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Context - Dioxins are mainly released by human activities such as incineration and fuel combustion. Some dioxins and some "dioxin-like" PCBs are known to be harmful. Though in general dioxin levels have been dropping in industrialized countries, some populations have been accidentally exposed to high doses. This raises concern about potential risks to our health and to the environment.

Questions on Dioxins 1. 2. 3. 4. 5. 6. 7.

What are dioxins ? How are humans exposed to dioxins ? What are the effects of dioxins in laboratory animals ? What are the effects of dioxins on human health ? How can dioxin exposure be linked to health effects ? Evaluation and conclusions Are there any different views ?

This is a faithful summary of the a leading scientific consensus report produced in 1998 by the WHO-IPCS (International Programme on Chemical Safety) "Assessment of the health risk of dioxins: re-evaluation of the Tolerable Daily Intake"

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Dioxins : Level 1 - Summary on Dioxins

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Level 1 - Summary on Dioxins 1. 2. 3. 4. 5. 6. 7.

What are dioxins ? How are humans exposed to dioxins ? What are the effects of dioxins in laboratory animals ? What are the effects of dioxins on human health ? How can dioxin exposure be linked to health effects ? Evaluation and conclusions Are there any different views ?

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1. What are dioxins ? 1.1. "Dioxins" refers to a group of chlorinated organic chemicals with similar chemical structures. Some have harmful properties, depending on the number and position of chlorine atoms in their chemical structure. One of the most harmful dioxins is known as TCDD. Some PCBs, which have similar properties, are considered "dioxin-like". More... 1.2. Unlike PCBs which were used in several industrial applications, dioxins have no uses. They are formed unintentionally and predominantly released as byproducts of human activities such as incineration and fuel combustion. They are also formed in minor quantities by natural processes such as forest fires and volcanoes. More... 1.3. Dioxins travel through the air and deposit on water or land. In water, dioxins initially bind to small particles or plankton. On land, dioxins deposit on plants or bind to the soil, most often without contaminating groundwater. Animals accumulate dioxins in fat through their food; concentrations increase at each step in the food chain. More...

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2. How are humans exposed to dioxins ? 2.1. Over 90 percent of the human intake of dioxins is through food, mainly from animal origin. The intake is ten to hundred times higher for breast fed babies than for adults with respect to their body weight. In most industrialized countries, dioxin exposure has been reduced by almost 50% compared to the early 90's. More... 2.2. Local populations have been accidentally exposed to high dioxin levels, e.g. in Seveso (Italy) after an explosion at a chemical factory, or in Japan and Taiwan with people eating rice oil accidentally contaminated with PCBs and dioxins. In the past, some workers have also been highly exposed to dioxins in waste incineration or chemical plants. More... 2.3. Dioxins are slowly bio-transformed in the body and are not easily eliminated. They tend to accumulate in fat and in the liver. By interacting with a cellular receptor, dioxins can trigger biological effects such as hormonal disturbances and alterations in cell functions. The mechanism of dioxin toxicity is similar in man and other vertebrates. More...

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3. What are the effects of dioxins in laboratory animals ? 3.1. Toxic dioxins may cause non-cancer effects to animals, affecting development, reproduction, the immune system and the uterus. Human background exposures in industrialized countries have sometimes reached levels at which these effects were seen in animals. More... 3.2. In laboratory testing, TCDD and some other types of dioxins increase the number of cancers in several animal species, in both sexes. They do not initiate cancers but promote the growth of existing precancerous cell. More...

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Dioxins : Level 1 - Summary on Dioxins

4. What are the effects of dioxins on human health ? 4.1. For workers accidentally exposed to the highest doses of dioxins, studies estimate that the risk of cancer increases by about 40%. However, the average exposure of the general population is much lower. More... 4.2. Some delay in nervous system development as well as changes of behavior were seen in children of mothers who had been highly exposed to dioxins and PCBs. In some cases these effects occurred even at current background levels. The effects were likely due to exposure through the placenta rather than through breast milk. However, at least in one case high levels of PCBs and dioxins in breast milk were shown to affect young children's neurobehavioural test results. More... 4.3. Other non-cancer effects observed on adults accidentally exposed to high levels of toxic dioxins include: diabetes, liver and heart diseases, skin problems (e.g. chloracne), conjunctivitis, fatigue, malaise and slowed nervous reactions. More...

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5. How can dioxin exposure be linked to health effects ? 5.1. The International Agency for Research on Cancer (IARC) of the World Health Organization (WHO) has proposed a model linking TCDD exposure to cancer in humans. However, studies on rodents show a wide variety of dose-effect relationships. More... 5.2. Models can not yet predict adequately non-cancer effects in humans but may be used to help understand the effects observed. More... 5.3. The evaluation of risk posed by mixtures of various dioxin types is more complicated. A Toxic Equivalency Factor (TEF) value has been determined for each toxic dioxin. Using these values, a total Toxic Equivalent (TEQ) value can be calculated for any dioxin mixture. More...

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Dioxins : Level 1 - Summary on Dioxins

6. Evaluation and conclusions 6.1. Dioxin levels in food, environmental samples and breast milk have decreased over the 1990s. In most industrialized countries, the daily dioxin intake is currently in the order of 1 to 3 pg I-TEQ/kg body weight per day. More... 6.2. At very high dioxin exposure, the risk for all cancers combined appears to increase. Non-cancer effects include cardiovascular diseases, diabetes and changes in blood composition. Infants of accidentally highly exposed mothers showed severe developmental and neurological effects. More... 6.3. A Tolerable Daily Intake (TDI) of 1 to 4 pg I-TEQ per kg body weight per day has been established for dioxins by the World Health Organization (WHO). The upper limit of 4 is provisional: the ultimate goal is to reduce human intake levels below 1 pg I-TEQ per kg body weight per day. This value was derived from the lowest doses causing adverse effects in experimental animals, divided by a safety factor of 10. This Tolerable Daily Intake (TDI) should be seen as an average over a life-time, implying that this value may be exceeded occasionally for short periods without expected health consequences. More... 6.4. Although breast-fed infants are more exposed to dioxins, under normal conditions the many beneficial effects of human milk generally outweigh the risks. Dioxin levels in human milk have been reduced since the early 90's. More...

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7. Other views on Dioxins This study is based on the WHO-IPCS "Assessment of the health risk of dioxins: re-evaluation of the Tolerable Daily Intake (TDI)". Although it is generally considered as a consensus document, some people and organizations propose different views: ●

Positions suggesting that Dioxins pose more risk.

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Positions suggesting that Dioxins pose less risk. Conclusion

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Other views on Dioxins

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Other views on Dioxins The links on this page have been selected as examples of view that differ from that of the WHO and the IPCS. This list of links is only a sample and neither pretends to be complete nor fully representative of all the views available. GreenFacts takes no position concerning the views expressed in these linked documents.

Is the WHO-IPCS report a consensus one? Most scientists globally agree with the conclusions of the WHO and the IPCS contained in the

Executive Summary

of the Assessment of the health risk of dioxins : re-evaluation of the Tolerable Daily Intake (TDI) produced in 1998. An other institution having reached similar conclusions: ●

In 2002, the Joint Expert Committee on Food Additives (JECFA) of the International Programme on Chemical Safety (IPCS) made a safety evaluation of dioxins present in food and established a provisional tolerable monthly intake (PTMI): More... http://www.inchem.org/documents/jecfa/ jecmono/v48je20.htm#10.0

Some of the sites advocating that dioxins present more risk ●

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A report by Greenpeace: www.greenpeace.org/~toxics/reports/azd/ azdrep.html A fact sheet by WWF: www.worldwildlife.org/toxics/pubres/ fact_dioxin.pdf

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A Campaign by Greenaction for Health and Environmental Justice: http://www.greenaction.org/ zerodioxin/healtheffects.shtml

Some of the sites advocating that dioxins present less risk ●

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An article of the Chlorine Chemistry Council (CCC): http://c3.org/chlorine_issues/understanding_dioxin/ dioxin_exposures.html From workers in the chlorine and PVC-industry and their allies (Chlorophiles): http://www.ping.be/~ping5859/en/en_index.html An article of the Environmental Science & Technology Online News from the American Chemical Society (ACS):

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Other views on Dioxins

http://pubs.acs.org/subscribe/journals/esthag-w/2001/apr/policy/CC_dioxin.html The links on this page have been selected as examples of view that differ from that of the WHO and the IPCS. This list of links is only a sample and neither pretends to be complete nor fully representative of all the views available. GreenFacts takes no position concerning the views expressed in these linked documents.

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Dioxins : Level 2 - Details on Dioxins

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1. What are dioxins ? ❍ 1.1. What are dioxins chemically ? ❍ 1.2. How are dioxins formed ? ❍ 1.3. What happens to dioxins when they enter the environment ? ? 2. How are humans exposed to dioxins ? ❍ 2.1. What are the principal source of exposure to dioxins ? ❍ 2.2. What are the other possible sources of dioxin contamination ? ❍ 2.3. How do dioxins act on living organisms ? 3 . What are the effects of dioxins in laboratory animals ? ❍ 3.1. What are the non-cancer effects on animals ? ❍ 3.2. Do dioxins cause cancer in laboratory animals ? 4. What are the effects of dioxins on human health ? ❍ 4.1. Have dioxins caused cancer to humans ? ❍ 4.2. What non-cancer effects have been observed in children ? ❍ 4.3. What non-cancer effects have been observed in adults ? 5. How can dioxin exposure be linked to health effects ? ❍ 5.1. Is there a known relationship between dioxin exposure and cancer ? ❍ 5.2. Can a model predict non-cancer effects ? ❍ 5.3. How are dioxins mixtures accounted for ? 6. Evaluation and conclusions ❍ 6.1. Human exposure to Dioxins ❍ 6.2. Observed health effects ❍ 6.3. Tolerable Daily Intake set by WHO for dioxins ❍ 6.4. Breastfeeding 7. Other views on Dioxins (level 1 only)

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Dioxins : 1. What are dioxins ?

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1. What are dioxins ? 1.1. What are dioxins chemically ? 1.2. How are dioxins formed ? 1.3. What happens to dioxins when they enter the environment ?

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1.1. What are dioxins chemically ? The term "dioxins", commonly covering polychlorinated dibenzo-dioxins (PCDDs) and polychlorinated dibenzo-furans (PCDFs), refers to a group of chlorinated organic chemicals with similar chemical structures. Chlorine atoms can be attached to 8 different places on the molecule, numbered from 1 to 8. Dioxins can have varying harmful health effects depending on the number and position of the chlorine atoms. 2,3,7,8-TCDD or simply TCDD, a molecule with 4 chlorine atoms, is one of the two most toxic dioxins. Only dioxins having more chlorine atoms added to the 2,3,7,8-TCDD structure are also toxic, but to a lesser extent. Other dioxins do not show this dioxin-type toxicity.

Chlorinated chemicals with comparable structural and biochemical properties, such as certain polychlorinated biphenyls (PCB), are called "dioxin-like compounds" and can act similarly in terms of dioxin-type toxicity.

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Dioxins : 1. What are dioxins ?

Dioxins are almost insoluble in water but have a very high affinity for lipids (fat). They also tend to associate with organic matter such as ash, soil and plant leaves. More...

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1.2. How are dioxins formed ? Dioxins mainly derive from human activities, but can to a lower extent also be generated naturally by forest fires or volcanic activity. Dioxins have no use as such and are formed unintentionally by industrial processes and incomplete combustion, for instance: municipal and domestic waste incineration, burning fuels (wood, coal or oil), chlorine bleaching of pulp and paper and chlorinated pesticides manufacturing. Burning of many materials containing chlorine, such as plastics, wood treated with pentachlorophenol (PCP), pesticide-treated wastes, other polychlorinated chemicals (PCBs), and even bleached paper can produce dioxins. Cigarette smoke, home-heating systems, and exhaust from cars also contain small amounts of dioxins. PCBs have been widely used as a dielectric and cooling fluid for electrical equipment such as transformers. More...

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1.3. What happens to dioxins when they enter the environment ? After emission in the atmosphere, dioxins are deposited on land or water, close to or far from the emission sources depending on the size of the particles they associate with. Dioxins in water bind strongly to small particles, organic matter or plankton. Dioxins deposited on land bind strongly to the soil and therefore most often do not contaminate groundwater. Most of the dioxins found in plants come from air and dust or from dioxin-containing pesticides or herbicides. Plants and animals are eaten by larger animals, which accumulate dioxins in their body and milk (bioaccumulation). Because dioxins bind to fat and are very stable, their concentrations increase with each step in the food chain (biomagnification). More...

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Dioxins : 2. How are humans exposed to dioxins ?

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2. How are humans exposed to dioxins ? 2.1. What are the principal sources of exposure to dioxins ? 2.2. What are the other possible sources of dioxin contamination ? 2.3. How do dioxins act on living organisms ? Three ways of exposure to dioxins exist: background exposure (mainly through diet), industrial accidents and workplace contamination.

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2.1. What are the principal source of exposure to dioxins ? 2.1.1. Over 90 percent of human background exposure to dioxins occurs through the diet, essentially with fats from animal origin. Dioxins emitted by various sources deposit on farmland and water bodies and bioaccumulate in the food chains. Other sources of food contamination include contaminated animal feed, sewage sludge contaminated with dioxins, flooding of pastures, waste effluents and inappropriate food processing. More... 2.1.2. In industrialized countries, the daily intake of dioxins (PCDDs and PCDFs) is in the order of 1-3 pg I-TEQ per kg body weight per day, which is close to the Tolerable Intake value set by the World Health Organization (WHO) (see question 7.3). If PCBs are included, the daily intake can be 2 or 3 times higher. Diets low in animal fat result in lower intakes, while consumption of highly contaminated foodstuffs may lead to higher intakes. The body burden of dioxins increases during childhood and reaches an equilibrium around the age of 20. More... 2.1.3. During growth, the intake per kilogram of body weight decreases partly as a result of an increasing average body weight. Recent studies from the Netherlands, United Kingdom and Germany show decreasing dioxin levels in food and consequently a dietary intake lower by almost 2 since the early 90's. More... 2.1.4. For breast fed babies, the daily intake of dioxins per kg of body weight may be ten to hundred times greater than for adults. Breast milk is more contaminated in industrialized areas (10-35 pg I-TEQ/g milk fat) than in

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Dioxins : 2. How are humans exposed to dioxins ?

developing countries (< 10 pg I-TEQ/g milk fat). However, the levels are decreasing, especially in industrialized countries. Individual contamination can vary by a factor of 5 to 10, depending on age of the mother, number of breastfed babies, length of nursing period and food habits. More...

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2.2. What are the other possible sources of dioxin contamination? 2.2.1. Local populations can be accidentally exposed to high dioxin levels, like in Seveso (Italy) in 1976, after an explosion at a chemical factory, or from fires in electrical equipment containing PCBs. Accidental contamination of rice oil in Japan and Taiwan resulted in intakes of dioxin-like compounds many thousand times higher than normal. More... 2.2.2. Industrial activities in which dioxins are unintentionally produced (such as waste incineration or production of certain pesticides or chemicals) may result in exposures of certain workers. In the past, some workers accidentally exposed to high concentrations of dioxins had TCDD blood levels up to thousands of times higher than usual, but today, many industrial sources of dioxins have been identified and the workers' overall exposure has been reduced or eliminated. More...

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2.3. How do dioxins act on living organisms? 2.3.1. The toxic dioxins can alter key biochemical and cellular functions by interacting with a cellular receptor called Ah, affecting the hormonal system and the way cells grow and develop. The mechanism of action of dioxins appears to be the same in both humans and animals. More... 2.3.2. Being highly lipophilic, dioxins dissolve in fat. They need to be transformed in the liver to become water soluble before they can be excreted. However, dioxins are metabolized slowly and therefore tend to bioaccumulate, especially in fat and in the liver. The speed of elimination of dioxins can vary with dose, quantity of body fat, age and sex. The process of elimination of dioxins and PCBs is similar in animals and man, but it is faster in most other mammals. Rodents only reach the same body burdens, or tissue concentration, at much higher exposure compared to humans. This is why body burden must be used as a reference when comparing risks for humans and animals. The biological half-life, which technically characterizes the speed of elimination, varies largely for the various dioxins and dioxin-like compounds. However the average half-life of 2,3,7,8-TCDD is being used for practical purposes. More...

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Dioxins : 3. What are the effects of dioxins in laboratory animals ?

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3. What are the effects of dioxins in laboratory animals ? 3.1. What are the non-cancer effects on animals ? 3.2. Do dioxins cause cancer in laboratory animals ?

3.1. What are the non-cancer effects on animals ? Toxic dioxins, especially 2,3,7,8-TCDD, can cause multiple non-cancer effects in animals at varying doses. Direct effects can be toxic or not. Non-toxic effects observed at low dose may or may not result subsequently in toxic effects in the animal or its offspring. Some of the toxic effects observed at lower exposures are endometriosis (uterine disease), neurobehavioral (cognitive) effects, reduced sperm counts, female urogenital malformations and effects on the immune system. Dioxin levels in the general population of industrialized countries sometimes reach the lower levels at which significant effects have been observed in animals. More...

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3.2. Do dioxins cause cancer in laboratory animals ? 2,3,7,8-TCDD has been shown to be carcinogenic to multiple animal species of both sexes. Most dioxins do not initiate cancer as such, but indirectly promote growth and proliferation of previously initiated cancerous lesions. The cancer observed at the lowest exposure are liver tumors in rats. 2,3,7,8-TCDD also caused thyroid tumors in male rats. Several other dioxin types have also been shown to be cancer promoters. More... Back to Summary

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Dioxins : 4. What are the effects of dioxins on human health ?

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4. What are the effects of dioxins on human health ? 4.1. Have dioxins caused cancer to humans ? 4.2. What non-cancer effects have been observed in children ? 4.3. What non-cancer effects have been observed in adults ?

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4.1. Have dioxins caused cancer to humans ? 4.1.1. Most information on the carcinogenicity of the dioxin 2,3,7,8-TCDD in humans comes from epidemiological studies of both accidentally exposed workers in herbicide plants and people living near the Seveso chemical factory in Italy. However, most studies concern mixtures of several kinds of dioxins. As such, the evaluation of risks for individual dioxins is difficult. The 2,3,7,8-TCDD levels of exposed herbicide workers were comparable to the ones that induced liver cancers in rats, but on average, the exposures around Seveso were lower. More... 4.1.2. Herbicide plant workers heavily exposed to dioxins had more cancers of all types combined than the general population. The number of cancers increased with exposure (dose-response relationship). In Seveso, the number of deaths due to cancer has not increased since the accident, but it is still too early to reach definite conclusions. However, several studies showed excess risks for some specific cancers. A 22 year study of people in Japan who ate rice oil highly contaminated with PCBs and other dioxin-like compounds, showed an increase in liver cancer. No cancer increase was found after 12 years for another group in Taiwan who ate rice oil that was less contaminated. In summary, there is strong evidence that people accidentally exposed to the highest dioxin levels had an increased

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overall cancer risk (about 40% increase); there is less strong evidence of increased risks for specific cancers. In comparison, the average exposure of the general population is a hundred to a thousand times lower for TCDD and ten to hundred times lower for all dioxins combined. More...

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4.2. What non-cancer effects have been observed in children ? Studies showed neurodevelopmental delays and neurobehavioral effects in children. The effects are attributed to exposure of the unborn child through the placenta rather than through breast feeding. These effects even occurred at background levels, but only affected the infants with the highest exposure. In at least one US study, mothers were, however, simultaneously exposed to chlorinated pesticides and heavy metals. Following the rice oil contamination incidents in Japan and Taiwan, effects, at least partly related to dioxins, were observed in new born children due to pre-birth exposure. Effects included skin defects, general persistent development delays, low birth-weight, mild behavioral disorders, decrease in penis length at puberty, reduced height among girls at puberty and hearing loss. A study in the Netherlands showed that breast fed infants had a better neurobehavioural development compared to formula fed infants. However, within the group of breast fed infants, those receiving milk with higher dioxin content had poorer neurobehavioural test results. In Seveso, it was observed that fathers highly exposed to TCDD had a lower boy to girl birth ratio than normal. More...

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4.3. What non-cancer effects have been observed in adults ? Information on effects in adults comes from several studies of populations exposed to high levels of dioxins: the US Air Force staff who were exposed to the Agent Orange defoliant in Vietnam, a second study in Vietnam, studies in the populations around the Seveso chemical factory, and of the contaminated rice oil incidents in Japan and Taiwan. Exposed workers showed biochemical effects including elevated levels of gamma GT, triglyceride and glucose in blood and an increase in diabetes. In Seveso, data show an increased death rate in women from diabetes and from cardiovascular diseases in men. A higher rate of heart diseases was also observed in some occupationally exposed groups of men. Adults affected by contaminated rice oil experienced various effects including a skin rash called chloracne, conjunctivitis, sebaceous cysts and inflammation, decreased nerve conduction velocity, fatigue and malaise, skin problems (hyperpigmentation and hyperkeratosis), as well as an increased death rate from non-cancer liver diseases. More...

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5. How can dioxin exposure be linked to health effects ? 5.1. Is there a known relationship between dioxin exposure and cancer ? 5.2. Can a model predict non-cancer effects ? 5.3. How are dioxins mixtures accounted for ?

5.1. Is there a known relationship between dioxin exposure and cancer ? 5.1.1. Lifetime dose-effect relationships for cancer were derived from workers moderately exposed to dioxins. The results suggest that a continuous exposure at work to between 2 and 7 pg TCDD per kg body weight per day increases the risk of cancer by 1%. Over a lifetime, this would result in a body burden of 3 000 to 13 000 pg TCDD per kg body weight. More... 5.1.2. To compare humans and animals, only body burdens are relevant; indeed, rats and mice need to ingest much more dioxins than humans to reach the same body burden. Two approaches were used to evaluate cancer risks from experimental animal studies and led to very different results. The first one is based on the knowledge of mechanisms that increase cell multiplication, inducing liver tumors in female rats. It concluded that a body burden of 2 600 pg per kg body weight increases the risks of cancer by 1%. A second, graphical model used the results of a series of cancer studies on rats and mice; it concluded that a body burden of 10 000 to 746 000 pg per kg body weight increases the risk of cancer by 1%. More...

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5.2. Can a model predict non-cancer effects ? Currently, models cannot adequately predict non-cancer effects in humans, partly because the mechanisms of action are not yet fully understood. However, they may provide additional insights in understanding the effects observed in experiments. More...

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5.3. How are dioxins mixtures accounted for ? 5.3.1. Dioxins are generally found in mixtures containing several kinds of dioxins and dioxin-like compounds, each having its own degree of toxicity. Therefore each is attributed a specific toxic factor called Toxic Equivalency Factor (TEF). This factor indicates a relative toxicity compared to the most toxic dioxin 2,3,7,8-TCDD, which is given a reference value of 1 (see table 3). The TEF scheme refers only to adverse effects (e.g. cancer) following interactions with the cellular Ah-receptors Other toxic effects of dioxins and dioxin-like compounds cannot be quantified by this method. The overall toxicity of a dioxin mixture is calculated by: 1. multiplying the individual quantity of each compound by its specific TEF value and 2. summing the values obtained to get a total TCDD "toxic equivalent" (TEQ) for the mixture. TEF values are attributed on the assumptions that a compound must: ● ● ● ●

show a structural relationship to the dioxins (PCDD's and PCDF's). bind to the dioxin cellular Ah-receptors. cause effects via this Ah receptor. be persistent and accumulate in the food chain. More...

5.3.2. In the majority of experimental studies, the effects are additive and the TEQ calculation works well. However some non-additive effects of PCDD, PCDF and PCB mixtures have been reported. These may be due to effects of the individual compounds on each others metabolism and, for some PCBs, to other mechanisms of action than those occurring via the Ah-receptor. When used with caution, the TEF approach is a valuable tool for expressing a daily intake for most dioxins and comparing it to the Tolerable Daily Intake (TDI). More...

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6.1. Human exposure to dioxins 6.1.1. In most industrialized countries, concentrations of dioxins in environmental samples, foods, human tissues and breast milk have decreased during the 1990s, mainly due to enforced environmental regulations. In industrialized countries, the daily intake of dioxins (PCDDs and PCDFs) is in the order of 1 to 3 pg I-TEQ per kg body weight per day. If PCBs are included, the daily intake is up to 3 times higher, hereby exceeding the Tolerable Daily Intake (TDI) as put forward by the World Health Organization (WHO) (see 6.3). Breast milk is less contaminated in developing countries (<10 pg/g milk fat) than in industrialized countries (10-35 pg/g milk fat). For breast-fed infants, the daily intake per kg of body weight is ten to hundred times greater than for adults, but has been reduced since the early 90´s by up to 50% in most industrialized countries. Generally 2,3,7,8-TCDD accounts for only 10 to 20 % of the total dioxin TEQ-exposure and for less than 5% when dioxin-like PCBs are included. More... 6.1.2. Several factors determine the persistence of dioxins in the body, including dose, quantity of body fat, binding to liver proteins and rate of metabolic transformation and excretion. Both humans and animals accumulate dioxins. Body burden is the most appropriate parameter to compare exposure and effects between species. Because of differences in the above factors, rodents need to ingest 100 to 200 times http://www.greenfacts.org/dioxins/l-2/dioxins-99.htm (1 of 4) [26/08/2004 10:12:00]

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more dioxins than humans to reach a same body burden. Because dioxins remain in the human body for a relatively long time, higher intakes for a short period will not result in significant changes to the long-term body burden. More...

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6.2. Observed health effects Dioxins can alter key biochemical and cellular functions by binding to the cellular Ah-receptor. The broad range of Ahreceptor binding affinities seen in human placenta samples suggests that the response to dioxins varies significantly from one person to another (see question 2.3). A number of biochemical effects have been observed in experimental animals at body burdens comparable to those of the general human population. These effects may be harmful or not, and may or may not be due to interactions with the cellular Ah-receptors. To evaluate the risks for human populations, studies usually focus on the effects observed at the lowest doses. Toxic effects were observed on animals at body burdens in the range of 10 000 to 73 000 pg per kg body weight. A human daily intake can be calculated which would correspond to these animal body burdens. The following non-cancer effects were observed: ●

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Mothers that were accidentally exposed to very contaminated rice oil, leading to an extremely high body burden of 2 to 3 million pg TEQ per kg body weight, gave birth to infants showing severe and persistent developmental and neurological effects. In workers exposed to high levels of dioxins in their workplace, health effects were observed at body burdens ranging from 28 000 to 400 000 pg per kg body weight. These effects include changes in the blood composition and increased cardiovascular diseases and diabetes. Some of the Seveso population, which was exposed to PCDDs and PCDFs at levels up to ten to hundred times higher than normal, suffered some temporary effects, such as a skin rash called chloracne and blood biochemistry changes. An increase in male cardiovascular deaths and a decrease in the boy to girl birth ratio were observed.

Humans may be as sensitive as animals to the carcinogenic effects of dioxins. Accidental exposure to TCDD at levels hundred to thousand times higher than those of the general population (ten to hundred times higher TEQ values in terms of total dioxins) increases the risk for all cancers combined by 40%. Concerning the effects on birth weight, thyroid hormone effects and nervous system development, the interpretation of the results is complicated by simultaneous exposure to other chemicals. Some effects were observed at dioxin levels only slightly higher than the exposure of the general population. More...

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6.3. Tolerable Daily Intake set by WHO for dioxins 6.3.1. The World Health Organization (WHO) recommends a Tolerable Daily Intake (TDI) of 1 to 4 pg WHO-TEQ/kg body weight per day. This figure is based on the lowest exposures at which adverse effects were observed in experimental animals. It includes an overall uncertainty factor of 10, in order to account for possible differences in susceptibility between humans and experimental animals and in between people. More... 6.3.2. The TDI represents a tolerable daily intake for a life-time exposure. Occasional exceeding of the TDI should have no health consequences, provided that the averaged intake over longer periods remains below it. In industrialized countries, some people exceed the TDI and may therefore show some subtle effects which have, however, not been proven to be harmful. The upper limit of 4 pg WHO-TEQ/kg body weight per day is provisional: the ultimate goal is to reduce human intake levels below 1 pg WHO-TEQ/kg body weight per day. The World Health Organization (WHO) recommended that every effort should be made to limit emissions of dioxins and related compounds in order to reduce their presence in the food chain. Immediate efforts should specifically target exposure reductions of highly exposed sub-populations. More...

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6.4. Breastfeeding Breast-fed infants have higher intakes of dioxins but only during a small period of their life. Some studies found subtle effects in children of mothers exposed to dioxins, but these effects are, in all but one study, probably due to exposure through the placenta rather than through breast milk. Breastfeeding has many beneficial effects. Therefore, the World Health Organization (WHO) promotes breastfeeding while recommending the reduction of dioxin emissions. Dioxin levels in human milk have decreased since the early 90's. More...

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1. What are dioxins ? ❍ 1.1. What are dioxins chemically ? ❍ 1.2. How are dioxins formed ? ❍ 1.3. What happens to dioxins when they enter the environment ? 2. How are humans exposed to dioxins ? ❍ 2.1. What are the principal source of exposure to dioxins ? ❍ 2.2. What are the other possible sources of dioxin contamination ? ❍ 2.3. How do dioxins act on living organisms ? 3. What are the effects of dioxins in laboratory animals ? ❍ 3.1. What are the non-cancer effects on animals ? ❍ 3.2. Do dioxins cause cancer in laboratory animals ? 4. What are the effects of dioxins on human health ? ❍ 4.1. Have dioxins caused cancer to humans ? ❍ 4.2. What non-cancer effects have been observed in children ? ❍ 4.3. What non-cancer effects have been observed in adults ? 5. How can dioxin exposure be linked to health effects ? ❍ 5.1. Is there a known relationship between dioxin exposure and cancer ? ❍ 5.2. Can a model predict non-cancer effects ? ❍ 5.3. How are dioxins mixtures accounted for ? 6. Evaluation and conclusions ❍ 6.1. Human exposure to Dioxins ❍ 6.2. Observed health effects ❍ 6.3. Tolerable Daily Intake set by WHO for dioxins ❍ 6.4. Breastfeeding 7. Other views on Dioxins (level 1 only)

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1. What are dioxins ? 1.1. What are dioxins chemically ? 1.2. How are dioxins formed ? 1.3. What happens to dioxins when they enter the environment ?

1.1. What are dioxins chemically ? "CDDs are a family of 75 different compounds commonly referred to as polychlorinated dioxins. These compounds have varying harmful effects. The CDD family is divided into eight groups of chemicals based on the number of chlorine atoms in the compound. The group with one chlorine atom is called the mono-chlorinated dioxin(s). The groups with two through eight chlorine atoms are called di-chlorinated dioxin (DCDD), tri-chlorinated dioxin (TrCDD), tetra-chlorinated dioxin (TCDD), penta-chlorinated dioxin (PeCDD), hexa-chlorinated dioxin (HxCDD), heptachlorinated dioxin (HpCDD), and octa-chlorinated dioxin (OCDD). The chlorine atoms can be attached to the dioxin molecule at any one of eight positions. The name of each CDD indicates both the number and the positions of the chlorine atoms. For example, the CDD with four chlorine atoms at positions 2, 3, 7, and 8 on the dioxin molecule is called 2,3,7,8-tetrachlorodibenzo-p-dioxin or 2,3,7,8-TCDD. 2,3,7,8-TCDD is one of the most toxic of the CDDs to mammals and has received the most attention. Thus, 2,3,7,8-TCDD serves as a prototype for the CDDs. CDDs with toxic properties similar to 2,3,7,8-TCDD are called "dioxin-like" compounds. In the pure form, CDDs are colorless solids or crystals. CDDs enter the environment as mixtures containing a variety of individual components and impurities. In the environment they tend to be associated with ash, soil, or any surface with a high organic content, such as plant leaves. In air and water, a portion of the CDDs may be found in the vapor or dissolved state, depending on the amount of particulate matter, temperature, and other environmental factors. 2,3,7,8-TCDD is odorless. The odors of the other CDDs are not known." Source & © : ATSDR "

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1.2. How are dioxins formed ? "CDDs are known to occur naturally, and are also produced by human activities. They are naturally produced from the incomplete combustion of organic material by forest fires or volcanic activity. CDDs are not intentionally manufactured by industry, except in small amounts for research purposes. They are unintentionally produced by industrial, municipal, and domestic incineration and combustion processes. Currently, it is believed that CDD emissions associated with human incineration and combustion activities are the predominant environmental source. CDDs (mainly 2,3,7,8-TCDD) may be formed during the chlorine bleaching process used by pulp and paper mills. CDDs occur as a contaminant in the manufacturing process of certain chlorinated organic chemicals, such as chlorinated phenols. 2,3,7,8-TCDD is a by-product formed during the manufacture of 2,4,5-trichlorophenol (2,4,5TCP). 2,4,5-TCP was used to produce hexachlorophene (used to kill bacteria) and the herbicide, 2,4,5trichlorophenoxyacetic acid (2,4,5-T). Various formulations of 2,4,5-T have been used extensively for weed control on crops and range lands, and along roadways throughout the world. 2,4,5-T was a component of Agent Orange, which was used extensively by the U.S. military in the Vietnam War. In most industrialized countries the use of products contaminated with CDDs has been greatly reduced. Use of hexachlorophene and the herbicide 2,4,5-T is currently restricted in the United States. Other chlorinated chemicals, like pentachlorophenol (PCP), used to preserve wood, do contain some of the more highly chlorinated CDDs (those with more chlorine atoms), but 2,3,7,8-TCDD is not usually found. The use of PCP has been restricted to certain manufacturing applications. Currently, CDDs are primarily released to the environment during combustion of fossil fuels (coal, oil, and natural gas) and wood, and during incineration processes (municipal and medical solid waste and hazardous waste incineration). While incineration may be the primary current source of release of CDDs into the environment, the levels of CDDs produced by incineration are extremely low. CDDs are associated with ash generated in combustion and incineration processes. Emissions from incinerator sources vary greatly and depend on management practices and applied technologies. CDDs also have been detected at low concentrations in cigarette smoke, home-heating systems, and exhaust from cars running on leaded gasoline or unleaded gasoline, and diesel fuel. Burning of many materials that may contain chlorine, such as plastics, wood treated with pentachlorophenol (PCP), pesticide-treated wastes, other polychlorinated chemicals (polychlorinated biphenyls or PCBs), and even bleached paper can produce CDDs. Although this public health statement will focus on CDDs, it is important to note that CDDs are found in the environment together with other structurally related chlorinated chemicals, such as chlorinated dibenzofurans (CDFs) and polychlorinated biphenyls (PCBs). Therefore, people are generally exposed to mixtures of CDDs and other classes of toxicologically and structurally similar compounds. 2,3,7,8-TCDD is one of the most toxic and extensively studied of the CDDs and serves as a prototype for the toxicologically relevant or "dioxin-like" CDDs. Based on results from animal studies, scientists have learned that they can express the toxicity of dioxin-like CDDs as a fraction of the toxicity attributed to 2,3,7,8-TCDD. For example, the toxicity of dioxin-like CDDs can be half or one tenth or any fraction of that of 2,3,7,8-TCDD. Scientists call that fraction a Toxic Equivalent Factor (TEF)." Source & © : ATSDR "

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1.3. What happens to dioxins when they enter the environment ? "CDDs are released into the air in emissions from municipal solid waste and industrial incinerators. Exhaust from vehicles powered with leaded and unleaded gasoline and diesel fuel also release CDDs to the air. Other sources of CDDs in air include: emissions from oil- or coal-fired power plants, burning of chlorinated compounds such as PCBs, and cigarette smoke. CDDs formed during combustion processes are associated with small particles in the air, such as ash. The larger particles will be deposited close to the emission source, while very small particles may be transported longer distances. Some of the lower chlorinated CDDs (DCDD, TrCDD, and some of the TCDDs) may vaporize from the particles (and soil or water surfaces) and be transported long distances in the atmosphere, even around the globe. It has been estimated that 20 to 60% of 2,3,7,8-TCDD in the air is in the vapor phase. Sunlight and atmospheric chemicals will break down a very small portion of the CDDs, but most CDDs will be deposited on land or water. CDDs occur as a contaminant in the manufacture of various chlorinated pesticides and herbicides, and releases to the environment have occurred during the use of these chemicals. Because CDDs remain in the environment for a long time, contamination from past pesticide and herbicide use may still be of concern. In addition, improper storage or disposal of these pesticides and waste generated during their production can lead to CDD contamination of soil and water. CDDs are released in waste waters from pulp and paper mills that use chlorine or chlorine-containing chemicals in the bleaching process. Some of the CDDs deposited on or near the water surface will be broken down by sunlight. A very small portion of the total CDDs in water will evaporate to air. Because CDDs do not dissolve easily in water, most of the CDDs in water will attach strongly to small particles of soil or organic matter and eventually settle to the bottom. CDDs may also attach to microscopic plants and animals (plankton) which are eaten by larger animals, that are in turn eaten by even larger animals. This is called a food chain. Concentrations of chemicals such as the most toxic, 2,3,7,8-chlorine substituted CDDs, which are difficult for the animals to break down, usually increase at each step in the food chain. This process, called biomagnification, is the reason why undetectable levels of CDDs in water can result in measurable concentrations in aquatic animals. The food chain is the main route by which CDD concentrations build up in larger fish, although some fish may accumulate CDDs by eating particles containing CDDs directly off the bottom. CDDs deposited on land from combustion sources or from herbicide or pesticide applications bind strongly to the soil, and therefore are not likely to contaminate groundwater by moving deeper into the soil. However, the presence of other chemical pollutants in contaminated soils, such as those found at hazardous waste sites or associated with chemical spills (for example, oil spills), may dissolve CDDs, making it easier for CDDs to move through the soil. The movement of chemical waste containing CDDs through soil has resulted in contamination of groundwater. Soil erosion and surface runoff can also transport CDDs into surface waters. A very small amount of CDDs at the soil surface will evaporate into air. Certain types of soil bacteria and fungus can break CDDs down, but the process is very slow. In fact, CDDs can exist in soil for many years. Plants take up only very small amounts of CDDs by their roots. Most of the CDDs found on the parts of plants above the ground probably come from air and dust and/or previous use of CDDcontaining pesticides or herbicides. Animals (such as cattle) feeding on the plants may accumulate CDDs in their body tissues (meat) and milk." Source & © : ATSDR "

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2. How are humans exposed to dioxins ? 2.1. What are the principal sources of exposure to dioxins ? 2.1.1. How do dioxins enter the human body ? 2.1.2. What is the average intake of dioxins ? 2.1.3. Has the average intake changed lately ? 2.1.4. What is the intake for breast fed babies ? 2.2. What are the other possible sources of dioxin contamination ? 2.2.1. Accidental exposure 2.2.2. Occupational exposure 2.3. How do dioxins act on living organisms ? 2.3.1. Mechanism of action 2.3.2. Toxicokinetics

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2.1. What are the principal sources of exposure to dioxins ? 2.1.1. 2.1.2. 2.1.3. 2.1.4.

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2.1.1. How do dioxins enter the human body ? "EXPOSURE Background exposure 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. PCDDs and PCDFs contamination of food is primarily caused by deposition of emissions from various sources (e.g. waste incineration, production of chemicals) on farmland and waterbodies followed by bioaccumulation up terrestrial and aquatic foodchains. 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." Source & © : WHO-IPCS

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2.1.2. What is the average intake of 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 bw/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 ITEQ/kg body weight. If the dioxin-like PCBs (non-ortho and mono-ortho PCBs) are also considered, the daily TEQ intake can be a factor of 2-3 higher. Special consumption habits, particularly one low in animal fat or consumption of highly contaminated food stuffs may lead to lower or higher TEQ intake values, respectively. The intake of PCDDs/PCDFs and PCBs increases during childhood and stabilizes in adults of about 20 years of age." Source & © : WHO-IPCS

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2.1.3. Has the average intake changed lately ? "However, the intake on a per kilogram basis decreases in this period due to the increasing body weight. Despite differences in the absolute levels of PCDDs/PCDFs/PCBs, the congener profiles caused by background contamination are usually very similar. Recent studies from countries which started to implement measures to reduce dioxin emissions in the late 80s, such as The Netherlands, United Kingdom and Germany, clearly show decreasing PCDD/PCDF and PCB levels in food and consequently a significantly lower dietary intake of these compounds by almost a factor of 2 within the past 7 years." Source & © : WHO-IPCS

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2.1.4. What is the intake for breast fed babies ? "Compared to adults, the daily intake of PCDDs/PCDFs and PCBs for breast fed babies is still 1-2 orders of magnitude higher on a per body weight basis. The latest WHO field study showed differences between the PCDD/PCDF and PCB contamination of breast milk, with higher mean levels in industrialized areas (10-35 pg I-TEQ/g milk fat) and lower mean levels in developing countries (< 10 pg I-TEQ/g milk fat). Within one country an individual variation of a factor of 5-10 was observed for most congeners, mainly due to age of the mother, number of breastfed babies, length of nursing period and consumption habits. There is now clear evidence of a decrease in PCDD/PCDF levels in human milk over time in almost every region for which suitable data exist. The WHO field study also showed that the highest rates of decrease have been in the areas with the highest initial concentrations. Latest results from Germany revealed a decrease of PCDD/PCDF levels in human milk of approximately 65% between 1989 and 1997. These data support the substantial reduction in intake of PCDDs and PCDFs in the past few years." Source & © : WHO-IPCS

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2.2. What are the other possible sources of dioxin contamination ? 2.2.1. Accidental exposure 2.2.2. Occupational exposure

2.2.1. Accidental exposure "Well-known examples of accidental exposure of the local population to PCDDs, PCDFs and PCBs include the incident at Seveso, and fires in PCB filled electrical equipment. In Seveso, the serum levels for 2,3,7,8-TCDD ranged up to 56000 pg/g lipid, with median levels of 450 pg/g lipid for Zone A and 126 pg/g lipid for Zone B. High exposure may also be caused by food items accidentally contaminated. Known examples are the contamination of edible oil, such as the Yusho (Japan) and Yu-Cheng (Taiwan) food poisoning. For a group of Yusho patients, average intake by ingestion of the Kanemi rice oil contaminated with PCBs, PCDFs and polychlorinated quarterphenyls (PCQs) was estimated at 154000 pg I-TEQ/kg bw/day, which is five orders of magnitude higher than the reported average background intake in several countries." Source & © : WHO-IPCS

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2.2.2. Occupational exposure "Industrial activities in which 2,3,7,8-TCDD and related compounds are unintentionally produced, such as waste incineration or production of certain pesticides or chemicals may also result in additional human exposure. While many industrial sources of 2,3,7,8-TCDD and related compounds have been identified and worker exposure has been reduced or eliminated historic median 2,3,7,8-TCDD levels in blood of highly exposed workers, estimated by extrapolation back to the time of last exposures, ranged from 140 to 2000 pg/g lipid. These estimates are 1-3 orders of magnitude higher than the blood levels measured in the general population. Body burdens caused by accidental or occupational exposure show congener patterns that are different from background exposure and are normally dominated by only a few congeners. This is because of direct exposure vs. indirect exposure through the food supply where bioaccumulation may modify congener patterns." Source & © : WHO - IPCS

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Dioxins : 2. How is population exposed to dioxins ?

2.3. How do dioxins act on living organisms ? 2.3.1. Mechanism of action 2.3.2. Toxicokinetics

2.3.1. Mechanism of action "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 Ah (dioxin) receptor in mediating the biological effects of dioxin. 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. Pharmacological structureactivity and mouse genetic studies using Ah-receptor-deficient animals and cells have demonstrated a key role for the receptor in mediating toxic effects of TCDD. For instance, a reduction or lack of acute toxicity in receptor-deficient mice has been documented. The activated receptor exerts two major types of functions: enhancement of transcription of a battery of genes containing responsive elements in their promoter regions, and immediate activation of tyrosine kinases. A number of genes encoding drug-metabolizing enzymes, such as cytochrome P4501A1, 1A2, 1B1, glutathione S-transferase, and UDP-glucuronosyltransferase are members of an Ah receptor target gene battery. Alteration of expression of other networks of genes may be directly or indirectly regulated by the Ah receptor. Activation of the receptor by a ligand can result in endocrine and paracrine disturbances and alterations in cell functions including growth and differentiation. Some of these effects have been observed both in humans and animals, suggesting the existence of common mechanisms of action." Source & © : WHO-IPCS

Assessment of the health risk of dioxins:

re-evaluation of the Tolerable Daily Intake (TDI) page 4

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2.3.2. Toxicokinetics "The toxicokinetic determinants of dioxin and related chemicals depend on three major properties: lipophilicity, metabolism, and binding to CYP1A2 in the liver. Lipophilicity increases with more chlorination and controls absorption and tissue partitioning. metabolism is the rate-limiting step for elimination. The persistent compounds are slowly metabolized and eliminated, and therefore bioaccumulate. Induction of CYP1A2, which is partially under the control of the aryl hydrocarbon receptor (Ahr), leads to hepatic sequestration of TCDD. The structure/activity relationships for induction are different from that for binding to CYP1A2. Binding to this inducible hepatic protein results in non-linear dose dependent tissue distribution: as the dose increases, the relative concentration in extra-hepatic tissues decreases while that in liver increases. The induction of this protein occurs in both animals and people and results in a increase in the liver to fat ratio of these compounds. This effect has a minor impact on free TCDD and serum TCDD at the range of environmental exposure. The basic determinants of pharmacokinetic behaviour are similar in animals and people. Several robust classical and physiologically based models have been used to describe the kinetic behaviour. They have contributed to the understanding that the apparent half-life is not absolute, but may vary with dose, body composition, age, and sex. Given that these are persistent, bioacumulative compounds, what is the appropriate dose metric to use to equate risk across species? Free concentration in the target tissue would be the most appropriate measure. However, the body burden, which is highly correlated with tissue and serum concentration, integrates the differential half-lives between species. Much higher daily doses are required in rodents to achieve the same body burden, or tissue concentration, as a lower daily dose in people. Body burden is readily estimated in both people and rodents. Therefore, in order to compare risks between humans and animals, the body burden is the metric of choice. It is important to note that predictions of body burden based on lipid concentrations at high exposures may underestimate the total body burden http://www.greenfacts.org/dioxins/l-3/dioxins-2.htm (5 of 6) [26/08/2004 10:12:26]

Dioxins : 2. How is population exposed to dioxins ?

and over- or underestimate specific tissue concentrations because of the hepatic sequestration. Use of PBPK models can readily allow for interconversion of body burden with tissue concentrations, as well as with daily dose. Less complicated models such as a steady state/ body burden models using first order kinetics will give approximately the same results at exposures in the environmental range. There is a range of apparent half-lives for the various PCDDs, PCDFs, and dioxin-like PCBs. However, the TEQ is driven by a relatively small subset of these compounds. When background exposures are involved, an average halflife similar to that of TCDD may be used, but will underestimate daily exposure in short half-life chemicals and overestimate exposure for those with longer than average half-lives. However, if high levels of exposure are involved, such as in occupational settings, it is important to include the pharmacokinetic data on the individual chemicals." Source & © : WHO-IPCS

Assessment of the health risk of dioxins:

re-evaluation of the Tolerable Daily Intake (TDI) page 4-5

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Dioxins : 3. What are the effects of dioxins in laboratory animals ?

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3. What are the effects of dioxins in laboratory animals ? 3.1. What are the non-cancer effects on animals ? 3.2. Do dioxins cause cancer in laboratory animals ?

3.1. What are the non-cancer effects on animals ? "Non-carcinogenic effects A plethora of effects have been reported to occur in multiple animal studies following exposure to PCDDs, PCDFs and PCBs. The most extensive dataset on dose-response effects is available for 2,3,7,8-TCDD; less information is available for the other dioxin-like compounds. Therefore the focus of the evaluation of the animal data is on the effects of 2,3,7,8-TCDD. Due to the multitude of different effects at various dose levels the most sensitive toxic and biochemical endpoints are presented in Table 1. In this table information on the lowest daily doses or body burdens resulting in the observed effects are included. The effects observed are each characterized either as an adverse (toxic) effect or as a biochemical and functional effect. The biochemical effects observed at the lowest body burdens, or tissue concentrations are early expressions of cascades of events induced by dioxin-like compounds that may or may not result in adverse effects in the animal or its progeny. Among the most sensitive endpoints (on a body burden basis) are: endometriosis, developmental neurobehavioral (cognitive) effects, developmental reproductive (sperm counts, female urogenital malformations) effects, and immunotoxic effects, both adult and developmental . The most sensitive biochemical effects are CYP1A1/2 induction, EGF-receptor down-regulation and oxidative stress (Table 1). The lowest doses giving rise to statistically significant effects in the most sensitive endpoints following exposure, have resulted in body burdens (e.g. 3 to 73 ng of TCDD/kg) in the exposed animals that overlap, at the lower end, the range of body burdens expressed as TEQ that are found in the general population in industrialized countries exposed to background levels of PCDDs, PCDFs and PCBs." Source & © : WHO-IPCS

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Dioxins : 3. What are the effects of dioxins in laboratory animals ? re-evaluation of the Tolerable Daily Intake (TDI) page 7

Table 1. MOST SENSITIVE EFFECTS OF 2,3,7,8-TCDD IN ANIMALS

Exposure (LOEL or LOAEL)

Maternal body burden (increment to background)*

~160 pg/kg/d

42 ng/kg**

- decreased sperm count

64,000 pg/kg***

28 ng/kg**

- vaginal threads

200,000 pg/kg***

73 ng/kg**

Effect

Species

Adverse effects

Developmental effects - neurotoxicity (object learning)

Rhesus monkey

Reproductive toxicity

rat

Immunotoxicity

rat

100,000 pg/kg***

50 ng/kg**

Immunological (viral sensitivity)

mouse

10,000 pg/kg***

10 ng/kg**

Hormonal (endometriosis)

Rhesus

~160 pg/kg/d

42 ng/kg**

mouse

150 pg/kg/d

3 ng/kg

rat

100 pg/kg/d

3 ng/kg

-CYP1A2

mouse

450 pg/kg/d

10 ng/kg

-EGFR

rat

100 pg/kg/d

3 ng/kg

monkey

Effects which may or may not lead to adverse effects

Biochemical effects

-CYP1A1

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Dioxins : 3. What are the effects of dioxins in laboratory animals ?

-IL1beta

mouse

300 pg/kg/d

~10 ng/kg

-oxidative stress

mouse

450 pg/kg/d

10 ng/kg

-lymphocyte subsets

marmoset

~200 pg/kg/d

6-8 ng/kg

Functional effects

monkey

* Background body burden in rats and mice is about 4 ng/kg (TEQ)s ** Body burden at the end of dosing period *** Note: single dose

Source & © : WHO-IPCS

Assessment of the health risk of dioxins:

re-evaluation of the Tolerable Daily Intake (TDI) page 7

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3.2. Do dioxins cause cancer in laboratory animals ? "Carcinogenic effects 2,3,7,8-TCDD has been shown to be carcinogenic in several chronic studies at multiple sites in multiple species in both sexes. Short-term studies observed a lack of direct DNA-damaging effects including covalent binding to DNA by TCDD, which underscores that TCDD is not acting as an initiator of carcinogenesis. However, secondary mechanisms may be important in the observed carcinogenicity of TCDD and related dioxin-like compounds. The lowest observed adverse effect of TCDD in the Kociba study was the development of hepatic adenomas in rats at an intake of 10 ng/kg bw/day and the no observed effect level was 1 ng/kg/day. At the no observed effect level, body burdens were 60 ng TCDD/kg bw. TCDD also causes thyroid tumours in male rats. This has been indicated to proceed through a mechanism which involves altered thyroid hormone metabolism, and consequent increases in feedback mechanisms (TSH) which results in a chronic proliferative stimulation of thyroid follicular cells. Studies in the mouse skin support a lack of initiating activity and an ability to promote the growth of previously initiated lesions indicative of a promoting agent. Mouse skin tumour promotion indicates that the Ah receptor is involved in tumour promotion by TCDD. Extensive examination of liver tumour promotion in the female rat liver also supports a non-genotoxic mechanism for the induction of liver neoplasms by TCDD. The ability of TCDD to enhance proliferation and inhibit apoptotic processes in focal hepatic lesions further supports an indirect mechanism of carcinogenicity.

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Dioxins : 3. What are the effects of dioxins in laboratory animals ?

Several PCDDs, PCDFs, non-ortho and mono-ortho PCBs have also been shown to be tumour promoters." Source & © : WHO-IPCS

Assessment of the health risk of dioxins:

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Dioxins : 4. What are the effects of dioxins on human health ?

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4. What are the effects of dioxins on human health ? 4.1. Have dioxins caused cancer to humans ? 4.1.1. Which studies have been used to evaluate dioxins carcinogenicity ? 4.1.2. Were cancers observed in highly contaminated populations ? 4.2. What non-cancer effects have been observed in children ? 4.3. What non-cancer effects have been observed in adults ?

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4.1. Have dioxins caused cancer to humans ? 4.1.1. Which studies have been used to evaluate dioxins carcinogenicity ? 4.1.2. Were cancers observed in highly contaminated populations ?

4.1.1. Which studies have been used to evaluate dioxins carcinogenicity ? "EFFECTS IN HUMANS In the evaluation of the evidence of effects of PCDDs, PCDFs and PCBs, only studies with serum or adipose tissue measurements were considered. Human carcinogenicity data The most informative studies for the evaluation of the carcinogenicity of 2,3,7,8-TCDD are four cohort studies of

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Dioxins : 4. What are the effects of dioxins on human health ?

herbicide producers (one each in the United States and the Netherlands, two in Germany), and one cohort of residents in a contaminated area from Seveso, Italy. In addition, the multi-country cohort study from IARC includes three of the four high-exposure cohorts and other industrial cohorts, many of them not reported in separate publications, as well as some professional herbicide applicators. In most epidemiological studies considered exposure was to mixtures of PCDDs including TCDD, as contaminants of phenoxy herbicides and chlorophenols. The cohorts examined in these epidemiological studies do not allow an evaluation of the risk associated with exposure to higher PCDDs separate from exposure to TCDD. These studies involve subjects with the highest recorded exposures to 2,3,7,8-TCDD. In these cohorts the blood lipid levels of 2,3,7,8-TCDD estimated to the last time of exposure were 2000 ng/kg (mean) (up to 32,000 ng/kg) in the US cohort, 1434 ng/kg geometric mean (range 301 -3683 ng/kg) among workers involved in the clean up of a TCP reactor accident in the Dutch cohort, 1008 ng/kg (geometric mean) in the group of workers with severe chloracne in the accident cohort in Germany, and up to 2252 ng/kg in the Boehringer cohort in Germany. These calculated blood 2,3,7,8-TCDD levels of workers at time of exposure were in the same range as the estimated blood levels in the Kociba two-year rat carcinogenicity study. Exposures in Seveso (median in zone A, 443 ng/kg; median in Zone B, 94 ng/kg) were, on average, lower than those of the industrial cohorts. The upper range of the high-exposed individuals was similar to that of the occupational cohorts (upper 75th percentile in Zone A, about 2000 ng/kg); there were 736 persons in Zone A." Source & © : WHO-IPCS

Assessment of the health risk of dioxins:

re-evaluation of the Tolerable Daily Intake (TDI) page 8

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4.1.2. Were cancers observed in highly contaminated populations? "Increased risks for all cancers combined were seen in the occupational cohort studies. The magnitude of the increase was generally low; it was higher in sub-cohorts considered to have the heaviest 2,3,7,8-TCDD exposure. Positive dose - response trends for all cancers combined were present in the largest and most heavily exposed German cohort, and in the smaller German cohort where an accident occurred with release of large amounts of 2,3,7,8-TCDD. Increased risks for all cancers combined were also seen in the longer-duration longer-latency sub-cohort of the United States study, and among workers with the heaviest exposure in the Dutch study. These positive trends with increased exposure tend to reinforce the overall positive association between all cancers combined and exposure. The large German cohort evaluated dose-response both for estimated exposure to TCDD and for PCDDs/PCDFs using ITEQ and identified a positive trend in both analyses. In Seveso, all-cancer mortality did not differ significantly from that expected, in any of the contaminated zones, although excess risks were seen for specific cancers. Follow-up for the Seveso cohort was shorter than for the occupational cohorts. In most of these studies excess risks were observed for soft tissue sarcoma and also for lung cancer, non-Hodgkin lymphoma and digestive tract cancers. Statistically significant excess risks were observed in individual cohorts for a variety of other cancer sites including multiple myeloma, oral cavity, kidney cancer, leukaemia and breast cancer in women. A single study in Seveso examined cancer in children 0-19 years of age. Excess risks were observed for ovarian and thyroid cancer and for some neoplasia of the haematopoietic tissue; these results were based on small numbers. Two studies have evaluated cancer risk among subjects exposed to contaminated rice oil in Japan (Yusho) and Taiwan (Yucheng). The Japanese oil contained in the order of 1000 mg/kg PCBs and 5 mg/kg PCDFs. Estimates of intake are based on a study of 141 cases (Masuda, 1994). These patients consumed about 600 ml of oil over about one month, and ingested about 600 mg of PCBs and 3.5 mg of PCDFs total. Assuming a body weight of 60 kg, the daily dose was thus: 0.33 mg PCBs/kg/day and 0.002 mg PCDFs/kg/day. The Taiwanese oil contained about 100 mg/kg PCBs and 0.4 mg/kg PCDFs. Estimates are based a study of 99 cases. Patients consumed about 1 gram of PCBs and 3.8 mg of PCDFs over a period of about 10 months. Daily doses were approximately 0.06 mg PCBs/kg/day and 0.0002 mg PCDFs/kg/day. The contaminated rice oil contained a complex mixture of chlorinated ring compounds, http://www.greenfacts.org/dioxins/l-3/dioxins-4.htm (2 of 5) [26/08/2004 10:12:31]

Dioxins : 4. What are the effects of dioxins on human health ?

including dioxin- and non-dioxin-like PCBs, PCQuaterphenyls, PCTerphenyls, as well as the PCDFs. There was an excess liver cancer risk in Japan (OR = 3.1) at 22 years of follow-up, and no excess risk in Taiwan (OR = 0.8) at 12 years. In summary, the epidemiological evidence from the most highly 2,3,7,8-TCDD- exposed cohorts studied produces the strongest evidence of increased risks for all cancers combined, along with less strong evidence of increased risks for cancers of particular sites. The relative risk for all cancers combined in the most highly exposed and longer-latency sub-cohorts is 1.4. While this relative risk is not likely to be explained by confounding, this possibility cannot be excluded. It should be borne in mind that the general population is exposed to 2-3 orders of magnitude lower levels of TCDD, and 1-2 orders of magnitude lower levels of PCDDs/PCDFs than those experienced, as an equivalent lifetime dose in the industrial populations examined or the population at Seveso." Source & © : WHO-IPCS

Assessment of the health risk of dioxins:

re-evaluation of the Tolerable Daily Intake (TDI) page 8-9

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4.2. What non-cancer effects have been observed in children ? Non-cancer effects in children Two US birth cohorts with measured background exposure to PCBs have been followed since 1980, and 2 Dutch birth cohorts with measured background levels of PCBs, PCDDs and PCDFs have been followed since 1990. In Asia, some data are available on Japanese children exposed transplacentally to contaminated rice oil, and detailed follow-up is available on transplacentally exposed children in Taiwan. The estimated upper 10 percentile of total PCBs in breast milk lipid among mothers in the US cohorts was around 1.5 mg/kg; measurement of specific PCBs was limited by analytical methods available at the time of the studies. Mothers in these US cohorts were also exposed to other chlorinated pesticides and heavy metals. In the Dutch cohorts the mean TCDD I-TEQ concentration in human milk was 30.2 pg/g lipid (range 11.1 - 76.4 pg/g) and the estimated PCB concentration was 0.64 mg/g lipid. Neurodevelopmental delays and neurobehavioral effects including neonatal hypotonia occurred in the three largest cohorts, two in the US and one in The Netherlands, although the age at which the effects occurred and the tests used to detect them were not the same. In the two US cohorts the observed neurobehavioral effects were limited to the infants with the highest decile of transplacental exposure, with some indication of a non-linear effect. Thyroid hormone levels were evaluated in the two cohorts in The Netherlands with similar exposure to PCDDs/DFs and total PCBs. In utero exposure to total TEQs, as measured in mother's milk, may have influenced thyroid hormone status (TT4, TSH) in infants up to 3 months of age. In Japan and Taiwan effects on children exposed transplacentally to the contaminants in the rice oil included ectodermal defects, global persistent developmental delays, low birthweight, mild persistent behaviour disorders, decrease in penile length at puberty, reduced height among girls at puberty and hearing loss. It should be noted however, that it is not clear to what extent dioxin-like and/or non-dioxinlike compounds are contributing to these effects when considering the complex mixtures that human individuals are exposed to. In all the studies of infants and children, effects were primarily associated with in utero, rather than lactational exposure. Breast fed infants in the Rotterdam/Groningen cohort were shown to have better neurobehavioural development compared to formula fed infants. Within the group of breast-fed infants, however, those with higher exposure within the cohort to total TEQs (> 50 pg/g milk fat) tended to have poorer neurobehavioral test results (Bayley PDI) compared to those with lower exposure (< 50 pg TEQs/g milk fat). In children in Seveso who were highly exposed to TCDD, small, transient increases in hepatic enzymes, total lymphocyte counts and subsets, complement activity, and non-permanent chloracne were observed. Also an alteration of the sex ratio (excess female to male) was observed in children born to parents highly exposed to TCDD."

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Dioxins : 4. What are the effects of dioxins on human health ? Source & © : WHO-IPCS

Assessment of the health risk of dioxins:

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4.3. What non-cancer effects have been observed in adults ? "Non-cancer effects in adults Several persistent, exposure-related effects occurred in two or more adult populations exposed to PCDDs, PCDFs and PCBs. These populations include the industrial cohorts previously described: US Air Force Ranch Hands (exposed to TCDD during spraying of Agent Orange, median serum TCDD levels back-extrapolated at time of exposure around 50 pg/g lipid), Centers for Disease Control Vietnam Experience Study (exposed to TCDD during a one year tour in Vietnam, mean serum TCDD levels at time of study in 1987, 4 pg/g lipid), and the Seveso, Yusho and Yucheng cohorts. The effects are elevated GGT in the NIOSH, Ranch Hands and Vietnam Experience cohorts (NIOSH: out-of-range GGT levels, OR=2.27, 95%CI, 1.17-4.39: Vietnam Experience Study: OR 1.3, 95%CI, 1.0-1.8: Ranch Hand mean GGT concentration in highest exposed group 33.3 pg/g lipid TCDD compared to referent group, p<0.001); statistically nonsignificant dose-related increases in Triglyceride levels in the NIOSH cohort (and significant increases in Ranch Hands with serum TCDD concentrations above 15 pg/g lipid; significantly increased mean fasting plasma glucose levels among Ranch Hands with 2,3,7,8-TCDD concentrations > 94 pg/g lipid (OR=1.5, 95%CI 1.2, 2.0), an increased prevalence of diabetes among workers in the NIOSH cohort with serum concentrations above 1500 pg/g lipid and mortality from diabetes among females in all zones of Seveso, particularly in zone B (Zone A, Obs=2, RR=1.8, 95%CI 0.4-7.3; Zone B, Obs=13, RR=1.9, 95%CI 1.1-3.2; Zone R, Obs=74, R.R. 1.2, 95%CI 1.0-1.6). Increased mortality from cardiovascular diseases occurred in multiple industrial cohorts and in males of Zones A and R of the Seveso cohort. Positive dose-response trends were also observed for ischaemic heart disease in the heavily exposed German occupational cohort study, the Dutch occupational cohort and the IARC multicenter study. Among Yusho and Yucheng adults, chronic exposure-related effects included chloracne, conjunctivitis, and sebaceous cysts and inflammation, decreased nerve conduction velocity, fatigue and malaise, hyperpigmentation and hyperkeratosis, and increased mortality from non-malignant liver disease. In summary, noncancer endpoints were evaluated among groups exposed to dioxins, dioxin-like and non-dioxin-like polychlorinated aromatic compounds in a variety of exposure scenarios, from background to extremely high exposures. Among children exposed in utero to background levels, effects include subtle developmental delays (U.S.and Dutch children) and subtle thyroid hormone alterations (Dutch infants to age 3 month). Multiple, persistent effects occurred among highly exposed children in Yusho and Yucheng who had transplacental exposure. Of the many effects evaluated in exposed adult study populations, many were transient effects disappearing after the end of exposure. A few conditions appear to be in excess among the exposed cohorts when compared to unexposed referent groups including alterations in lipid, fasting plasma glucose and GGT concentrations as well as mortality from cardiovascular disease. Both of the Asian cohorts showed excess death from non-malignant liver disease." See Table 2 : Estimated tissue concentrations in human populations exposed to dioxin and dioxin-like compounds Source & © : WHO-IPCS

Assessment of the health risk of dioxins:

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Dioxins : 5. How can dioxin exposure be linked to health effects ?

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5. How can dioxin exposure be linked to health effects ?

5.1. Is there a known relationship between dioxin exposure and cancer ? 5.1.1. Human cancer 5.1.2. Experimental studies 5.2. Can a model predict non-cancer effects ? 5.3. How are dioxins mixtures accounted for ? 5.3.1. What are TEFs and TEQs ? 5.3.2. What are the limits of the TEF concept ? DOSE-EFFECT MODELLING The key issues concerning modelling which were discussed included: the appropriateness of the data sets for the relevant endpoints, the kind of model used, the uncertainties in the model, and the transparency of the model with regard to the base assumptions. The model requires validation, e.g. with multiple data sets, before acceptance; this is often not done. In addition, use of raw data rather than summary data will substantially improve the models.

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Dioxins : 5. How can dioxin exposure be linked to health effects ?

5.1. Is there a known relationship between dioxin exposure and cancer ? 5.1.1. Human cancer 5.1.2. Experimental studies

5.1.1. Human cancer "The choice of data sets is determined to a large extent by the richness and completeness of the data. Therefore, in modelling human cancer, the most useable data sets are the industrial cohorts discussed by IARC in their 1997 monograph. In all these cohorts, exposure is back calculated from serum levels measured after the exposure had ceased. Average body burden over a lifetime was estimated assuming constant background levels of exposure before and after employment, and an assumption of continuous exposure to TCDD alone in the work place. The back calculation from the lipid adjusted serum levels observed after the end of the industrial exposure assumed a constant half-life of 7.1 years. A multiplicative linear hazard model was used to estimate a slope, using a maximum likelihood estimate. The ED01 to maintain the steady state body burden associated with a 1% excess risk over a lifetime results in a body burden of 3 -13 ng/kg, which is associated with a daily dose in the range of 2-7 pg/kg/day. If risk is related to peak exposure, rather than to continuous exposure, the estimate would be low. If the majority of exposure in the studied cohorts occurred within the earliest year instead of uniformly over the span of employment, the ED01 would increase by approximately a factor of three. It is important to note that the average exposure over time is not very different from these values (e.g., in the NIOSH cohort in the lower "exposure" group, those with less than one year of occupational exposure, resulted in an average lifetime body burden of approximately 10 ng/kg). However, the model does assume linearity within the range of the data, which is likely to provide a conservative position." Source & © : WHO-IPCS

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5.1.2. Experimental studies "Experimental cancer studies Two approaches to modelling were used: mechanistic and curve fitting. It is important to note that the mechanistic model had many assumptions and that other assumptions may be equally plausible and can lead to other models that adequately describe the data sets. Mechanistic Model Molecular, cellular, and promotion data was used to predict the incidence of liver Tumours in the female Sprague Dawley rat observed in the Kociba study. The model assumed that dioxin exposure induced increased cellular proliferation and indirectly led to an increase in mutation rate due to induction of hepatic enzymes leading to oxidative stress. The hypothesis of no mutational effect was tested and could not be rejected for this model. Each part of the model was allowed to vary independently and was not constrained a priori to either a linear or nonlinear association. The ultimate best fit linear model lead to an excess 1% lifetime cancer risk associated with a steady state body burden of 2.6 ng/kg, resulting from a daily exposure of 150 pg/kg/day. Thus, while the ED01 on a daily dose base for rodents is much higher than that for humans, the steady state body burden for rodents is in the same range as that estimated for humans. This is due to the pharmacokinetic differences between the species. Curve Fitting Model The Armitage-Doll model was used to calculate a shape parameter to describe the results of multiple animal tumour

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Dioxins : 5. How can dioxin exposure be linked to health effects ?

studies in both rats and mice. The shape of the curve could be fitted by either linear or various non-linear power functions. 8 Out of 13 studies were best fitted by a linear model. However, the data may be described by a non-linear model. The ED01 based on a steady state body burden ranged from 10 ng/kg to 746 ng/kg, associated with daily doses of 1.3 ng/kg/day to 41.4 ng/kg/day. If these results are compared to the human cancer estimates, the body burdens again are similar, but the daily doses, as expected from pharmacokinetic considerations, are much higher in rats and mice. The animal estimates do not involve a large extrapolation to go from the observed data to a calculated ED01." Source & © : WHO-IPCS

Assessment of the health risk of dioxins:

re-evaluation of the Tolerable Daily Intake (TDI) page 14

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5.2. Can a model predict non-cancer effects ? "Non-cancer No models have been evaluated for non-cancer effects in humans. The animal data sets that were modelled involved those with at least four dose groups and those in which a maximal response was at least approached, if not achieved. The Hill equation was used with non-linear least squares to fit the parameters and weighted for the observed variance and the shaping function was applied to assess linearity or non-linearity. For multiple dose studies, the average body burden at steady state was calculated as in the cancer studies. For the bolus studies, the body burden was assumed to be equivalent to the administered dose or that estimated by calculation at the time of response measurement based on first order elimination kinetics. Modelling of 45 non-cancer studies in rodents demonstrated that 21 were best fitted by a near-linear model, while 24 demonstrated non-linearity. The biochemical endpoints were mainly linear; but most of the clearly adverse endpoints were non-linear. However, the decline in sperm count following prenatal exposure was linear. When the ED01 for the biochemical endpoints was compared with the observed LOEL, the ED01 was often higher than the measured response. This may reflect the sensitive measurements that can be made for biochemical responses. For the decrease in sperm count, the ED01 was lower than the LOAEL. This may reflect measurement sensitivity, study design, and complexity of response. In some studies, estimation of the maximum response was problematic and the biological plausibility of the curve fits was unclear, underlying the need for mechanistic models for non-cancer endpoints. The utility of the models is that they allow a common method of comparison, e.g. a 1% excess response. Use of this methodology allows comparison across responses. This benchmark methodology is less sensitive to the "ability to detect" a response based on the different study designs used to assess different endpoints. It is important to note that the ED01 for many of the non-cancer endpoints ranged for <1 to 100 ng/kg body burden. This is also true for cancer. Regarding the importance of modelling to the human risk assessment for dioxin, the predictions of effects were compared with the actual data. At times, obvious discrepancies arise, leading to caution in the use of models. While recognizing that modelling is not suitable for human risk assessment of dioxins yet, it provides additional insights into the observational data, and adds to the transparency of the review." Source & © : WHO-IPCS

Assessment of the health risk of dioxins:

re-evaluation of the Tolerable Daily Intake (TDI) page 14-15

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5.3. How are dioxins mixtures accounted for ? 5.3.1. What are TEFs and TEQs ? 5.3.2. What are the limits of the TEF concept ?

5.3.1. What are TEFs and TEQs ? "APPLICABILITY OF TEF CONCEPT The complex nature of polychlorinated dibenzo-p-dioxin (PCDD), dibenzofuran (PCDF), and biphenyl (PCB) mixtures complicates the risk evaluation for humans. For this purpose the concept of toxic equivalency factors (TEFs) has been developed and introduced to facilitate risk assessment and regulatory control of exposure to these mixtures. TEF values for individual congeners in combination with their chemical concentration can be used to calculate the total TCDD toxic equivalents concentration (TEQs) contributed by all dioxin-like congeners in the mixture using the following equation which assumes dose additivity:

The majority of studies assessing the manner in which binary and complex mixtures of dioxin-like PCDD, PCDF and PCB congeners interact to cause toxicity have demonstrated that the interaction does not deviate significantly from dose additivity. This includes investigations conducted in various classes of vertebrates (fish, birds and mammals) and on environmental relevant mixtures. TEFs for dioxin-like compounds apply only to AhR-mediated responses. The criteria for including a compound in the TEF scheme for dioxin-like compounds are that the compound must: ● ● ● ●

Show a structural relationship to the PCDDs and PCDFs Bind to the Ah-receptor Elicit Ah receptor-mediated biochemical and toxic responses Be persistent and accumulate in the food chain.

To reassess the TEFs for mammals a WHO expert group recently applied a tiered approach in which results of animal toxicity studies, especially those involving (sub)chronic exposure, were given significantly more weight than results of in vitro or biochemical studies. The results of this activity are summarized in Table 3.

Table 3. WHO TEFs for human risk assessment based on the conclusions of the World Health Organization meeting in Stockholm, Sweden, 15-18 June 1997 (Van den Berg et al., 1998). Congener

TEF value

Dibenzo-p-dioxins 2,3,7,8-TCDD 1,2,3,7,8-PnCDD 1,2,3,4,7,8-HxCDD 1,2,3,6,7,8-HxCDD 1,2,3,7,8,9-HxCDD 1,2,3,4,6,7,8-HpCDD OCDD

1 1 0.1 0.1 0.1 0.01 0.0001

Dibenzofurans 2,3,7,8-TCDF

0.1

Congener

TEF value

Non-ortho PCBs PCB 77 PCB 81 PCB 126 PCB 169

0.0001 0.0001 0.1 0.01

Mono-ortho PCBs PCB 105 PCB 114 PCB 118 PCB 123

0.0001 0.0005 0.0001 0.0001

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Dioxins : 5. How can dioxin exposure be linked to health effects ?

1,2,3,7,8-PnCDF 2,3,4,7,8-PnCDF 1,2,3,4,7,8-HxCDF 1,2,3,6,7,8-HxCDF 1,2,3,7,8,9-HxCDF 2,3,4,6,7,8-HxCDF 1,2,3,4,6,7,8-HpCDF 1,2,3,4,7,8,9-HpCDF OCDF

0.05 0.5 0.1 0.1 0.1

PCB PCB PCB PCB

156 157 167 189

0.0005 0.0005 0.00001 0.0001

0.1 0.01 0.01 0.0001

Van den Berg, M., Birnbaum, L., Bosveld, B.T.C., Brunström, B., Cook, P., Feeley, M., Giesy, J.P., Hanberg, A., Hasegawa, R., Kennedy, S.W., Kubiak, T., Larsen, J.C., van Leeuwen, F.X.R., Liem, A.K.D.,Nolt, C., Peterson, R.E., Poellinger, L., Safe, S., Schrenk, D., Tillitt,D., Tysklind, M., Younes, M., Waern, F.,Zacharewski, T. Toxic Equivalency Factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environmental Health Perspective, 106 (12), 775792, 1998" Source & © : WHO-IPCS

Assessment of the health risk of dioxins:

re-evaluation of the Tolerable Daily Intake (TDI) page 15-16

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5.3.2. What are the limits of the TEF concept ? "While additivity predominates in the majority of experimental studies, non-additive interactions of PCDDs, PCDFs and PCB mixtures have been reported at greater than environmental levels of exposure. These non-additive effects are considered to be due to multiple mechanisms of action of individual congeners and/or to pharmacokinetic interactions. For the mono- ortho PCBs especially, certain endpoints such as carcinogenicity, porphyrin accumulation, alterations in circulating thyroid hormone concentrations and neurotoxicity could arise by both Ah-receptor-mediated and non-Ah receptor-mediated mechanisms. In addition, non-Ah receptor-mediated mechanisms of action of the mono-ortho PCBs may be shared by certain di-, tri-, and tetra-chloro ortho-substituted PCBs. This increases uncertainty in the use of TEFs for mono-ortho PCBs. While recognizing that these and other uncertainties exist in the use of the TEF concept for human risk assessment, pragmatically it remains the most feasible approach. Use of TCDD alone as the only measure of exposure to dioxinlike PCDDs, PCDFs and PCBs severely underestimates the risk to humans from exposure to these classes of compounds. Thus, the TEF approach is recommended for expressing the daily intake in humans of PCDDs, PCDFs, non-ortho PCBs and mono-ortho PCBs in units of TCDD equivalents (TEQs) for comparison to the tolerable daily intake (TDI) of TCDD." Source & © : WHO-IPCS

Assessment of the health risk of dioxins:

re-evaluation of the Tolerable Daily Intake (TDI) page 16-17

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6. Evaluation and conclusions 6.1. Human exposure to Dioxins 6.1.1. Exposure 6.1.2. Toxicokinetics 6.2. Observed health effects 6.3. Tolerable Daily Intake set by WHO for dioxins 6.3.1. How did WHO derive the intake limit ? 6.3.2. How must this limit be understood ? 6.4. Breastfeeding

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6.1. Human exposure to Dioxins 6.1.1. Exposure 6.1.2. Toxicokinetics

6.1.1 Exposure "Substantial information on the concentrations of PCDDs/PCDFs and limited information on dioxin-like PCBs in environmental samples, foods, human tissues, as well as breast milk are available for a number of mainly industrialized countries. The information indicates that the concentrations of these compounds have decreased during the last 10 years, mainly due to enforced regulations that have limited their dispersal to the environment and hence the food chains. The available information derived from food surveys in numerous 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 bw/day for a 60 kg adult. This intake results in average human tissue levels in the range of 10-30 pg I-TEQ/g lipid, equivalent to a body burden of 26 ng I-TEQ/kg body weight. If the dioxin-like PCBs (non-ortho and mono-ortho PCBs) are also considered, the daily TEQ intake may be greater by a factor of 3-fold. Based on results from the latest WHO field study on human breast milk contaminant concentrations, average PCDD/PCDF levels, expressed on an I-TEQ basis, ranged from less than 10 pg/g milk fat in developing countries to 1035 pg/g milk fat in industrialized countries. When dioxin-like PCBs are included, the total TEQ concentration increases in the order of 2-fold. For example, in a large sample of Dutch breast milk samples collected in 1990-91, the mean concentration of PCDD/PCDF TEQs was 34.4 pg/g milk fat; when dioxin-like PCBs were included in the calculation, the total TEQ value increased to 72.3 pg/g milk fat. The average daily intake of a breast- fed infant, on a body weight basis, therefore may be almost 1-2 orders of magnitude greater than that of an adult. It should be noted that the majority of industrialized countries have recorded decreases of up to 50% in the concentration of PCDDs/PCDFs and total PCBs in breast milk within the past. When TEQ calculations (based on 1997 WHO TEFs) for exposure and body burden are considered on an individual congener basis in background populations TCDD generally accounts for only 10-20 % of the PCDD/PCDF-TEQs. When dioxin-like PCBs are also included TCDD often contributes less than 5 % to the total TEQ.10 years. The consultation recommended that the new TEFs for PCDD/PCDF and dioxin-like PCB derived by WHO in 1997 (see Applicability of the TEF concept) should be used for future calculations of TEQs. This will result in an approximate 10% increase in TEQ calculations, compared to using I-TEFs and the initial 1994 WHO TEFs for PCBs." Source & © : WHO-IPCS

Assessment of the health risk of dioxins:

re-evaluation of the Tolerable Daily Intake (TDI) page 17-18

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6.1.2. Toxicokinetics "The key determinants in the kinetics and the half-lives of these compounds are amount of fat stores in the body, binding to CYP 1A2 in the liver, and rate of metabolism and excretion. The dose also plays a significant role and it was found that humans also sequester these compounds in the liver at higher doses, as do experimental animals. However, because of species variation in the above mentioned determinants, rodents require appreciably greater doses (100-200-fold) to reach the same equivalent body burdens as has been determined in humans exposed only to background concentrations to dioxin and related compounds. From a pharmacokinetic point of view, estimates of body burden are considered the most appropriate dosimetric parameter for interspecies comparison. The existence of a relationship between average daily intake and resulting tissue levels in humans is supported by data from Germany which showed that decreases in average daily dioxin TEQ intake over the course of 7 years (19891996) were associated with similar declines in human milk and blood concentrations. Due to the relatively long halflives in humans of dioxins and related compounds, steady-state body burden estimates usually reflect a stable condition in which brief intake above background will not result in significant changes to the body burden." Source & © : WHO-IPCS

Assessment of the health risk of dioxins:

re-evaluation of the Tolerable Daily Intake (TDI) page 18

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6.2. Observed health effects "Health effects The consultation noted that PCDDs, PCDFs, and the dioxin-like PCBs (non-ortho and mono-ortho substituted PCBs) exert a number of biochemical and toxicological effects mediated through the Ah receptor. Ah receptor binding affinity and responses directly dependent on Ah receptor activation suggest that humans may be less susceptible to TCDD than "responsive" rodent strains, whereas other biochemical or cellular effects are suggestive of a comparable susceptibility. The broad range of Ah-receptor binding affinities seen in human placenta samples suggests considerable variability of this parameter may exist within the general population. A number of biochemical effects (CYP1A1/2 induction, EGFR down regulation, etc.) have been observed in experimental animals at body burden comparable to those of the general human population. These effects may or may not have implications for the toxicity of TCDD. In the course of evaluating the adverse effects of dioxins at low doses, the usefulness of toxicokinetic and doseeffects modelling to calculate a "benchmark" (ED01) for comparison in the assessment was explored. It was noted that the outcome of using such models would strongly depend on the assumptions used and there are still a number of uncertainties in the interpretation of the results. Therefore, more traditional approaches using simple body burden calculations and empirical observations (LOAELs and NOAELs) have been used in this evaluation. As discussed earlier, a wide variety of effects has been observed in studies of TCDD, and to a more limited extent of other PCDDs, PCDFs and dioxin-like PCBs, in animals and also in studies of complex mixtures of these compounds in human populations. For the purposes of a risk assessment of human exposure to dioxin-like compounds the consultation focused on effects seen at low doses. Table 1, Animal End-points non-cancer effects, presents a range of reported animal LOAELs which are considered adverse and which occur at body burdens in the range of 10-73 ng/kg. This suite of effects represents critical studies for the assessment of low dose effects of PCDDs/PCDFs. Among these are developmental and reproductive effects in rats and monkeys. Responses are presented along with information on the increment to background body burdens in the experimental animals. These body burdens can

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Dioxins : 6. Evaluation and conclusions

readily be transformed into estimated daily human intakes that on a chronic basis would be expected to lead to similar body burdens in humans. Under steady state conditions, it is possible to estimate intakes as:

Intake (ng/kg/day) = Body Burden (ng/kg)*(ln(2)/half-life)/f

where f is the fraction of dose absorbed and is assumed to be 50% for absorption from food for humans, and an estimated half-life for TCDD of 7.5 years assumed. The results of such calculations appear in Table 4. Considering the very large differences in the half lives of dioxin-like compounds in various species, it is best to compare across species using this measure. It should be noted that the estimated human daily intakes are related to the body burdens in animals where adverse effects have been reported. The consultation also considered a study of enhanced viral sensitivity in mice following acute exposure to TCDD but did not consider it appropriate for inclusion in the range of LOAELs as the lack of a dose-response relationship implies that there may be an unknown mechanism of action. In addition, children from Seveso with chloracne, who had been exposed acutely to high doses of TCDD, exhibited only minor transient alterations in various non-specific immune system parameters (see later). Similar analyses of sensitive responses in chronic animal cancer studies allow estimation of human daily intake values of about 150 pg/kg/day for the LOAEL (10 ng/kg/day) of the Kociba rat study corresponding to a body burden of 294 ng TCDD/kg, respectively. In addition to the adverse effects reported, numerous biochemical changes have been noted in experimental animals at body burdens within the range of 3-10 ng/kg. Several of these are also shown in Table 1. While these effects are observed at the lowest body burdens, they are considered to be early markers of events induced by dioxin-like compounds in animals and in humans and may or may not result in adverse effects. In humans, maternal ingestion of high levels of a complex mixture of congeners from heat degraded PCBs (PCBs, PCDFs, PCQs) resulted in a variety of persistent severe adverse developmental and neurological effects in the infants. Maternal body burdens at the time of exposure were estimated to be 2-3 µg TCDD TEQs/kg. Non-cancer effects observed in mainly adult male workers occupationally exposed to high levels of TCDD and, to a lesser extent, higher chlorinated PCDDs included changes in serum lipids, elevated serum GGT, increased incidence of cardiovascular disease and diabetes. These effects were associated with mean body burdens at the time of last exposure ranging from 28-400 ng/kg. TABLE 4. ANIMAL BODY BURDENS TCDD AND RELATED HUMAN ESTIMATED DAILY INTAKES (EDI)

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- Gehrs, B.C., Riddle, M.M., Williams, W.C. and Smialowicz, R.J. Alterations in the developing immune system of the F344 rat after perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. II. Effects on the pup and the adult. Toxicology 122:229-240, 1997b. - Gehrs, B.C. and Smailowicz, R.J. Persistent suppression of delayed-type hypersensitivity (DTH) in rats perinatally exposed to TCDD. Toxicologist 42:1501, 1998. - Gray, L.E., Ostby, J.S. and Kelce, W.R. A dose-response analysis of the reproductive effects of a single gestational dose of 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD) in male Long Evans hooded rat offspring. Toxicol. Appl. Pharmacol. 146:11-20, 1997a. - Gray, L.E., Wolf, C., Mann, P. and Ostby, J.S. In utero exposure to low doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters reproductive development of female Long Evans hooded rat offspring. Toxicol. Appl. Pharmacol. 146:237-244, 1997b. - Rier, S.E., Martin, D.C., Bowman, R.E., Dmowski, W.P. and Becker, J.L. Endometriosis in Rhesus Monkeys (macaca mulatta) following chronic exposure to 2,3,7,8,-tetrachlorodibenzo-p-dioxin. Fundam. Appl. Toxicol. 21:433-441, 1993. - Schantz, S. and Bowman, R.E. Learning in monkeys exposed perinatally to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Neurotoxicol. Teratol. 11:13-19, 1989.

In Seveso residents (children and adults) acutely exposed to high levels of TCDD alone resulting in median serum lipid TCDD concentrations of 450 ng/kg in individuals in the zone of highest exposure (zone A), a variety of transient effects were seen including chloracne, increases in a serum enzyme activity (GGT) and alterations in lymphocyte counts. Studies on children from zone A did not reveal effects on immune competence. Mortality studies have indicated an excess of deaths due to cardiovascular diseases in males from zone A while an alteration in the sex ratio (excess females) of infants born to parents who both resided in zone A has also been reported. As noted previously, back calculated blood concentrations of 2,3,7,8-TCDD determined in occupational cohorts which provide limited evidence of a human cancer response associated with dioxin exposure overlap with the blood concentrations determined in rats of the highest dose group (100 ng/kg/day) of the Kociba study. These and other data suggest that humans might be as sensitive as other animals to the adverse effects of dioxin and related compounds although data to evaluate comparable endpoints are frequently lacking. The consultation recognized that the epidemiological evidence for the most highly TCDD-exposed cohorts studied produces the strongest evidence of increased risks for all cancers combined, along with less strong evidence of increased risks for cancers of particular sites. The relative risk for all cancers combined in the most highly exposed and longer latency sub-cohorts was 1.4. While the relative risk is not likely to be explained by confounding, this possibility cannot be excluded. http://www.greenfacts.org/dioxins/l-3/dioxins-99.htm (5 of 8) [26/08/2004 10:12:37]

Dioxins : 6. Evaluation and conclusions

In the industrial populations or the population of Seveso in which cancer statistics were examined, the exposure to TCDD was higher by 2-3 orders of magnitude (to PCDD/DFs by 1-2 orders of magnitude) than that in the general population. The median body burdens associated with these exposures were 20 - 100 ng/kg. The interpretation of the results from cohort studies concerning the effects on birth weight, maternal and new-born circulating thyroid hormones, and on the infant's developing nervous system is complicated by the simultaneous exposure to non-dioxin like PCBs (and maybe other compounds) that also might have played a significant role in eliciting these effects. These effects were observed at TEQ body burdens only slightly higher than that of the average general population, and thus point to the need for continuing efforts to reduce human exposure to these compounds, by controlling their input to the environment." Source & © : WHO-IPCS

Assessment of the health risk of dioxins:

re-evaluation of the Tolerable Daily Intake (TDI) page 18-22

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6.3. Tolerable Daily Intake set by WHO for dioxins 6.3.1. How did WHO derive the intake limit ? 6.3.2. How must this limit be understood ?

6.3.1. How did WHO derive the intake limit ? "Derivation of TDI Estimation of a TDI for dioxin and related compounds would require that either a reliable No-Adverse-Effect-Level (NOAEL) or a reliable LOAEL be identified for the most sensitive (and relevant) adverse response, that can serve as a surrogate for all other adverse responses that might be expected from exposure to these compounds. The LOAELs for the most sensitive adverse responses reported in experimental animals (Table 4) were associated with body burdens from which a range of estimated long-term human daily intakes of 14-37 pg/kg/ day was calculated. The consultation noted that the lower and upper end of this estimated range was related to effects following acute gavage (bolus) exposure to rats, but that this range also included effects seen after dietary exposure of monkeys for a prolonged period of time (4 years), the latter more resembling the conditions of human intake of these compounds. In view of the uncertainties in establishing a single, most appropriate LOAEL for derivation of a TDI, the consultation concluded that the range of estimated human daily intakes of 14 - 37 pg/kg/day provided a reasonable basis for the evaluation of the health risk of dioxin-like compounds. In order to arrive at a TDI based on TEQs, the use of uncertainty factors also had to be addressed in order to allow: a) the use of a range of LOAELs instead of a NOAEL, b) the possible differences between humans and experimental animals in susceptibility to these compounds, c) the potential differences in susceptibilities within the human population, and d) differences in half-lives of elimination for the compounds of a complex TEQ mixture. Since body burdens have been used to scale doses across species, the use of an uncertainty factor to account for species differences in toxicokinetics is not required. With regards to the potential differences in susceptibility to the effects of these compounds, it is mentioned before that for some endpoints humans might be as sensitive as experimental animals to the adverse health effects of dioxin and related compounds. This implies that only a small uncertainty factor needs to be employed for differences in susceptibility. As the LOAELs presented in Table 4 were considered to be within a factor of 2-3 to the NOAELs, and the differences in half-lives between the dioxins and dioxin-like PCBs were also small (and partly accounted for in the establishment of the TEF values), the consultation was of the opinion that a composite uncertainty factor of 10 would be adequate." Source & © : WHO-IPCS

Assessment of the health risk of dioxins:

re-evaluation of the Tolerable Daily Intake (TDI) page 22-23

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6.3.2. How must this limit be understood ? "The consultation emphasized, that the TDI represents a tolerable daily intake for life-time exposure and that occasional short-term excursions above the TDI would have no health consequences provided that the averaged intake over long periods is not exceeded. In addition, it recognized that certain subtle effects may be occurring in some sections of the general populations of industrialized countries at current intake levels (2-6 TEQ pg/kg bw/day) and body burdens (4-12 TEQ ng/kg bw), but found it tolerable on a provisional basis as these reported subtle effects were not considered overtly adverse and there were questions as to the contribution of non-dioxin-like compounds to the observed effects. The consultation therefore stressed that the upper range of the TDI of 4 pg TEQ/kg bw should be considered a maximal tolerable intake on a provisional basis and that the ultimate goal is to reduce human intake levels below 1 pg TEQ/kg bw/day. The consultation therefore recommended that every effort should be made to limit environmental releases of dioxin and related compounds to the extent feasible in order to reduce their presence in the food chains, thereby resulting in continued reductions in human body burdens. In addition, immediate efforts should be made to specifically target exposure reductions towards more highly exposed sub-populations." Source & © : WHO-IPCS

Assessment of the health risk of dioxins:

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6.4. Breastfeeding "Breast-fed infants are exposed to higher intakes of these compounds on a body weight basis, although for a small proportion of their lifespan. However, the consultation noted that in studies of infants, breastfeeding was associated with beneficial effects, in spite of the contaminants present. The subtle effects noted in the studies were found to be associated with transplacental, rather than lactational, exposure. The consultation therefore reiterated conclusions of previous WHO meetings on the health significance of contamination of breast milk with dioxin-like compounds; namely that the current evidence does not support an alteration of WHO recommendations which promote and support breastfeeding. Based on new clinical data which supports the biological plausibility of certain experimental observations, continued and enhanced effort should be directed towards identifying and controlling sources of environmental input of these substances. The consultation noted that within the last 10 years there is clear evidence of a decrease in dioxin levels in human milk in almost every region for which suitable data exists. This is most probably attributable to enhanced identification and control of environmental input sources. A future consultation in approximately 5 years should evaluate progress towards these goals." Source & © : WHO-IPCS

Assessment of the health risk of dioxins:

re-evaluation of the Tolerable Daily Intake (TDI) page 23-24

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The National Institute of Environmental Health Sciences (NIEHS) Q&As: http://www.niehs.nih.gov/oc/factsheets/dioxin.htm The World Health Organisation (WHO) Q&As: http://www.who.int/mediacentre/factsheets/fs225/en/ The Chlorine Chemistry Council (CCC) Q&As: http://dioxinfacts.org/questions_answers/index.html The Agency for Toxic Substances and Disease Registry (ATSDR) Q&As: http://www.atsdr.cdc.gov/tfacts104.html The International Food Information Council Foundation (IFICF) provides answers to frequent questions about food safety and information: http://www.ific.org/publications/qa/dioxinqa.cfm The US Environmental Protection Agency (EPA) FAQs: http://www.epa.gov/ncea/dioxinqa.htm (the source for Question 1 of this study)

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2. Some more information for the non-specialist ●

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Health Canada provides information on its environment site about dioxins and furans: http://www.hc-sc.gc.ca/english/iyh/environment/dioxins.html The French Food Safety Agency (AFSSA) addresses dioxins at: http://www.afssa.fr/Object.asp?IdObj=15913, and together with the Institut de Veille Sanitaire addresses children exposure to dioxins via breast feeding at: www.invs.sante.fr/presse/2002/communiques/dioxines_0302/avis_dioxines0302.html (in French).

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3. Some dioxin news sites ●

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The Environmental Health Perspectives (EHP) journal of the U.S. National Institute of Environmental Health Science presents Environews on the topic of dioxins: http://ehis.niehs.nih.gov/topic/dioxin.html The Healthfinder of the U.S. Department of Health and Human Services (HHS) links to recent carefully selected information and Web sites from over health-related organizations: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=3684

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4. Policy related websites ●

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EU dioxin inventory and strategy of the Environment DG of the European Commission: http://europa.eu.int/comm/environment/dioxin/ The National Center for Environmental Assessment of the US EPA provides a site on Dioxin and Related Compounds, including assessments and regulations. http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=55264 The Agency for Toxic Substances and Disease Registry (ATSDR) has adopted this interim policy guideline on dioxin and dioxin-like compounds in soils: http://www.atsdr.cdc.gov/dioxindt.html

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5. Other recent scientific evaluations on dioxins ●

In 2002, the Joint Expert Committee on Food Additives (JECFA) of the International Programme on Chemical Safety (IPCS) made a safety evaluation of dioxins present in food and established a provisional tolerable monthly intake (PTMI): More... http://www.inchem.org/documents/jecfa/jecmono/v48je20.htm#10.0

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GreenFacts : Sources for the Dioxins study

Home > Studies > Dioxins > About this study

Scientific Facts on

Dioxins

Source document: WHO-IPCS (1998) Summary & Details: GreenFacts (2004)

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GreenFacts Copyright Policy

About this Dioxin Study 1. Sources for this Study 2. Current Status 3. Study Publication History

1. Sources for this Study The material content of most of the texts on Level 3 are directly sourced from the Executive Summary of the Assessment of the health risk of dioxins : re-evaluation of the Tolerable Daily Intake (TDI), a leading scientific report produced in 1998 by a large international panel of scientists of the IPCS (International Programme on Chemical Safety) and WHO (World Health Organisation). The Levels 1 & 2 were written by Dr. Ludo Holsbeeck in collaboration with the GreenFacts team. More on the Source and Copyright

2. Current Status Final draft and peer review completed, awaiting aproval of the Scientific Board.

3. Dioxin Study Publication History The GreenFacts publication process is designed to ensure as high a degree of objectivity as possible.

First draft The first draft of this study was produced by Dr. Ludo Holsbeeck in June 2003 on the basis of a canvas prepared by the GreenFacts Team.

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Second draft The second draft of this study has been produced in January 2004 by Dr. Ludo Holsbeeck after review by the GreenFacts Team.

Preliminary review The final draft of this study will be produced in early 2004 by Dr. Ludo Holsbeeck after pre-review by experts from environmental and industrial organizations (see our pre review form).

Peer review The final draft has been peer reviewed by 3 independent scientists selected by the GreenFacts Scientific Board peer review form) and final corrections have been added under the supervision of the GreenFacts

(see our

Scientific Board.

Publication Final publication will be authorized by the President of the GreenFacts Scientific Board in July 2004.

Updates or subsequent post-publication revisions No update or revision at present. GreenFacts Copyright Policy

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