An extensive data base provides information pertinent to the evaluation of exposure of humans to dioxin and related compounds. An even larger data base of equal quality suggests that exposure to dioxin results in a broad spectrum of biochemical and biological effects in animals and, based on limited data, some of these effects occur in humans. Relatively speaking, these exposures and effects are observable at very low levels in the laboratory and in the environment when compared with other environmental toxicants. Despite the large amount of information available on exposure and effects of dioxin and related compounds, this risk characterization serves to highlight significant data gaps and identifies information needed to reduce uncertainty in its conclusions.

An extensive data base detailing dioxin emissions and dioxin levels in environmental media and in human serum and tissue indicates widespread, low-level human exposure. Much of the public concern for this potential exposure revolves around the characterization of these compounds as among the most toxic "man-made" chemicals ever studied. These compounds, which are generally unwanted by-products of chemical reactions, are extremely potent in producing a variety of effects in experimental animals based on traditional toxicology studies at levels hundreds or thousands of times lower than most synthetic chemicals of environmental interest. In addition, human studies demonstrate that exposure to dioxin and related compounds is associated with subtle biochemical and biological changes whose clinical significance is as yet unknown and, at higher levels, with chloracne, a serious skin condition. Laboratory studies suggest that exposure to dioxin-like compounds may be associated with other serious health effects, including cancer. Human data, while limited in their ability to answer questions of hazard and risk, are consistent with some observations in animals. The ability to determine the expression in humans of adverse effects noted in laboratory studies or to detect these effects in human population studies is dependent on the dose absorbed and the intrinsic sensitivity of humans to these compounds. The large data base on exposure coupled with toxicity data from animal experiments, as well as more limited human information, forms the basis for the risk characterization of dioxin and related compounds.

A large variety of sources of dioxin have been identified and others may exist. 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 widespread, low-level exposure of the general population to dioxin-like compounds. 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.

Dioxin-like compounds are released to the environment in a variety of ways and in varying quantities, depending on the source. Despite a growing body of literature from laboratory, field, and monitoring studies examining the environmental fate and environmental distribution of CDDs, CDFs, and PCBs, the fate of these environmentally ubiquitous compounds is not yet fully understood. The available information suggests that the presence of dioxin-like compounds in the environment has occurred primarily as a result of industrial practices and is likely to reflect changes in release over time. Further work to confirm declining concentrations in environmental samples and to relate these data to human exposures will be required.

The principal identified sources of environmental release of CDDs and CDFs may be grouped into four major types: combustion and incineration sources; chemical manufacturing/processing sources; industrial/municipal processes; and reservoir sources. PCBs were produced in relatively large quantities for use in such commercial products as dielectrics, hydraulic fluids, plastics, and paints. They are no longer produced in the United States but continue to be released to the environment through the use and disposal of these products. A similar situation exists for the commercially produced PBBs that are produced for a number of uses such as flame retardants. Additional measurement data will be needed to gain an adequate appreciation for the nature and magnitude of major U.S. sources and releases of CDDs, CDFs, and polyhalogenated biphenyls.

CDDs, CDFs, and PCBs have been found throughout the world in practically all media, including air, soil, water, sediment, fish and shellfish, and agricultural food products such as meat and dairy products. The highest levels of these compounds are found in soils, sediments, and biota; very low levels are found in water and air. The widespread occurrence observed, particularly in industrialized countries, is not unexpected, considering the numerous sources that emit these compounds into the environment and the overall resistance of these compounds to biotic and abiotic transformation. The levels of dioxin and related compounds in environmental media and in food in North America are based on few samples and must be considered quite uncertain. However, they seem reasonably consistent with levels measured in a number of studies in Western Europe and Canada. The consistency of these levels across industrialized countries provides reassurance that the U.S. estimates are reasonable. Collection of additional data to reduce uncertainty in U.S. estimates of dioxin-like compounds in the environment and in food represents an important data need.

This assessment adopts the hypothesis that the primary mechanism by which dioxin-like compounds enter the terrestrial food chain is via atmospheric deposition. Dioxin and related compounds enter the atmosphere directly through air emissions or indirectly, for example, through volatilization from land or water or from resuspension of particles. Deposition can occur directly onto soil or onto plant surfaces. At present, it is unclear whether atmospheric deposition represents primarily current contributions of dioxin and related compounds from all media reaching the atmosphere or whether it is past emissions of dioxin and related compounds 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 in assessing the effectiveness of control strategies focused on either current or past emissions of dioxins in attempting to reduce the levels in food.

Throughout this document, concentrations of dioxin and related compounds have been presented as TCDD equivalents (TEQs). Total TEQs are the sum of the products of concentrations of individual dioxin-like compounds in a complex environmental mixture times the corresponding TCDD toxicity equivalence factor (TEF) for that compound [Total TEQs = S C_congener ´ TEF_congener]. The strengths and weaknesses as well as the uncertainties associated with the TEF/TEQ approach have been discussed in this chapter. As noted, the use of the TEQ approach is fundamental to the evaluation of this group of compounds and, as such, represents a key assumption on which many of the conclusions in this characterization hinge.

The term "background" exposure has been used throughout this reassessment to describe exposure of the general population that is not exposed to readily identifiable point sources of dioxin-like compounds. Data on human tissue levels suggest that body burden levels among industrialized nations are reasonably similar (Schecter, 1991). These data can also be used to estimate background exposure through the use of pharmacokinetic models. Using this approach, exposure levels to 2,3,7,8-TCDD in industrialized nations are estimated to be about 0.3-0.6 pg TCDD/kg body weight/day^**. This is generally consistent with the estimates derived using diet-based approaches to estimate total TCDD intake. Pharmacokinetic approaches have not been applied to estimate exposures to CDDs or CDFs other than TCDD, which contribute substantially to the body burden of dioxin-like compounds. Estimates of exposure to dioxin-like CDDs and CDFs based on dietary intake are in the range of 1-3 pg TEQ/kg body weight/day. Estimates based on the contribution of dioxin-like PCBs to toxicity equivalents raise the total to 3-6 pg TEQ/kg body weight/day. This range is used throughout this characterization as an estimate of average background exposure to dioxin-like CDDs, CDFs, and PCBs. This average background exposure leads to body burdens in the human population that average 40-60 pg TEQ/g lipid (40-60 ppt) when all dioxins, furans, and PCBs are included. High-end estimates of body burden of individuals in the general population (approximately the top 10% of the general population) may be greater than three times higher.

In addition to general population exposure, some individuals or groups of individuals may also be exposed to dioxin-like compounds from discrete sources or pathways locally within their environment. Examples of these "special" exposures include occupational exposures, direct or indirect exposure to local populations from discrete sources, exposure to nursing infants from mother’s milk, or exposures to subsistence or recreational fishers. These exposures have been discussed previously in terms of increased exposure due to dietary habits (see Exposure Document) or due to occupational conditions or industrial accidents (see Chapter 7). Although exposures to these populations may be significantly higher than to the general population, they usually represent a relatively small percentage of the total population. Inclusion of their levels of exposure in the general population estimates would have little impact on average population estimates. Simply evaluating these exposures as average daily intakes prorated over a lifetime might obscure the potential significance of elevated exposures for these subpopulations, particularly if exposures occur for a short period of time during critical windows of biological sensitivity.

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. This reassessment concludes that the effects elicited by exposure to 2,3,7,8-TCDD are shared by other chemicals that have a similar structure and Ah receptor-binding characteristics. Consequently, the biological system responds to the cumulative exposure of Ah receptor-mediated chemicals rather than to the exposure to any single dioxin-like compound.

Based on our understanding of dioxin mechanism(s) to date, it is accurate to say that interaction with the Ah receptor is necessary, that humans are likely to be sensitive to many of the effects of dioxin demonstrable in laboratory animals, and that there is likely to be a variation between and within species and between tissues in individual species based on differential responses "downstream" from receptor binding. Further analyses of dioxin action may provide more insight into the mechanisms by which TCDD and related compounds produce effects that are of particular public health concern. A major challenge for the future will be the establishment of experimental systems in which complex biological phenomena associated with these effects are amenable to study at the molecular level.

The concept of toxicity equivalence based on a unifying mechanism of action within this class of compounds and the use of toxicity equivalence factors as described in this document and elsewhere have been extensively reviewed and are widely used. While some uncertainty remains with regard to the additivity of complex mixtures of these compounds and with the impacts of co-exposure to nondioxin-like compounds, the use of this approach is consistent with the Agency’s guidance on the evaluation of complex mixtures in the absence of data on the impact of the actual mixture. This approach to the evaluation of dioxin and related compounds, while considered an interim procedure to be used in the absence of more specific data, is an integral part of this reassessment. Additional validation studies to reduce uncertainty in the use of TEFs/TEQs will be very important.

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 support the inference that humans are likely to respond with a broad spectrum of effects from exposure to dioxin and related compounds, if exposures are high enough. These effects will likely range from adaptive changes at or near background levels of exposure to adverse effects with increasing severity as exposure increases above background levels.

Enzyme induction, changes in hormone levels, and indicators of altered cellular function represent examples of effects of unknown clinical significance and 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 potentiate toxic effects. Demonstration of examples of both of these situations is available in the published literature.

Clearly adverse effects, including perhaps cancer, may not be detectable until exposures exceed background by one or two orders of magnitude. The mechanistic relationships of biochemical and cellular changes seen at very low levels of exposure to production of adverse effects detectable at higher levels remain uncertain and controversial.

Individual species vary in their sensitivity to any particular dioxin effect. However, the evidence available to date indicates that humans most likely 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 suggests that humans, in general, are neither extremely sensitive nor insensitive to the individual effects of dioxin-like compounds. Human data provide direct or indirect support for evaluation of likely effect levels for several of the end points discussed in previous sections, although the influence of variability among humans remains difficult to assess. Discussions in previous chapters have highlighted certain prominent, biologically significant effects of TCDD and related compounds. These biochemical, cellular, and organ-level end points have been shown to be affected by TCDD, but specific data on these end points do not generally exist for other congeners. Despite this lack of congener-specific data, there is reason to infer that these effects may occur for all dioxin-like compounds, based on the concept of toxicity equivalence.

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 or near levels to which people in 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. Evaluation of effects in this health assessment document is based on the concept that lipid- adjusted serum levels approximate the body burden of dioxin and related compounds and that there will be a dose-response relationship between effects and body burden. 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 exposure coinciding with a window of sensitivity of biological processes. It is reasonable to assume that developing organisms may be particularly sensitive to adverse impacts from temporary increases above average background exposure levels. Such exposures may also lead to higher tissue levels over the long term because of the long half-life for elimination of dioxin and related compounds.

In TCDD-exposed men, subtle changes in biochemistry and physiology, such as enzyme induction, altered levels of circulating reproductive hormones, or reduced glucose tolerance, have been detected 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 (equal to 3-6 to 60 pg TEQ/kg body weight/day or 40-60 to 600 ppt in lipid). As body burdens increase within and above this range, the probability and severity as well as the spectrum of human noncancer effects most likely increase. It is not currently possible to state exactly how or at what levels humans in the population will respond, but the margin of exposure (MOE) between background levels and levels where effects are detectable in humans in terms of TEQs is considerably smaller than previously estimated.

Average human daily intakes of TCDD are in the range of 0.3-0.6 pg TCDD/kg body weight/day. Using the TEQ approach, average human daily intakes of dioxin and related compounds, including the dioxin-like PCBs, are in the range of 3-6 pg TEQ/kg body weight/day. This intake results in average body burdens estimated to be in the range of 30-60 pg TEQ/g lipid (30-60 ppt) or 5-10 ng TEQ/kg body weight. Subtle changes in biochemistry and physiology described above and discussed in detail in previous chapters are seen with TCDD exposures at or just several fold above these average TEQ levels. Since exposures within the general population are thought to be log-normally distributed, individuals at the high end of the general population range (with body burdens estimated to be three, and perhaps as high as seven, times higher than the average) may be experiencing some of these effects. These facts and assumptions lead to the inference that some more highly exposed members of the general population or more highly exposed, special populations may be at risk for a number of adverse effects, including developmental toxicity based on the inherent sensitivity of the developing organism to changes in cellular biochemistry and/or physiology, reduced reproductive capacity in males based on decreased sperm counts, higher probability of experiencing endometriosis in women, reduced ability to withstand an immunological challenge, and others. This inference that more highly exposed members of the population may be at risk for various noncancer effects is supported by observations in animals, by some human information from highly exposed cohorts, and by scientific inference.

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 affect cellular regulation and the broad range of species that have proven to respond with adverse effects. 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 not currently possible to state exactly how or at what levels people will respond with adverse impacts on development or reproductive function. Fortunately, there have been few human cohorts identified with TCDD exposures in the high end of the exposure range, and when these cohorts have been examined, few clinically significant effects were detected. The lack of adequate human information and the focus of most currently available epidemiologic studies on occupationally TCDD-exposed adult males make difficult the evaluation of the inference that noncancer effects associated with exposure to dioxin-like compounds may be occurring. 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 has 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 involved in the reassessment as authors and reviewers have indicated that such 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.

The likelihood that noncancer effects may be occurring in the human population at environmental exposure levels is often evaluated using a margin of exposure approach. A MOE is calculated by dividing the human-equivalent animal lowest observed adverse effect level or no observed adverse effect level with the human exposure level. MOEs in the range of 100 to 1,000 are generally considered adequate to rule out the likelihood of significant effects occurring in humans based on sensitive animal responses. The average levels of intake of dioxin-like compounds in terms of TEQs in humans described above would be well within a factor of 100 of levels representing lowest observed adverse effect levels in laboratory animals exposed to TCDD or TCDD equivalents. For several of the effects noted in animals, a MOE of less than a factor of 10, based on intake levels or body burdens, is likely to exist.

The previous basis for MOE calculations was the observation that exposure in the range of 1-10 ng TEQ/kg/day represented a no observed adverse effect level for a sensitive noncancer end point in laboratory animals and, therefore, that an intake of up to 10 pg TEQ/kg/day might represent an adequate MOE for all other noncancer effects in humans. Recent data suggest that "high-end" average exposures in the general population are likely to approach this intake level and that several effects, both subtle and frank, can be demonstrated to occur in animals at intake values significantly lower than 1-10 ng TEQ/kg/day. This information, coupled with limited human data suggesting measurable effects, which may or may not be considered adverse, at or near average background intake levels, makes it highly unlikely that a margin of exposure of 100 or more currently exists for these effects at background intake levels, at least for some members of the human population. Whether the current MOE is adequate to protect public health is beyond the purview of this document and represents a risk management decision. The reassessment points to the need to continue to monitor trends in human intake and body burden for dioxin and related compounds. If levels are declining, the relationship of background body burdens to observed effect levels in animal and human studies will need to be reevaluated.

Another approach that has been used to evaluate the likelihood of noncancer effects of environmental chemicals is the reference dose (RfD). The EPA has frequently defined a reference dose for toxic chemicals to represent a scientific estimate of the dose below which no appreciable risk of noncancer effects is likely to occur following chronic exposures. In the case of dioxin and related compounds, calculation of an RfD based on human and animal data and including standard uncertainty factors to account for species differences and sensitive subpopulations would likely result in reference intake levels on the order of 10 to 100 times below the current estimates of daily intake in the general population. For most compounds where RfDs are applied, the compounds are not persistent and background exposures that are generally low are not taken into account. Dioxin and related compounds present an excellent example of a case where background levels in the general population are likely to have significance for evaluation of the relative impact of incremental exposures associated with a specific source. Since RfDs refer to the total chronic dose level, the use of the RfD in evaluating incremental exposures in the face of a background intake exceeding the RfD would be inappropriate and make the calculation of an Rfd for dioxin-like compounds of doubtful significance.

In addition to the concern for various noncancer health end points discussed above, the potential immunotoxicity of dioxin and related compounds represents a special situation. Impairment of the immune system can be considered an adverse outcome in its own right, being responsible for induced pathologies. At the same time, immunotoxicity can function as a modulator of the disease process. It has been clearly established that TCDD is immunotoxic and that it can impair normal immune function in laboratory animals at very low levels (see Table 9-5). Epidemiological studies provide conflicting evidence for the immunotoxicity of these compounds in humans. Few changes in the immune system in humans associated with dioxin body burdens have been detected when exposed adult males have been studied. It is possible that humans may be less sensitive than certain animal models to dioxin immunotoxicity, or that available studies have lacked the power or the specificity to evaluate the impact of immunotoxic responses to dioxin and related compounds in humans. Despite the possibility that these compounds may be immunotoxic at some level in humans, the impact of dioxin and related compounds on the immune system and implications for characterizing risk are largely unknown at this time.

With regard to carcinogenicity, a weight-of-the-evidence evaluation suggests that dioxin and related compounds (CDDs, CDFs, and dioxin-like PCBs) are likely to present a cancer hazard to humans. While major uncertainties remain, efforts of this reassessment to bring more data into the evaluation of cancer potency have resulted in a risk-specific dose estimate (1 ´ 10^-6 risk or one additional cancer in one million exposed) of approximately 0.01 pg TEQ/kg body weight/day. This risk-specific dose estimate represents a plausible upper bound on risk based on the evaluation of animal and human data. "True" risks are not likely to exceed this value, may be less, and may even be zero for some members of the population.

Based on bioavailability and uptake studies, a cancer hazard is likely by oral, inhalation, and dermal routes of exposure. As daily doses through these routes and subsequent body burdens approach those seen in occupational studies, the uncertainty of the hazard characterization is reduced. The epidemiological data alone are not yet deemed sufficient to characterize the cancer hazard of this class of compounds as being "known." However, combining suggestive evidence of recent epidemiology studies with the unequivocal evidence in animal studies and inferences drawn from mechanistic data supports the characterization of dioxin and related compounds as likely cancer hazards, that is, likely to produce cancer in some humans under some conditions. It is important to distinguish this statement of cancer hazard from the evaluation of cancer risk. 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 hormonal status.

The current evidence suggests that both receptor binding and most early biochemical events such as induction of CYP1A1 and CYP1A2, as described in Chapter 8, 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 in the low-dose region 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 two orders of magnitude (100 times) higher than average TCDD body burdens in the general population. The average body burden in these occupational cohorts is within one to two orders of magnitude (10 to 100 times) of average background body burdens in the general population in terms of TEQ. Thus, there is no need for large-scale low-dose extrapolations. Nonetheless, the relationship of apparent increases in cancer mortality in these populations to calculations of general population risk remains uncertain.

With regard to average intake, humans are currently exposed to background levels of dioxin-like compounds on the order of 3-6 pg TEQ/kg body weight/day, including dioxin-like PCBs. This is more than 500-fold higher than the EPA’s 1985 risk-specific dose associated with a plausible upper-bound, one in a million (1 ´ 10^-6) risk of 0.006 pg TEQ/kg body weight/day and several hundredfold higher than revised risk-specific dose estimates presented in Chapter 8 of this reassessment. Plausible upper-bound risk estimates for general population exposures to dioxin and related compounds, therefore, may be as high as 10^-4 to 10^-3 (one in ten thousand to one in a thousand).

The fact that dioxin-like compounds are ubiquitous in the environment may have further implications for low-dose risk assessment. Special populations may receive identifiable, incremental exposures, based on proximity to specific sources or specific human activity patterns such as consumption of higher amounts of foods containing average or higher levels of dioxin-like compounds. The additive background model of Crump et al. (1976) implies that the addition of an incremental dose to an existing background exposure would support the use of a dose response model containing the assumption of linearity. This assumption is particularly appropriate, in the absence of more definitive data on dose response, if the exposure range (i.e., background exposure plus the added incremental exposure) is within one to two orders of magnitude (10 to 100 times) of the range of observation of purported dioxin-induced tumors in highly exposed humans. In other words, the proximity of background exposures to the range of observation of tumors in animals and humans provides added support for the assumptions of additivity to background and linearity of response.

TCDD has been clearly shown to increase malignant tumor incidence in laboratory animals. In addition, a number of studies analyzed in Chapter 8 elucidate other biological effects of dioxin related to the process of carcinogenesis. These studies have been used to develop biologically based models of the pharmacokinetics of dioxin, of binding to the Ah receptor, and of induction of various proteins that may be involved in the carcinogenic process. In addition, bioassay data on TCDD reported by Kociba have been analyzed using the two-stage clonal expansion model of carcinogenesis. There is evidence to suggest that hormones and growth factors may be involved in TCDD carcinogenesis. The role of such factors warrants additional study. Ideally, a biologically based model for cancer induction by TCDD should explicitly consider hormonal influences. Initial attempts to construct a biologically based model for certain dioxin effects as a part of this reassessment will need to be continued and expanded to accommodate more of the available biology and to apply to a broader range of potential health effects associated with exposure to dioxin-like compounds.

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.