A publication of Work On Waste USA, Inc., 82 Judson, Canton, NY 13617 315-379-9200 DECEMBER 1994

Dioxin and Human Health:
A Public Health Assessment of
Dioxin Exposure in Canada

by Tom Webster
Boston University School of Public Health
Department of Environmental Health
Talbot 3C, 80 E. Concord St., Boston, MA 02118-2394
Tel: 617-638-4641. Fax: 617-638-4857.

Every Canadian is exposed to dioxin and carries this persistent toxic compound in their body and passes it on to their children. The Canadian government maintains this exposure of the general population is safe, or in their words, “without appreciable risk of deleterious effects” (Feeley and Grant, 1993).

New scientific research and prudent principles of public health indicate that Canada’s dioxin guideline is not protecting the human population. Dioxin may not have a “safe” dose, making it prudent to assume that it poses some health risk at any dose. The “no effect level” upon which Health and Welfare Canada relies is unsound and outdated. The levels of dioxin and dioxin -like compounds found in the general human population are at or near the levels associated with adverse effects.

Much of the new research was undertaken in the wake of the United States Environmental Protection Agency’s (USEPA) reassessment of the toxicity of dioxin which began in 1991. After over three years of study, dioxin seems more dangerous than ever.

The judgement that the dioxin problem is more serious than previously thought relies on several findings. Dioxin is an extremely powerful growth disregulator -- in more popular terms, an “environmental hormone” --- perturbing important physiological signalling systems. Effects on development, reproduction and the immune system have been found at extremely low levels. These levels are close enough to the concentrations of dioxin and dioxin-like compounds found in the average person to be of concern. Indeed, people who are more highly exposed may already be experiencing some of these effects. Wildlife serve as a warning: dioxin-like compounds appear to contribute to the reproductive and developmental problems observed in many species of Great Lakes wildlife. Finally, the combined weight of evidence from human epidemiological studies, animal cancer studies and biochemical research indicates that dioxin presents a cancer hazard to people.1

These findings suggest that the environment -- and our own bodies -- are already over-burdened with dioxin-like compounds. Given their persistence and toxicity, the prudent course of action is pollution prevention: the elimination of preventable sources of dioxin to the environment.

Dioxin and Dioxin-like Compounds

In common usage, the term dioxin typically refers to a compound called 2,3,7,8-tetrachlorodibenzo-p-dioxin: 2,3,7,8-TCDD or TCDD, for short. Dioxin was the substance of primary concern in Agent Orange. It was also the contaminant that forced the evacuation of Seveso, Italy and Times Beach, Missouri.

TCDD is only the most potent member of a whole class of toxic compounds which are thought to affect health in the same way. Although qualitatively similar in toxicity, these “dioxin-like” compounds differ in their relative potency. They can be roughly ranked against TCDD by numbers called toxic equivalence factors. These factors

1. The opinions in this paper are those of the author. As the EPA’s reassessment is not yet completed, the agency’s final conclusions are not known with certainty. In a draft of the reassessment’s risk characterization chapter, EPA uses somewhat weaker language, stating that “a weight-of-the evidence evaluation suggests that dioxin and related compounds are likely to present a cancer hazard to humans” (USEPA, 1994). While a review of human epidemiology is beyond the scope of this report, I believe that the evidence is stronger than this (Webster and Commoner, 1994). have been internationally adopted for TCDD’s immediate family members, the polychlorinated dibenzo-p-dioxins, as well as the closely related polychlorinated dibenzofurans and certain types of polychlorinated biphenyls (PCBs) (Ahlborg et al., 1994). Although these other dioxin-like compounds are less potent than TCDD, many are present in the environment in much greater quantities and typically dominate the overall “dioxin-like” toxicity.

Canadian Guideline for
Human Exposure to Dioxin

The Canadian government’s guideline for human exposure to dioxin is 10 picograms per kilogram body weight per day (pg/kg/d).2 According to Health and Welfare Canada, this so-called “tolerable daily intake” or TDI “represents the amount of chemical that can be taken in daily through diet averaged over a lifetime (70 years) without appreciable risk of deleterious effects” (Feeley and Grant, 1993).

The Canadian government estimates that the average person is exposed to about 2-4 pg/kg/d of TCDD equivalents from all sources -- food ingestion, air inhalation, water consumption, etc. Since the average Canadian receives less than the assumed tolerable daily intake, the Canadian government concludes that the average citizen is adequately protected (Boddington et al., 1990; Gilman et al., 1991; Feeley and Grant, 1993).

Health and Welfare Canada’s determination of the TDI is principally based on two classic experiments performed on rats. One examined the increased rate of cancer in rats fed various amounts of TCDD over a two-year period (Kociba et al., 1978). The other looked for certain reproductive and developmental effects in rats exposed over three generations (Murray et al., 1979). Although cancer, reproductive and developmental effects were found at higher doses, the authors claim that no adverse effects were observed at a dose of 1000 pg/kg/d.3

Canada derived the TDI by reducing this experimental level by a safety factor of 100 (Boddington et al., 1990; Feeley and Grant, 1993). The TDI for humans is set 100 times lower than the level at which no adverse affects were reported in the rat studies in order to protect against the possibility that humans might be more sensitive than rats as well as likely differences in sensitivity between people.

This seemingly straight-forward procedure involves three questionable assumptions:

1) dioxin has a “safe” dose, i.e., it has a threshold, a level below which no deleterious effect occurs;

2) the rat experiments on which the TDI is based identified the most sensitive deleterious effects;

3) potential harm to human health can be judged by comparing average daily human exposure with the doses which damage animals.

As we shall see, new data indicate that all three assumptions are either incorrect or imprudent.

Dioxin May Not Have a “Safe” Dose

Health and Welfare Canada presumes that TCDD has a “safe” dose or threshold because: a) “no observed adverse effect levels” have been identified for cancer, reproductive and developmental effects; b) TCDD promotes tumors instead of causing cancer by damaging DNA; c) the effects of TCDD are triggered by a receptor molecule in living cells (Feeley and Grant, 1993). Each of these points merits careful examination.

a) No Effect Levels. When a large dose of a chemical increases the rate of a toxic effect relative to unexposed control animals but a small dose does not, one possible explanation could be the existence of a threshold dose. However, it is also possible that the effect really does occur at lower levels, but that the experiment was not powerful enough to detect it.

For instance, if the true probability of developing cancer at a certain does is 1 in 1000 and only 50 animals are tested, it is unlikely that an increased number of tumors will be observed. In this example, lack of an observed increase does not by itself prove the existence of a threshold. Proper interpretation of “no effect levels” therefore requires an understanding of the underlying biology and the limitations of experimental protocols. Regulatory agencies generally presume thresholds, even when biological knowledge is limited.

b) Carcinogenesis. Carcinogens that damage DNA are typically the one important exception made by regulatory agencies to the threshold presumption. Current theory holds that cancer develops via a series of heritable changes in cells, leading progressively to uncontrolled growth and, in the worst case, invasion of other tissues. These heritable changes are normally thought be to associated with DNA damage (to oncogenes and tumor suppressor genes). Cancer may begin with damage to a single cell; even tiny doses of a DNA-damaging agent may have some probability of leading to a deleterious event. If this cell begins to grow and proliferate, it may eventually progress into a tumor. In this way, initial small effects are amplified into a life-threatening disease. Consequently, many regulatory agencies prudently assume that DNA-damaging carcinogens have no threshold.

On the other hand, some agents are thought to increase the proliferation of mutated cells, contributing to tumor development without directly causing DNA damage. This is one way that a compound may “promote” cancer. A promoter is partly defined experimentally as something which does not cause tumors by itself, but instead greatly increases the number of observed tumors that were initiated by another agent. Unlike DNA-damaging carcinogens, promoters are often presumed to possess thresholds.

2. One picogram (pg) is a trillionth of a gram. A nanogram (ng) equals one billionth of a gram.

3. Thyroid cancer may be a more sensitive endpoint (National Toxicology Program, 1982; Zeise et al., 1990; USEPA, 1992).

Health and Welfare Canada argues that TCDD possesses a threshold because it promotes cancer rather than causing genetic damage. This is an overly simplistic view. TCDD does not appear to directly damage DNA (i.e., cause mutations). However, it may indirectly cause DNA damage via its ability to induce enzymes capable of converting certain other compounds into DNA-reactive forms.4 TCDD can cause cell proliferation and enhance the carcinogenic effect of some compounds, fulfilling one criterion of a tumor promoter. But it also leads to cancer when administered to animals alone (Huff et al., 1994) and can transform certain human cells grown in cell culture into cancerous forms (Yang et al., 1992).

c) Receptor Model. It is generally thought that the actions of dioxin-like compounds are mediated by a receptor molecule within the cell. Dioxin tightly binds to this receptor, like a key fitting into a molecular lock. In combination with other factors, this complex alters gene expression and changes cell biochemistry. It has been suggested that dioxin must bind a minimum number of receptors for any effect to occur, i.e., that doses below this threshold will have no biochemical consequences. This notion of an underlying biological threshold achieved prominence at the Banbury scientific meeting in late 1990, providing one of the technical sparks for the USEPA’s reassessment (Roberts, 1991).

This hypothesis was seriously damaged by some of the early results of the USEPA’s reassessment. Experiments on the response of certain biochemical endpoints in animals exposed to dioxin showed no indication of a threshold5 (Tritscher et al., 1992; Portier et al., 1993; Birnbaum, 1994). Further work showed increased biochemical activity at levels corresponding to those experienced by the average person (Vanden Heuvel et al., 1992). This suggests that people are already exposed to sufficient dioxin-like compounds to be above a biological threshold -- even if one exists. It is unclear precisely how these biochemical endpoints relate to cancer or other toxicological endpoints, since the mechanism by which TCDD causes disease is poorly understood. The response of other effects at low does may well be different. Nevertheless, these findings argue against the idea that action via a receptor necessitates a threshold.

In sum, Health and Welfare Canada’s assumption that dioxin has a “safe” dose is unwarranted. Thresholds for some effects of dioxin may be established through detailed mechanistic analysis. However, in order to protect public health, the burden of proof needs to be reversed: the existence of “safe” doses needs to be proven, rather than assumed.

Dioxin Causes Effects at Lower Doses than Previously Thought

In establishing a tolerable daily intake, Canadian researchers do not consider the most sensitive effects of exposure to dioxin. Recent research shows that dioxin causes effects at lower doses than previously thought.

1. Endometriosis

Endometriosis is a non-cancerous disorder of the female reproductive system in which cells that normally line the uterus grow and proliferate outside of that organ. It is often associated with pain and infertility. Prevalence of this disease is estimated at roughly 10 percent of reproductive-age women (Rier et al., 1993).

One of the most startling pieces of research in the last few years was the observation of a significant increase in the prevalence and severity of endometriosis in rhesus monkeys chronically exposed to TCDD years earlier (Rier et al., 1993). The discovery in monkeys was made serendipitously after autopsy of a few animals revealed widespread endometriosis. The whole group of exposed females was then examined.

Significantly increased levels of endometriosis were found at the lowest dose tested; 5 parts per trillion (ppt) in the animals’ feed (administered from 1977-1982). This corresponds to a dose of about 130 pg/kg/d (Peterson et al., 1993). Previous work showed an association between endometriosis and PCBs in rhesus monkeys (Campbell et al., 1985). Although its cause is unknown, endometriosis may involve defects of the immune system and regulation of hormone-like factors, both effects consistent with the action of dioxin-like compounds (Rier et al., 1993).

These results in primates indicate that the Canadian dioxin guideline is not protective of human health; increased endometriosis was found at a dose nearly ten times lower than the assumed “no adverse effect level” on which the human intake guideline is based.

These results also illustrate the fragility of risk assessment. Endometriosis was not found during the original tests of the reproductive effects of TCDD on rhesus monkeys, but years later. In addition, endometriosis is only found in animals that menstruate. Such effects would not be seen in the rat reproductive study relied upon by Health and Welfare Canada.6

2. The Male Reproductive System

Hormones are one of the body’s indispensable chemical messenger systems, involved in everything from

4. Induction of CYPIA enzymes by TCDD may increase the reactivity of some compounds, and decrease the toxicity of others. The precise effect may also depend on dosing schedule (USEPA, 1992; Huff et al., 1994; Webster and Commoner, 1994). This phenomenon may explain the increased frequency of sister chromatid exchanges in human lymphocytes exposed to both dioxin-like polychlorinated dibenzofurans and alpha-naphthaflavone (Lundgren et al., 1986). The latter is converted to a reactive form by the induced enzymes.

5. Examined biochemical endpoints include CYP1A1, CYP1A2 and internalization of epidermal growth factor receptor. The potential relevance of these endpoints is discussed in USEPA, 1992; Huff et al., 1994; Webster and Commoner, 1994.

6. Endometriosis is not observed in rodents under normal circumstances. However, use of a rodent model based on surgical procedures appears to confirm the results in monkeys (L. Birnbaum, USEPA, personal communication, May 1994). reproduction to regulation of metabolic activity and embryonic development. Dioxin-like compounds have the ability to upset the proper functioning of a number of these systems, by affecting the body’s response to certain hormones or by increasing or decreasing their concentration.7

There is increasing evidence that the human male reproductive system is a target of dioxin. Loss of libido was reported decades ago in workers exposed to dioxin (WHO, 1989). Testicular abnormalities were found in “Ranch Hands,” the men who handled Agent Orange in Vietnam (Wolfe et al., 1992a). Reduced levels of testosterone -- the primary male sex hormone -- were recently reported in chemical workers exposed to dioxin (Egeland at al., 1994). Levels of other reproductive hormones were altered as well. Furthermore, preliminary reports indicate reduced penis size in adolescents whose mothers were exposed during the Yu-Cheng poisoning incident in Taiwan (Guo et al., 1993). These people consumed rice oil contaminated with PCBs, polychlorinated dibenzofurans and related compounds.

These observations are made more credible -- and worrisome -- by experimental work with rats. Altered levels of reproductive hormones are also observed in adult male rats exposed to relatively high doses of dioxin. However, effects on the male reproductive system are seen in rats at much lower doses when the animals are exposed during development.8 Exposure of pregnant rats to TCDD during a critical period of development resulted in a number of permanent alterations in their male offspring, including reduced sperm production, smaller secondary sex organs and altered reproductive behavior (Mably et al., 1992a,b,c; Peterson et al., 1992, 1993). Some of these effects were seen at the lowest dose tested, 64 ng/kg, making them some of the most sensitive effects ever observed for a single dose of dioxin. Lower daily doses might be expected to produce the same results since long- term dosing of the mother leads to accumulation in her tissue and transfer to the fetus.

The parallels between human and rat results suggest that the male reproductive system of the two species may be responding in similar ways. It is possible that the developing human may also be much more sensitive than the adult. If true, then the levels of dioxin-like compounds found in the general human population may be at or near the levels which damage the male reproductive system.

As rats produce excess amounts of sperm, decreased production may have little effect on fertility. Tests of fertility in rats -- such as those relied upon by Health and Welfare Canada -- may not pick up this effect. Humans are not so fortunate: the number of sperm per ejaculate is close to that required for fertility (Peterson et al, 1992). Hence the possibility that current body burdens of dioxin-like compounds may decrease male fertility is very troubling.

There is some evidence that human sperm counts declined during the last half-century (Carlsen et al., 1992). It is possible that dioxin-like compounds contributed to this decline, along with compounds that act through an estrogenic mechanism (Sharpe and Skakkebaek, 1993).9 Lake sediments from North America and Europe show that dioxin levels were very low until approximately 1930 (Czuczwa et al., 1984 a,b, 1985, 1986; Hagenmaier et al., 1986; Smith et al., 1992). Contamination of the environment with dioxin-like compounds rose dramatically around mid-century.

3. Other Sensitive Effects

a) Development and Neurobehavioral impacts. By modulating hormones and other biological signalling molecules, dioxin can alter the growth differentiation and viability of cells. These processes are particularly important during development from a single fertilized egg to a complete organism. Along the way, cells grow and differentiate into body tissues. There is an increasing amount of evidence suggesting that the biochemical systems affected by dioxin -- the molecular receptor and the genes and proteins it regulates -- may play some important role in this process (Abbott et al., 1994). Effects of dioxin have now been observed at extremely early stages of fetal development (Blankenship et al., 1993).

This suggests that the developing organism may be particularly sensitive to the effects of dioxin. As discussed earlier, this appears to be true for the male reproductive system (at least in the rat). Other work suggests that the nervous system and immune system of offspring may also be very sensitive.

Subtle learning and behavioral effects have been observed in the offspring of rhesus monkeys exposed to low doses of dioxin. These limited but concerning effects were observed at the lowest dose tested, about 130 pg/kg/d (Bowman et al., 1989a; Schantz and Bowman, 1989;

7. TCDD can alter regulation of a number of hormones as well as growth factors and cytokines, substances involved in regulation of the immune system. The mechanisms vary. For instance, TCDD reduces testosterone in the adult male rat by slowing production of the hormone while interfering with normal feedback mechanisms of the hypothalamic pituitary axis (reviewed in Peterson et al., 1993).

8. Female rats were dosed on day 15 of pregnancy. The fetuses were exposed in utero and via lactation. 4Forthcoming studies by Peterson’s group will determine which is more important by use of a cross-fostering experiment. Other forthcoming studies from Birnbaum’s group appear to have found abnormalities in the reproductive system of females exposed during development.

9. The mechanism whereby TCDD affects the developing male reproductive system is unknown; it may involve an anti-androgen effect (see note 7). TCDD does not bind to the estrogen receptor. Indeed, it can act as an anti-estrogen in some tissues by reducing the number of estrogen receptors and/or increasing estrogen metabolism. However, it is not at all clear that dioxin and environmental estrogens will “cancel out,” as some have suggested. Peterson et al., 1993).

These results are generally consistent with observations of psychomotor developmental delay in children of human mothers exposed to mixtures of dioxin-like and non-dioxin-like compounds. The children of relatively highly exposed women who consumed rice oil contaminated with polychlorinated dibenzofurans and PCBs exhibited leaning problems and behavioral disorders. These children also suffered abnormal skin pigmentation, deformed nails, early tooth growth, and smaller size. (Rogan et al., 1988, 1989; Chen et al., 1992). While humans may not be as prone to dioxin-induced cleft palate as mice (Birnbaum, 1991), more subtle developmental effects need to be taken into account.

Reduced short term memory and other cognitive deficits were seen in infants and four-year old children of women who consumed Lake Michigan fish. These women consumed on average only about two or three salmon or lake trout meals per month. Effects in children were more highly correlated with the concentrations of PCBs in umbilical cord blood than with breast milk, suggesting that prenatal exposure had the dominant effect (Jacobson et al., 1990, 1992, 1993). Both dioxin-like and non-dioxin-like compounds may have contributed to the observed cognitive impairments.

b) Immune System Impacts. The immune system has to recognize and eliminate foreign substances from the body, including micro-organisms that it first met decades before or that it has never encountered at all. On the other hand, the body must recognize and avoid reacting against itself. Errors in either direction are problematic: an over-reactive immune system may lead to autoimmune disease, while suppression may lead to increased susceptibility to disease and cancer. Proper functioning of the immune system involves delicate control over growth and maturation of immune system cells and the hormone-like compounds which regulate them.

Perturbation of the immune system may be one of the most sensitive effects of dioxin. Exposure to dioxin significantly increases mortality in mice challenged with influenza virus. This effect was found with a single 100 ng/kg dose (House et al., 1990) and most recently with only 10 ng/kg (Burleson et al., 1994). Alterations in the relative numbers of certain immune system cells have been noted in rhesus monkeys at body burdens of 270 ng/kg and in marmoset monkeys at body burdens as low as 6-8 ng/kg. (Hong, et al., 1989; Neubert et al., 1992).10 The clinical significance of this effect is not known. Similar effects were seen in the children of mothers who lived in dioxin-contaminated Times Beach, Missouri during and after pregnancy (Smoger et al., 1993). Immune alterations were observed in victims of the Taiwanese rice oil poisoning. Children born to exposed women had elevated rates of bronchitis (reviewed in Rogan, 1989; Vos et al., 1991).

c) Other. A recent Dutch study suggests hormonal changes in the general population. Levels of certain thyroid hormones in 38 healthy new-born infants depended significantly on the concentrations of dioxin-equivalents in the breast milk of their mouthers (Pluim et al., 1992, 1993). Dioxin has been shown to alter thyroid hormone levels in experimental animals. Subtle changes in the regulation of thyroid hormones may affect cognitive development (Pluim et al., 1993). A contribution to this effect by other unreported chemicals cannot be excluded.

Finally, altered uptake of glucose (blood sugar) by fat cells has been reported at very low doses in guinea pigs (Enan et al., 1992). This finding is intriguing since two studies have found that people with elevated TCDD had an increased risk of diabetes or elevated glucose levels (Sweeney et al., 1992; Wolfe et al., 1992b).

Body Burden: A Better Measure
of Biological Effect than Dose

Health and Welfare Canada computes it tolerable daily intake for dioxin by dividing the dose associated with a “no observed adverse effect level” by a safety factor of 100. This assumes that relative effects in rats and humans can be adequately compared based on average daily dose. However, it does not appear that this traditional toxicological procedure is adequate for biologically persistent compounds like dioxin which tend to accumulate in the body.11

Biological effects probably depend less on dose than on the concentrations present in the target organ over some critical length of time.12 TCDD is far more persistent in humans than in rats.13 Given the same daily dose, it will accumulate in humans to higher concentrations. The limited evidence regarding the relative response of human and animal cells exposed to the same concentration of TCDD suggests that people are no less sensitive to certain biochemical effects than rats (Lucier, 1991).

The fetus may be particularly susceptible to certain effects of dioxin. Since dioxin-like compounds move across the

10. The results of Neubert et al., 1992 are complicated. CD4+CDw29+ (so-called T-helper-inducer or “memory”) lymphocytes were increased after dosing with 0.3 ng/kg/d and decreased after the dose was raised to 1.5 ng/kg/d. A body burden of 6-8 ng/kg was reached during the second dosing regime. The ratio of CD4+CDw29+/CD4+CD45RA+ cells was a very sensitive marker for the effect of TCDD.

11. Given a steady dose (external exposure), concentrations in the body (principally fat) __?__ tend to increase until input equals the limited rate of output.

12. The critical time period depends on the effect. For developmental effects in utero, it may be quite short. For chronic diseases such as cancer, it may be a significant fraction of a lifetime. An improved measure of internal exposure might be the “area under the curve” for the appropriate target organ and time period.

13. Persistence is often measured in terms of half-life, the length of time it would take for concentrations to decrease by 50 percent if there is no new input. The half-life of 2,3,7,8-TCDD in humans is on the order of 5-11 years, extremely long for a toxic compound (Schlatter, 1991; Wolfe et al., 1994; Ryan et al., 1993). placenta, accumulation of these compounds in the mother’s body over her life before pregnancy should be of prime concern. The levels in the mother’s body also determine the amount in her breast milk. Breast-feeding infants are exposed to relatively high doses of dioxin-like compounds compared with the average adult. However, the limited evidence available suggests that exposure of the fetus to dioxin in utero is of greater concern. Since breast-feeding has clear benefits, preventing exposure of the mother to dioxin in the years prior to child-bearing is the best solution.

Current Human Body Burdens of
Dioxin-Like Compounds
May Pose a Health Hazard

The average North American is believed to be exposed to dioxin-like compounds primarily through food. This relatively constant exposure leads to an accumulation of dioxin-like compounds in our bodies. The resulting body burden can most readily be compared with experiments in which animals are also chronically exposed.

As shown in Table 1, the body burdens of TCDD associated with endometriosis in rhesus monkeys is only a few times greater than the levels of dioxin-like compounds found in the average person in North America. Since increased endometriosis was found in rhesus monkeys at the lowest level tested, it is probable that effects will be seen at lower levels. Hence, certain segments of the population may be exposed to levels of dioxin-like compounds sufficient to cause endometriosis in rhesus monkeys.14 Whether dioxin causes endometriosis in humans is unknown, but prudent public health policy advises assuming that it might.

Subtle neurobehavioral effects were also seen in the offspring of rhesus monkeys with the same low body burden. Another semi-chronic animal experiment of concern is the effect on immune system cells in marmoset monkeys at body burdens of about 6-8 ng/kg of TCDD. While the medical implications of this effect are unknown, it appears to occur at about the average human body burden of dioxin-like compounds.

The body burden of the average North American person can also be compared with the levels found in groups of people who have been studied for dioxin’s health effects. Reduced testosterone levels were noted in men occupationally exposed to TCDD. At the time these effects were observed, their body burdens were within about an order of magnitude of the average population. As these men were exposed years earlier, the TCDD levels in their bodies have decreased over time. While the effects may be residual of these earlier high levels, it would be prudent to have additional evidence before assuming this is so.15

Neurobehavioral effects and disturbance of thyroid hormone levels have been observed in the children of non-occupationally exposed people. While these effects are plausibly associated with dioxin, non-dioxin-like compounds may have also contributed to these effects. This both adds to concern about the general population and suggests that the focus on dioxin is overly narrow: the whole spectrum of bioaccumulating toxic compounds needs scrutiny.

Table 1 also lists a number of effects associated with very low single (acute) doses of TCDD. These experiments cannot be easily compared with human body burdens since acute and chronic doses of TCDD will differ in the way they initially distribute in the body. However, given the accumulation of these compounds in the body, lower chronic doses might be expected to produce the same results. These results further add to concern when placed in the context of other information. For instance, mice were more susceptible to viral infection after a single dose of only 10 ng/kg of TCDD. Given that the numbers of certain immune system cells are altered at very low body burdens, current human body burdens may pose a hazard of increased susceptibility to disease. The possibility of male hormone perturbation in men at body burdens not too different from background, combined with the sensitivity of the developing male reproductive system in rats, suggests that average human body burdens may pose a reproductive hazard for the developing male.

These comparisons suggest that certain effects of dioxin may be observed at body burdens within about a factor of ten of that found in the average North American. This allows no margin of safety for the following reasons:

i) as some effects were observed at the lowest level tested, they probably occur at even lower body burdens;

ii) some people will have above average body burdens, including consumers of relatively large

14. The comparison in this section involve several important assumptions. i) Humans and animals have about the same sensitivity to dioxin with respect to these endpoints. ii) The toxic endpoint is assumed to be mediated by the Ah receptor. While it is unknown whether this is true, it is generally thought to be likely for most and possibly all of the biological effects of dioxin. iii) The next assumption (conditional on the second), is that the body burden of dioxin-like compounds can be approximated using toxic equivalence factors (which are often derived on a dosage or in vitro basis.) iv) Comparisons of body burdens are a reasonable surrogate for comparing concentrations in target organs (i.e., organ concentration are proportional to body burden). This may only be approximate if distribution differs. Where possible, it is interesting to compare concentrations in body fat since, for chronic dosing, concentrations in body fat should be in rough equilibrium with concentrations in o