United States	Office of Research	June 12, 2000
Environmental Protection	and Development
Agency	Washington, DC 20460	
Information Sheet 2
Dioxin: Scientific Highlights from Draft
Reassessment (2000)
Scientists from the Environmental Protection Agency (EPA), other federal agencies and the
general scientific community have conducted a comprehensive reassessment of dioxin exposure and human
health effects since 1991. See the discussion of the process in the companion document entitled, "Dioxin
Reassessment Process: EPA is Moving Toward Completion of the Dioxin Reassessment." In the next few
pages, the Agency summarizes the scientific highlights of the updated, draft reassessment of dioxin and
related compounds, including the updated and revised "Dose Response" Chapter (Part II. Chapter 8), the
new "Toxicity Equivalence (TEF)" Chapter (Part H Chapter 9), and the updated, revised, and reformatted
"Integrated Summary and Risk Characterization" (Part III) which are currently undergoing public comment
and peer review.
Throughout this reassessment, concentrations of dioxin and related compounds are presented as
2,3, 7,8-tetrachl orodi benzo-/>dioxin (TCDD) equivalents (TEQs). One compound, TCDD is the best studied
of this class of compounds and is the reference compound for assignment of toxicity equivalence factors
(TEFs) for related congeners. The strengths and weaknesses as well as the uncertainties of the TEF/TEQ
approach have been discussed in the report and, particularly, in a newly developed chapter (Part n. Chapter
9). Use of the TEQ approach is widely accepted in the international scientific community and is fundamental
to the evaluation of this group of compounds which always exist in nature as complex mixtures of dioxins.
The use of the TEQ approach represents a key assumption upon which many of the conclusions in this
characterization hinge.
The reassessment finds that there is adequate evidence based on all available information, including
studies in human populations as well as in laboratory animals and from ancillary experimental data, to
suspect that humans may respond with a broad spectrum of effects from exposure to dioxin and related
compounds. Research has highlighted certain prominent, biologically significant effects of TCDD. These
biochemical, cellular, and organ-level endpoints have been shown to be affected by TCDD in experimental
systems, but specific data on these endpoints do not generally exist for many of the other TCDD-like
congeners. Despite this lack of congener specific data, there is reason to infer that these effects may occur
for all dioxin-like compounds, as embodied in the concept of toxicity equivalence. A few of these effects
have been observed under high exposure conditions in human populations; many others have not been
investigated with well-designed human studies or in relevant populations. The mechanistic relationships of
biochemical and cellular changes seen at very low levels of exposure in animals and humans to production of
adverse effects generally detectible at higher levels remains uncertain and controversial. Based on the
experience of the scientific community using animal models and evaluating a limited human data base, it is
reasonable to infer that effects in the human population may span a wide range. These effects may range
from changes in biology or biochemistry which may be judged by some to be adaptive (with little or no
adverse impact), or which may arguably be considered by others to be adverse, at or near background levels
of exposure to clearly adverse effects with increasing severity as exposure increases above background levels
by orders of magnitude (10 to 100 times background). Enzyme induction, changes in levels of gene
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regulators or related receptors, and indicators of altered cellular function represent examples of biomarkers
of exposure of unknown clinical significance which may or may not be early indicators of toxic response.
Induction of activating/ metabolizing enzymes at or near background levels, for instance, may be adaptive or
may be considered adverse since induction may lead to more rapid metabolism and elimination of potentially
toxic compounds, or may lead to increases in reactive intermediates and may result in toxic effects.
Demonstration of examples of both of these situations is available in the published animal literature. Other
potentially adverse effects have been reported to be associated with exposure to dioxin and related
compounds in human populations at or near average background population levels (within a factor of 10 of
these levels). These include delay of developmental milestones, impacts on immune function, and, perhaps,
increased incidence or susceptibility to disease, e.g., elevated incidence of adult onset diabetes. While
potentially present in exposed populations, clearly adverse effects, including cancer, may not be detectable as
increased incidence of disease until exposures exceed background by one or two orders of magnitude (10 or
100 times).
With regard to sensitivity, it is well known that individual species vary in their sensitivity to any
particular dioxin effect. However, the evidence available to date indicates that humans may fall in the middle
of the range of sensitivity for individual effects among animals rather than at either extreme. In other words,
evaluation of the available data using comparable dose metrics suggests that humans, in general, are neither
extremely sensitive nor insensitive to the individual effects of dioxin-like compounds as compared to other
animals. Human data provide direct or indirect support for evaluation of likely effect levels for several of the
endpoints discussed in the reassessment although the influence of variability among humans remains difficult
to assess.
The scientific community has identified and described a series of common biological steps that are
necessary for most if not all of the observed effects of dioxin and related compounds in vertebrates including
humans. Binding of dioxin-like compounds to a cellular protein called the "Ah receptor" represents the first
step in a series of events attributable to exposure to dioxin-like compounds including biochemical, cellular
and tissue-level changes in normal biological processes. Binding to the Ah receptor appears to be necessary
for all well-studied effects of dioxin but is not sufficient, in and of itself, to elicit these responses; further steps
beyond receptor binding are required. The effects elicited by exposure to TCDD are shared by other
chemicals which have a similar structure and Ah receptor binding characteristics. Consequently, it is
reasonable to assume that the biological system responds to the cumulative exposure to other dioxin-like
chemicals instead of exposure to any single dioxin-like compound. Based on our understanding of dioxin
mode(s)-of-action to date, it is reasonable to conclude that interaction with the Ah receptor is necessary, that
at comparable doses (e.g. similar body burdens) humans are likely to respond with many of the effects of
dioxin demonstrable in laboratory animals, and that there is likely to be a variation among and within species
and among tissues in individual species based on differential responses "down stream" from receptor binding.
Some of the effects of dioxin and related compounds such as enzyme induction, changes in hormone
levels and indicators of altered cellular function have been observed in laboratory animals and humans at
body burdens comparable to exposures at or near levels to which segments of the general population are
exposed. Other effects are detectable only in highly exposed populations, and there may or may not be a
likelihood of response in individuals experiencing lower levels of exposure. Adverse effects associated with
temporary increases in dioxin blood levels based on short term high level exposures, such as those that might
occur in an industrial accident or in infrequent contact with highly contaminated environmental media, may
be dependent on the impact of exposure on total body burden.

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The exposure document (Part I) has been revised to reflect comments from the public and the
Agency's Science Advisory Board (SAB). It presents an up-to-date (1999) and comprehensive emission
inventory of dioxin and related compounds for the United States. A large variety of sources of dioxin have
been identified, and characterized but others may exist. The available information suggests that the presence
of dioxin-like compounds in the environment is primarily a result of formation of unintentional by-products of
combustion or industrial practices and is likely to reflect changes in release over time. The principal identified
sources of environmental release may be grouped into five types: Combustion and Incineration Sources;
Metals Smelting, Refining and Processing; Chemical Manufacturing/Processing; Reservoir Sources; and
Biological and Photochemical Processes. The Exposure Document provides "snapshots" of estimated
emissions for the years 1987 and 1995. Because of the nature of the available data and the need to
extrapolate national emission levels, confidence in these estimates varies. However, EPA's best estimates of
releases of dioxin and related compounds (CDDs/CDFs) to air, water and land from reasonably quantifiable
sources suggests an 80% decrease between 1987 and 1995, due primarily to reductions in air emissions from
municipal and medical waste incinerators. Regulations promulgated in 1995 for municipal waste combustors
and 1997 for medical waste incinerators should result in a greater than 95% reduction in dioxin emissions
from these two categories.
Because dioxin-like chemicals are persistent and accumulate in biological tissues, particularly in animals,
the major route of human exposure is through ingestion of foods containing minute quantities of dioxin-like
compounds. This results in wide-spread exposure of the general population to dioxin-like compounds. It appears
that daily intakes have come down since the 1970s and that, as of the mid-90s, adult daily intakes of dioxin and
related compounds, including dioxin-like PCBs average 70 pgTEQDFPWH098/day. Certain segments of the
population may be exposed to additional increments of exposure by being in
proximity to point sources or because of dietary practices. The estimated levels of dioxin and related
compounds in the environment and contributing to daily intakes in the U.S. are based on additional data
collected since 1995. Further data collection is underway in studies by EPA, FDA and USDA scientists.
Current estimated U.S. levels are consistent with levels reported for Western Europe and Canada, and support
a conclusion that increased dioxin exposures are associated with industrialization. The consistency of U.S. levels
with those of other industrialized countries also provides additional reassurance that the U.S. estimates are
reasonable in the face of the limited data on U.S. levels, recognizing that some differences among countries will
reflect national and international control efforts.
The reassessment presents the hypothesis that the primary mechanism by which dioxin-like compounds
enter ecological food chains and human diet is via atmospheric deposition. Dioxin and related compounds enter
the atmosphere directly through air emissions and are widely spread in the environment as a result of a number of
physical and biological processes, for example, through erosion and run-off, volatilization from land or water, or
from re-suspension of particles. Deposition can occur directly on to soil or plant surfaces. At present, it is
unclear whether atmospheric deposition represents primarily current contributions of dioxin and related
compounds from all media, or past emissions that persist and recycle in the environment. Understanding the
relationship between these two scenarios will be particularly important in understanding the relative
contributions of individual point sources of these compounds to the food chain and assessing the effectiveness of
control strategies focused on current or past emissions of dioxins in attempting to reduce dioxin exposures.
The term "background" exposure has been used throughout this reassessment to describe exposure of
the general population, which is not exposed to readily identifiable point sources of dioxin-like compounds. Data
on human tissue levels suggest that body burden among industrialized nations are reasonably similar. Average
background exposure led to body burdens in the late 1980s ranged from 30-80 pg TEQ/g lipid (this equates to

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30-80 ppt), with a mid-point of approximately 55 pg TEQ/g lipid, when all dioxins, furans and dioxin-like PCBs
are included. High-end estimates of body burden of individuals in the general population (approximately the top
1% of the general population) may be more than 3 times higher, based on evaluation of blood-level data and on
consumption of fat as a surrogate for dioxin intake. The average CDD/CDF/PCB tissue level for the general
adult U.S. population appears to be declining and the best estimate of current (late 1990s) average body burden
levels is 25 ppt (TEQDFP-WH098, lipid basis).
In addition to general population exposure, some individuals or groups may also be exposed to dioxin-
like compounds from discrete sources or local pathways, including occupational exposures, direct or indirect
exposure of local populations to discrete sources, exposure of nursing infants from mother's milk, or exposures
of subsistence or recreational fishers. Daily exposures to these individuals may be significantly higher than
among the general population. However, the differences in average body burden are expected to be much less
than the differences in daily intake, particularly if these elevated exposures are periodic or for short duration. In
addition, while it is often difficult, the health benefits of dietary components must factor into assessment of
overall risk.
As described above, subtle changes in biochemistry and physiology such as enzyme induction, altered
cellular function, and other potentially adverse effects have been detected in dioxin-exposed populations in a
limited number of available studies. These findings, coupled with knowledge derived from animal experiments,
suggest the potential for adverse impacts on human metabolism, and developmental and/or reproductive biology,
and, perhaps, other effects in the range of current human exposures. Given the assumption that TEQ intake
values represent a valid comparison with TCDD exposure, some of these adverse impacts may be occurring at or
within one order of magnitude of average background TEQ intake or body burden levels. As body burdens
increase within and above this range, the probability of occurrence, as well as the spectrum of human noncancer
response, most likely increases. Because of the basic biological level at which dioxin and related compounds act,
and because of the potential diversity of "down-stream" responses to a dioxin body burden, it is not currently
possible to state exactly how or at what levels individuals in the population will respond. It is clear, that as recent
data have developed, the margin of exposure (M-O-E)1 between body burdens associated with background levels
of exposure and levels where effects are detectable in humans, in terms of body burden TEQs, is considerably
smaller than previously estimated and, in some cases, may be 1 or even less. For certain effects, including subtle
behavioral impacts, a "no effect level" has yet to be established.
These facts and assumptions lead to the inference that some members of the general population or more
highly exposed, special populations may be at risk for a number of adverse effects. These may include, for
instance, developmental toxicity based on the inherent sensitivity of the developing organism to changes in
cellular biochemistry and/or physiology, impaired reproductive capacity based on structural or functional
impacts, less ability to withstand an immunological challenge and others. This inference that more highly
1 The likelihood that noncancer effects may occur in the human population at environmental exposure
levels is often evaluated using a "margin of exposure" (MOE) approach. A MOE is calculated by dividing
the human, or human-equivalent animal, lowest observed adverse effect levels (LOAEL) or no observed
adverse effect level (NOAEL) with the human exposure level of interest. MOEs in range of 100 -1000 are
generally considered adequate to rule out the likelihood of significant effects in humans based on sensitive
animal responses. The average intake levels of dioxin-like compounds in terms of TEQs in humans
described above would be well within a factor of 100 of levels representing LOAELs in laboratory animals
exposed to TCDD or TCDD equivalents. For several of the effects noted in animals, a MOE of less than a
factor often, based on intake levels or body burdens, is likely to exist.

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exposed members of the population may be at risk for various noncancer effects is supported by observations in
animals, by human information, and by other scientific observations.
The deduction that humans are likely to respond with noncancer effects from exposure to dioxin-like
compounds is based on the fundamental level at which these compounds impact cellular regulation and the broad
range of species which have proven to respond adversely. Since, for example, developmental toxicity following
exposure to TCDD-like congeners occurs in fish, birds, and mammals, it is likely to occur at some level in
humans. It is impossible to state exactly how or at what levels individuals in the population will respond with
adverse impacts on development or reproductive function, but some subtle effects on development have been
noted in infants at near background exposures. Fortunately, there have been few human cohorts identified with
TCDD exposures exceeding the high end of the background exposure range. When these cohorts have been
examined, few clinically significant effects were detected. The focus of most currently available epidemiologic
studies on occupationally TCDD-exposed adult males makes evaluation of noncancer effects in the general
population difficult. It is important to note, however, that when exposures to very high levels of dioxin-like
compounds have been studied, such as in the Yusho and Yu-Cheng cohorts, a spectrum of adverse effects have
been detected in men, women and children. Some have argued that to deduce that a spectrum of noncancer
effects will occur in humans in the absence of better human data overstates the science; most scientists in the
reassessment as authors and reviewers have indicated that such an inference is reasonable given the weight-of-
the-evidence from available data. As presented, this logical conclusion represents a testable hypothesis that may
be evaluated by further data collection as more sensitive methods for evaluating human responses to dioxin
exposure become available.
With regard to carcinogenicity, a weight-of-the-evidence evaluation suggests that TCDD should be
characterized as a " human carcinogen"2 and that related compounds (other dioxin-like CDDs and CDFs, and
dioxin-like PCBs) should be considered "likely" to present a cancer hazard to humans. The epidemiological
data alone are not yet deemed sufficient to characterize the cancer hazard of TCDD as being a "human
carcinogen." However, combining consistent, suggestive evidence from epidemiology studies with the
unequivocal evidence in animal studies and inferences drawn from mechanistic data supports the
characterization of complex mixtures of dioxin and related compounds as "likely" cancer hazards. The
confidence in this statement for specific environmental mixtures increases with the level of available congener-
specific information. It is important to distinguish this statement of cancer hazard from the evaluation of cancer
risk. While major uncertainties remain, efforts of this reassessment to bring more data into the evaluation of
cancer potency have resulted in estimates in the range of 5 x 10"3 to 5 x 10"4 per pgTEQ/kgBW/day. These slope
factors and resulting risk specific dose estimates represents a plausible upper bound on risk based on evaluation
of human and animal data within the range of observation and at a minimally detectable response level (ED01).
These values are 3 to 30 times higher than previous estimates (1985, 1994)based on fewer data. Considering
these slope factors and current intake levels, upper bound (>95%-ile) risks for the general population are in the
range of 10"3 (1 in 1,000) to 10"2 (1 in 100). "True" risks are not likely to exceed this value, are likely to be less,
and may even be zero for some members of the population. The extent of cancer risk will depend on such
parameters as route and level of exposure, overall body burden, dose to target tissues, individual sensitivity and
2 "Human carcinogen" and "likely" to present a cancer hazard to humans are descriptors which
are consistent with the latest draft revised EPA Guidelines on Carcinogen Risk Assessment
(1999). They are roughly equivalent to the terms "known" and "probable" human carcinogen
which were contained in earlier (1986) EPA guidelines.

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hormonal status. This range of upper bound risk for the general population has increased an order of magnitude
from the risk described at background exposure levels based on EPA's earlier (1994) draft of this reassessment
(10"4-10"3).
The current evidence suggests that both receptor binding and most early biochemical events such as
enzyme induction are likely to demonstrate low-dose linearity. The mechanistic relationship of these early events
to the complex process of carcinogenesis remains to be established. If these findings imply low-dose linearity in
biologically-based cancer models under development, then the probability of cancer risk will be linearly related to
exposure to TCDD at low doses. Until the mechanistic relationship between early cellular responses and the
parameters in biologically based cancer models is better understood, the shape of the dose-response curve for
cancer below the range of observation can only be inferred with uncertainty. Associations between exposure to
dioxin and certain types of cancer have been noted in occupational cohorts with average body burdens of TCDD
approximately 1-3 orders of magnitude (10 to 1,000 times) higher than average TCDD body burdens in the
general population. In terms of total TEQ, the average body burden in these occupational cohorts level is within
1-2 orders of magnitude (10-100 times) of average background body burdens in the general population. Thus,
there is no need for large scale low dose extrapolations to estimate upper bounds on general population cancer
risk or to evaluate the impact of incremental exposures above background. Nonetheless, the relationship of
apparent increases in cancer mortality in these populations to calculations of general population risk remains
uncertain.
In summary, based on all of the data reviewed in this reassessment and scientific inference, a picture
emerges of TCDD and related compounds as potent toxicants in animals with the potential to produce a
spectrum of effects. Some of these effects may be occurring in humans at very low levels and some may be
resulting in adverse impacts on human health. The potency and fundamental level at which these compounds act
on biological systems appears to be analogous to several well studied hormones. Dioxin and related compounds
have the ability to alter the pattern of growth and differentiation of a number of cellular targets by initiating a
cascade of biochemical and biological events with the potential for a spectrum of responses in animals and
humans. Despite this potential, and given the limited body of epidemiological evidence associating dioxin
exposure with increases in various effects, there is currently no clear indication of increased disease in the general
population attributable to dioxin-like compounds. The lack of a clear indication of disease in the general
population should not be considered strong evidence for no effect of exposure to dioxin-like compounds.
Rather, lack of a clear indication of disease is more likely a result of the inability of our current data and scientific
tools to directly relate effects to dioxin exposure and related compounds at these levels of human exposure.
Several factors suggest a need to further evaluate the impact of these chemicals on humans at or near current
background levels. These are: the weight of the evidence on exposure and effects; an apparently low margin-of-
exposure for noncancer effects; and potential for significant risks to some portion of the general population and
additivity to background processes related to carcinogenicity in the case of incremental exposures above
background.
EPA CONTACT:
William H. Farland, NCEA, ORD (860ID), Washington, DC 20460
E-Mailfarland.william@epa.gov
Tel: 202-564-3322; FAX: 202-565-0090

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