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[[Category:Dioxin]]
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Tomas Trnovec, Anton Kocan, and Lubica Palkovicova
Slovak Medical University, Bratislava, Slovak Republic


===Introduction===

Excellent reviews on dioxin toxicology have been published (Schecter and Gasiewics, 2003). "Dioxins" are a family of chemicals containing carbon, hydrogen and chlorine, a group of 75 closely-related compounds which are known as polychlorinated dibenzo-p-dioxins (PCDDs). Dioxins also commonly include polychlorinated dibenzofurans (PCDFs). PCDDs, PCDFs and PCBs are 3 of the 12 UNEP internationally recognised Persistent Organic Pollutants (POPs). There are  210 different forms of dioxins and furans (75 dioxins and 135 furans), with the most toxic being 2,3,7,8-tetrachlorodibenzo-p-dioxin or TCDD. Dioxins are not deliberately manufactured. Rather, it is the unintended by-product of industrial processes that use or burn chlorine in the presence of organic materials a process catalyzed by metals. They occur naturally in small quantities as a result of volcanic activity and brush and forest fires. The top three sources of dioxins are municipal waste and hospital incinerators and backyard burn barrels. Additional sources include the production of iron and steel, metal recycling<sup></sup>sites, specifically sites that recycle aluminium, wood burning, especially if the wood has been chemically treated, fuel burning, including diesel fuel and fuel for agricultural purposes and home-heating, electrical power generation, chemical processing facilities that use chlorine to make products such as polyvinyl chloride (PVC) plastic and pesticides and pulp mills that use chlorine to bleach wood pulp to make paper white.


===Relevant exposure metrics===

As dioxins are fat soluble, they will accumulate in fatty tissue. In general, it is only the biologically active (molecules containing the 2,3,7,8 substitution) congeners that accumulate, with levels of the higher homologues predominating. There are a possible 75 PCDD and 135 PCDF congeners<sup></sup>(dibenzodioxins and dibenzofurans with up to eight chlorine<sup></sup>atoms), but of these, only 17 are considered to be biologically<sup></sup>active. Of all the PCDDs and PCDFs, only those containing 4 to 8 chlorine atoms, and with chlorine atoms in the 2,3,7,8 positions are currently considered toxic. The compounds only containing 0 to 3 chlorine atoms are currently not considered toxic. As additional chlorines are added, the toxicity decreases, except that 2,3,4,7,8-pentachlorodibenzofuran is more toxic than 2,3,7,8-tetrachlorodibenzofuran. Structure activity studies have demonstrated that optimal biological activity and Ah-receptor binding requires congeners with a planar conformation and chlorines at the corners of the molecule at the 2,3,7,8 positions. Chlorines at both ortho positions in these molecules (i.e., positions 1 and 9) sterically hinder a planar conformation that lessens the congeners’ biological activity.

Human exposure to PCDDs, PCDFs, and PCBs may occur through background (environmental) exposure, and accidental and occupational contamination. Over 90 percent of human background exposure is estimated to occur through the diet, with food from animal origin being the predominant source. PCDD and PCDF contamination of food is primarily caused by deposition of emissions from various sources (e.g. waste incineration, production of chemicals) on farmland and water bodies followed by bioaccumulation up terrestrial and aquatic food chains. Other sources may include contaminated feed for cattle, chicken and farmed fish, improper application of sewage sludge, flooding of pastures, waste effluents and certain types of food processing. When dioxins are released into the air they land on plants and soil, as well as on buildings, roads, and other structures. Dioxins remain in the soil for decades. Chickens raised on the ground will constantly peck at and eat soil. Dioxins remain in the fat of the chicken and eggs produced by these chickens will contain dioxins. Bioaccumulation of dioxins is continuing along the trophic chain and releases go on from landfills, polluted soils or sediments. 

There have been concerns over the years about the potential health impact of dioxins found in the environment and in the food supply. In recent decades these concerns have prompted significant coordinated U.S. government regulatory and industry efforts to reduce dioxin emissions to the environment. The results are impressive. According to Environmental Protection Agency (EPA) data, dioxin emissions from quantified sources have dropped by over 90 percent since 1987.The sharp decrease of "background levels" in the environment in the last 20 years will probably not be repeated in the coming decades.

Each congener of compound of dioxins or dioxin-like (DL) PCBs (currently 12 PCB congeners with a coplanar structure) presents a different level of toxicity. To sum up the toxicity of these different congeners, the concept of toxic equivalency factors (TEFs) has  been introduced to facilitate risk assessment and regulatory control. This means that the analytical results of all congeners or compounds of toxicological relevance (17 dioxin and 12 dioxin-like PCB congeners) are converted into one result which summarizes all and is expressed as TCDD toxic equivalent concentration or "TEQ" (Van den Berg M, et al. 2006). 

The use of body burden as the dose metric is the most reasonable and pragmatic approach at the present time. Mean background levels of 2,3,7,8-TCDD in human tissues today are in the range of 2-3 ng/kg fat. Available data suggest that these levels have decreased by a factor of 3 to 5 since the late 1970s, when the development of gas chromatography/mass spectrometry methodology first permitted these extremely low levels of PCDDs/PCDFs in tissues and the environment to be measured accurately. Similarly, since the mid-1980s, mean tissue levels of total PCDDs  and PCDFs (measured as international toxic equivalents (I-TEQs)) in the general population have decreased by two- to three-fold. Human exposures related to occupation or accidents have led to tissue levels of 2,3,7,8-TCDD up to several orders of magnitude higher than background levels (IARC). Data on dietary intake of dioxins and related PCBs by the population of EU Member States is available (Report SCOOP Task 3.2.5 Dioxins). The available information derived from numerous studies in industrialized countries indicates a daily intake of PCDDs and PCDFs in the order of 50-200 pg I-TEQ/person/day, or 1-3 pg I-TEQ/kg b.w./day for a 60 kg adult. This results in average human background levels in the range of 10-30 pg I-TEQ/g lipid, equivalent to a body burden of 2-6 ng I-TEQ/kg body weight (Assessment ….1998). The dietary exposure to PCDDs/PCDFs and DL-PCBs in the range of 1.2-3 pg/kg b.w. and day exceeds the Tolerable Weekly Intake (TWI) or the Tolerable Daily Intake (TDI) for a considerable part of the European population (Opinion … 2001; Community … 2001). The Committee (Opinion … 2001) established a group TWI for dioxins and DL-PCBs of 14 pg WHO TEQ /kg b.w. This TWI is in line with the provisional Tolerable Monthly Intake of 70 pg/kg body weight/month established by the JECFA (Joint… 2001) and concurs with the lower end of the range TDI of 1-4 pg WHO-TEQ/kg body weight, established by the World Health Organization (WHO 1998). 


===Health effects of short- and long-term exposures===

A broad variety of data primarily on TCDD but also on other members of the class of dioxin-like compounds has shown the importance of the aromatic hydrocarbon receptor (AhR) in mediating the biological effects of dioxins. These data have been collected in many experimental models in multiple species including humans. The precise chain of molecular events by which the ligand-activated receptor elicits these effects is not yet fully understood. However, alterations in key biochemical and cellular functions are expected to form the basis for dioxin toxicity. (WHO 1998).  Exposure to dioxins can lead to a wide array of adverse health effects including cancer, birth defects, diabetes, learning and developmental delays, endometriosis, and immune system abnormalities. Dioxins can disrupt the normal function of hormones-chemical messengers that the body uses for growth and regulation. It interferes with thyroid hormone levels in infants and adults, alters glucose tolerance, and has been linked to diabetes. Effects on the immune system appear to be among the most sensitive endpoints studied. Animal studies show that dioxins decreased immune response and increased susceptibility to infectious disease. In human studies, dioxins were associated with immune system depression and alterations in immune status leading to increased infections. Dioxins are known carcinogens, 2,3,7,8-TCDD is carcinogenic to humans (Group 1) (IARC1997; US EPA 2003).

Dioxins have been the subject of intensive scientific research and environmental controls since the 1970s (US EPA 2003). In July 2006 the National Research Council (NRC) of the National Academies published a report evaluating a previous review of the scientific literature and a draft assessment of the health risks of dioxin conducted by the Environmental Protection Agency (EPA) in 2003 (US EPA 2003). According to the NRC (NAS 2006), the previous risk assessment did not adequately quantify the uncertainties associated with the risks, nor did it adequately justify the assumptions used to estimate the risks. The use of different and more scientifically supportable assumptions may result in a lower estimated cancer risk for humans exposed to low doses of dioxins and related compounds. In other words, the 2003 risk assessment may have over estimated the cancer risks associated with the low levels of exposure experienced by most people and animals.

Although the NRC review committee did not go so far as to suggest that there is a lower cancer risk to humans through exposure to dioxins in food, water, or the environment, it gave no reason for increased concern. More on this issue can be found in the documents in brackets (Report …GAO-02-515; Questions and Answers about Dioxins 2006).


===What health endpoints might be quantified===

Several models ranging from very simple to complex have been developed to describe the toxicity of TCDD. It is obvious that the biology governing the toxicity of TCDD, beyond a few initial critical events, is not straightforward. These critical events, the first of which is binding to the AhR, are generally response-independent. The response-dependent events are species-, sex-, organ-, tissue-, cell- and developmental stage-specific. In general, the available data indicate that receptor involvement is necessary for most if not all low-dose actions of TCDD. However, it is clear that for many responses, the dose-response curves are different from receptor binding curves. Furthermore, although the AhR has been detected in many kinds of cells, not all of these exhibit toxic responses. These data suggest that  there must be other factors that are necessary for TCDD-induced toxicity. A variety of models have been applied: In the case of human cancer data linear and nonlinear models were fitted to the data. With the rodent cancer data a simple multistage model was fitted with the BMD software program. For non cancer data  the Hill model as the default for continuous responses was deployed, with a power model as the alternative when the Hill model failed to fit the data computationally. Also the Weibull model as the default for quantal non cancer data proved useful. Flexible mathematical models (e.g., the Hill and Weibull models) are recommended to account for both nonlinear and linear shapes of the dose response both for non cancer effects and cancer data (US EPA 2003).


===Is there evidence of a threshold or "safe " level===

Although the law of mass action predicts that a single molecule of ligand can interact with a receptor, thereby inducing a response, it is also widely held that there must be some dose that is so low that receptor occupancy is trivial and therefore no perceptible response is obtainable. Therefore, the same receptor occupancy assumption of the classic receptor theory is interpreted by different parties as support for and against the existence of a threshold. This has led to renewed attempts to claim that dioxins are not as toxic as was thought, fuelled by the desire of industry to declare present levels tolerable. The EPA has now begun to reassess its tolerable level, to take into account the likelihood of a threshold effect. One of the conclusions of the Evaluation of the Reassessment made by NAS is that the current weight of evidence on TCDD, other dioxins, and DL-compounds carcinogenicity favors the use of nonlinear methods for extrapolation below the point of departure (POD) of mathematically modelled human or animal data. However, it is not scientifically possible to exclude totally a linear response at doses below the POD. For cancer risk assessment, the threshold approach should be used in addition to the linear approach (NAS 2006). In relation to carcinogenicity, the UK Committee on Carcinogenicity (COC) concluded in 2001 that "TCDD should be regarded as a probable human carcinogen" [http://annhyg.oxfordjournals.org/cgi/content/full/48/5/425]. It was also  noted that "a threshold approach to risk assessment was  likely to be appropriate", meaning that there may be an  exposure level at which there is no increased risk of cancer  above background rates. Although COC could not state what this  exposure might be, it noted that "the excess cancer mortality  reported in the heavily-exposed industrial cohorts was small"  and that "any increased risk of cancer at background levels  of exposure is likely to be extremely small and not detectable  by current epidemiological methods".


===What sub-groups of the population are most susceptible or otherwise will need special consideration in quantification===

The issue of children’s risk from exposure to dioxins has been addressed in a number of papers. Health outcomes identified have included low birth weight, hormone fluctuation, neurobehavioral function and altered immune function. Data suggest a sensitivity of response in both humans and animals during the developmental period, both, prenatally and postnatally. Fetuses are most sensitive to dioxin exposure, and newborns may also be more vulnerable to certain effects. However, data are limited. Because evaluation of the impacts of early exposures on both children’s health and health later in life is important to a complete characterization of risk, collection of additional data in this area should be a high priority to reduce uncertainties in future risk assessments. No epidemiological data and limited animal data are available to address the question of the potential impact of exposure to dioxin-like compounds on childhood cancers or on cancers of later life. Given the relative impact of nursing on body burdens, direct impacts of increased early postnatal exposure on the carcinogenic process are expected to be small. This conclusion is based on the reasonable assumptions that cancer risk is a function of average lifetime body burden or that dioxin later in life might be more important than those received earlier (US EPA 2003). 


===References===

(Dioxins and Health, Second Edition - Arnold Schecter, Thomas A. Gasiewicz (Eds.), Wiley, New York, 2003; INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY ENVIRONMENTAL HEALTH CRITERIA 88 POLYCHLORINATED DIBENZO'''-'''PARADIOXINS AND DIBENZOFURANS; ATSDR)

Assessment of the health risk of dioxins: re-evaluation of the Tolerable Daily Intake (TDI). WHO Consultation May 25-29 1998, Geneva, Switzerland Available at [http://www.who.int/ipcs/publications/en/exe-sum-final.pdf]

ATSDR (Agency for Toxic Substances and Disease Registry). 1998. Toxicological Profile for Chlorinated Dibenzo-p-dioxins. U.S. Department of Health and Human Services, Public Health Service, Atlanta, GA. Available at [http://www.atsdr.cdc.gov/tfacts104.pdf]

COC. (2001) Carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin, COC/01/S2, July 2001. Available at [http://www.doh.gov.uk/tetrachl.htm]

Community Strategy for Dioxins, Furans and Polychlorinated Biphenyls. COMMISSION OF THE EUROPEAN COMMUNITIES. COMMUNICATION FROM THE COMMISSION TO THE COUNCIL, THE EUROPEAN PARLIAMENT AND THE ECONOMIC AND SOCIAL COMMITTEE Brussels, 24.10.2001 COM(2001) 593 final.Available at [http://eur-lex.europa.eu/LexUriServ/site/en/com/2001/com2001_0593en01.pdf]

Dioxins and Health, Second Edition - Arnold Schecter, Thomas A. Gasiewicz (Eds.), Wiley, New York, 2003

INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY ENVIRONMENTAL HEALTH CRITERIA 88: POLYCHLORINATED DIBENZO-PARA-DIOXINS AND DIBENZOFURANS. Available at [http://www.inchem.org/documents/ehc/ehc/ehc88.htm]

Joint FAO/WHO Expert Committee on Food Additives (JECFA) at its fifty-seventh meeting (Rome, 5-14 June 2001) Available at [http://www.who.int/ipcs/food/jecfa/summaries/en/summary_57.pdf]

NAS Health Risks from Dioxin and Related Compounds Evaluation of the EPA. Reassessment Committee on EPA’s Exposure and Human Health Reassessment of TCDD and Related Compounds. Board on Environmental Studies and Toxicology, Division on Earth and Life National Research Council of the National Academies. The National Academies Press Washington, D.C. Available at [http://www.ejnet.org/dioxin/nas2006.pdf]
Opinion of the Scientific Committee on Food on the Risk Assessment of Dioxins and Dioxin-like PCBs in Food. Update based on new scientific information available since the adoption of the SCF opinion of 22nd November 2000. Adopted on 30 May 2001. CS/CNTM/DIOXIN/20 final Available at [http://ec.europa.eu/food/fs/sc/scf/out78_en.pdf]

Questions and Answers about Dioxins 2006. Available at [http://www.cfsan.fda.gov/~lrd/dioxinqa.html#r1]

Report SCOOP Task 3.2.5 (Dioxins): EUROPEAN COMMISSION HEALTH & CONSUMER PROTECTION DIRECTORATE GENERAL. Directorate C - Scientific Opinions C3 - Management of scientific committees II; scientific co-operation and networks Reports on tasks for scientific cooperation. Report of experts participating in Task 3.2.57 June 2000 Assessment of dietary intake of dioxins and related PCBs by the population of EU Member States. Available at
[http://ec.europa.eu/dgs/health_consumer/library/pub/pub08_en.pdf]

Report to Congressional Requesters April 2002 ENVIRONMENTAL HEALTH RISKS
Information on EPA’s. Draft Reassessment of Dioxins, GAO-02-515 Available at
[http://www.gao.gov/new.items/d02515.pdf]

SUMMARY REPORT. DIOXINS: Methodologies and principles for setting tolerable intake levels for dioxins, furans and dioxin-like PCBs. 28-29 June 2004, Brussels, Belgium. [http://www.efsa.europa.eu/EFSA/Scientific_Document/efsa_dioxins1,0.pdf]

US EPA. The Exposure and Human Health Reassessment of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and Related Compounds (EPA 2003a, Part I; 2003b, Part II; 2003c, Part III) Available at [http://cfpub2.epa.gov/ncea/cfm/part1and2.cfm?ActType=default] 

Van den Berg M, Birnbaum LS, Denison M, De Vito M, Farland W, Feeley M, Fiedler
H, Hakansson H, Hanberg A, Haws L, Rose M, Safe S, Schrenk D, Tohyama C, Tritscher A, Tuomisto J, Tysklind M, Walker N, Peterson RE. The 2005 World Health Organization reevaluation of human and mammalian toxic equivalency factors for dioxins and dioxin-like compounds. Toxicol Sci 2006, 93, 223-41. 

WHO European Centre for Environment and Health International Programme on Chemical Safety Assessment of the health risk of dioxins: re-evaluation of the Tolerable Daily Intake (TDI). WHO Consultation May 25-29 1998, Geneva, Switzerland

WORLD HEALTH ORGANIZATION. INTERNATIONAL AGENCY FOR RESEARCH ON CANCER. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Volume 69. Polychlorinated Dibenzo-para-Dioxins and Polychlorinated Dibenzofurans. Summary of Data Reported and Evaluation POLYCHLORINATED DIBENZO-para-DIOXINS POLYCHLORINATED DIBENZOFURANS 1997. Available at [http://monographs.iarc.fr/ENG/Monographs/vol69/volume69.pdf]