
| '''''nooraa'''''<br />
|-----<br />
| [http://www.facebook.com/home.php?#!/aino.paakkinen?ref=ts aino ;D]<br />
| element<br />
| element<br />
|-----<br />
| element<br />
| element<br />
| element<br />
|}<br />
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[[Category:food]]<br />
<br />
heimoi<ref>noora</ref><br />
<br />
===viitteet===<br />
<br />
<references/></div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=User:Minttu&diff=15571
User:Minttu
2010-06-08T11:35:33Z
<p>Minttu: </p>
<hr />
<div>{{encyclopedia|moderator=minttu}}<br />
==kengännumero 38==<br />
[[File:viikset.jpg|100px|right]]<br />
<br />
[[user:Aino|Aino's page]]<br />
<br />
[http://www.facebook.com naamakirjaan!!]<br />
<br />
[[:op_fi:etusivu]]<br />
<br />
[[op_fi:etusivu]]<br />
<br />
*plöö<br />
*plää<br />
**ölmölöplöö<br />
#grrr<br />
##grrrr<br />
###grrr<br />
*#moimoimoi<br />
:heimoi<br />
<br />
{|{{prettytable}}<br />
! noora<br />
! pieta<br />
! heta<br />
|-----<br />
| '''aiinoo'''<br />
| ''heetaaa''<br />
| '''''nooraa'''''<br />
|-----<br />
| [http://www.facebook.com/home.php?#!/aino.paakkinen?ref=ts aino ;D]<br />
| element<br />
| element<br />
|-----<br />
| element<br />
| element<br />
| element<br />
|}<br />
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[[Category:food]]<br />
<br />
heimoi<ref>noora</ref><br />
<br />
===viitteet===<br />
<br />
</references></div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=User:Minttu&diff=15566
User:Minttu
2010-06-08T11:28:11Z
<p>Minttu: </p>
<hr />
<div>{{encyclopedia|moderator=minttu}}<br />
==kengännumero 38==<br />
[[File:viikset.jpg|100px|right]]<br />
<br />
[[user:Aino|Aino's page]]<br />
<br />
[http://www.facebook.com naamakirjaan!!]<br />
<br />
[[:op_fi:etusivu]]<br />
<br />
[[op_fi:etusivu]]<br />
<br />
*plöö<br />
*plää<br />
**ölmölöplöö<br />
#grrr<br />
##grrrr<br />
###grrr<br />
*#moimoimoi<br />
:heimoi<br />
<br />
{|{{prettytable}}<br />
! noora<br />
! pieta<br />
! heta<br />
|-----<br />
| '''aiinoo'''<br />
| ''heetaaa''<br />
| '''''nooraa'''''<br />
|-----<br />
| [http://www.facebook.com/home.php?#!/aino.paakkinen?ref=ts aino ;D]<br />
| element<br />
| element<br />
|-----<br />
| element<br />
| element<br />
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[[Category:food]]</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=User:Minttu&diff=15565
User:Minttu
2010-06-08T11:27:21Z
<p>Minttu: </p>
<hr />
<div>{{encyclopedia|moderator=minttu}}<br />
==kengännumero 38==<br />
[[File:viikset.jpg|100px]]<br />
<br />
[[user:Aino|Aino's page]]<br />
<br />
[http://www.facebook.com naamakirjaan!!]<br />
<br />
[[:op_fi:etusivu]]<br />
<br />
[[op_fi:etusivu]]<br />
<br />
*plöö<br />
*plää<br />
**ölmölöplöö<br />
#grrr<br />
##grrrr<br />
###grrr<br />
*#moimoimoi<br />
:heimoi<br />
<br />
{|{{prettytable}}<br />
! noora<br />
! pieta<br />
! heta<br />
|-----<br />
| '''aiinoo'''<br />
| ''heetaaa''<br />
| '''''nooraa'''''<br />
|-----<br />
| [http://www.facebook.com/home.php?#!/aino.paakkinen?ref=ts aino ;D]<br />
| element<br />
| element<br />
|-----<br />
| element<br />
| element<br />
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|}<br />
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[[Category:food]]</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=User:Minttu&diff=15564
User:Minttu
2010-06-08T11:26:53Z
<p>Minttu: </p>
<hr />
<div>{{encyclopedia|moderator=minttu}}<br />
==kengännumero 38==<br />
[[File:viikset.jpg|100vx]]<br />
<br />
[[user:Aino|Aino's page]]<br />
<br />
[http://www.facebook.com naamakirjaan!!]<br />
<br />
[[:op_fi:etusivu]]<br />
<br />
[[op_fi:etusivu]]<br />
<br />
*plöö<br />
*plää<br />
**ölmölöplöö<br />
#grrr<br />
##grrrr<br />
###grrr<br />
*#moimoimoi<br />
:heimoi<br />
<br />
{|{{prettytable}}<br />
! noora<br />
! pieta<br />
! heta<br />
|-----<br />
| '''aiinoo'''<br />
| ''heetaaa''<br />
| '''''nooraa'''''<br />
|-----<br />
| [http://www.facebook.com/home.php?#!/aino.paakkinen?ref=ts aino ;D]<br />
| element<br />
| element<br />
|-----<br />
| element<br />
| element<br />
| element<br />
|}<br />
<br />
[[Category:food]]</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=User:Minttu&diff=15562
User:Minttu
2010-06-08T11:25:47Z
<p>Minttu: </p>
<hr />
<div>{{encyclopedia|moderator=minttu}}<br />
==kengännumero 38==<br />
[[File:viikset.jpg]]<br />
<br />
[[user:Aino|Aino's page]]<br />
<br />
[http://www.facebook.com naamakirjaan!!]<br />
<br />
[[:op_fi:etusivu]]<br />
<br />
[[op_fi:etusivu]]<br />
<br />
*plöö<br />
*plää<br />
**ölmölöplöö<br />
#grrr<br />
##grrrr<br />
###grrr<br />
*#moimoimoi<br />
:heimoi<br />
<br />
{|{{prettytable}}<br />
! noora<br />
! pieta<br />
! heta<br />
|-----<br />
| '''aiinoo'''<br />
| ''heetaaa''<br />
| '''''nooraa'''''<br />
|-----<br />
| [http://www.facebook.com/home.php?#!/aino.paakkinen?ref=ts aino ;D]<br />
| element<br />
| element<br />
|-----<br />
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| element<br />
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[[Category:food]]</div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=File:Viikset.jpg&diff=15560
File:Viikset.jpg
2010-06-08T11:23:30Z
<p>Minttu: </p>
<hr />
<div></div>
Minttu
http://en.opasnet.org/en-opwiki/index.php?title=User:Minttu&diff=15559
User:Minttu
2010-06-08T11:22:58Z
<p>Minttu: </p>
<hr />
<div>{{encyclopedia|moderator=minttu}}<br />
==kengännumero 38==<br />
[[File:viikset.jpg]]<br />
<br />
[[user:Aino|Aino's page]]<br />
<br />
[http://www.facebook.com naamakirjaan!!]<br />
<br />
[[:op_fi:etusivu]]<br />
<br />
[[op_fi:etusivu]]<br />
<br />
*plöö<br />
*plää<br />
**ölmölöplöö<br />
#grrr<br />
##grrrr<br />
###grrr<br />
*#moimoimoi<br />
:heimoi<br />
<br />
{|{{prettytable}}<br />
! noora<br />
! pieta<br />
! heta<br />
|-----<br />
| '''aiinoo'''<br />
| ''heetaaa''<br />
| '''''nooraa'''''<br />
|-----<br />
| [http://www.facebook.com/home.php?#!/aino.paakkinen?ref=ts aino ;D]<br />
| element<br />
| element<br />
|-----<br />
| element<br />
| element<br />
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[[Category:food]]<br />
[[File:[[File:Example.jpg]][[File:Example.jpg]]]]</div>
Minttu