Science

This report provides a summary of new scientific research on the toxic effects caused by or associated with exposure to dioxin. The information in this report is drawn from a comprehensive assessment of the sources, fate, and health effects of dioxin contained in the Technical Support Document (TSD) to this report. The key points and conclusions of the TSD provide the basis for this report. Most of the research and studies discussed in this report have been published since a well publicized draft report on dioxin was released by the U.S. Environmental Protection Agency (EPA) in 1994. The American People's Dioxin Report is intended to inform the public and their representatives in government so appropriate action can be taken to safeguard the health of the American people. The scientific findings of this report make it clear that there is an extensive body of high quality scientific information describing the toxic effects of dioxin in people. This data indicates that dioxin is a potent chemical that produces a wide variety of toxic effects in animals and that some of these effects are occurring in people.

The report's most striking finding is the impact of dioxin on the growth and development of children. Most of the new studies on dioxin address its effects on children, notably the effects on the development of the immune, reproductive, and nervous systems, in particular cognitive and learning abilities. While exposure of the general population occurs through ingestion of many common foods, children exposed in utero (in the womb) during critical periods of development appear to be the most sensitive and vulnerable to the toxic effects of dioxin.

In particular, dioxin has been associated with IQ deficits and increased susceptibility to infections in Dutch children exposed to "background" levels of dioxins. (These "background" levels are essentially the average daily intake of dioxin from food.) Studies in Finland have shownthat dioxin interferes with normal tooth development in infants exposed to "background" levels. The Dutch studies have also shown an association between dioxin and a higher prevalence of withdrawn/depressed behavior in children. An association between PCBs and adverse effects on attentional processes and an increase in hyperactive behavior in children has also been reported in these studies.

This new evidence from human studies provides strong confirmation of the toxicity of dioxin and its impact on the general American public. With this in mind, Americans have a choice: take action to protect public health by eliminating dioxin creation or continue to allow dioxin to be created and not burden industry with the short term transition costs of elimination. Prudent public health policy would make every effort to eliminate environmental releases of dioxin and related compounds.

Description of Dioxin

Dioxin belongs to a family of chemicals with related properties and toxicity. There are 75 different dioxins, or polychlorinated dibenzodioxins (PCDDs), 135 different furans, or polychlorinated dibenzofurans (PCDFs), and 209 different polychlorinated biphenyls (PCBs). Each different form is called a "congener."

Not all of the "dioxin-like" chemicals have dioxin-like toxicity, and the toxic ones are not equally toxic. Only 7 of the 75 dioxins, 10 of the 135 furans, and 12 of the 209 PCBs have dioxin-like toxicity. These 29 different dioxins, furans, and PCBs all exhibit similar toxic effects caused by a common mechanism: binding to a particular molecule known as the aryl hydrocarbon or "Ah" receptor (see Chapter 5 of the TSD).

It is believed that the tighter the binding to the Ah receptor, the more toxic the chemical. The most potent member of this family is 2,3,7,8-tetrachlorodibenzo-p-dioxin or TCDD, which also has the greatest affinity for the Ah receptor.

The word "dioxin" is often used imprecisely. Some people restrict its use only to 2,3,7,8-TCDD, the most toxic and most studied dioxin. Others extend its use to the whole class of chemicals with similar toxicity and whose effects are controlled or triggered by the Ah receptor. In this report, the terms "dioxin" and "dioxins" are used to refer to any of the dioxin family members that bind to the Ah receptor and elicit dioxin like effects.

Toxic Equivalents

Although all dioxin-like compounds are thought to act in the same way, they are not all equally toxic. Their different toxicities may be due to their unique properties of absorption, distribution, metabolism, and elimination in a body and/or strengths of binding to the Ah receptor. Therefore, the health risk of each congener is assessed by rating their toxicities relative to TCDD, the most potent of the dioxins. TCDD is assigned a value of "1" and each of the 17 toxic dioxins/furans and 12 PCBs is assigned a "toxicity factor" that estimates its toxicity relative to TCDD. The resulting estimates are called toxic equivalency factors (TEFs), which have been recently updated by the World Health Organization.¹ The toxic equivalency (TEQ) is determined by multiplying the concentration of a dioxin congener by its toxicity factor. The total TEQ in a sample is then derived by adding all of the TEQ values for each congener. While TCDD is the most toxic form of dioxin, 90% of the total TEQ value results from dioxin-like compounds other than TCDD.

The TEQ system is not perfect, but it is a reasonable way of estimating the toxicity of a mixture of dioxin-like compounds. There is good experimental support for the assumptions that underlie the TEQ system.^1,2 TEQs make it possible to take toxicity data on TCDD, a compound about which our knowledge is vast, and estimate toxicity for other compounds about which much less is known.

Sources of Dioxins

Dioxin is found everywhere in the world - in water, air, soil, and sediment - even in places where dioxin or dioxin-containing products have never been used. This broad distribution is evidence that the sources are multiple and that dioxins can travel long distances. Unlike most chemicals, dioxins have no intended use or value. Dioxins are unintended by-products of many chemical and combustion processes which involve chlorine. They get into the environment from industrial air emissions, wastewater discharges, disposal activities, and from burning material that contains chlorine. The EPA estimates that 2,745 grams (gm) TEQ   released into the air each year.³ Municipal solid waste incinerators, secondary copper smelting, and medical waste incinerators are identified as the top three sources of dioxin released into the air. Combustion sources account for nearly 80% of air sources. Dioxins are also released to water, soil and into consumer products, but these sources are poorly defined and only a few estimates have been made. A list of EPA's dioxin sources is shown in Table 1.

In developing a "national inventory" of dioxin sources, EPA only made estimates for 20 of 54 identified air source categories, due to their lack of confidence in the available data.³ Preliminary estimates are made for 12 of the 34 poorly defined source categories, but these estimates are not included in the national inventory. EPA assigned "negligible" emissions to another 11 of these source categories and made no estimates for another 8 source categories even though there is some evidence of emissions. Overall, EPA's confidence in the data used to define dioxin releases to air, water, land, and products is weak and underestimates dioxin releases.

Source categories that are left out of EPA's dioxin inventory include iron ore sintering, polyvinyl chloride (PVC) production, accidental/structural fires, landfill fires, backyard burning, releases from petroleum refineries, asphalt mixing plants, and contaminated sites and other "reservoirs" of dioxin. Regrettably, there are apparently no efforts to collect such data from these and other sources. Some of these source categories, if included, would contribute substantially to the national inventory and significantly increase the amount of dioxins estimated to be released into the environment.

Environmental Fate

Dioxins enter the atmosphere either directly from air emissions or indirectly from volatilization from land or water, or from resuspension of particles. Depending on temperature and each congener's vapor pressure, dioxins are present in air as particulates or vapor. The more chlorinated compounds tend to bind to particulates and are protected from chemical and sunlight degradation. This protection may account for their relative abundance in the environment.
 
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Airborne dioxins can be carried large distances downwind from their sources as well as contribute significantly to local deposition.^4,5 Eventually, airborne dioxins settle onto soil, plants, and water where they enter the food chain. Dioxin will fall out onto crops that are fed to dairy cows and beef cattle where it accumulates in the milk and meat of these animals. Dioxin is attracted to and accumulates in fat. People who consume the contaminated meat and dairy products ingest substantial amounts of dioxin. When dioxin falls out onto waterways, it settles in sediments or remains suspended in the water for long periods of time because dioxins generally do not dissolve in water. Here too, the dioxins move up the aquatic food chain to fish and then into people.

Dioxin in Food

Americans accumulate harmful levels of dioxins in their bodies mostly through the ingestion of food. Some segments of the population, such as nursing babies and people who eat a diet high in animal fat or foods contaminated because of their proximity to dioxin release sites, are exposed to higher than average levels of dioxin.⁶ Others, such as Vietnam veterans and some chemical plant workers, have accumulated additional dioxins because of their exposure to Agent Orange or other dioxin-contaminated chemicals in the workplace.⁷

Approximately 90%,^6,7 and perhaps as much as 98%, ⁸ of the dioxin that average Americans are exposed to comes from the foods they regularly eat. Because dioxins accumulate in fatty tissue, they are found mostly in meat, fish, and dairy products. Consequently, when people consume these foods, they also consume dioxins. As Table 2 shows, ground beef has the highest dioxin content, with 1.5 picograms per gram (pg/gram) which is equivalent to 1.5 parts per trillion (ppt), of all meats consumed by Americans. Depending on what and how much people eat, the average daily intake of dioxins for Americans is approximately 2.2 pg TEQ/kg body weight (bw),⁹ ranging from 1 to 3 pg TEQ/kg bw.¹⁰ Daily intake increases to 3 to 6 pg TEQ/kg bw if dioxin-like PCBs are included. The ingestion of dioxin in common foods has resulted in widespread low-level exposure of the general population.
 
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The average daily intake of dioxin results in an average dioxin tissue concentration in Americans that ranges from 28 to 41 nanograms (ng) TEQ/kg lipids (fat) and from 36 to 58 ng TEQ/kg lipids if dioxin-like PCBs are included.^11,12 A single national average of 28 ng TEQ/kg or 28 ppt was estimated as part of the most extensive survey of dioxin in humans, the National Human Adipose Tissue Survey (NHATS). This survey was first conducted by the EPA in 1982.¹³ In 1987, the survey was repeated, and the results suggest some decreases in average dioxin body burdens, but the decreases may be due to improved analytical methods or to other issues involving methods of study. For most congeners, including TCDD, the differences between 1982 and 1987 tissue levels are not statistically significant.¹⁴

In addition to measuring exposure to dioxin by its daily intake, exposure can also be estimated by measuring how much of it builds up in the body. This is referred to as the "body burden" and is defined as the total accumulation of dioxin at any one time per kilogram of body weight.¹¹ For a person this would be how much they have accumulated up to the time of the testing. Using the average tissue concentrations from the studies above, estimated average dioxin body burdens range from 6 to 9 ng TEQ/kg body weight. If dioxin-like PCBs are included, the average dioxin body burden ranges from 8 to 13 ng TEQ/kg body weight.¹¹ In these estimates, TCDD contributes approximately 15% of the total TEQ.

These estimates represent average body burdens for a middle-aged person. Approximately 10% of the population can be expected to have at least three times this level and others as much as seven times these levels. These high exposure groups include nursing infants, children, some workers and farmers, people who rely on fish as a main staple of their diet such as some indigenous peoples and some fishermen, and people who live near dioxin-contaminated sites or dioxin-producing facilities. These groups have suffered a disproportionate share of dioxin exposure and many have already suffered the adverse health effects caused by these exposures.

Indigenous peoples, for instance, who eat fish and sea mammals from the Arctic regions are exposed to dioxin at higher than average levels because dioxin and PCB levels are particularly high in these foods.¹⁵ Dairy cows, meat cattle, or other animals fed crops grown on soil contaminated with dioxin in the low part per trillion (ppt) levels accumulate significant amounts of dioxins.¹⁶ An incinerator in the Netherlands that emitted large amounts of dioxins contaminated milk from cows grazing nearby. This milk was so contaminated that it was declared to be hazardous waste by the Dutch government.¹⁷ On the other hand, vegetarians, who consume less meat and dairy products, have below-average body burden levels of dioxin.¹⁸
 

Dioxin in Breast Milk

Dioxin accumulates in breast milk because it readily dissolves in the milk's rich fat content. During nursing, dioxin is transferred from mother to baby ^{19, 20, 21, 22, 23, 24} who may absorb as much as 95% of the dioxin in the milk.^{19, 20} Several studies reporting dioxin in human breast milk indicate that levels range from 20 to 30 ng TEQ /kg lipids in industrial countries and from 3 to 13 ng TEQ/kg lipids in less industrialized countries (Table 3).^{6, 7} The World Health Organization (WHO) reports a worldwide mean of 20 ng TEQ/kg lipids, with values ranging from a low of 3.1 ng TEQ/kg lipids to a high of 110 ng TEQ/kg lipids.²⁵

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Nursing infants ingest considerably more dioxins each day than adults. Studies in the U.S. and in the Netherlands have estimated daily intake of dioxins according to infant age. The U.S. study found that nursing infants typically consume between 35 and 53 pg TEQ/kg body weight (bw) per day in breast milk.²⁶ The more current Dutch study found that nursing infants typically consume about 112-118 pg TEQ/kg bw/day.²⁷ If the Dutch study is correct and infants consume dioxin at the rate of about 112-118 pg TEQ/kg bw/day, and adults typically ingest between 3 and 6 pg TEQ/kg bw/day,¹⁰ then nursing infants consume about 50 times more dioxin per day than adults, confirming results from other studies.^{15, 26} It is estimated that approximately 10-14% of total lifetime exposure can occur via nursing.^{27, 28}Breast-fed babies accumulate far more dioxins than do formula-fed babies. In one study, dioxin intake was 50 times greater in breast-fed infants than it was in formula-fed infants.²³ In this same study, TEQ concentrations in blood from 11 month old formula-fed infants were less than one fourth the concentrations of the mother's blood and about 10 times less than the concentrations in infants that are breast-fed for six to seven months.

Although nursing infants are at increased risk because of their higher intake of dioxins, extensive studies in the Netherlands indicate that the benefits of nursing outweigh the risks. Breast milk contains all the nutrients in ideal proportion for optimum growth and development; the psychological benefits of nursing are invaluable; ²⁹ and breast-fed babies have fewer respiratory illnesses, fewer skin problems, cry less, have fewer allergies, and are less constipated than other babies. For these and other reasons, despite the dioxin levels found in breast milk today, the World Health Organization (WHO) and the federal Agency for Toxic Substances and Disease Registry (ATSDR) both promote and support breast feeding.^{6, 10}

A "Safe" Level of Dioxin

Three separate government agencies have established a "safe" or tolerable daily dose of dioxins. These guideline values are shown in Table 4. The table also shows how much dioxin exposure is "allowed" according to the guideline. This value is determined by multiplying the guideline value, in picograms per kilogram (pg/kg) of body weight, by the body weight of an average person, which is typically 70 kilograms or about 150 pounds. For example, to convert ATSDR's Minimum Risk Level, multiply 1 pg/kg by 70 kg which results in 70 pg. This means that any daily intake greater than 70 pg would exceed the lowest measure of safety set by ATSDR. As the table shows, the average daily dioxin intake of the American people exceeds the two federal government guidelines and is within the range of the international guideline. This average daily intake is more than 200 times higher than EPA's guideline, over twice ATSDR's guideline, and in the middle of the range of the WHO guideline.
 
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According to the EPA, the American people's lifetime risk of getting cancer from exposure to dioxin is 1 in 10,000.³⁰ The risk attributable to dioxin for highly exposed members of the population is 1 in 1,000. These risk estimates are based on ingesting a "risk specific dose" of 0.01 pg TEQ/kg bw/day over a 70-year lifetime. At this dose, there will be one additional cancer for every one million exposed people. One cancer per million is often considered an "acceptable risk" value.³¹ Since the average daily intake of dioxin ranges from 1 to 3 pg/kg bw/day (3-6 pg/kg bw/day if dioxin-like PCBs are included), everyday the general American public is exposed to a cancer risk that is 100 to 300 times higher than the one-in-a-million "acceptable" cancer risk. Table 4 shows that the American people are already well above several federal and international guidelines for dioxin exposure as well as the typical "acceptable" cancer risk value.
 

"Safe" Body Burdens

The biological effects of a toxin depend on the concentrations of that substance in a target organ over a critical period of time. These concentrations in turn depend on three important factors: the absorption, distribution and persistence of the toxin throughout the body. These factors help determine a person's lifetime accumulation, or body burden, of dioxin. As discussed earlier, body burden is the concentration of a substance in tissue or blood per kilogram of body weight. Because body burden measurements account for differences in absorption, distribution and persistence across species and between individuals, ³² they can be used to compare the doses needed to produce similar adverse effects in different species.

Such a comparison was made by the World Health Organization which made a list of the most sensitive adverse health effects associated with exposure to dioxin in animals. These health effects, which are shown in Table 5, are primarily effects on the reproductive and immune systems. The WHO found that the lowest observed adverse effect levels (LOAELs), which ranged from 10 to 73 ng/kg, are all within a factor of 10 of the average body burden of 10 ng/kg in the human population. The USEPA made a similar comparison in their draft reassessment report in 1994.³⁰ The EPA included sensitive adverse effects in people, which are included at the bottom of Table 5. This table shows that adverse effects are occurring in some people with body burden levels similar to those that produce adverse effects in animals. The table also shows that the average body burden levels in the general American population is just below the levels that are causing adverse effects in animals.

Comparisons have also been made between the body burden levels of dioxin in animals and people that result in cancer. The body burden levels of dioxin at which exposed workers and experimental animals have higher numbers of cancers are similar. For both the workers and experimental animals, these body burden levels are also substantially higher than the body burden levels of dioxin in the general human population.^{12, 25}
 
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Sensitive Non-Cancer Effects Observed in the General Population

The Dutch Studies - Neurodevelopmental and Immune Effects

Main findings: Four point deficit in IQ and increased susceptibility to infections in 42 month old children exposed to typical daily intake levels of dioxins/PCBs.

Effects of dioxins and PCBs on neurodevelopment, the immune system and thyroid hormones were observed in children from the general population of the Netherlands.^{43, 44} These studies found that prenatal (before birth) exposure to typical daily intake levels of dioxins/PCBs are associated with:
 

• Reduced birth weight and reduced growth from birth through 3 months of age; ⁴⁵

• Delays in psychomotor development at 3 months; ⁴⁶

• Neurodevelopmental delays at two weeks ⁴⁷ and 18 months; ⁴⁸

• Alterations in thyroid hormones at birth and at 3 months; ⁴⁹ and

• Alterations in immune status from birth to 42 months.^{50, 51}

The adverse neurological effects found at birth and at 18 months could not be detected at 42 months.⁵² However, a decrease in cognitive function as measured by a 4 point deficit in IQ was measured for the first time at 42 months.⁵³ This difference may be explained by the different testing procedures used. Prenatal exposure to dioxins/PCBs were also found to be associated with other neurodevelopmental and behavioral effects at 42 months including a decrease in high level play, ⁵⁴ an increase in non play activity, ⁵⁴ and an increased prevalence of being withdrawn and depressed.⁵⁵ These Dutch studies also found that postnatal (after birth) exposure to typical daily levels of dioxins/PCBs was associated with:

• Delays in psychomotor development at 7 months; ⁴⁶

• Alterations in thyroid hormones at 3 months; ⁴⁹

• Alterations in immune status as indicated by an increased prevalence of recurrent middle ear infections and decreased prevalence of allergic reactions to food, pollen, dust and pets at 42 months; ⁵¹ and

• An increase in mean reaction times, a decrease in sustained attention, and an increase in hyperactive behavior at 42 months.⁵⁴

The Finnish Study - Developmental Effects

Main findings: An association between dioxin exposure and hypo-mineralization defects of permanent teeth.

A study of breast-fed Finnish children found an association between dioxin exposure and hypo-mineralization defects of permanent teeth.^{56, 57, 58} These findings suggest that the observed effects are primarily due to lactational exposures. In contrast, the effects observed in the Dutch children were associated primarily with in utero exposure and not in children who were breast-fed. Teeth defects are also observed in the rice oil poisonings in both Japan ⁵⁹ and Taiwan.⁶⁰ There are some toxicological data in animals to support effects of dioxin on tooth development. Dioxin causes defects of dental hard tissues in rats, ⁶¹ perhaps by altering the action of epidermal growth factor receptor.⁶² Dental defects and changes in ameloblasts (enamel-forming cells) in rhesus monkeys exposed to PCBs have been reported.⁶³

Miscellaneous Studies - Neurodevelopmental and Reproductive Effects

Two studies of children in the U.S. found similar neurodevelopmental effects associated with exposure to typical daily exposure levels of PCBs.^{64, 65} An ongoing German study also found neurodevelopmental effects associated with low-level PCB exposure.⁶⁶ Some of the results differ among these studies. In a study of children from the general Japanese population, exposure to dioxin-like compounds are associated with adverse effects on thyroid hormones and the immune system.^{67, 68}

Children of women exposed in utero to a complex mixture of PCDFs, PCBs and other compounds in the Taiwan rice oil poisoning incident of "Yu-cheng"(which translates to oil poisoning), suffered a number of effects including damage to the nervous and respiratory system;⁶⁹ higher than normal incidence of middle ear infections; ⁷⁰ and reduced penis size at adolescence.⁷¹

In Seveso, Italy, the site of a major plant explosion that sent a cloud of dioxin into the community, children who developed chloracne experienced transient changes in immune parameters, but no adverse immunological effects.⁷² Also, the sex ratio of children born (48 females to 26 males) in Seveso was not normal for several years following dioxin exposure, ⁷³ but the same effect is not seen after dioxin exposure in the Yu-cheng children.⁷⁴ Though a major study of women exposed to dioxin at Seveso is underway, the existing epidemiological evidence showing the effect of dioxin exposure on endometriosis is limited and mixed.

One study in Israel found higher levels of dioxin in the blood of women with endometriosis than in controls.⁷⁵ Workers with chloracne who worked at the Nitro, West Virginia trichlorophenol plant reported higher than expected sexual dysfunction and lower than normal libido.⁷⁶

In summary, some evidence indicates that dioxin exposure interferes with normal growth and development in children from the general population. Developmental neurotoxicity associated with dioxin exposure includes cognitive deficits, behavioral alterations such as increased withdrawal/depression, hyperactive behavior, and attentional difficulties. Other effects that are transient are decreased neuro-optimality (nerve function) and decreased psychomotor ability. Developmental effects on the immune system include increased susceptibility to infections, altered lymphocyte subsets, and increased respiratory disease and otitis (inflammation of the ear) in highly exposed infants. Developmental and reproductive effects include altered sex ratio (more females born than males), small penis and endometriosis. Many of the effects on the development of the nervous system are more associated with in utero exposure than with breast-feeding. The dental effects observed in the Finnish children are more strongly associated with dioxin exposure from breast milk, a finding consistent with the timing of tooth mineralization in humans.
 

Hormonal Effects

Major findings: Decrease in testosterone in workers and an increased risk of diabetes associated with exposure to dioxin.

Exposure to dioxin has a variety of effects on hormone function in animals and in people. In a group of U.S chemical plant workers (the NIOSH cohort), dioxin-exposed workers have lower than normal testosterone levels and higher than normal follicle-stimulating and luteinizing hormone levels, both of which can reduce sperm counts.⁴²

Dioxin interferes with the hormone insulin and alters glucose tolerance which leads to diabetes. In one study of 55 exposed workers evaluated 10 years after exposure, 50% of the workers were diabetic or have abnormal glucose tolerance, an early indicator of diabetes.⁷⁷ Since this striking finding, there have been mixed findings of diabetes or glucose tolerance in several studies. In the NIOSH workers, the risk of diabetes increased 12% for every 100 ppt dioxin in blood lipid.⁷⁸

In a study of the Ranch Hand veterans, the soldiers who had the highest exposures to Agent Orange, those with blood dioxin greater than 33.3 pg/gm (ppt) have a relative risk of 2.5 for diabetes.⁴¹ A relative risk of 1.0 means that an exposed person is no more likely to develop the disease than an unexposed person. In a follow-up study, the veterans exposed to dioxin had a relative risk of 1.4 for glucose abnormalities, 1.5 for diabetes, and 2.3 for the use of oral medications to control diabetes.⁷⁹

This study also found that Ranch Hand veterans exposed to dioxin develop diabetes at an earlier age than other veterans and that non-diabetic Ranch Hands exposed to dioxin have a relative risk of 3.4 for serum insulin abnormalities.

In the ongoing study of the residents of Seveso, Italy, there is an increase in deaths from diabetes in females in the second highest exposure area and a slightly elevated increase (not statistically significant) in males.⁷² Deaths from diabetes in the highest exposed area showed a suggestive but not statistically significant increase, though the number of deaths are too few to draw any conclusions.
 

Cancer Effects

Epidemiological data from high exposure situations suggest that a number of the effects of dioxin exposure seen in animals also occur in humans . However, because studies in humans cannot be done under the same controlled conditions as studies in experimental animals, dioxin's effects on humans are not as clear cut as they are in animal models. Nevertheless, similarities between humans and experimental animals allow reasonable comparisons and projections from dioxin's effects in animals to its effects on humans: they both have the Ah receptor and associated factors; a number of biochemical responses are similar; and, on a body burden basis, many human responses to dioxin are reasonably comparable to the responses in animals.^{11, 12}

Updates of ongoing studies indicate that dioxin exposure causes cancer in humans in a dose-dependent fashion. The most important of these studies are the series of studies by Flesch-Janys and colleagues in Germany and by Bertazzi and colleagues in Italy. The studies of the German chemical plant workers attempt to quantify the dose-response relationship between estimated TCDD exposure and total mortality.^80,81 The Italian studies of mortality among those exposed to the Seveso plant accident also focus on cancer mortality in populations grouped by exposure level.⁸² Both research groups recognize limitations and uncertainties in their studies including estimating exposure and defining specific causes of death, among other limitations of epidemiologic studies. However, both series of studies strengthen the conclusion that dioxin exposure is related to cancer mortality in humans in a dose-related fashion.

Two additional important studies are the update of the NIOSH chemical workers in the U.S.⁸³ and analysis of a group of Dutch workers ⁸⁴ that is part of a larger international group of workers.⁸⁵ The NIOSH update also shows a dose-response relation between dioxin exposure and cancer mortality. 

These studies together provide strong support for the decision by the World Health Organization's International Agency for Research on Cancer (IARC) to define TCDD as "carcinogenic to humans."²⁵ In making an overall judgement of dioxin's carcinogenicity in humans, IARC now includes mechanistic information as well as human and animal data. For example, the importance of the Ah receptor in mediating dioxin's toxic effects and its presence in both humans and experimental animals is acknowledged. This decision is further supported by strong evidence in animal studies that show dioxin causes cancer in all studies that have been conducted. The U.S. National Toxicology Program (NTP) had upgraded dioxin from its status as "reasonably anticipated to be a human carcinogen" to "known to cause cancer in humans" in 1997,⁸⁶ but reconsidered their decision based on procedural errors pointed out by industry. NTP has not decided whether they will upgrade dioxin or leave it as "reasonably anticipated to be a human carcinogen."

As discussed earlier, the lifetime risk of getting cancer from exposure to dioxin is 1 in 10,000 for the general American population and 1 in 1,000 for highly exposed members of the population.³⁰ These risk estimates are based on ingesting a "risk specific dose" of 0.01 pg TEQ/kg bw/day over a 70-year lifetime. If these estimates are taken seriously, then the average exposure of the American people to dioxin poses an uncertain but potentially substantial risk, a point made at least a decade ago.⁸⁷
 

Sensitive Non-Cancer Effects Observed in Animal Studies

Studies of dioxin's effects in experimental animals indicate that it causes a host of toxic effects including cancer; reproductive and developmental toxicity; damage to the immune system; neurotoxicity; endocrine disruption; liver and skin toxicity. Among the sensitive effects observed in animals are a number of biochemical and cellular effects that occur at body burden levels of about 10 ng/kg or less, levels comparable to those found in the average person.⁸⁸ These effects include production of the liver enzymes CYP1A1 and CYP1A2; alterations in hormones, such as epidermal growth factor (EGF), that affect growth and development; oxidative damage; and alterations in lymphocyte subsets,¹² a measure of immune function. These observations suggest that dioxins cause biological effects at levels comparable to those found in the average American. At present, it is unclear if these effects are adverse or not.

Developmental neurotoxicity: Subtle deficits in object learning are observed in the offspring of rhesus monkeys chronically exposed to dioxin in utero and from breast milk.³⁶ Similar exposure to dioxin also adversely affects long-lasting learning and memory in rats.⁸⁹ In this study, deficits in exposed animals of both sexes for different learning tasks were observed. Some of these tasks may represent a response strategy rather than improvement in learning or memory.

Endometriosis: The incidence and severity of endometriosis in rhesus monkeys chronically exposed to dioxin rises as the dose increases.³⁵ Surgically-induced endometriosis has been enhanced in dioxin-exposed monkeys ⁹⁰ and in rats and mice.⁹¹ In human endometrial tissue, the Ah receptor is expressed, suggesting that it is involved during the reproductive phase of this tissue.⁹²

Effects on the Developing Reproductive System: Pregnant rats exposed to a single dose of dioxin during the development of fetus' organs give birth to both male and female offspring with permanent damage to their reproductive systems.^{34, 39}

Immunotoxicity: Pregnant female rats exposed to dioxin give birth to offspring with an immune system problem called "delayed type hypersensitivity" ^{37, 38} which renders the animals more susceptible to viral infections. Captive harbor seals fed Baltic fish with 210 ng TEQ/kg lipid in their blubber develop delayed type hypersensitivity relative to controls which were fed cleaner Atlantic fish with only 62 ng TEQ/kg lipid in their blubber.⁹³ The seals fed the contaminated fish were less able to mount a normal immune response. Eight week old mice treated with 10 ng/kg of dioxin die more frequently than controls when exposed to influenza virus.³³ This viral susceptibility occurs at the lowest level of any effect observed in animals. This represents the most sensitive adverse effect of dioxin exposure on record.
 

Conclusion: The American People are at Serious Risk from their Daily Intake of Dioxin in Food

This report integrates all the information including the newest studies on dioxins' effects on human health and comes to the following conclusions:
 

• All American children are born with dioxin in their bodies. The greatest impact appears to be on the growth and development of children. Disrupted sexual development, birth defects and damage to the immune system may result.

• Dioxin exposure has been associated with IQ deficits, increased prevalence of withdrawn/depressed behavior, adverse effects on attentional processes, and an increase in hyperactive behavior in children. These effects have been reported in 42-month old Dutch children whose exposure to dioxins/PCBs came primarily before birth.

• Dioxin exposure has been associated with alterations in immune function including increased susceptibility to infections and changes in T-cell lymphocyte populations. These effects have been reported in 42-month old Dutch children whose exposure to dioxins/PCBs came primarily before birth. Altered immune function, reported at birth, 3, and 18 months of age, persists to 42 months of age in these children. Reported immune effects include an increase in middle ear infections and chicken pox, and a decrease in allergic reactions.

• There is evidence of both developmental and reproductive effects in children exposed to dioxin. These effects include defects in permanent teeth, adverse effects on thyroid hormones, altered sex ratio (more females than males), and increased respiratory disease.

• The average daily intake of dioxin in food poses a substantial cancer risk to the general American population. The lifetime risk of getting cancer from exposure to dioxin is 1 in 10,000 for the general American population and 1 in 1,000 for highly exposed members of the population. These risks are 100 and 1,000 times higher, respectively, than the one-in-a-million "acceptable" cancer risk.

• Nearly all Americans are exposed to dioxin through ingestion of common food, mostly meat and dairy products. Dairy cows and beef cattle absorb dioxin by eating dioxin contaminated feed crops. The crops become contaminated by airborne dioxins that settle onto soil and plants. Dioxins enter the air from thousands of sources including incinerators that burn medical, municipal, and hazardous waste.

• The average daily intake of the American people is already well above several federal guidelines and at mid-range of international guidelines for dioxin exposure. The average daily intake of the American people is more than 200 times higher than EPA's cancer risk guideline, over twice ATSDR's lowest adverse effect level, and in the middle of the range of the World Health Organizations's tolerable food intake.

• At higher risk of exposure to dioxin are children, nursing infants, some workers and farmers, people who eat fish as a main staple of their diet such as some indigenous peoples and fishermen, and people who live near dioxin release sites. These groups of people are likely exposed to at least 10 times as much dioxin as the general population.

Dioxin is an ubiquitous poison that is in our food and that causes many toxic effects in people and animals. The neurodevelopmental and reproductive effects observed in children may be the most disturbing new evidence. The small shifts in cognitive ability or thyroid levels may be the tip of the iceberg of the impact of dioxin on the general American public.

We know that the daily dioxin intake of Americans is already too high, and exceeds several federal risk guidelines. We also know that some members of the general population are particularly sensitive to exposure to dioxin and others are exposed to higher than average daily levels. These are infants and children, people who live near contaminated sites, fishermen and indigenous people who rely on fish as a main staple of their diet, workers, and others with high exposures. These groups have suffered a disproportionate share of dioxin exposure and many have already suffered the adverse health effects caused by these exposures. Every effort should be made to eliminate environmental releases of dioxin and related compounds. Americans have a choice: take action to protect public health by eliminating dioxin creation or continue to allow dioxin to be created and not burden industry with the short term transition costs of elimination and related compounds.
 
 

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