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|authors=M.J. Tijhuis, [[User:Mikko|M.V. Pohjola]], H. Gunnlaugsdóttir, N. Kalogeras, O. Leino, J.M. Luteijn, S.H. Magnússon, G. Odekerken-Schröder, M. Poto, [[User:Jouni|Jouni T. Tuomisto]], Ø. Ueland, B.C. White, F. Holm, H. VerhagenVerhagen
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This page (including the files available for download at the bottom of this page) contains a draft version of a manuscript, whose '''final version is published and is available in the [http://www.sciencedirect.com/science/article/pii/S0278691511006351 Food and Chemical Toxicology 50 (2012) 77–93]'''. If referring to this text in scientific or other official papers, please refer to the published final version as: '''M.J. Tijhuis, M.V. Pohjola, H. Gunnlaugsdóttir, N. Kalogeras, O. Leino, J.M. Luteijn, S.H. Magnússon, G. Odekerken-Schröder, M. Poto, J.T. Tuomisto, Ø. Ueland, B.C. White, F. Holm, H. Verhagen: Looking beyond borders: Integrating best practices in benefit–risk analysis into the field of Food and Nutrition. Food and Chemical Toxicology 50 (2012) 77–93 {{doi|10.1016/j.fct.2011.11.044}}'''.

==Title==

Editing Looking beyond borders: Integrating best practices in benefit–risk analysis into the field of Food and Nutrition

==Authors and contact information==

:M.J. Tijhuis, correspondence author
:(mariken.tijhuis@rivm.nl)
:(National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands)
:(Maastricht University, School of Business and Economics, Maastricht, The Netherlands)

:M.V. Pohjola
:(National Institute for Health and Welfare (THL), Kuopio, Finland)

:H. Gunnlaugsdóttir
:(Matís, Icelandic Food and Biotech R&D, Reykjavík, Iceland) 

:N. Kalogeras
:(Maastricht University, School of Business and Economics, Maastricht, The Netherlands)

:O. Leino
:(National Institute for Health and Welfare (THL), Kuopio, Finland)

:J.M. Luteijn
:(University of Ulster, School of Nursing, Northern Ireland, United Kingdom)

:S.H. Magnússon
:(Matís, Icelandic Food and Biotech R&D, Reykjavík, Iceland)

:G. Odekerken-Schröder
:(Maastricht University, School of Business and Economics, Maastricht, The Netherlands)

:M. Poto
:(University of Turin, Facoltà di Giurisprudenza, Dipartimento di Scienze Giuridiche, Torino, Italy)
:(Precon Food Management BV, Bunnik, The Netherlands)

:J.T. Tuomisto
:(National Institute for Health and Welfare (THL), Kuopio, Finland)

:Ø. Ueland
:(Nofima, Ås, Norway)

:B.C. White
:(University of Ulster, Department of Pharmacy & Pharmaceutical Scienes, School of Biomedical Sciences, Ireland, United Kingdom)

:F. Holm
:(FoodGroup Denmark & Nordic NutriScience, Ebeltoft, Denmark)

H. Verhagen
:(National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands)
:(Maastricht University, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht, The Netherlands)
:(University of Ulster, Northern Ireland Centre for Food and Health (NICHE), Northern Ireland, United Kingdom)

==Article info==

Article history:
Available online 2 December 2011

==Abstract==

An integrated benefit–risk analysis aims to give guidance in decision situations where benefits do not
clearly prevail over risks, and explicit weighing of benefits and risks is thus indicated. The BEPRARIBEAN
project aims to advance benefit–risk analysis in the area of food and nutrition by learning from other
fields. This paper constitutes the final stage of the project, in which commonalities and differences in benefit–
risk analysis are identified between the Food and Nutrition field and other fields, namely Medicines,
Food Microbiology, Environmental Health, Economics and Marketing–Finance, and Consumer Perception.
From this, ways forward are characterized for benefit–risk analysis in Food and Nutrition. Integrated benefit–
risk analysis in Food and Nutrition may advance in the following ways: Increased engagement and
communication between assessors, managers, and stakeholders; more pragmatic problem-oriented
framing of assessment; accepting some risk; pre- and post-market analysis; explicit communication of
the assessment purpose, input and output; more human (dose–response) data and more efficient use
of human data; segmenting populations based on physiology; explicit consideration of value judgments
in assessment; integration of multiple benefits and risks from multiple domains; explicit recognition of
the impact of consumer beliefs, opinions, views, perceptions, and attitudes on behaviour; and segmenting
populations based on behaviour; the opportunities proposed here do not provide ultimate solutions;
rather, they define a collection of issues to be taken account of in developing methods, tools, practices
and policies, as well as refining the regulatory context, for benefit–risk analysis in Food and Nutrition
and other fields. Thus, these opportunities will now need to be explored further and incorporated into
benefit–risk practice and policy. If accepted, incorporation of these opportunities will also involve a paradigm
shift in Food and Nutrition benefit–risk analysis towards conceiving the analysis as a process of
creating shared knowledge among all stakeholders.

===Abbreviations===

CVD, cardiovascular disease; DALY, disability adjusted life year;
EFSA, European Food Safety Authority; HTA, health technology assessment; QALY,
quality adjusted life year.

==Keywords==

Benefit–risk,
Food & nutrition,
Best practice,
Assessment,
Management,
Shared understanding

==Introduction and approach==

Benefit–risk analysis of Food and Nutrition is developing fast.
Benefit–risk analysis aims to give guidance in decision situations
where both benefits and risks have been identified; when the benefits
do not clearly prevail over the risks, explicit weighing of benefits
and risks is indicated. Benefit–risk analysis can be seen as a
triad of the (1) assessment, (2) management and (3) communication
of integrated benefits and risks, analogous to the common
contemporary risk analysis paradigm (Fig. 1) (WHO/FAO, 1995).

Benefit–risk assessment of Food and Nutrition comprises a science-
based process intended to qualitatively or quantitatively estimate
the benefits and risks for humans following exposure (or lack
of exposure) to a particular food or food component and includes
the potential to integrate them into comparable measures. Benefit–
risk management entails the process of weighing policy alternatives
in light of the results of benefit–risk assessment and other
relevant information. Benefit–risk communication covers the interactive
exchange of information and science-based opinions concerning
benefits and risks among assessors, managers, consumers
and other stakeholders.

The scope of Food and Nutrition risk assessment is fairly well
established (Renwick et al., 2003); it deals with the assessment of adverse
health effects caused by physical or chemical agents, occurring
naturally in foods or as environmental contaminants, or resulting
from food preparation or manufacturing processes. However, in
the benefit–risk context, the scope of benefit-assessment is a point
of discussion. A beneficial effect can be looked at as the reverse of
an adverse effect (WHO, 1994), i.e. a physical or other change within
a person that improves functional capacity or the capacity to deal
with stress or that decreases susceptibility to harmful effects. This
can be measured as prevention of disease, i.e. reduction of risk, but
currently it is difficult to measure benefits directly, at an early stage
or as an ‘above-normal’ capacity. Cases where the benefit is obvious
but where different risks are involved (in severity and mechanism)
could also be taken under the wing of benefit–risk analysis. Benefit–
risk analysis presents up-to-date knowledge in a dynamic public
health process, aimed at optimization, i.e. looking for ways to maximize
benefits while minimizing risk.

In recent years, many projects have done significant work to
identify the possibilities and difficulties of benefit–risk analysis
in the Food and Nutrition field (Tijhuis et al., 2011). Much progress
has already been made, but benefit–risk thinking and practise have
not yet become commonly established. Therefore, for further
development, the field of Food and Nutrition could benefit from
looking beyond its borders and learning from other fields of research (and possibly also vice versa) and this is the explicit goal of
BEPRARIBEAN project (http://en.opasnet.org/w/Bepraribean) (Verhagen
et al., 2011). To serve this goal, we recently compiled reviews
covering the state of the art in benefit–risk analysis for
Food and Nutrition (Tijhuis et al., 2011) and five other fields: Medicines
(Luteijn et al., 2011), Food Microbiology (Magnússon et al.,
2011), Environmental Health (Pohjola et al., 2011a), Economics
and Marketing–Finance (Kalogeras et al., 2011) and Consumer Perception
(Ueland et al., 2011). The individual reviews were led by
the researchers from within the respective fields and were contributed
to by the researchers from the other fields. Summaries of the
key issues from the reviews and a summary of the contemporary
regulatory context for Food and Nutrition management and assessment
are presented in Section 2.

In Section 3, the focus is on identifying how the benefit–risk approaches
in the different areas compare to and differ from the benefit–
risk approaches in the area of food and nutrition. In order to
exemplify the (combined) perspectives and approaches from within
the different areas, we include an example of a case: the effects
of replacing current animal protein sources by more sustainable
dietary protein sources. This topic was considered suitable because
it is inherently multi-disciplinary and currently of global interest.
This example is meant as an illustration and does not aim to be a
conclusive analysis.

From this, in Section 4, we aim to identify opportunities for further
development of benefit–risk analysis in food and nutrition.

In Section 5, we sum up the main points of this paper, and the
whole BEPRARIBEAN project, and indicate some implications that
these points will or may have for Food and Nutrition benefit–risk
analysis in the future.

==Summaries of key issues by focus area and EU regulatory context for Food and Nutrition==

In 2.1–2.6 we summarize the key issues from the 6 state of the
art reviews: Food and Nutrition (Tijhuis et al., 2011), Medicines
(Luteijn et al., 2011), Food Microbiology (Magnússon et al., 2011),
Environmental Health (Pohjola et al., 2011a), Economics and Marketing–
Finance (Kalogeras et al., 2011) and Consumer Perception
(Ueland et al., 2011). They are complemented in 2.7 with a short
overview of the contemporary regulatory context for Food and
Nutrition management and assessment in the European Union.

===Benefit–risk analysis in Food and Nutrition (Tijhuis et al., 2011)===

This paper addresses the three components of benefit–risk analysis,
but focuses on assessment. Benefit–risk assessment in Food
and Nutrition is geared to weigh the beneficial and adverse effects
a food or food component may have, in an integrated measure, in
order to make better-informed policy decisions regarding public
health issues.

Historically, the assessments of risks and benefits have been
separate processes. In risk assessment, toxicology is the main contributor
as the toxicological approach is demanded by regulation. It
traditionally assumes that a maximum safe dose can be determined
from studies in experimental animals or sometimes humans
and that division of this dose by appropriate safety factors defines
the ‘safe’ intake for the human population. Epidemiology plays a
minor role in risk assessment. Epidemiology describes associations
between risk (or beneficial) factors and disease endpoints in humans.
It has traditionally focussed more on relative than on absolute
risks. Nutrition, as a science, uses a mixture of methodologies
and is involved in estimating risks specifically for nutrients and
other dietary factors. Benefit assessment for Food and Nutrition
is newly developing in regulatory terms, but has been the subject
of nutritional epidemiological research for a long time. Benefit
assessment is working on concepts such as whether reduction of
risk of disease should be termed a benefit, whether a benefit can
be measured as a state rising above the average health and in
which time frame (short or long term), and how broad its scope
should be. In nutrition, current interest is in ‘optimal’ food and
nutrient intake, implying knowledge of both intakes where risks
occur and intakes where benefits occur. In this, there is a scientific
development away from general population intakes towards an intake
based on subgroups. In summary, the goal of risk assessment
in food and nutrition is to reasonably guarantee absence of an effect
(risk) whereas the goal of benefit assessment is to reasonably
guarantee the presence of an effect (benefit). This distinction affects
the assessment approach, the evaluation of the generated
data and the way these can be used. In both risk and benefit assessment,
good dose–response data, i.e. with relevant intake levels and
suitable for the target population, are scarce. Better integration of
all underlying disciplines and an approach focussed more on humans
and continuous data is indicated.

Current approaches to bring benefit and risk assessment together
mirror the traditional risk assessment paradigm of hazard
identification, hazard characterization, exposure assessment and
risk characterization. A tiered approach is advocated, as this allows
for transparency, in-between consultancy with the benefit–risk
manager and the possibility of an early stop in the assessment
and thus increased efficiency. There is agreement about the importance
of a good description of the benefit–risk question and the
uncertainties in its assessment. Benefit–risk comparison can be
qualitative and quantitative, with increasing data requirements.
In a quantitative comparison, benefits and risks are expressed in
a common currency. Severity of disease can be taken into account
by attributing weights, e.g. using disability adjusted life years
(DALY’s). These integrated measures need to be accompanied by
at least (1) a description of the unintegrated benefits and risks
on subgroups and (2) data uncertainties. In the quantification process,
deterministic input may be substituted by probabilistic input;
well-accepted methodology for probabilistic assessment is
available.

Close communication, between and within benefit–risk assessors
and managers, requires attention. In benefit–risk management
some risk will have to be considered acceptable in order to achieve
more benefits. Thus, current risk management will also need to
consider a shift from striving for zero risk towards explicit weighing
of risks and benefits in order to achieve an optimal outcome.
The communication of benefits and risks to the public used to be
separate, but the impact of combined benefit–risk messages is
being explored.

In conclusion, benefit–risk assessment is developing steadily in
the field of food and nutrition. General point of attention is the
communication between fellow scientists, managers and the general
public. General strengths are the ability to systematically
and transparently show the current knowledge and its gaps and
to provide what is likely the best answer to a question with a large
potential impact on public health.

===Benefit–risk analysis in Medicines (Luteijn et al., 2011)===

Medicines can lead to significant health benefits. The health
benefits come at the risk of potential adverse drug reactions. Since
the thalidomide disaster in the early 1960s, increased regulatory
attention has been placed in the benefit–risk profiles of medicines.
This key-event has lead to not only demands on safety demonstration
before registration of a medicine, but also to demands in regard
to demonstration of efficacy, i.e. the effectiveness of a
medicine under controlled conditions.

Benefit–risk assessment in medicine is highly regulated and has
been developed for decennia. Benefit–risk assessment (and monitoring)
takes place both in the pre-registration and the post-registration
phase of a medicine. In the pre-registration phase, the
candidate medicine goes through a process of phase I–III trials,
involving populations of increasing size and different aims and designs
as discussed in the state of the art paper. These clinical trials
are conducted by the manufacturer and involve a considerable
financial investment. Trials will only be continued if the manufacturer
feels the drug stands a chance to successfully gain marketing
authorization by sufficient proof of efficacy and safety. Data gathered
by these clinical trials, reinforced by animal model data and
possible post-marketing experience with similar compounds, will
provide the safety and efficacy data for the marketing authorization
procedure. The pre-marketing clinical trials have been criticized
for being designed for fast approval instead of the
generation of scientific knowledge. A number of mainly quantitative
benefit–risk methods are employed during the pre marketing
phase, including ‘number needed to treat’ and ‘number needed to
harm’. Expert opinions play a big role in benefit–risk assessment
of medicines, both pre-registration and post-registration. There is
no standard protocol for analyzing the benefit–risk profile of a
drug, after the manufacturer submits the clinical trial data, responsible
authorities will take the evidence into account and form an
expert opinion on the registration submission. Both the benefits
(efficacy) and the risk (adverse drug reactions, ADRs) play a role
in this expert opinion: larger benefits can justify larger risks. No
consensus has been reached on a standardized methodology for
benefit–risk assessment in medicine registration. The European
Committee for Medicinal Products for Human Use recommends
the use of multiple types of mainly qualitative, benefit–risk methodology
and argues that use of quantitative methodology can lead
to a misleading feeling of precision.

====Pre-registration====

The pre-registration clinical trials themselves suffer from a
number of practical limitations; these include the small number
of subjects in clinical trials, a restricted population in terms of
age, gender and ethnicity, restricted co-medication and co-morbidity,
a short duration of exposure and follow up and statistical problems
with assessing multiple outcomes. These problems are
acknowledged by the responsible authorities. Because the clinical
trials take place in a controlled environment, situations of off-label
use, drug–drug interactions and non-compliance will be limited to
theoretical consideration. Therefore, clinical trials will provide
information on the efficacy of a medicine, rather than effectiveness
of a medicine. Despite the differences between efficacy and effectiveness,
efficacy will provide an indication of effectiveness of a
drug. It should be realized there is no solution for the majority of
these problems. For example; it would be ethically unacceptable
to conduct safety experiments in pregnant women. Experience in
this population will be limited to animal models and post-registration
data.

During the application process, a risk management program
will be submitted along with the clinical trial data, outlining risk
minimization and post marketing surveillance activities.

====Post-registration====

After registration, the benefit–risk profile of medicines will be
monitored by post-marketing surveillance. Pre-marketing knowledge
on the benefit–risk profile of a medicine will be limited for
reasons mentioned above. Post-marketing surveillance is conducted
by responsible authorities, marketing authorization holders
and independent researchers in order to collect data on ADRs and
monitor the effectiveness of existing risk management activities. In
case a new ADR is discovered, responsible authorities can reassess
the benefit risk profile forming a new expert opinion. Information
discovered during post-marketing surveillance can lead to modification
of marketing authorizations, risk management programs or
even suspension of marketing authorizations in the case of serious
ADRs. Many recent developments and initiatives are currently
ongoing in post-marketing surveillance, many of them involving
large databases to collect information on ADRs. The more statistical
power, the better the investigators are able to detect ADRs. For this
reason, an increasing amount of international cooperation is taking
place in Europe. Other problems include different legislation between
European countries.

A different type of benefit–risk assessment in the post-registration
phase is Health Technology Assessment (HTA). In HTA, the
health impact and economic impact of a new health technology
are assessed using (economic) modelling techniques, usually in order
to be included in public formularies. The main challenge of HTA
is to assess the trade-offs between financial investment and health
benefits. For this purpose, indexes such as QALY and DALY have
been developed. The trade-off between financial investment and
health benefits is perceived as controversial by many. Marketing
authorizations have become less meaningful without reimbursement
(after a positive HTA assessment) in many countries. The
mandate and methodology of HTA agencies differ between
countries.

The state of the art paper concluded that no ‘one size fits all’ approach
is available for benefit–risk assessment in medicines.
Choice of methodology depends on the context of the benefit–risk
assessment, including indication, patient groups and the stage of
the regulatory process. Also, use of multiple methodologies is
encouraged due to each having its own specific strengths and
weakness. Furthermore, improved cooperation between responsible
authorities and HTA agencies can be of value in benefit–risk
assessment.

===Benefit–risk analysis in Food Microbiology (Magnússon et al., 2011)===

Microorganisms, i.e. bacteria, fungi and viruses, are all constituents
of our natural environment. The field of food microbiology
concerns the multitude of microorganisms that inhabit and contaminate
our foods. Food and nutrition are essential for sustaining
human life. However, no food carries zero risk for microbiological
hazards. The risk varies considerably depending on food types
and matrices. Some foods have a higher risk than others of containing
microbiological contaminants and pathogenic microorganisms
that can be hazardous to our health and well being. Furthermore,
consumer sub-groups can be variably susceptible to foodborne
infections and intoxications; the elderly, young children and individuals
with underlying diseases being more at risk.

Food microbiology is largely focused on food safety and limiting
public exposure to harmful foodborne pathogens. However, the
great majority of microorganisms are harmless to our health and
many microorganisms are even important to various food production
processes e.g. the making of cheese, wine, beer and bread.
Microorganisms are used in various ways for the benefits of humans
e.g. through advances in medical technology, biotechnology,
agriculture and in food processing, to name a few. Although microorganisms
can be seen as indirectly beneficial to human health
through the above-mentioned activities, the human health consequences
of microorganisms in foods are often either neutral or adverse.
In food microbiology the reduction in human exposure to
foodborne pathogens can commonly be regarded as the main public
health benefit. Probiotic microorganisms and the activities of
the gut microflora can be mentioned as an exception to this –
the effect of probiotics can be seen as directly beneficial to human
health. It must be noted, however, that to date all such probiotic health claims have been refuted by the European Food Safety
Authority (EFSA, http://www.efsa.europa.eu/en/topics/topic/article13.htm); currently, there is lack of evidence for the direct beneficial
effects as judged by EFSA’s criteria, but at the same time there
is lack of evidence that beneficial effects do not exist.

Benefit–risk analysis is a relatively new and to-date largely
undefined field of research within food microbiology. The benefit–
risk analysis approach is concerned with issues affecting public
health and improving public health management based on the balanced
weighing of risks and benefits. From a food microbiological
standpoint studies using methods that balance risks and/or risks
and benefits using composite metrics are scarce. Published studies
to date have mainly been intervention assessments or risk comparison
studies that apply risk assessment criteria for comparing the
level of two individual risk factors – with the purpose of identifying
the most important health risks – commonly a chemical risk
and the benefits of reduced microbiological risk. The criteria for
the assessment of risks are well established within food microbiology
(and are based on risk assessment criteria developed within
toxicology), but at present the criteria for assessing positive health
effects are not well defined.

A key issue in food microbiological benefit–risk analysis is how
to address the assessment of benefits and the multidisciplinary discussion
of how to aggregate risk and benefit estimates. The most
straightforward approach to be used for benefit–risk analysis in
food microbiology could be envisioned to follow the tiered approach
for benefit–risk analysis formulated in the field of food
and nutrition. Food microbiological benefit–risk analysis converges
largely with that of food and nutrition. In addition, it often involves
the evaluation of chemical as well as microbiological risks and
benefits.

Disability adjusted life years (DALY’s) have widely been opted
for as a metric of choice for ranking microbiological risk, including
foodborne pathogens. It can be used as the single metric for assessing
both microbiological and chemical hazards and could similarly
be implemented for evaluating benefits. DALY’s have previously
been used for assessing the global burden of disease, injury and
risk factors and currently the global burden of foodborne disease
is being estimated using DALY’s (http://www.who.int/foodsafety/foodborne_disease/ferg/en/index3.html). Based on this extensive
groundwork, as food microbiology benefit–risk analysis goes,
DALY’s are likely to be the common metric of choice, despite its
shortcomings.

In conclusion, the field of benefit–risk analysis in food microbiology
is in its infancy and the assessment criteria for benefits are
not well defined. Reduced pathogen risk can be seen as the principal
benefit regarding food microbiology while scientific data on direct
microbial benefits are lacking.

===Benefit–risk analysis in Environmental Health (Pohjola et al., 2011a)===

The field of environmental health is very broad and involves significant
physico-chemical, biological, technological and social
complexity. Consequently there is no single state-of-the-art approach,
but a multitude of approaches to assess environmental
health risks and benefits have been developed for different purposes
and contexts within the field. These approaches can be characterized
e.g. as either regulatory or academic, depending on the
context of development and application for the approach, or rather
traditional or novel, depending on how strictly and narrowly the
assessment scope and procedure are determined by the approach.

In comparison to the traditional and regulatory approaches the
emphasis among the more novel and academic approaches is on (a)
increased engagement between assessors, decision makers, and
stakeholders, (b) more pragmatic problem-oriented framing of
assessments, (c) integration of multiple benefits and risks from
multiple domains, and (d) inclusion of values, alongside scientific
facts, in explicit consideration in assessment. These tendencies
can be considered as responses to the challenge of complexity
within the field, but also as indications of the incapability of the
currently established approaches to adequately address all aspects
of this complexity. On the other hand, the all-embracing aims of
the novel academic approaches may also lead to lack of clarity in
comparison to the regulatory and traditional approaches, unless
duly designed and implemented.

The key issues in benefit–risk analysis in environmental health
are not so much related to the technical details of performing the
analysis, but rather to (i) the level of integration, and (ii) the perspective
to consider the relationship between assessment and the
use of its outcomes. The level of integration can range from producing
health risk estimates for single substances to aggregation,
weighing, and comparison of multiple benefits, risks, impacts,
and costs alongside explicit account of values of those concerned.
Significant differences are also brought about by whether an
‘‘assessment push’’ or an ‘‘information need pull’’ perspective is
adopted. The perspective largely defines what, how and why, issues
are considered in an assessment.

In the ‘‘assessment push’’ perspective, the issue to be assessed is
defined by those responsible for the assessment, and the focus of
assessment is to produce an objective estimate of the risks, benefits,
etc. according to certain defined principles and means, whatever
the estimate may be used for. Approaches taking an
assessment push perspective thus also predetermine the possible
levels of integration in terms of e.g. what phenomena are considered,
whether also benefits or costs are considered in addition to
risks, and what means of aggregation or comparison are used. In
the ‘‘information need pull’’ perspective the issue to be assessed,
as well as the principles and means for its assessment, is formulated
according to a specified practical need. The need thus determines
the suitable format of the assessment outcome, which
further determines how the assessment should be made. Therefore
inclusion of all relevant issues, all levels of integration, and all
means of aggregation and comparison are, at least in principle,
available for use as required to serve the need. Naturally, most of
the approaches to environmental health assessment fall somewhere
in between these extremes by incorporating aspects of both
push and pull. However it can be identified that the regulatory and
the most traditional, simultaneously the currently most established,
approaches clearly position themselves closer to the assessment
push end of the continuum.

Challenges lie in the aggregation, weighing, and/or comparison
of multiple benefits and risks. For example: the use of DALY’s,
QALYs or euro’s as general aggregate measures, incommensurability
of benefit estimates aiming for avoidance of false positives and
risk estimates aiming for avoidance of false negatives, and taking
account of perceived risks and benefits together with ‘‘scientifically
assessed’’ risk and benefit estimates.

In conclusion, probably most of all commonly known methods
for benefit–risk analysis are applied among the various different
approaches to environmental health assessment, but there is no
single view to dominate the whole broad field.

===Benefit–risk analysis in Economics and Marketing–Finance (Kalogeras et al., 2011)===

Risk is a key component of economic behaviour. All market participants
(e.g. investors, producers, consumers) accept a certain level
of risk as necessary to achieve certain benefits. There are many
types of risk including price, production, financial, institutional,
and individual human (e.g. health-related) risks. All these risks
should be effectively managed in order to derive the utmost of benefits and avoid disruption and/or catastrophic economic consequences
for the food industry and market participants’ wellbeing.

In (food) economics, finance and marketing-management literature,
the utility concept (total satisfaction received from consuming
a product/service) plays a crucial role in determining market
participants’ benefit–risk trade-offs that drive economic phenomena.
This utility is often derived from outcomes such as wealth, income,
profit, selling price, among others. That is, the outcome
domain is a monetary one. Yet, in behavioural economics, behavioural
finance, economic psychology, marketing and consumer
behaviour literature, market participants may also derive utility
from non-monetary outcomes by exposing a combination of cognitive
and affective behaviour.

The dominant paradigm in business economics on which decision
makers (e.g. farmer, food manufacturer, retailer, consumer)
rely in their benefit–risk trade-offs is the expected utility model.
This model is concerned with choices among risky prospects. The
goal of a decision maker is the maximization of his/her expected
utility. In the expected utility framework, the shape of the utility
function is assumed to reflect a decision maker’s risk preference.
Therefore, the expected subjective utility function of any prospect
reveals the individuals’ attitudes towards risk. There is a continuous
stream of research on decision makers’ risk preferences in
the fields of food economics and marketing–finance that employs
expected utility models that are objective or normative, i.e.
assumption and establishment of norms implying the rationality
principle in economic behaviour of market-participants: maximization
of their utility, by using time series and/or panel data for
production, consumption, pricing levels of food products; and subjective,
i.e. relaxing the rationality assumptions inherent in the
normative models by using survey- and experimental-based data
gathering instruments involving psychometric constructs or lotteries.
Both theoretical and empirical research accounts show that
decision makers can be simultaneously risk-seeking and riskaverse
in different domains, implying that risk preference is context-
specific.

In the context of agribusiness and food markets, concerns about
food safety, quality, and nutrition have persistently been present at
all levels of decision making (operational, tactical and strategic) by
food producers, manufacturers, commodity traders, retailers, and
consumers. However, business economic scholars are often confronted
with conceptual and methodological challenges due to
the unobserved and multidimensional nature of human decision
making process. That is, the actual behaviour of market participants
is not always consisted with the ‘‘true’’ level of risk that they
face.

Recent research in management sciences and decision analysis
argued that by decoupling the benefit–risk trade-offs of decision
makers into separate dimensions a more robust conceptualization
and prediction may be achieved. Specifically, market participants
have two kinds of evaluation systems on which perceived and/or
actual benefits of an investment or consumption object cognitively
rely on: (a) utilitarian dimension of instrumentality and (b) a hedonic
dimension. The first dimension refers to how useful or beneficial
the investment or consumption action is. The second
dimension of benefits refers to the experiential affect associated
with the investment and consumption. These two dimensions are
neither mutually exclusive nor need to be evaluative consistent.
Similarly, risk behaviour may be decoupled into the separate
dimension of risk attitude and risk perception. Risk attitude is
formed by one’s predisposition to the content of the risk in a specific
market situation and reflects a decision-maker’s interpretation
of this risk content in a specific way, whereas risk perception
refers to the likelihood of one’s exposure to the risk content. This
decoupling approach may serve as the basis for studying the decision-
making process of market participants regarding food safetyand
nutrition-related issues, in the light of benefit–risk trade-offs.
Yet, one may recognize the challenges for operationalising such a
framework, adapt it to specific decision contexts, and accounting
for its dynamics.

In conclusion, the study of market participants’ benefit–risk
trade-offs in business economics rely on the utility concept.
Although the dominant paradigm in economics is the expected
utility model that has a normative nature, the behavioural study
of market participants’ benefit–risk trade-offs emerges. Nowadays,
there are various and different approaches and techniques to businesses
economics to identify and evaluate the benefit–risk tradeoffs
on institutional or individual market participants. Yet, there
is no single view to dominate the whole discipline. The decoupling
of benefit–risk behaviour into separate components that deal with
both the utilitarian as well as hedonic aspects of benefits and risks
may offer more robust conceptualizations and predictions for
studying benefit–risk trade-offs in various highly uncertain decision
contexts entailed in the agribusiness and food markets.

===Benefit–risk analysis in Consumer Perception (Ueland et al., 2011)===

Food and nutrition are central to the survival of human beings as
well as to their well-being and quality of life. However, a ‘‘nutritionally
perfect life’’ is not necessarily consistent with consumers’ feelings
of how a perfect life should be which again has implications
for what motivates consumers’ food choice. The inconsistencies
are partly the result of consumers’ perceptions of benefits and risks
with regard to food and nutrition and of the way consumers trade off
between benefits and risks in order to maximize the outcome they
prefer. Thus, by incorporating the study of consumers’ perception
of benefits and risks in a food and nutrition context, possible outcomes
of food and nutrition measures can be better understood.

For consumers, benefit perception of food is usually more important
than risk perception. The benefits are particularly related to the
hedonic perspective; food should taste good, be pleasurable and fulfil
expectations to an enjoyable experience. Risks, on the other hand,
are more often subject to conscious deliberations and external factors,
such as available information, media coverage and personal
interest that contribute to consumers’ risk perception.

Consumers’ perception of risks is associated with mortality and
morbidity and goes along two main dimensions related to; the extent
that the risk is unknown, and what are the consequences of
the risk. Food risks are not perceived to be as severe as are for instance
risks associated with firearms or airplanes. However, some
foods, particularly those that score high on the unknown dimension,
are perceived with trepidation by consumers. Conversely,
foods that are perceived as risky are often foods that are unfamiliar
or produced by novel technologies. Furthermore, foods that are
(perceived to be) highly processed are considered to be less desirable
and more risky, than foods perceived to have a low level of
processing. The possibility to discern what the food product is
made of, or what it is derived from, contributes to a feeling of
safety and to lower risk perception among consumers.

There are ways to reduce perceived risk of foods for instance
through familiarising the consumer with the food, or by adding
characteristics that may be seen as benefits to the food product.
Increasing healthiness and enhancing taste are factors that make
consumers more willing to accept the product. Adding benefits to
a product does not reduce the risk itself but reduces the consumers’
perception of the risk. Benefit and risk perception of foods
are in many cases inversely correlated: when something is perceived
as being highly beneficial, it is correspondingly perceived
as having low risk. However, slightly different paths are used in
the formation of these perceptions; benefit perception is based
on heuristics and experience, while risk perception is largely the
result of cognitive information processing.

Nutrition is one aspect belonging to food products that is normally
not associated with hedonic benefits of foods. However,
nutrition is accepted as an essential part of consumers’ life, and
health attributes of foods are perceived as benefits when diet considerations
are important for the consumers. Consumers easily
perceive risks belonging to malnutrition, both related to overand
under-consumption of nutrients, but consumers’ may choose
not to pay attention to these risks.

In conclusion, in a food and nutrition setting it is important to
understand which food attributes related to perceived and real
benefits and risks that influence food choice, in order to provide
for an optimal diet from both a health perspective as well as from
a hedonic perspective.

===Contemporary regulatory context for Food and Nutrition assessment and management===

The EU Food Safety legislation (http://ec.europa.eu/food/food/foodlaw/index_en.htm)(EU, 2000) is built around high food safety
standards, of which the final aim is to protect the health of the consumers
and to reduce the risks connected to unsafe food (van der
Meulen and van der Velde, 2008).

The development of the requirements is the result of stratified
legislative measures, often approved by incidents (food safety crises
consequent to foodborne diseases) rather than by a systematic
legislative plan. Regulation EC/178/2002 is the General Food Law,
containing general provisions useful to orientate the interpreter
in understanding the mechanisms and procedures to be followed
in order to reduce risks related to unsafe food. The general principles
of food law may be considered the top of the ideal pyramid of
a regulatory food control systems. Regulations and directives have
been formulated within this frame.

The aim of EU food policy is to assure a high level of food safety,
animal health, animal welfare and plant health within the European
market. In this sense, the General Food Law constitutes the main reference
point of the EU food legislation. It applies to all stages of the
production, processing and distribution of food and also to feed produced
for, or fed to, food producing animals. More in detail, the General
Food Law establishes the principles of risk analysis in relation to
food and establishes the structures and mechanisms for the scientific
and technical evaluations which are undertaken by the European
Food Safety Authority (EFSA). As an exception of the general
tendency to regulate risks rather than benefits, it is worth mentioning
the EFSA health claims procedure under Regulation (EC) No
1924/2006, which plays a relevant role in the regulation of the benefits.
Nevertheless, also in this case, we may see that the final objective
of regulating benefits turns into the legislative intention to
prevent risks, both connected to the functioning of the market and
to the consumers’ protection, if we consider that the general objective
of the Regulation is to ensure the effective functioning of the
internal market as regards nutrition and health claims whilst providing
a high level of consumer protection (EC, 2006).

Food law, and in particular measures relating to food safety
have to be based on scientific expertise. The EU has developed
its own risk analysis principles in conformity with the International
standards. Regulation EC/178/2002 establishes in EU law
that the three phases of risk analysis (risk assessment, risk management
and risk communication) provide the basis for food law
as appropriate to the measure under consideration. Therefore,
the General Food Law states that scientific assessment of risk
must be undertaken in an independent, objective and transparent
manner based on the best available science. Risk management
is the process of weighing policy alternatives in the light
of results of a risk assessment and, if required, selecting the
appropriate actions necessary to prevent, reduce or eliminate
the risk to ensure the high level of health protection determined
as appropriate in the EU. In the risk management phase, the
decision makers need to consider a range of information in addition
to the scientific risk assessment. These include, for example,
the feasibility of controlling a risk, the most effective risk reduction
actions depending on the part of the food supply chain
where the problem occurs, the practical arrangements needed,
the socio-economic effects and the environmental impact. Regulation
EC/178/2002 establishes the principle that risk management
actions are not just based on a scientific assessment of
risk but also take into consideration a wide range of other factors
legitimate to the matter under consideration (see http://ec.europa.eu/food/food/foodlaw/principles/index_en.htm).

In sum, at a legislative level we may observe that the main
objective is to regulate risks connected to unsafe food, rather than
benefits and the balance between risks and benefits. Risk management
is a procedure which involves legislative tools together with
scientific expertise. The choice to regulate risks rather than benefits
is deeply linked to the necessity to reduce the risks on the market
by defining the tasks of the European Commission, the
European Food Safety Authority (http://www.efsa.europa.eu) and
the national competent authorities in charge to implement at local
level the European provisions.

==Commonalities and differences, and illustration in a case study==

This section contains some of the characteristics that the different
fields, described in the previous section, share in common
and in which they differ with respect to benefit–risk
analysis.

The general settings in which benefit–risk analyses within the
different fields currently may take place are described in Table 1.
The general characteristics of integrated assessment of benefits
and risks within different fields are described in Table 2. In order
to illustrate the commonalities and differences, a conceptual case
example of replacing animal protein with environmentally more
sustainable dietary protein is presented in Table 3. The case example
described here is meant as an aid, to illustrate and characterize
the different fields that form this paper. The attributes in the tables,
according to which benefit–risk analysis within the different
fields are described, are adapted from the framework applied for
characterizing approaches to benefit–risk analysis in the field of
environmental health in Pohjola et al. (2011a) and explained in
Table 4.

In Section 3.1, general commonalities and differences are described,
taking the main points from Tables 1 and 2. Issues arising
from the illustrative case study in Table 3 are discussed in
Section 3.2.

{|{{prettytable}}
|+'''Table 1.''' Current general setting for benefit–risk analysis within different fields.
|-
!Attribute<sup>a</sup>
!Food and Nutrition
!Medicines
!Food Microbiology
!Environmental Health
!Economics and Marketing–Finance
!Consumer Perception
|-----
|Management question
|What is the optimal decision for public health, where and how can the largest net population health gains be realised, with respect to food-related questions, e.g.
* recommendation of nutrients or foods
* policy for fortification
* food processing methods
* introduction of novel foods
|What is the optimal decision for public health, with respect to
* drug safety
* drug efficacy
* drug safety monitoring and management
* drug benefit–risk balance
* eligible patient populations
|What is the optimal decision for public health, with respect to microbial food safety and (to a lesser extent) microbiologically mediated health benefits?
|What is the optimal decision for public health when focusing on environmentally mediated direct and indirect health impacts? Can be considered in the context of other issues such as
* economic impacts
* equity and social well-being impacts
* impacts to the environment
|What is the optimal utility that market participants derive from outcomes based on benefit–risk trade-offs such as production, costs, sales, or consumption of a food product?
Other issues to be considered:
* cognitive vs. affective decision making
* risk attitudes (RA) and risk perceptions (RP) formation
* drivers of RA and RP (e.g. trust, knowledge)
* utilitarian vs. hedonic benefits/gains
|What is the optimal decision from an acceptance perspective (as well as from a health perspective)?
Who will benefit (identification)?
How can target groups be reached (communication/ marketing)?
Food production (taste and health optimisation)
|-----
|Main problem owners and stakeholders
|Policy makers (decisions), scientists (assessment)
|Policy makers (decisions), scientists (evaluation), pharmaceutical companies (assessment, evaluation), agencies (evaluation, supervision), general practitioners (advice on patient level), patients (decisions)
|Policy makers (decisions), Scientists (assessment)
|Policy makers, industry, citizens (decisions), scientists, industry, commerce, in some approaches<sup>b</sup>, NGOs, citizens, in some approaches anyone (assessment), industry, commerce, NGOs, citizens (evaluation)
|Producers, marketers, policy makers, consumers (decisions), financial analysts (assessment of technical feasibility), marketers (assessment of economic feasibility), industry managers and lobby representatives (managerial feasibility)
|Consumers (decisions, ad hoc assessment), Risk managers, marketers (communication), Policy makers (decisions)
|-----
|Assessment - management interaction
|Separate (physically and intellectually), but becoming more interactive
|Ranges from separate to intertwined. Also depends on the stage in the marketing process
|Functionally separate approaches, increasing consultation and interaction between the two
|Approachesb range from strictly separate to deeply intertwined
|Approaches range from aggregate to disaggregate. They involve ad hoc self-assessment in decision situations by consumers. More systematic assessment, often by external assessors regarding policy decisions, marketing decisions, investment decisions
|Ad hoc self-assessments by consumers in decision situations, communication of both scientific and marketing information to identified target groups
|}
<sup>a</sup> Attributes are explained in Table 4 and adapted from the framework applied for characterizing approaches to benefit–risk analysis in the field of environmental health in Pohjola et al. (2011a).
<sup>b</sup> Approach refers to different approaches to making benefit–risk assessments within the field of environmental health, e.g. health impact assessment, REACH, open assessment, etc. (Pohjola et al., 2011a).

===General commonalities and differences===

The purpose of benefit–risk management is to arrive at the optimal
decision, while accounting for all relevant issues. The purpose
of benefit–risk assessment is to provide the science-based information
on the integrated benefits and the risks to support in answering
the benefit–risk management question, i.e. to contribute to
evidence-based decision making. The focus of benefit–risk analysis
in the different fields is

* Food and Nutrition: improving public health/preventing disease by better food and nutrition and generating knowledge for food improvement or innovation and general understanding.

* Medicines: curing, slowing or preventing disease by means of medication and monitoring benefit–risk profiles of marketed medicinal products with or without its impact on budget.

* Food Microbiology: preventing foodborne disease caused by micro-organisms and generating knowledge for microbiological product innovation.

* Environmental Health: preventing damage to health mediated through the environment, possibly also reducing impact on economy, society and environment.

* Economics and Marketing–Finance: optimising public economic policies, corporate investment and marketing strategies.

* Consumer Perception: stimulating good food choice by using insights in consumers’ perceptions, attitudes and behaviour relating to a particular case and by increasing acceptance through information, increasing familiarity, reducing uncertainty, and product optimization.

The challenges of aggregating and weighing benefits and risks
are shared by the different fields. Two issues coming up in this connection
are the inclusion of multiple benefits and risks with different
scopes, and the explicit inclusion of subjective information.
Among the fields that are considered, assessments in Food and
Nutrition, Food Microbiology, Medicines and Environmental
Health focus predominantly at health/disease, mostly physical
health/disease (though several approaches in Environmental
Health are open to also include other domains). Quantitative
weighing of benefits and risks via DALYs or QALYs has been performed
in Food and Nutrition, Food Microbiology, Environmental
Health and in post-marketing modelling studies for Medicines.
Mostly this is done within strict and relatively narrow bounds,
e.g. focusing on the health effects of food compounds. In Economics
and Marketing–Finance as well as Consumer Perception, health is
not the centre of attention. In the latter two, human perception
and behaviour is an important topic of investigation, whereas the
former four strive for more ‘objective’ health information. However,
also there, the influence of perception and behaviour is
acknowledged, at least to some degree, e.g. in the form of the placebo
effect and compliance to prescriptions or advice. Qualitative
comparison and use of expert judgment are part of all fields, but
in differing degrees. For example, expert opinions/judgments in
different phases have an important role in the progress of medicine
benefit–risk analysis along the early stages of drug development. In
Food and Nutrition, (expert) value statements are explicitly named
only in comparison or combination of benefits and risks (e.g. qualitative
comparison, and disability weights). Non-expert value judgments
are increasingly taken into account particularly in
Environmental Health.

Another notable issue relates to differences in the valuation of
benefits and the acceptability of risks, both by consumers and
managers. In Food and Nutrition and Food Microbiology, chemical,
biochemical and microbiological risks are not accepted, i.e. food
safety issues are minimised to such a low level that risks are virtually
absent (see also Section 2.7). Especially Food Microbiology is
illustrative of the important role of ‘risk’ in public health. In contrast,
in many approaches to Environmental Health and in Medicines,
some risk is accepted for a greater benefit. In Medicines,
risk, in the form of adverse drug reactions, is accepted for the
greater benefit of recovery or of alleviation of symptoms. Also, by
observing the common everyday practices, some degree of risk
coming from the environment in the form of traffic, energy production,
radiation, disinfection, etc. can be considered as accepted in
order to meet the needs of modern society. However, the perceptions
of such risks may vary significantly among policy makers
and the public, and the differing perceptions may not always be
backed up with well-reasoned knowledge. Moreover, in Economics
and Marketing–Finance and Consumer Perception, (high) risks can
be accepted if the expected benefits are higher and at least some
degree of risk is accepted as necessary to bring about benefits in
general. Some differences with respect to the degree in which risk is accepted and benefit is valued are illustrated in Fig. 2. With respect
to Food and Nutrition, there appears to be a discrepancy:
risks brought about by unfavourable nutritional quality and/or
quantity of the diet (i.e. unbalanced intake of nutrients and foods
resulting in deficiencies and/or chronic disease), are more readily
accepted (as voluntary, right to choose) both by consumers and
policy makers.

The field of Medicines stands out by being aimed at a single
product or technology, which is tested within a controlled environment
(pre-registration); the situation in ‘real life’ (e.g. interference
from other medication or from food, low compliance) can be observed
only after market approval. In all phases of the life of a medicine,
the benefit–risk balance can be different. The benefit–risk
balance can also change during the life of an individual. Within
Medicines, as well as Consumer Perception, there is a stronger individual
basis than in the other areas.

Notable in Environmental Health is the development towards
more interaction between all those who are in some way related
to the process (assessors, managers, industry, NGO’s, and citizens)
and to let actual problems drive analyses. In Food and Nutrition,
increasing engagement between assessors and managers is recognized
to be valuable, but presently there is virtually no role for
stakeholders in assessment.

===Illustrative case example===

The case example presented here (Table 3) to illustrate Section
3.1 from a practical viewpoint deals with dietary protein
sources, in particular the effect of replacing less sustainable
sources with more sustainable sources. Protein and the amino
acids that build protein are important, as they form the body’s system
of structural and functional elements that exchange nitrogen
with the environment and have many other functions (Millward
et al., 2008; WHO, 2007). Converting plant protein sources into
animal protein sources is relatively inefficient and negatively affects
the ecosystem when applied on a large scale (FAO, 2006).
With the increasing world population and the net increased affluence,
the consumption of animal protein is increasing. Without
policy action, the ecosystem is overly pressured and food security
is endangered. Alternative protein sources, with less impact on the
ecosystem, are known. They include plant sources, algae, insects
and cultured meat. The aim of the benefit–risk assessment is to
support well-informed policy making with respect to a protein
transition by providing the best available science.

From Table 3 it can be seen that the fields of Food and Nutrition,
Medicines and Food Microbiology have a rather tight focus,
whereas the fields of Environmental Health, Economics and Marketing–
Finance and Consumer Perception apply broader scopes in
their assessments. Especially in the latter two the effect on
health/disease is only one of many considerations in the broader
implications that a shift in focus from animal to plant protein
has. Table 3 also shows the different types of measurements and
approaches used to answer the assessment question.

Furthermore, the case study shows that a successful protein
transition, even when a net benefit is supported in terms of health
and sustainability, co-depends on consumer perceptions and actions
in terms of its actual realization. Sustainability and health
are, for a large segment of consumers, less important drivers of
food choice than e.g. the liking of animal protein rich products.
For alternatives to be accepted, some criteria will have to be considered,
among others: taste, expense, use of technology/naturalness,
and trust. Marketing and communication strategies will be
essential in creating acceptance. However, if long-term net benefit
is to be achieved, there is also an essential role for the authorities
in actively ‘making the healthy and sustainable choice the easy choice’ and implementing necessary regulations towards food
industry.

From the regulatory point of view, the eventual choice to shift
to dietary protein sources that are more sustainable than the current
animal products should not constitute a further burden for the
legislator. In case new products are being introduced, the general
framework to regulate risks connected to these products remains
the General Food Law and in particular the Novel Foods Regulation
(EC 258/97).

==Opportunities for Food and Nutrition benefit–risk analysis==

In this section we discuss how benefit–risk analysis for food and
nutrition may improve from looking at other research areas. A number
of issues that require further attention in Food and Nutrition
have been identified (Tijhuis et al., 2011). To name some key issues:

''Paradigm.'' In the contemporary benefit–risk analysis paradigm
(Fig. 1), assessment and management are marked entities. Communication
and some degree of interaction, though acknowledged,
may not currently receive the attention they deserve, both within
and between the analysis components. In addition, management of
public health in Food and Nutrition is currently still very much focused
on risk and aimed at identifying numbers below which intake
is presumed to be safe.

''Data.'' The arms of the benefit–risk assessment paradigm are not
symmetric; they currently serve different goals (i.e. to demonstrate
presence of benefit and absence of risk), they are built on different
methodologies, they are rooted in different research traditions, etc.
For a benefit–risk analysis in Food and Nutrition it is essential that
quantitative data on beneficial and adverse effects are available,
covering the relevant exposure and target population. For many
foods and ingredients this is currently not available. A fundamental
difficulty in this is the translation of dose and effect found in animal
studies to the human situation. Apart from this species issue,
lack of dose–response data is also a problem for human studies.
There are several possible reasons for this, not always easily solvable:
performance of studies in humans is expensive, is ethically
not acceptable or scientists are not used to quantifying or presenting
dose–response information; also, in benefit assessment the legal
situation is new.

''Context and implementation.'' Besides issues relating to assessment
and comparison of benefits and risks, there is currently often
no explicit consideration of which benefits and risks should be considered
in different contexts and why; and whether only health
risks and benefits induced by foods and food ingredients are sufficient
in light of the practical uses of the benefit–risk analysis results.
With respect to outcomes in the form of advice, there is a
discrepancy between results from assessment of benefits and risks
in the form of advice, and consumers’ behaviour. Input of the public
and other more specified stakeholders into assessment and
management, to drive the analysis or to find solutions, is currently
not common.

Below, these issues are addressed further in the form of concepts
and practices from other fields that may be incorporated
(more) in Food and Nutrition benefit–risk analysis.

===Paradigm===

====Increased engagement and communication between assessors, managers, and stakeholders====

Thus far, benefit–risk analysis in Food and Nutrition has been
building on (the clearly demarcated) assessment and management,
and virtually no role has been provided for stakeholders in these processes.
However, the experiences from other fields indicate that
more intimate interaction between assessors, managers, and stakeholders
is essential for effective implementation of existing and
available knowledge. This would take form in assessors, managers,
and stakeholders in the field of Food and Nutrition each having their
specific roles and responsibilities while engaging in the shared process
of developing and applying knowledge (Fig. 3). Increased
engagement can enhance e.g. clarity of the relevance of assessment
questions and applicability of assessment results as well as acceptance
of the outcomes of their practical implementation.

Communication is (increasingly more) important between all
those involved in the analysis: next to a role for professional communication
specialists to address the stakeholders/general public,
the assessors and managers could benefit from increased communicational
skills between and amongst them, to result in a shared
understanding of science and values (Fig. 3). Standardized forms,
formats, practices, and procedures can be helpful in facilitating
communication e.g. by allowing participants in the analysis to focus
on the content instead of the format or by making the general
public more familiar with risk and benefit information. However,
the standardized formats and practices should not be made too
strict and coercive, yet be flexible enough so that they can adapt
to changing needs and contexts. For example, the information
structure of Opasnet, a web-workspace for conducting open assessments,
provides a universal information structure that is applicable
for describing any kinds of phenomena, but allows quite free formatting
of the actual substance of the descriptions (Pohjola et al.,
2011b). Another example is the web-based QALIBRA software for
quantitative benefit–risk assessment in foods. The software is
web-based and free to users after completing a short online training
session (www.qalibra.eu). It provides a consistent conceptual
framework to help think about, organise and execute benefit–risk
assessment, and optional sharing and discussion of assessments
and data with other users.

====More pragmatic problem-oriented framing of assessment====

One of the aspects that can be enhanced by increased engagement,
as also mentioned above, is framing of assessments and formulation
of assessment questions to better serve the practical
needs of those who (are intended to) use the assessment results
in practice. Although purely curiosity-driven question setting is
defendable in traditional science, assessments may better be considered
as processes of applying scientific means and knowledge
for practical problem solving, and thus adopting a demand-driven
pragmatic approach. In order to achieve this, incorporation of decision
makers as well as stakeholders, e.g. consumers and industry,
in analysis is necessary.

Along this line, in most cases food products that consumers
actually ingest (whole foods) may be more relevant objects of benefit–
risk than mere isolated food ingredients or substances in food.
Also, in addition to looking at only the health risks or benefits of
the food itself, the rest of the food pattern should receive some
attention to be practically useful.

====Accepting some risk: inevitable inter-linkage of risk and benefit====

Risk is omnipresent, but it should be realised that so is benefit.
Risk and benefit go together. Policy aimed at the combination of
minimizing risk and maximizing benefit may result in a net higher
benefit for public health than policy aimed at minimizing risk only
(van Kreijl et al., 2006). This approach implies accepting some level
of risk. Or, from a positive perspective, it means acceptance of taking
benefit into explicit consideration. This will not only result in
more informed public health decisions, but also create more public
support and understanding of the broader picture within which
decisions are made. Where the optimum for health lies needs to
be assessed on a case by case basis, addressing also the needs
and context of each specific case (see Section 4.3).

====Pre- and post-market analysis of benefits and risk of food products====

Based on the experiences from the medical area, both pre- and
post-market analyses could be required for certain food products.
A pre-market assessment may be conducted by the producer of relevant
foods or food ingredients (and evaluated by independent
authorities), prior to market introduction, to address benefits and
risks according to the current knowledge level. A post-market analysis
(also termed ‘postlaunch monitoring’ (de Jong et al., 2007) and
‘post-market monitoring’ (Hepburn et al., 2008) would engage all
stakeholders, in particular authorities, with inputs from consumer
organisations, science and industry. Post-market analyses may be
triggered whenever new important evidence is gained, thus resulting
in a follow-up over years. (Passive) surveillance systems can
form the first step in identifying signals of potentially unknown
risks. In addition, surveillance systems can also follow up on beneficial
physiological effects of food or food ingredients (de Jong
et al., 2007) and can be used for evaluation purposes: did a benefit–
risk advice or decision have effect? Such post-market effectiveness
monitoring may form an elegant and desirable addition to the health claims area (de Jong et al., 2007; Hepburn et al., 2008). This
post market effectiveness monitoring could be part of a dynamic
and pro-active management plan where there is feedback between
public health efficacy, management and manufacturers.

===Data===

====Explicit communication of the assessment purpose, input and output====

If benefit–risk analysis intends to achieve its goals of improving
public health through the realized net benefits of consuming food
products, it needs to produce explicit messages of their benefits
and risks as well as the factors that influence them. There is ongoing
discussion regarding the common currencies being developed
and applied for aggregating and communicating multifaceted
health and other outcomes (Tijhuis et al., 2011). One area of research
that is still open is how to better take account of above average
health states within the aggregated measures, e.g. quality
weights. Also, the long-accepted definition of health (WHO,
1948) is now increasingly being debated to include the ability to
adapt (Anonymous, 2009; Huber et al., 2011).

Often it is advisable, if possible, to use more than one outcome
measure, for example DALY and cost effectiveness. This will also
show the broader perspective that surrounds each case, and may
prevent or lower a false sense of security that quantification of
complex issues in one measure may give. Finding optimal (combinations
of) aggregated measures is important, however, it may be
even more important to consider how to best explicate the essential
aspects of the information produced in the analysis in different
situations and contexts.

It needs to be realized that allmodels are inherently false if the goal
is to 100% reflect reality; they can be useful, however,when used and
interpretedintherightway.Some input intothemodels is surrounded
by more uncertainty than other. This can be at least evaluated by sensitivity
analyses or value of information analysis (Saltelli and Annoni,
2010; Tuomisto et al., 2004). The uncertainties can be made explicit.
Some uncertainties may not be very important for the outcome.
Uncertainty ismore important for the parameters that drive the outcome,
or in otherwords: that form the basis for the ultimate decision.
It also needs to be realized that different expertises are involved and
required in creating the output, such asmathematicians,nutritionists,
toxicologists,medical doctors, etc. Increased interaction between disciplines
anddomainswilloptimize themodeling, theinput themodels
require and their interpretation.

====More human (dose–response) data and more efficient use of human data====

Human data are more valuable than animal data for assessing
both benefits and risks, as there is no need to extrapolate/translate
dose, effects and physiological differences. Human data, however,
are also less available: they are often more expensive and more difficult
(sometimes impossible) to obtain than animal data. On two
accounts, however, benefit–risk analysis could benefit relatively
easily from data that already exists or is conveniently available.

Firstly, researchers often can present more quantitative data in
their publications. For example, when presenting a group risk covering
a range of exposures (e.g. a quartile), information on exposure
and its variation can be included.

Secondly, human data can also be obtained in the post-market
phase for products for human use (see also Section 4.1). Obtaining
data in the post-market phase has advantages. It allows real-life
information to be incorporated into the assessment, such as compliance,
compensation behaviour and real-life effect size. Also, it benefits
from high numbers compared to pre-market data. Experience in
Medicines has also shown limitations of post-marketing surveillance,
however, such as reporting biasand selection bias. In the social
sciences there is a new trend to actively let consumers participate in
data generation, in the form of creating panels to obtain research
data. It may be informative to follow this development.
As the availability of applicable data is hampering the use of
benefit–risk analysis in Food and Nutrition, it may be relevant to
establish a database on benefit and risk data and research to promote
and coordinate its further development. However, selective
reporting should be prevented and thus a system of registration
before execution of the assessment (as required in the clinical trial
database) would have to be considered.

====Distinguishing physiologically different populations within the consumer population====

As in Medicines, where the dynamics of the benefit–risk profile
throughout the life cycle is recognized, some researchers in Food
and Nutrition are also developing towards a more inter- and intraindividualised
approach. For example, in the window of benefit approach,
inter- and intra-individual variation is explicitly takeninto account
(Tijhuis et al., 2011). One disadvantage of population health
measures is that its effects are not always visible for individuals (prevention
paradox). This could be overcome by a more individualised
approach, which may have an additional psychological advantage of
increased compliance. Difficulty is that the more a subgroup approaches
the individual (i.e., n = 1), the more difficult it becomes to
show the effectiveness of a measure, using traditional statistical
methods.

In some cases, benefits and risks apply to different population
segments. For example, by fortifying a staple food with folic acid,
the children of women in the 1st trimester of pregnancy (the target
group) will benefit from the risk reduction of neural tube defects,
but other groups may also be affected (and not always favorably)
(Hoekstra et al., 2008). Both an opportunity and a challenge lie in
specifically targeting the population groups that benefit most from
the food product.

==== Explicit consideration of value judgments in assessment====

Value judgments, based e.g. on opinions, interpretations and perceptions,
have an important influence on decisionmaking and behaviour
e.g. by food safety managers, food producers, marketers and
consumers. Therefore, identification and understanding of the values
thatdrive e.g.decisionsofmanagersandbehaviour of consumersneed
to be explicitly taken into account in systematic assessment alongside
scientific facts. This is essential for the assessments to serve the practical
needs of decision making. This is not to say that subjective value
judgment could replace systematically obtained research-based data
and information in assessment (though assumptions, choices and
interpretations are actually already an integral part of obtaining the
objectivequantitativedata,andthe use of assessment results is subsequently
guided by subjective opinions in policy making). But it can
complement scientific knowledge by making it more coherent, relevant,
and applicable. For example, in the context of the case study (Table
3), a good benefit–risk assessment must systematically consider
the differing value judgments regarding e.g. the importance of environmental
protection, biodiversity, human health, personal preferences
about different foods, and cultural traditions that relate to the
issue of replacing animal protein with protein from other sources in
the diet. Failing to do sowould likely result in assessment outputs that
are of little value in practical decision making. Value judgments are
thus relevant and valuable input to the science-based assessments
as parts of effective benefit–risk analysis.

===Context===

====Integration of multiple benefits and risks from multiple domains====

Integration of multiple benefits and risks from multiple domains
is an essential means for achieving enhanced applicability of assessment results. Most often, a reductionist approach to benefit–risk
analysis, focusing on narrowly bound problems, is not adequate
for serving practical real needs that do not obey disciplinary boundaries.
Therefore, assessment and management should allow for
broad integration of both benefits and risks from multiple domains,
according to needs. By taking a holistic view of benefit–risk analysis
at an early stage, decisions on which scientific areas should be included
in the benefit–risk analysis will focus the assessments. Not
all other factors can be integrated into a common measure and aspects
of health may remain in the focus of the process. However,
they can be placed within a reasonable context, or bigger picture,
provided by the other aspects to be considered. For example, benefit–
risk assessment on fish consumption can show that benefits prevail
over risks, but consideration of sustainability issues or consumer
preferences may steer the analysis towards inclusion of farmed fish
raised on sustainable feed or alternative non-fish sources.

The importance of integration and contextualization is also
illustrated by the case study in Section 3.2. In the field of Food
and Nutrition, dealing mostly with health, it can be quite relevant
to consider also consumer perception and behaviour, ethics, environment,
industry interests, etc. It should be noted that the relevance
of context is already part of the principles of Food Law as
‘‘other legitimate factors’’ http://ec.europa.eu/food/food/foodlaw/principles/index_en.htm, making room for consideration also of
benefits. However, good documenting of the factors and practices
to incorporate them are still lacking.

====Explicit recognition of the impact of consumer beliefs, opinions, views, perceptions, and attitudes on behaviour====

Consumers are an essential stakeholder group regarding food
and nutrition. In the process of benefit–risk analysis of Food and
Nutrition, it needs to be taken into account in what direction and
to what extent food and nutrition aspects may influence consumer
behaviour. This includes studies on human decision making, on
behaviour of market segments and on benefit–risk tradeoffs in
these groups. Alongside benefit–risk assessment on a physiological
level, consumer characteristics such as perceptions or values can
be measured in order to correct for differences between consumers
or target groups in how they behave with respect to the problem.
For example, in the case of monosodium glutamate (MSG), concerns
by consumers and consumer groups about MSG consumption
(Freeman, 2006; Williams and Woessner, 2009), influenced by
commonly available non-scientific information, override scientific
knowledge (Singh, 2011) to the extent that food industry has begun
reducing or removing MSG from their products (http://www.toro.no/index.php?mapping=344; http://www.unilever.com.vn/brands/foodbrands/knorr/index.aspx). Whether or not
the consumer behaviour in this case can be backed up by Food
and Nutrition research results, recognition of its existence and
understanding of its basis and impacts is important in assessment
as well as decision making by food safety managers, consumers,
producers, marketers and other stakeholders. Consumer studies
can qualitatively and quantitatively assess consumers’ compliance
with advice and why benefits and risks are acted upon in different
ways, both cognitively and unconsciously. The data thus provided
can be used as feedback in the benefit–risk analysis, to overcome
the difficulties associated with the traditional science-decisioncommunication
approach. Just as a hazard is not a risk until there
is exposure, a food is not healthy until it’s eaten. An important contribution
of consumer research to benefit–risk analysis in food and
nutrition is particularly related to how to implement measures to
achieve the best effects. Identification of relevant target groups
and formulating communication strategies that work, are major
aspects that could benefit the goals of benefit–risk analysis in food
and nutrition. From a management perspective, taking consumers’
view-points into account is relevant in the implementation phase
when the aim of the benefit–risk analysis is to provide advice,
directions or action plans. Specifically: in case consumer’s viewpoints
are not in conformity with current scientific insights, risk
managers should strive for means of an appropriate consumer
information and education.

====Segmenting market participants behaviour====

Differentiation of sub-groups can take place in terms of physiological
characteristics, as addressed before, but also in terms of
their cultural, cognitive and behavioural characteristics.

The segmentation criteria for grouping the behaviour of market
participants depending on whether the food offering is aiming to
reach the end-user (e.g. consumer) or another business are different.
The more typical criteria for segmenting prospects at a corporate
business level usually entail the industry type, the size of the
corporation, e.g. in terms of revenues or employees, time-related
factors, access to competitive offerings, and the need for customization,
among others. The criteria that are often used to group
the behaviour of individual market participants (e.g. consumers)
may include demographics, cultural-, economic-, religion-related,
social-status, accessibility to food offerings, and avocation-related
interests, among others. Yet, once the identification of specific segments
has been achieved, there is a series of subtle influences on
the buying behaviour such as the beliefs, views, concerns, attitudes,
perceptions, information needs, brand awareness, and commitment
to specific values and business operations of market
participants. That is, a series of unobservable (e.g. latent) factors
may influence the purchasing behaviour and/or decisions of different
segments of food producers, wholesalers, retailers, managers,
and consumers. Moreover, the differing preferences of market participants
that are attributable to their heterogeneous desires and
varying wants may be driven by several unobservable factors often
referred in the academic literature as behavioural anomalies, such
as humans’ personality traits (e.g. need for cognition, ambiguity,
need for certainty, risk-aversion, loss-aversion, myopia, overconfidence)
or heuristics (i.e., rules of thumb) that lead people to find
things out for themselves, usually by trial and error.

The consideration of a heterogeneous food market as a number of
smaller homogenous food markets, highlights the diversity in market
participants attitudes, perceptions and preferences and their
driving forces. This view reflects the market-orientation of the food
industry. Such an orientation is essential if segmentation of market
participants’ behaviour in the agribusiness and food markets may
be used as one of building blocks of effective food and nutrition policy-
making and marketing-management planning.

==Conclusions==

The BEPRARIBEAN project has looked into benefit–risk analysis
within six different, but somewhat interrelated, scientific fields.
The main findings of the project are described in the previous sections,
particularly in the form of the key messages in the section
‘Opportunities for food and nutrition benefit–risk analysis’.

While looking into benefit–risk analysis from different scientific
perspectives we realized that different fields are facing similar
problems. All fields struggle with the challenges of aggregation,
weighing, and comparison of multiple benefits and risks. This
stresses the need for an interdisciplinary approach and mutual
learning. We identified some differences with respect to the degree
in which risk is accepted (Fig. 2). Consumer and marketing sciences
could give useful insight in the psychological mechanisms behind
this and give advice in how to target specific groups or how to
put risk perceptions into perspective. Stakeholder participation is
increasingly valued as important, thereby granting it a position
in the benefit–risk analysis-triad next to assessment and management (Fig. 3). Increasing interaction between the three is essential
for making policy decisions addressing real public health issues,
using the best available scientific data on diet-health relations.
We want to emphasize again that interaction can and should take
place without each losing its own responsibilities, roles and interests.
The tiered approach and transparency in assessment proposed
for the Food and Nutrition field (Tijhuis et al., 2011) is one way to
support this.

Altogether, the key messages suggest that benefit–risk analysis
in Food and Nutrition should be considered as a joint process
where the experts, professional decision makers, as well as consumers
and other stakeholders come together to create shared
understanding (Fig. 3). In this, different domains of benefits and
risks are explicitly considered, as are their greatest net benefits
(taking subgroups into account). Focusing on food safety and not
addressing food benefits is a risk management decision just as
much as accepting some risk in order to achieve more benefits.
Either way, both policy makers and consumers should let go of
the artificial line between risk coming from chemicals and microorganisms
in the diet (captured in regulation for consumer protection)
and risk coming from a bad quality and quantity of the diet
(captured in dietary advice for consumer protection). In the end,
for both situations, the result is disease and burden to society; as
the former is currently relatively well taken care of, the latter currently
has much larger impact on public health and resources (Tijhuis
et al., 2011; UN, 2011; van Kreijl et al., 2006).

The identification of several key messages that describe how
Food and Nutrition benefit–risk analysis, as well as benefit–risk
analysis in general, should be practiced is not an end in itself.
Rather, it gives guidance for developing and implementing such
practices in order to make this vision a reality. This work will require
further development of the systems and tools started in previous
projects and adoption of new methods, tools, and data
sources to support the improved benefit–risk analysis practices.
Contributions are required from all relevant actors in the analysis
in order to promote the realization of improved benefit–risk analysis.
Regulatory frameworks may need to be adjusted to allow and
support the new contexts and practices of analysis. Managers may
need to adopt a more active role as participants in knowledge creation
and allow for broader involvement of other participants in
the analysis. Assessors also need to adapt their attitudes towards
considering themselves in the role of facilitating the development
of shared understanding, not only among experts, but also among
managers and stakeholders.

==Conflict of Interest==

The authors declare that there are no conflicts of interest.

==Acknowledgements==

The preparation of this manuscript was funded through Safefoodera
project BEPRARIBEAN (project ID 08192) by the Dutch
Food and Consumer Product Safety Authority (VWA), the Research
Council of Norway (RCN) and the Nordic Council of Ministers
(NCM) and supported by Matís, The National Institute for Health
and Welfare (THL), the University of Ulster and the National Institute
for Public Health and the Environment (RIVM).

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