Dioxins persist for a long time in the environment because they do not dissolve in water and are relatively immobile in soil and sediment. When animals consume plants, feed, and water contaminated with dioxins, they accumulate in the animals’ fatty tissue. Similarly, when humans consume these animals, the dioxins then accumulate in human fatty tissue. According to EPA, because dioxins also persist in the body for years, recent significant reductions in dioxin emissions into the air are unlikely to reduce human health risks in the near term. While EPA estimates that most exposure to dioxins occurs from eating commonly consumed foods, the draft reassessment report also estimates that limited exposure to dioxins results from breathing air containing trace amounts of dioxins; inadvertently ingesting soil containing dioxins; and absorbing through the skin minute levels of dioxins present in the soil. Some people may experience higher exposure levels than the general population as a result of food contamination incidents; workplace exposures; industrial accidents; or consuming unusually high levels of fish, meat, or dairy products. When calculating human exposures, dioxins are measured in picograms—that is, trillionths (0.000000000001) of a gram. Highly sophisticated measurement techniques and technologies are required to test foods for the presence of the 29 dioxins identified as having toxic effects. The several hundred known dioxin compounds can be placed in one of three closely related families: polychlorinated dibenzo-p-dioxins (CDD), polychlorinated dibenzofurans (CDF), and polychlorinated biphenyls (PCBs). CDDs and CDFs are byproducts of combustion and some industrial processes. According to EPA, U.S. emissions of CDDs and CDFs into the environment declined by 75 percent between 1987 and 1995 primarily as a result of reductions in emissions from municipal and medical waste incinerators. Some PCBs share certain characteristics with CDDs and CDFs and therefore are identified as “dioxin-like.” PCBs were at one time manufactured for use in products such as lubricants and industrial transformers but have not been made in the United States since 1977. However, because dioxins break down so slowly, past emissions remain in the environment for years—even decades—before they diminish. Consequently, a large part of humans’ current exposure to dioxins is due to releases of dioxins that were stored in soil and sediment, and to a lesser extent in vegetation and the atmosphere. These sources are called “reservoir sources.” EPA believes that with the reduction in current emissions from combustion and incineration, these reservoir sources have taken on more significance. According to EPA, dioxins always occur in the environment and in humans as complex mixtures of individual compounds. However, the complex nature of the dioxin mixtures to which people are exposed (through foods or other sources) complicates evaluation of the health risks such mixtures might pose. Scientists therefore developed the concept of toxic equivalency factors (TEFs) to facilitate risk assessment of exposure to these mixtures. Because TCDD is the best-understood dioxin, it is used as a frame of reference for estimating the toxicity of the other dioxins, and its TEF is set at 1.0. Only 1 of the other 28 dioxins included in EPA’s reassessment has a TEF of 1.0; most of the others have TEFs of 0.1 or less, meaning that they are considered less toxic to humans than TCDD. International experts review and periodically update the TEFs based on new data. For its reassessment of dioxins, EPA used the latest revisions that were made at an expert meeting organized by the World Health Organization in 1997. Since 1991, EPA has been updating its initial 1985 report assessing the health risks of dioxins. The October 2001 draft reassessment report exceeds 3,000 pages. Part I of the draft report provides information on exposure to dioxins, including chapters on dietary intake; part II addresses health assessment methodologies and specific health effects; and part III, the Integrated Summary highlights information in parts I and II on exposure and health effects and provides a risk characterization—a statement summarizing EPA’s assessment of the health risks associated with dioxins. In the reassessment, EPA studied the risks of cancer as well as noncancer health effects, such as neurological and reproductive impairments. Founded in 1948, the World Health Organization (WHO) is a specialized agency of the United Nations, with 191 member states. WHO’s functions include giving worldwide guidance in the field of health and setting global standards for health. WHO carries out these functions through a variety of offices and programs that often collaborate with each other and with other public health entities of WHO’s member states and nongovernmental organizations. The principal contributors to the WHO reassessments of dioxin risks that are discussed in this report have been (1) the International Agency for Research on Cancer, which coordinates and conducts both epidemiological and laboratory research into the causes of cancer; (2) the WHO European Centre for Environment and Health, which coordinates comprehensive efforts, in collaboration with the International Programme on Chemical Safety, to evaluate the possible health risks of dioxins as well as methods of prevention and control of environmental exposure of the general population to these chemicals; and (3) the Joint Expert Committee on Food Additives of the United Nations’ Food and Agriculture Organization and WHO, which provides scientific evaluations as a basis for the development of food standards by the Codex Alimentarius (food code) Commission. To estimate dietary exposure to dioxins, EPA obtained and reviewed information on (1) the dioxins present in 10 types of foods with high fat content, (2) the toxicity of individual dioxins contained in these food types, and (3) the quantities of these foods that people in the United States typically eat. EPA has incorporated new studies following improvements in analytical capabilities to detect dioxins in food during the 1990s. However, in its draft reassessment report, EPA identified a number of limitations with the food data used to estimate dietary exposure that add uncertainty to the agency’s overall estimate of current average daily dietary exposure to dioxins. For example, in some cases, the studies available on the presence of dioxins in foods were not designed to estimate national averages. Further, while EPA used the accepted method for estimating the toxicity of the dioxins found in the 10 food types, EPA and others acknowledge that the method has limitations. Finally, EPA estimated the quantities of these foods consumed using U.S. Department of Agriculture (USDA) data on U.S. adults’ food consumption based on surveys made between 1989 and 1991; however, EPA believes the dietary habits of Americans have changed very little over the course of the past decade. A body of scientific research on foods in Europe, North America, and other locations indicates that the primary source of human exposure to dioxins is the dietary intake of foods, especially those containing animal fat. According to EPA’s October 2001 draft reassessment report, the average adult in the United States receives about 95 percent of his or her exposure to dioxins by eating commonly consumed foods, such as beef, pork, and poultry; fish; and dairy products. (EPA estimated small exposures to dioxins from the air and soil as well.) The 10 types of foods EPA analyzed for its reassessment are beef; pork; poultry; other meats, such as lamb and baloney; eggs; milk; dairy products, such as cheese and yogurt; freshwater fish and shellfish; marine fish and shellfish; and vegetable fat, such as corn and olive oils and margarine. These foods, only one of which is not of animal origin, are believed to be the major contributors to dietary exposure to dioxins. Even though vegetable fat products are estimated to contain low levels of dioxins, EPA included these foods in its analysis because they are high in fat and common in the American diet. EPA excluded fruits and vegetables from its analysis because data on dioxins in U.S. fruit and vegetable products, which generally contain little or no fat, are extremely limited. The existing data indicate that typically these products contain low levels of dioxins, which generally stem from residues—deposits on outer layers with little penetration to inner portions. Until recently, chemical analyses of dioxins in foods have focused primarily on two of the families of dioxins, the CDDs and CDFs, with less attention on identifying and measuring specific PCBs. The draft reassessment report includes an evaluation of PCB levels in the 10 food types. The draft report identifies estimated exposures to CDDs and CDFs together and identifies the estimated exposure to PCBs separately. This approach provides information that can inform potential regulatory approaches, among other things, because CDDs and CDFs result primarily from combustion and industrial processes, whereas PCBs, which persist in the environment from the 1970s and earlier, are no longer being manufactured. As shown in table 1, EPA estimated that the average adult in the United States is exposed daily to about 63 picograms of dioxins through dietary intake, with the highest exposure coming from beef and freshwater fish and shellfish. According to EPA, this exposure level is close to the level that has caused adverse noncancer effects in animals, such as effects on the development of reproductive systems. It is important to note that EPA’s dietary exposure estimates are averages, and they do not apply to adults with additional or unusual exposure to dioxins—for example, from diets unusually high in fat content or diets of foods high in dioxin content. To estimate any population’s dietary intake of dioxins, the specific dioxins present in the various foods must be identified and measured through chemical analyses of the foods. However, reliable estimates of the average concentrations of dioxins in specific foods nationwide have only recently begun to be available. In the past, data were available only from studies of dioxin concentrations in a specific food product or products in a specific location or a few locations, and these data were not sufficient to reliably estimate average national exposure. During the 1990s, as analytical capabilities to detect dioxins at parts-per-trillion levels were developed, new studies of foods in the United States, some with broader scope than the earlier studies, became available. EPA has incorporated new studies into its analysis of dietary exposure to dioxins to try to develop more reliable national estimates of such exposure. As a result, the estimates presented in the October 2001 draft reassessment report are based on more food data than the drafts developed just a few years ago. Nevertheless, in its October 2001 draft reassessment report, EPA said that the amount and the representativeness of the food data it used to estimate the average U.S. adult’s dietary exposure to dioxins vary. Further, EPA officials acknowledged that some of the available studies were not designed to estimate national average exposures. As discussed below, the food sample data are limited in part by the timing of the sampling, variations in the methods used to collect the samples, and the types of samples collected and analyzed. In commenting on a draft of this report, EPA officials said that these food data limitations do not represent major weaknesses in its estimates of dietary exposure to dioxins. As reported in the draft reassessment, most of the food samples were collected between 5 and 8 years ago. Current samples would be expected to have lower dioxin levels because emissions containing dioxins declined by about 75 percent from 1987 to 1995, and EPA believes the downward trend is continuing. Nevertheless, EPA believes that the exposure estimates based on food data from the mid-1990s are representative of current dietary exposure for several reasons. First, EPA believes that because most of the food samples the agency used for its reassessment were collected after the 75-percent decrease in emissions, much of the decrease should already be reflected in the foods’ dioxin concentration numbers. Second, EPA said that, because most municipal and medical waste incinerators are located far from and downwind of concentrated meat and dairy production areas, the impact of any emission reductions since 1995 on the commercial food supply should be proportionately less than on the environment in general. Third, EPA said that because reservoir sources of dioxins account for half or more of current exposure, and because some sources of dioxins are unknown, it is unlikely that emission reductions that occurred after most of the food samples were taken would significantly affect the current estimate of general population exposure from the commercial food supply. According to EPA, while its analyses of some of the foods are based on national samples collected from food processing or food monitoring locations, such as federal slaughtering establishments, other analyses are based on limited “market basket surveys”—random purchases of selected products, such as eggs, direct from grocery stores—in a small number of U.S. and Canadian cities. Depending on their design, national surveys would generally be more representative of average dietary exposures to dioxins than limited surveys. Some of the analyses of the foods were derived from individual food samples, while others were from composite samples. Using composites is more economical than using individual samples, and EPA believes they are appropriate for use in analyzing dioxin concentrations to establish average, or mean, exposure estimates. However, EPA acknowledges that data on the variability or range of results from individual samples typically are not available from studies analyzing composite samples. As a result, information that can provide insight into the reliability of the estimates is not available. Table 2 shows the number(s), type(s), and date(s) of the samples EPA used for each of the 10 food categories. According to the draft reassessment report, data from some of the food studies were sufficient to estimate exposure to total dioxins—the CDDs, CDFs, and PCBs. However, the report shows that in other cases, the data only provided support for estimating exposure to CDDs and CDFs. As a result, for four food categories, different studies are used for estimating exposure to CDDs and CDFs than those used for PCBs. As reported in the draft reassessment, these studies analyzed fewer samples, a number of which were collected 14 or more years ago and therefore provide data on dioxins that may not reflect current levels. Table 3 shows information on the four foods for which EPA used different samples to estimate exposure to PCBs than those used to estimate CDDs and CDFs. As EPA acknowledges in the draft report, its analyses of dioxins present in foods are based on uncooked foods, even though dioxin levels can be different in cooked and uncooked foods. According to EPA, while many studies indicate that foods have similar dioxin concentrations whether they are cooked or uncooked, the studies show that some foods have lower concentrations of dioxins when they are cooked, while others have higher levels when they are cooked. These differences reflect, in part, the fact that different cooking methods (frying, boiling, grilling, etc.) may have different effects on dioxin levels. On the basis of the available data, which it believes are not conclusive, EPA states in the draft reassessment report that uncooked food is a reasonable surrogate to use for identifying and quantifying dioxin concentrations in cooked food. Because the primary focus of EPA’s exposure assessment was on foods produced and consumed in the United States, EPA’s analysis does not address imported food products that may vary from domestic sources in dioxin content. Despite these limitations, the data on dioxin levels in foods supporting the October 2001 draft report reflect a significant improvement compared with the data EPA had available for use in its 1994 draft reassessment report, which was peer reviewed in 1995 by EPA’s Science Advisory Board. Specifically, in the 1994 draft, EPA provided estimates of levels of CDDs and CDFs for seven food types; the October 2001 draft provided estimates for ten food types. With the exception of an estimate for fish that was based on 60 samples, the 1994 draft estimates were developed from samples ranging in number from 2 to 14; as table 2 shows, the number of samples used for the 2001 draft is greater. In addition, while EPA recognized that PCBs were being identified in foods, the agency did not have sufficient data at that time to develop estimates of the levels of specific PCBs in foods; the 2001 draft does include estimates of PCB levels in foods. The following sections describe in greater detail the samples EPA used to identify the level of dioxins in 9 of the 10 foods studied—beef, pork, and poultry; freshwater and marine fish; milk, dairy, and eggs; and vegetable fat—and any associated limitations or uncertainties. (The draft reassessment report does not provide any information supporting EPA’s estimate of the types and amounts of dioxins in other meats, the tenth food type. In commenting on a draft of our report, EPA said that information on other meats would be provided in its final report.) In estimating exposure to dioxins from beef, pork, and poultry, EPA used data from the first statistically designed national surveys of dioxin levels in these foods sponsored by EPA and USDA. These surveys were designed to be representative of all U.S. regions and all classes of animals slaughtered in federally inspected slaughtering establishments. EPA believes the three surveys provide reasonable estimates of the average national concentrations of dioxins in beef, pork, and poultry. Nonetheless, information EPA provided in the draft reassessment report about these samples identifies some limitations and uncertainties about these studies. The samples are now between 6 and 8 years old and therefore may not reflect current exposures. To address this data gap, EPA and USDA are conducting a follow-up study on dioxin levels in beef, pork, and poultry that will commence in 2002 and provide updated information. However, EPA officials said the results of this survey will likely not be available for incorporation into the dioxin reassessment report that EPA plans to publish this year. The animal samples for beef, pork, and poultry were not meat products sold in grocery stores but rather were cuts of fat generally not consumed—either back fat, abdominal fat, or belly fat from slaughtering establishments. Some uncertainty therefore surrounds the accuracy of EPA’s estimates of dietary intake of dioxins because of comparability concerns. EPA used this approach because USDA federal inspectors could obtain the samples with little disruption to the slaughtering establishments and because the samples’ high fat content would enable more accurate measurement of dioxins, since the analysis would be of highly concentrated fat samples. However, this approach assumes that edible meat products sold in grocery stores contain the same types and amounts of dioxins as the fat samples (adjusted for differences in percentages of fat). According to EPA, this assumption is supported by a well-developed understanding of the manner in which dioxins distribute across fat reservoirs in vertebrates. Therefore, EPA concluded that the fat samples for all three foods were comparable to the edible meat samples. EPA also based its conclusion on its analysis of beef samples—comparing five back fat samples with other cattle parts, including muscle tissue, which could be representative of edible beef products. For the five samples, the ratios of CDDs and CDFs in muscle fat to CDDs and CDFs in back fat varied by up to 300 percent, ranging from 0.58 to 1.7; and the ratios for PCBs varied by up to 50 percent, from 1.0 to 1.5. Although some of the variation may result from imprecision inherent in measuring picograms, this limited analysis indicates that using fat samples may overstate or understate to some extent the dioxin levels in beef, pork, and poultry products. EPA reported that it excluded 2 of the 80 samples of abdominal fat from poultry because they had significantly higher concentrations of certain dioxins than the other samples. EPA, USDA, and the Food and Drug Administration investigated the cause of these elevated dioxin levels and determined that it stemmed from contaminated animal feed that had been distributed to poultry, fish, hog, and cattle producers in several southern and southwestern states. EPA considered the two poultry fat samples inappropriate for the dioxins study, which was aimed at identifying typical exposures to dioxins. However, it is not clear that the poultry samples with high concentrations of dioxins were anomalies because the incidence of dioxin contamination in animal feeds is not known. For example, this instance of contaminated animal feed was discovered by the first national poultry sample, which tested only 80 samples nationwide. In response to suggestions from a peer review panel, when the data were sufficient to do so, EPA presented a standard deviation—the typical amount of variability around the mean—on its estimates of the average levels of dioxins in the foods, as well as the range of the levels of dioxins identified in the samples. For beef, pork, and poultry, EPA was able to provide this information for the CDDs and CDFs. These data indicated considerable variability in the levels of CDDs and CDFs in the foods. For example, the estimated level of 0.28 picograms of dioxins in a gram of pork has a standard deviation of plus or minus 0.28. In other words, the standard deviation is equal to or greater than the mean. Accordingly, the estimated dioxin level is subject to a wide range of uncertainty. Because EPA did not have sufficient information to develop a standard deviation for PCBs, the agency could not develop a standard deviation for total dioxins (the combination of CDDs, CDFs, PCBs) in beef, pork, and poultry. As a result, EPA could not state with any degree of certainty that exposure to total dioxins or to PCBs would fall within specified levels. EPA believes this limitation is a minor one because it considers the average exposure level, rather than the more limited extreme exposures, to be of greater public health interest. Nonetheless, this additional analysis, if available, would enable policymakers, scientific peer reviewers, and other users to better evaluate the extent to which the data may be representative of average national exposures. Though EPA analyzed more fish samples for the current reassessment draft than for earlier drafts, the current draft report acknowledges that the levels of dioxins in fish are more uncertain than those in the other foods for two reasons. First, the data lack the “geographic coverage and statistical power” of the other food surveys. That is, while the sample sizes for CDDs and CDFs in fish are considerably larger than those used for the analyses of other foods, they do not provide data that are nationally representative because of the diversity of fish and bodies of water. Specifically, there are a significant number and variety of freshwater and marine fish species living in numerous bodies of water that contain differing types and levels of dioxins. Moreover, fish consumed in the United States include both farm-raised and wild fish. Second, EPA based its estimates for levels of PCBs in fish on a much smaller data set than it used for CDDs and CDFs. EPA used 222 samples to estimate the levels of CDDs and CDFs in freshwater fish and shellfish and 158 samples for marine fish and shellfish compared with 7 and 6 composite samples for PCBs for freshwater and marine fish, respectively. Further, most of the samples for PCBs were from Canadian rather than U.S. cities, and the analyses of levels of PCBs in them did not evaluate all of the PCBs identified as being toxic. For example, according to the report, only one of the composite samples for marine fish and shellfish, collected between 1984 and 1986, was analyzed for the presence of the most common and toxic PCB, referred to as PCB-126. For these reasons, EPA acknowledges in the draft report that the resulting estimates are not representative of the level of dioxins in fish nationally. We note that the limitations of the data used to estimate the levels of PCBs in fish are particularly significant because in the report, EPA estimates that freshwater fish contains the highest levels of PCBs (and total dioxins) of all the foods studied. The samples EPA used to estimate the levels of dioxins in fish were derived from EPA’s National Bioaccumulation Study and three market basket surveys in the United States and Canada. Samples for the bioaccumulation study were collected between 1986 and 1989, whereas the samples for the market basket surveys were collected about a decade later, between 1995 and 1999. Some of the limitations and uncertainties associated with these samples that EPA acknowledged in the draft report are highlighted below. Most of the fish samples used for the reassessment draft were collected 5 or more years ago; some are between 13 and 16 years old. EPA did not have sufficient data to estimate exposure to PCBs from eating freshwater or marine shellfish. Some of the estimates for freshwater fish, such as trout, are based on samples from the bioaccumulation study that may be more representative of wild fish (i.e., fish caught in recreational fishing) than fish typically purchased by the general population at grocery stores, which is largely farm-raised. Specifically, in cases in which EPA did not have data on farm- raised freshwater fish or fish purchased in grocery stores, the agency used the concentration of CDDs and CDFs from samples of wild caught fish from the bioaccumulation study. This use of older data on wild fish increases the uncertainty about the representativeness of EPA’s exposure estimate. For some fish species, such as mullet and mackerel, estimates were based entirely on samples collected in the Mississippi area and therefore may not be representative of levels seen in other locations. EPA did not have sufficient data to estimate a standard deviation for the average levels of dioxins in freshwater or marine fish. As a result, EPA cannot state with any degree of certainty what the related dietary exposure to dioxins is. The milk samples upon which both the milk and dairy estimates are based came from a national survey. In this survey, samples were collected during the four seasons, providing information on seasonal (temporal) variations. The milk samples were collected from 51 sampling stations, located in a majority of the states, that support EPA’s Environmental Radiation Ambient Monitoring System. In contrast, the estimates for CDDs and CDFs in eggs are based on Food and Drug Administration market basket surveys in 1997 in California, Georgia, Minnesota, New York, Ohio, Oregon, Pennsylvania, and Wisconsin. The estimates for PCBs in eggs are based on market basket surveys in San Diego, California; Atlanta, Georgia; Binghamton, New York; and five major Canadian cities. EPA used composite samples of milk and eggs to identify and measure the presence of specific dioxins in milk, dairy, and eggs. Information provided in the draft report identifies some limitations associated with these data. Most of the milk samples were collected 6 years ago. The egg samples used to support the analyses for CDDs and CDFs were collected 5 or more years ago. The estimates for PCBs in eggs are based, in part, on samples obtained in five Canadian cities between 14 and 16 years ago. Only one of the six composite samples used to estimate the level of PCBs in eggs was analyzed for the presence of the most common and toxic PCB. According to EPA, its estimates of CDDs and CDFs in vegetable fat were developed from a market basket survey that was not representative of edible oil consumption in the United States. The 30 samples of various oils, solid shortening, margarine, and an oil spray were obtained from grocery stores in nine U.S. cities or metropolitan areas: Chicago, Illinois; Cincinnati, Ohio; Denver, Colorado; Miami, Florida; Minneapolis, Minnesota; Salt Lake City, Utah; San Antonio, Texas; San Francisco, California; and the Washington, D.C., metropolitan area. Although neither the reassessment report nor the study (published in 1996) states when the samples were collected, there is typically at least a 1-year lag between collection and publication, indicating that the samples were collected 8 or more years ago. EPA used limited data to estimate the level of PCBs in vegetable fat. This estimate is derived from five composite samples of cooking fats and salad oils, each of which was obtained 14 or more years ago from one of five major (unidentified) Canadian cities. As a result of these limitations that EPA identified in the draft report, the estimate for dietary exposure to dioxins from eating vegetable fats is unlikely to reflect current average dietary exposure in the United States. After using the chemical analyses discussed previously to identify the types and quantities of dioxins present, EPA estimated the toxicity of the dioxins in the 10 types of foods, using measures called toxic equivalency factors. (As noted earlier, these measures—called TEFs—are used to create a frame of reference by comparing the potential toxicity of individual dioxins in a sample with the toxicity of the most toxic and best understood dioxin, TCDD, which is assigned a TEF of 1.) EPA used the TEFs that were updated by WHO in 1997. For each of the types of foods, EPA multiplied the measured types and amounts of the dioxins present by the related TEFs to arrive at a “dioxin toxic equivalence value” for that particular food category/dioxin combination. For each food category, the total dioxin toxic equivalency is the sum of these products—that is, the sum of the toxic equivalence values for (1) CDDs and CDFs and (2) PCBs. This provides an indicator of the relative toxic concentration of dioxins in each food category. As table 4 shows, EPA estimated that freshwater fish and shellfish had the largest per-gram concentration of dioxins with toxic effects. The toxic equivalence approach using TEFs has evolved over the last 20 years and is the internationally accepted scientific approach for risk assessments of dioxins. This approach has been formally adopted by several countries and as guidance by international organizations, such as WHO. TEFs are used to decrease the overall uncertainty in assessing the health risks of dioxins because they provide a framework for addressing the complex mixtures of dioxins to which people are most often exposed. Nonetheless, a number of uncertainties are involved in the use of the TEF concept. As a result of these uncertainties, estimates of the concentrations of dioxins in foods based on this approach may be overstated or understated. The draft reassessment report acknowledges that there are still many questions about the use of the TEF method and the validity of some of the underlying assumptions. The report states that many assumptions are necessary because of lack of data. Specifically, the derivation of TEFs is limited by the amount of available data on the relative potency of different dioxins compared with TCDD. For many dioxins, the available data on relative potency may be limited to only a few experimentally observed effects. Some of these effects may not be considered toxic by themselves, but they still might provide evidence that exposure to dioxins led to biological or chemical effects in experimental subjects. For example, EPA noted that only TCDD and one mixture of certain dioxins have been tested for carcinogenicity. Therefore, in order to develop a TEF that estimates the cancer potency of a mixture including other dioxins, scientists have assumed that the relative potencies observed for noncancer effects approximate those for cancer. In other words, once derived, TEFs apply to all effects, not just those for which relative potency data were available. Nonetheless, after considering a number of the uncertainties and limitations of this approach, the international experts who derived the current TEFs concluded that the TEF concept is still the most plausible and feasible approach for risk assessment of dioxins. Furthermore, the TEF values for individual dioxins are reevaluated and updated periodically to reflect the available evidence. When WHO established the most recent TEFs in 1998, it suggested that the toxic equivalency scheme be reevaluated every 5 years and that the TEFs and their application to risk assessment be reanalyzed to account for emerging scientific information. To develop its estimate of the daily dietary intake of dioxins by the average adult in the United States, EPA needed to calculate the amount of food containing dioxins that Americans typically eat. EPA obtained this information for the 10 food types from USDA food intake surveys. The USDA survey data include information on the amounts of specific foods consumed in a day by an average person weighing 70 kilograms (154 pounds). USDA obtained its data from detailed food surveys prepared by thousands of individuals selected from statistical samples. In these surveys, individuals generally provided detailed information on food consumption for 2 days. The surveys used statistical sampling to ensure that all seasons, geographic regions of the United States, and demographic and socio- demographic groups were represented. EPA’s analysis of these data tabulated intake rates for the major foods, as well as for individual food items. The total quantity of each food eaten by the survey population in a survey day was tabulated and weighted to represent the quantity eaten by the entire U.S. population in a typical day. For the draft reassessment report, EPA averaged USDA’s data for three age groups of adults ranging from ages 20 to 70 and over. Table 5 provides EPA’s estimates of the daily dietary intake of 10 food types by adults in the United States. While EPA prefers to use USDA food data from the 1989-91 USDA Continuing Survey of Food Intake By Individuals because it has conducted a statistical analysis of these data and includes them in the agency’s Exposure Factors Handbook, the draft reassessment report uses other data for fish and does not provide information on the basis for its estimates of dietary intake of other meats. Specifically, the draft reassessment report derived its estimates of the daily dietary intake of beef, pork, poultry, milk, dairy products, vegetable fats, and eggs from USDA’s Continuing Survey Food Intake By Individuals conducted from 1989 through 1991. In contrast, the daily dietary intake of freshwater and marine fish and shellfish were derived from a March 2000 report on the consumption of fish prepared by EPA’s Office of Water. This report used data from USDA’s Continuing Survey of Food Intakes By Individuals conducted in 1994, 1995, and 1996. In this report, EPA weighted its estimates of exposure to dioxins from fish by the species-specific concentrations according to species-specific fish consumption rates for the U.S. population. However, in cases where species-specific concentration data were not available, EPA used default values. For example, EPA used data from the bioaccumulation study as the default for certain freshwater fish. The use of various default assumptions adds uncertainty to the exposure estimates. EPA officials said that EPA did not use more current dietary intake data from USDA in the October 2001 draft reassessment because EPA has not yet fully reviewed surveys subsequent to the 1989-91 surveys that it uses in its Exposure Factors Handbook. EPA officials told us that they did not believe it was necessary to use more current data because the dietary habits of Americans have changed very little over the course of the past decade. These officials cited data collected in surveys conducted between 1994 and 1996 that show little change in the intake of the 10 foods compared with surveys conducted between 1989 and 1991. EPA and WHO have undertaken extensive efforts to reassess the health risks of exposure to dioxins. EPA’s comprehensive dioxin reassessment objective has been to characterize the potential human health risks posed by exposure to dioxins. To do this, EPA used an extensive, multiyear review process. In contrast, WHO had more narrowly focused primary objectives and conducted its reassessments of dioxins through a succession of individual reviews and meetings. Nonetheless, EPA and WHO used very similar analytical methods to identify the types of potential human health hazards associated with exposure to dioxins and assess the probability and severity of harm given different levels of exposure. Moreover, the conclusions EPA and WHO reached on the basis of their respective reassessments also reflected much agreement. However, there were some significant issues on which EPA and WHO differed, such as whether there are threshold doses of dioxins to which humans could be exposed over a lifetime without significant risk of cancer and whether dioxins other than TCDD are human carcinogens. In general, both EPA and WHO focused their evaluations of the health effects and risks associated with dioxins on TCDD and 28 other related chemical compounds (including 12 dioxin-like PCBs) for which consensus toxic equivalency factors had been established through a 1997 meeting organized by WHO. However, there were important differences in some of the specific objectives of EPA’s and WHO’s dioxin reassessments and the processes used by EPA and WHO to develop the reassessments. EPA’s overall objective has been very broad: to characterize the available scientific information on the potential health risks posed by exposures to dioxins. EPA therefore addressed each of the four major components of a chemical risk assessment: hazard identification, dose-response assessment, exposure assessment, and risk characterization. The resulting characterization of risks posed by dioxins can be used to inform risk management decisions, such as whether and where to set or revise regulatory standards, but other information and factors would also enter into such decisions. The process by which EPA has undertaken this task has been a comprehensive, multiyear review. Moreover, the EPA reassessment has included multiple independent scientific peer reviews of various draft reports by EPA’s Science Advisory Board and others. EPA has also solicited public review and comments on its draft reassessment. update. See Martin Van den Berg, et al., “Toxic Equivalency Factors (TEFs) for PCBs, PCDDs, PCDFs for Humans and Wildlife,” Environmental Health Perspectives (1998): Vol. 106, No. 12: 775-792.) integrated process such as EPA’s, WHO’s process consisted of individual evaluations and meetings for each of those particular objectives. In 1997, the International Agency for Research on Cancer (IARC), a chief contributor to WHO’s dioxin risk assessments, published monographs covering TCDD and 16 other dioxins. (This agency publishes the results of its evaluations of specific chemicals in its series IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. In the rest of this report, we call the monographs covering TCDD and other dioxins the 1997 cancer monographs.) The primary objective leading to these monographs was to classify TCDD and other specific dioxins under a standard scheme that identifies whether and under what circumstances substances are human carcinogens. Essentially, this objective corresponds to the hazard identification step of EPA’s four-step risk assessment process. Under its activities related to the European Centre for Environment and Health, WHO organized two meetings of experts addressing issues on the health effects of dioxins. In June 1997, WHO convened experts in Stockholm, Sweden, to derive consensus toxic equivalency factors for 29 dioxins that could be used for human, fish, and wildlife risk assessments. In May 1998, WHO convened 40 experts from 15 countries in Geneva, Switzerland, to evaluate scientific data on the health risks and exposures of dioxins with the principal objective of updating the estimated amount of dioxins to which humans can be exposed daily without appreciable harm. In the rest of this report, we call these efforts, respectively, the 1997 TEF meeting and the 1998 consultation. At the 57th meeting of the Food and Agriculture Organization of the United Nations/WHO Joint Expert Committee on Food Additives in June 2001 in Rome, Italy, the committee for the first time evaluated the risks associated with the presence of dioxins in food. The participants specifically evaluated dioxins (among other specific food additives and contaminants), with the view toward recommending acceptable intakes for dioxins contained in foods. The committee used the 1998 consultation’s assessment as the starting point for its evaluation but took into account newer studies. In the rest of this report, we call this evaluation the 2001 food additives meeting. Appendix I highlights some of the major milestones in the EPA and WHO assessments of dioxin risks, with a particular focus on the reassessment efforts that both entities began in the 1990s. Despite differences in some of the specific objectives and processes of their respective reassessment efforts, EPA and WHO used similar analytical methods to identify and assess the potential health risks of dioxins. Through these analyses, EPA and WHO identified the types of potential hazards that might be associated with exposure to dioxins, the circumstances under which these substances could cause adverse effects, and the probability and severity of expected effects given different levels of exposure to dioxins. Specifically, both EPA and WHO reviewed available scientific data from many studies of humans and animals covering a variety of effects potentially associated with exposure to dioxins; continued to consider cancer risks, as in the original dioxin risk assessments, but also paid increasing attention to noncancer health effects, such as changes in reproductive and developmental functions and the immune and nervous systems, as well as other health problems, such as chloracne (a chronic and disfiguring skin disease) and alterations in liver enzyme levels; reviewed evidence regarding other biochemical, molecular, or cellular effects that have been observed in various studies, agreeing that these effects might be precursors to subsequent adverse effects; and considered a range of analytical methods, models, and approaches to assess the dose-response relationships for exposure to dioxins. EPA and WHO also used some analytical concepts and methods that they agreed were more appropriate to the analysis of dioxins than those that are often used for risk assessments of other chemicals. For example, both entities used body burden—the concentration of dioxins in the body— instead of other dose measures, such as daily intake, to compare risks between humans and animals and determine doses that would be of equivalent risk in humans and animals. The organizations also concurred that the concept of toxic equivalency should be used to facilitate risk assessment of dioxins and complex mixtures of dioxins. Furthermore, in contrast to chemical risk assessments in general, EPA and WHO often had sufficient data to focus on the dose level associated with a 1-percent increase in a particular effect (rather than being limited to the level associated with a 10-percent increase) and seldom had to extrapolate outside the observed doses or exposures from the studies that they used to prepare the reassessments. Much of the scientific data available to EPA and WHO on the potential effects of exposure to dioxins came from animal studies, mainly studies of TCDD on a variety of species. (According to WHO, most other dioxins and dioxin-like compounds are “relatively poorly studied” compared with TCDD.) However, EPA’s and WHO’s recent reassessment efforts also benefited from the increasing quantity and quality of data on the effects of dioxins in humans that became available during their reassessments. Among the sources of these human data were studies of occupational exposure of people who produce and apply herbicides; residents in a contaminated area of Seveso, Italy (where an accident at a chemical factory had released a cloud of toxic chemicals, including dioxins, in 1976); and noncancer effects in infants and children. The conclusions EPA and WHO reached on the basis of their respective dioxin reassessments were frequently similar, but some significant differences also emerged. With respect to the major areas of agreement, both EPA and WHO concluded that TCDD is a human carcinogen and that dioxins can cause a variety of both cancer and noncancer health effects, dioxins act in the same way within the body to cause the effects observed in animals and humans, dioxins adversely affect human health at lower exposure levels than some effects could occur at or near the levels to which the general population is now being exposed. EPA and WHO not only concurred at the broad level of these conclusions but also on many of the supporting details. For example, both entities had similar reasons for concluding that TCDD is a human carcinogen: the combination of sufficient evidence that TCDD causes cancer in animals, more limited evidence of carcinogenicity from human data, and strong evidence that TCDD operates through the same mode, or mechanism, of action in animals and humans. The major differences of opinion between EPA and WHO concerned whether (1) there is a threshold below which exposure to dioxins would not be expected to cause cancer, (2) it is useful to calculate a “tolerable” dose of dioxins or estimate a dose without appreciable risk of deleterious effects to which humans can be exposed over a lifetime, and (3) both mixtures of dioxins and dioxins other than TCDD are likely human carcinogens. In addition, EPA quantified the general population’s possible additional risk of developing cancer from exposure to dioxins, while WHO did not. Such differences may make it more difficult for interested parties to compare the results of EPA and WHO dioxin risk assessments. The following sections provide additional information on each of these differences. EPA and WHO disagreed about whether there is a threshold below which exposure to dioxins would not cause cancer. EPA concluded that available evidence was insufficient for the agency to depart from its default linear cancer risk assessment approach, which is based on an assumption that no threshold exists regarding adverse effects (i.e., any exposure to carcinogenic substances, no matter how small, poses some risk of developing cancer). In contrast, WHO concluded that there is a threshold for all adverse effects, including cancer. Specifically, WHO concluded that dioxins do not initiate cancer through a direct effect on genetic material (that is, they are non-genotoxic carcinogens) and, therefore, do not warrant a linear (no threshold) assessment of risk. WHO also concluded that noncancer health effects occurred at lower body burdens (concentrations) of dioxins than the body burdens at which cancer occurred in animals. Accordingly, WHO determined that establishing a tolerable intake based on estimated thresholds for noncancer effects would also address any cancer risks (that is, if the intake were set to avoid appreciable noncancer health consequences, it should also avoid appreciable consequences concerning cancer). WHO programs estimated a tolerable daily intake for dioxins in 1998 and a tolerable monthly intake in 2001. These measures represent the amounts of dioxins that the WHO experts believe a human could ingest daily or monthly for a lifetime without appreciable health consequences. Expressing these estimates as “tolerable” intakes generally does not connote that such intakes are acceptable or risk free, but rather that any health consequences would be judged to be tolerable while exposure is continuing to be reduced. EPA’s related (but not identical) measure is the reference dose, which would estimate a daily exposure to the human population, including sensitive subgroups, that is likely to be without an appreciable risk of deleterious effects during a lifetime. EPA, however, chose not to calculate a reference dose for dioxins, as it generally does for noncancer health assessments of other substances. According to EPA, it did not do so because any reference dose that it would recommend for dioxins would likely be below (perhaps considerably below) the current background intake levels and body burdens of the U.S. population. EPA pointed out that reference doses are typically calculated to address the risks of incremental exposures over background exposure. In the case of dioxins, however, background exposure is a significant component of total exposure. Therefore, in EPA’s opinion, a reference dose would be uninformative to risk managers for safety assessment. EPA also noted that, if it were to set a reference dose, its estimate likely would be more stringent than the tolerable intake levels for dioxins proposed by WHO because EPA’s traditional approach for setting a reference dose gives more weight to scientific uncertainties than the approach WHO used in setting its tolerable intake level. EPA chose instead to use an alternative approach, the margin of exposure, to characterize noncancer risks. The margin of exposure is a ratio that shows how far the actual (or estimated) total human exposure to a particular substance is from levels at which adverse effects have been demonstrated to occur in human or animal studies. The margin of exposure is an alternative way of characterizing the likelihood that noncancer effects may be occurring in the human population at environmental exposure levels. A reference dose, on the other hand, estimates a level of exposure below which EPA considers it unlikely that any adverse effects will occur. EPA generally considers margins of exposure of 100 or more as adequate to rule out the likelihood of significant effects occurring in humans. However, for the most sensitive effects identified with dioxins (i.e., those that occurred at the lowest doses of exposure), the margins of exposure ranged from 15 to less than 1. EPA and WHO both characterize TCDD as carcinogenic to humans. While EPA further characterizes other individual dioxins and mixtures of dioxins as “likely to be human carcinogens,” WHO does not. Specifically, WHO states that the carcinogenicity of dioxins other than TCDD cannot be determined because of insufficient data. This difference of opinion largely reflects the specific objectives and scopes of EPA’s and WHO’s assessments. EPA’s conclusion reflects a “weight of the evidence” judgment—that is, it is based on EPA’s entire reassessment of dioxins (resting, in particular, on the conclusion that all dioxins share a similar mode of action and using evidence from both animal and human studies). In contrast, WHO’s cancer monographs looked only at individual dioxins, focusing on whether they met specific criteria. Consequently, WHO’s conclusions reflected a narrower data set and did not address the risks posed by mixtures of dioxins. However, because most human exposure is to mixtures rather than individual dioxins, and both EPA and WHO advocate using the same toxic equivalency factors for assessing the dioxins in such mixtures, any differences in the carcinogenicity classifications may have little practical impact. Quantifying the lifetime cancer risk to the general population from exposure to dioxins was an important component of EPA’s dioxin reassessment. EPA estimated that the upper bound on the general population’s lifetime risk for all cancers from dioxins might be on the order of 1 in 1,000 or more (i.e., people might experience a 1 in 1,000 increased chance of developing cancer over their lifetime because of exposure to dioxins). EPA’s reassessment also states that the vast majority of the population is expected to have less risk per unit of exposure and some may have zero risk. WHO did not carry out such a quantitative assessment of the general population’s cancer risk for two main reasons. First, calculations of population risk are beyond the scope of WHO’s IARC cancer monographs, which evaluate whether and under what circumstances particular substances could pose a cancer risk to humans but generally do not provide quantitative risk estimates. Second, as noted previously, WHO’s conclusion about a cancer threshold for dioxins led it to focus on noncancer effects when deriving tolerable intake levels for dioxins. However, WHO did explore the calculation, through modeling, of a cancer “benchmark dose,” the dose or body burden estimated to result in a 1-percent increase in cancer mortality. But WHO noted that its estimates for this benchmark dose ranged quite widely and strongly depended on the assumptions made during the modeling. Appendix II provides a more detailed comparison of the EPA and WHO conclusions regarding a number of major issues covered by the entities’ dioxin risk assessments. Two independent peer review panels, including an EPA Science Advisory Board panel, reviewed major sections of EPA’s draft dioxin reassessment report in 2000. Both panels generally agreed with a number of key assumptions and approaches that EPA used to develop its updated health risk assessment of dioxins. Each of the peer review panels had a number of recommendations and suggestions for EPA to address or consider, most of which focused on the approaches and methodologies used to depict the health risks associated with dioxins. EPA made a number of revisions to its draft report in response to these recommendations and comments. The peer review panels disagreed with EPA on a few major points, and the Science Advisory Board panel emphasized the need for additional research to bridge gaps in data. Both an independent expert peer review panel and one convened by EPA’s Science Advisory Board reviewed the draft reassessment report on dioxins in 2000. These reviews resulted in part from the Board’s review of an earlier version of EPA’s draft reassessment report. In 1995, a Board panel had reviewed the draft reassessment and requested that EPA make substantive revisions to the chapter on dose-response modeling and to the Integrated Summary. The Board had also requested that EPA develop a separate chapter on toxicity equivalence factors and submit the revised dose-response and new toxicity chapters to external peer review before the next Board review of these sections. In response, EPA revised the chapter on dose-response modeling and had it peer reviewed in 1997. Similarly, EPA wrote a chapter on toxicity equivalence factors and had it peer reviewed as part of the July 2000 review. In July 2000, EPA organized an independent peer review panel to review the revised Integrated Summary and the new chapter on toxicity equivalence factors. To obtain an objective critique, EPA had a contractor select 12 independent individuals with expertise in several technical fields, including risk characterization and communication; toxicology; epidemiology; sources of, and population exposure to, dioxins and related compounds; mechanisms and mode of action; and toxic equivalency. The panel addressed 20 questions about the reassessment report regarding exposure to and the health risks of dioxins. Table I of appendix III lists the questions the July 2000 panel addressed in its review. The panel generally agreed with the approaches and methodologies EPA used in its reassessment, and noted, among other things, the following: Body burden—the concentration of dioxins in the body—is an appropriate “dose metric” (measure) for comparing health risks across species. The use of margin of exposure—a ratio that shows how far actual or estimated human exposure is from levels at which adverse effects have been demonstrated to occur in human or animal studies— is a more logical approach to characterizing noncancer risk of dioxins than comparing exposure to a reference dose. The report’s information on noncancer effects in animals and humans was adequately assembled, and the explanation of why dioxins’ effects observed in animals are of concern to humans was also sufficient. The history, rationale, and support for the toxicity equivalence approach, which is used to assess risks posed by dioxins and complex mixtures of dioxins on the basis of their toxicity relative to an equivalent dose of TCDD, were adequately presented. As discussed further below, the July 2000 panel also provided several recommendations and suggestions and identified the topics of greatest concern for finalizing the Integrated Summary. Once the July 2000 panel published its recommendations and suggestions in August 2000, EPA addressed them and sent its revised draft to the Science Advisory Board’s dioxin reassessment review subcommittee panel in September 2000. The panel comprised several professors and directors employed by medical institutions and representatives of industry-affiliated research organizations, consulting firms, and state health agencies. The Board panel met to review the revised sections of the draft reassessment report in November 2000. The Board agreed to answer 20 questions on the reassessment report regarding exposure to and the health risks of dioxins. Most of these questions were similar to those asked of the July 2000 panel. The Board panel completed its review and published a report in May 2001. Table 2 of appendix III lists the questions the Board panel addressed in its review. The Board panel, as the July 2000 panel before it, endorsed several key aspects of the reassessment, noting that, among other things, EPA had used appropriate dose metrics, such as body burden, to equate risks assembled and distilled a large and diverse body of literature on noncancer effects into a coherent document; properly chosen the margin-of-exposure approach to characterize used toxicity equivalence factors to effectively address the joint effects of complex mixtures of dioxins on human health; and compiled an outstanding inventory of dioxin sources and effectively characterized the estimates of background exposure to dioxins using the available scientific data. The Board panel stated that, overall, EPA had prepared a thorough and objective summarization of the data and had addressed the key issues the Board had set forth in its 1995 review of the draft. The Board panel concluded that there was no need to submit further revisions of the reassessment report and that EPA should proceed to complete and release the document. However, as discussed in the following section, the Board panel provided several recommendations and suggestions for EPA to improve the draft document before its release. The Board panel also recognized the need for additional research to bridge gaps in data that limit EPA’s ability to determine the magnitude of the health risks associated with dioxins. In essence, the Board panel viewed this reassessment as an interim assessment, recognizing that the data gaps are not likely to be addressed in the foreseeable future. While the peer review panels generally agreed with the methodologies and approaches used by EPA, they made a number of recommendations and suggestions, and the Board asked specifically that the agency either address them before this reassessment is released in 2002 or in a future assessment of dioxins. The panels’ recommendations generally reflected either a consensus of the panelists or the opinion of a majority. EPA generally addressed the panels’ recommendations and suggestions by performing additional analyses, adding or revising text, identifying the recommendations or suggestions as related to EPA’s long-term research goals, or indicating that the data currently available are not adequate to address the recommendation or suggestion. Additional changes are now being made as EPA prepares the draft for external interagency review. Four of the five recommendations by the July 2000 panel regarded improvements EPA could make to the section on health risks associated with dioxins. The July 2000 panel recommended that EPA explicitly explain the relationship between body burden and daily intake, serum levels, and tissue dose; include a table in the final reassessment report summarizing the various noncancer effects observed in animals and humans at low-level exposures; improve the methodologies used in determining the cancer risks of dioxins—such as requesting more detail on exactly how the cancer slope factor for estimating cancer risks of the general population was derived; and reexamine the basis for its estimate of the upper bound cancer risks to the general population. The fifth recommendation of the July 2000 panel involved the use of specific terminology in the exposure section. In addition, this panel had several suggestions regarding the health risks associated with dioxins, including that EPA provide more detail in the Integrated Summary on the implications of using the margin-of-exposure approach rather than comparing exposure with reference doses; more clearly describe the significance of the upper bound cancer risks to add discussion of the uncertainties associated with using various dose metrics specifically for evaluating childhood risks. Ten of the 13 recommendations made by the Board panel also focused on the need to improve the section on health risks associated with dioxin. These recommendations included that EPA calculate a reference dose to evaluate risk in addition to using the margin- of-exposure approach to provide information on the minimum dose that humans can receive without suffering harm, improve its margin-of-exposure approach by more clearly explaining its choice to use dose levels associated with a 1-percent increase in a particular effect and also by calculating a dose level associated with the 10-percent increase more commonly used in chemical risk assessments, and provide better justification for using a specific dose metric and identify the important data gaps that could affect the results of those choices. Three of 13 recommendations asked that EPA improve the section on exposure to dioxins by evaluating the sources that contribute most to dioxins in the food chain, discussing all “special population” exposure in more detail, and extending breast-feeding exposure scenarios beyond 1 year. EPA made many additions and changes to the draft reassessment in response to the peer review reports by both panels. For example, in response to recommendations from both panels, EPA revised and added text in several places to better explain the variety of dose metrics available and why body burden is the best choice for assessing dioxins, while acknowledging that EPA will need to address data gaps on body burden in the future as further research is completed. Tables 1 and 2 in appendix IV highlight the actions EPA took to address both panels’ recommendations, suggestions, and concerns. Overall, the peer review panels agreed with EPA’s approach to the reassessment, and EPA generally addressed the recommendations, suggestions, and concerns of the peer review panels. In a few cases, EPA disagreed with the panels’ recommendations or suggestions. In these cases, the agency explained its position in the text and, in the case of the July 2000 panel, addressed it in a separate written document. For example, although the Board panel had recommended that EPA calculate a reference dose and add it to the text, EPA chose to continue to use only the margin-of-exposure approach and not calculate a reference dose. EPA stated in the revised draft report that a calculated reference dose would be lower than most people’s daily exposure and added a more detailed explanation of why it chose to use the margin-of-exposure approach. In addition to disagreeing with EPA on a few key scientific issues, the peer review panels could not agree among themselves in some cases on EPA’s findings. In such cases, the panels refrained from making recommendations or suggestions to the agency. For example, members of both peer review panels did not reach consensus on the strength of evidence used by EPA to support the classification of TCDD as a human carcinogen and other dioxin compounds as likely human carcinogens. EPA officials believe that the weight of scientific evidence on human and animal exposure supports classifying TCDD as a known human carcinogen, a view also held by WHO and the U.S. Department of Health and Human Services. Although neither panel specifically recommended that EPA change its classification of TCDD as a human carcinogen to a lesser category, such as a likely human carcinogen, for various reasons most of the peer reviewers did not endorse EPA’s classification. For example, while the July 2000 panel agreed that TCDD is clearly a potent carcinogen in many species of animals, most of the panel thought that human epidemiology studies were too limited, and the results not consistent enough, to serve as a basis for showing increased cancer mortality. As a result, the majority felt that the characterization of TCDD as a known human carcinogen was not justified. Similarly, the Board panel also noted limitations in the scientific data, questioning the epidemiological data that indicated dioxins are carcinogens in humans, as well as the data that supported similar modes of action occurring in both animals and humans. Almost one-half of the Board did not support classification of TCDD as a known human carcinogen for various reasons. Those who did support the classification believed that the results from studies of TCDD-exposed workers were persuasive and that the variety of studies from researchers in different countries provided limited but convincing evidence of TCDD’s carcinogenicity in humans. A decade in the making, EPA’s draft reassessment report on dioxins was both improved and limited by the passage of time, particularly in estimating the daily dietary intake of dioxins by the typical American adult. That is, EPA was able to include new food studies in the reassessment as they became available. At the same time, however, these and earlier studies that EPA relied on became less current with the passage of time. Overall, while EPA’s draft reassessment report has advanced the state of knowledge on dietary exposure to dioxins in the United States, the extent to which the estimate accurately reflects current average daily exposure is not known. EPA acknowledges the need for additional research on dietary intake, identifying a number of data limitations associated with the estimates it developed in its October 2001 draft report. Future efforts could eliminate most of the food data limitations of the reassessment. Such efforts could include periodic, comprehensive food surveys that analyze samples of the most commonly eaten food products in each type of food studied, with samples collected within the same time frames and analyses performed using standardized methodologies. Further, when they become available, the results of the ongoing EPA/USDA follow-up study on dioxin levels in beef, pork, and poultry should provide quantitative information on the changes, if any, in dioxin levels in these foods from the mid-1990’s to the present. We provided EPA with a draft of this report for its review and comment and the draft segment comparing EPA’s and WHO’s assessments of dioxins to WHO. In commenting on the draft report, EPA’s assistant administrator, Office of Research and Development, said that the report was well researched and written and provided a balanced treatment of the information. However, EPA believed that additional information on some of the data limitations discussed in the section on EPA’s estimates of the dietary intake of dioxins would better enable readers to evaluate the impact of the data limitations. Where appropriate, we revised the report to reflect the views EPA presented in its comments. For example, we added information concerning the strength of the food concentration data used in estimating national mean levels of exposure to dioxins, the sampling of animal fat rather than meat and poultry products sold in grocery stores, and the likelihood that current dioxin levels in food have significantly declined since the mid-1990s. EPA’s comments and our evaluation of them are provided in appendix V. In commenting on the draft segment comparing EPA’s and WHO’s analyses, a senior advisor of health and environment, the Department of Protection of the Human Environment, World Health Organization, said the report was well written and accurate. To describe the types and extent of data EPA used to reassess human dietary exposure to dioxins in the United States, we reviewed the relevant portions of the October 2001 draft reassessment, the 1994 and 2000 drafts that were peer reviewed, and the initial 1985 health risk assessment. We also reviewed EPA documents and journal articles on the agency’s national sampling of beef, pork, and poultry samples, and information about the other samples used for milk, eggs, fish, dairy products, and vegetable fats. We discussed the samples and methodology issues about them with EPA officials and contractor staff. We did not validate or verify EPA’s estimates of dietary exposure to dioxins. To compare EPA’s objectives, processes, analytical methods, and conclusions with those of WHO, we analyzed EPA’s October 2001 draft reassessment report and various WHO publications on its objectives, analyses, and conclusions. We discussed the similarities and differences with EPA and WHO officials. To determine the extent to which EPA’s draft dioxin reassessment reflects the views of two independent peer review panels, we analyzed the recommendations, suggestions, and concerns in the reports by the EPA Science Advisory Board’s dioxin reassessment review subcommittee panel—on reviews performed in 1994 and 2000—and a report from another independent peer review panel on its July 2000 review. Recommendations of the Board panel were noted in bold print in the executive summary, and we considered other statements to be “suggestions” when they were the consensus opinion of the panelists or the opinion of a majority or of some of the panelists. We considered the July 2000 panel’s statements to be “recommendations,” “suggestions,” or “concerns,” when those particular words were used in the executive summary and where the statements reflected either a consensus or the opinion of a majority or of some of the panelists. We also reviewed EPA documentation to determine the changes EPA has made to its draft reassessment as a result of being peer reviewed, including comparing the agency’s previous drafts of the reassessment with each other and reviewing the written responses to the July 2000 panel’s recommendations and suggestions. We also met with EPA officials to identify the agency’s responses to the panels’ recommendations, suggestions, and concerns, including discussing those with which it disagreed. We conducted our work from July 2001 through March 2002 in accordance with generally accepted government auditing standards. We will send copies of this report to the administrator, EPA, and make copies available to others who request them. This report will also be available on GAO’s Web site (www.gao.gov). If you or your staff have questions about this report, please call me on (202) 512-3841. Key contributors to this report are listed in appendix VI. Appendix I: Major Milestones in the EPA and WHO Dioxin Risk Assessment Efforts (1991) reassessment. reassessment. EPA completes EPA completes external review external review meetings and workshops. workshops. interim toxic interim toxic equivalency equivalency factor (TEF) factor (TEF) by dioxins. by dioxins. holds public meetings. meetings. 1992 - EPA procedures for estimating risks estimating risks associated with associated with convenes two peer- review workshops. review workshops. dioxins. dioxins. mixtures of dioxins. mixtures of dioxins. of external review draft. review draft. holds a third peer- holds a third peer- review workshop. review workshop. (1987) (1987) Experts at Experts at meeting in meeting in Bilthoven, Bilthoven, monographs on monographs on carcinogenicity carcinogenicity of some dioxins. of some dioxins. intake for TCDD. TCDD. review. review. Science Advisory Science Advisory Board completes Board completes pending. final internal final internal review draft review draft report, which report, which incorporates incorporates revisions in revisions in response to pending. Board and an independent independent panel of peer panel of peer reviewers review reviewers review major segments major segments of EPA’s revised of EPA’s revised peer review panel peer review panel recommendations recommendations draft report. draft report. and comments. and comments. is pending. is pending. Stockholm meeting. Stockholm meeting. in Rome, Italy, in Rome, Italy, evaluate risks evaluate risks associated with associated with dioxins in foods dioxins in foods and establish a and establish a in Geneva, Switzerland, Switzerland, reevaluate the reevaluate the risks to human risks to human dioxins. dioxins. dioxins. dioxins. Sweden, derive consensus TEFs daily intake daily intake for dioxins. for dioxins. for dioxins for for dioxins for human, fish, human, fish, and wildlife risk assessments. assessments. Exposure to dioxins can produce a wide variety of effects in animals (including cancer and noncancer health effects) and might produce many of the same effects in humans. Exposure to dioxins may be linked to a variety of adverse effects. Short-term human exposure to high levels of dioxins may result in skin lesions (such as chloracne) and altered liver function. EPA characterizes dioxin and related compounds as carcinogenic and developmental, reproductive, immunological, and endocrinological hazards and makes the following specific points. Long-term exposure is linked to impairment of the immune system, the developing nervous system, the endocrine system, and reproductive functions. Exposure to TCDD leads to an increased risk of generalized cancers at multiple organ sites, including lung cancer. Long-term noncancer consequences of exposure to TCDD in types of cancer. Human data from occupational or accidental exposure has produced evidence of increased risks for all cancers combined, along with less strong evidence of increased risks for cancers of particular sites. adults include chloracne, elevated gamma glutamyl transferase levels, and altered testosterone levels. Among the possible noncancer consequences of exposure to TCDD or other dioxin and dioxin-like compounds are dermatological conditions such as chloracne; liver diseases; and kidney, nervous system, and lung disorders. Although available data suggest an association between TCDD exposure and other adverse outcomes, further study is required of circulatory and heart disease, diabetes and glucose metabolism, reproductive and developmental outcomes, and immunologic disorders. Mode of action through which exposure to dioxins can lead to adverse effects Dioxins are structurally related and elicit their effects through a common mode of action—binding of dioxins to a cellular protein called the aryl hydrocarbon receptor. Binding to the aryl hydrocarbon receptor appears to be necessary for all well-studied effects of dioxins but is not sufficient, in and of itself, to elicit these responses. A broad variety of data has shown the importance of the aryl hydrocarbon receptor in mediating the biological effects of dioxins. The precise chain of molecular events by which the receptor elicits these effects is not yet fully understood. However, alterations in key biochemical and cellular functions are expected to form the basis for dioxin toxicity. TCDD and related compounds have a common mode of action in animals and humans. Therefore, there is no reason to expect, in general, that humans would not be similarly affected as animals at some dose. Experimental data indicate that TCDD and probably other polychlorinated dibenzo-p-dioxins (CDD) and polychlorinated dibenzofurans (CDF) are not direct-acting genotoxic agents (i.e., do not directly affect genetic material). Dioxins act through the same mode of action in animals and humans. Use of the toxicity equivalency (TEQ) concept EPA and the international scientific community have adopted TEQ of dioxins as prudent science policy. The complex nature of CDD, CDF, and polychlorinated biphenyls (PCB) mixtures complicates the risk evaluation for humans. The concept of TEFs has been developed to facilitate risk assessment and regulatory control of exposure to these mixtures. (EPA recommended that the TEFs derived by WHO in 1997— published in 1998—be used to assign TEQ to complex environmental mixtures for assessment and regulatory purposes.) (WHO derived updated consensus TEFs for 29 dioxins in 1997, with the results of the meeting published in 1998. Subsequent WHO assessments of dioxins used this updated set of TEFs for their calculations.) Whether dioxins are human carcinogens Complex mixtures of dioxins are highly potent, “likely” human carcinogens. TCDD is a human carcinogen (group 1), considering limited evidence in humans, sufficient evidence in experimental animals, and evidence of a mode of action that functions the same way in humans as in experimental animals. dioxins are strong cancer promoters and weak direct or indirect initiators and are likely to present a cancer hazard to humans. Because dioxins and related compounds always occur in the environment and in humans as complex mixtures of individual congeners, it is appropriate that the characterization apply to the mixture. Individual congeners can also be characterized as to their carcinogenic hazards. Other dioxins are not classifiable as to their carcinogenicity to humans (group 3). Depending on the specific compound evaluated, the International Agency for Research on Cancer (IARC) noted that the available data provided inadequate evidence for carcinogenicity in humans or limited evidence, inadequate evidence, or evidence suggesting lack of carcinogenicity in experimental animals. TCDD is best characterized as “carcinogenic to humans.” Based on the weight of all evidence (human, animal, and mode of action), TCDD meets the criteria that allow EPA and the scientific community to accept a causal relationship between TCDD exposure and cancer hazard. Other individual dioxin-like compounds are characterized as “likely to be human carcinogens” primarily because of the lack of epidemiological evidence associated with their carcinogenicity, although the inference based on TEQ is strong that they would behave in humans as TCDD does. Other factors, such as the lack of compound-specific chronic animal studies, also support this characterization. Whether there appears to be a “threshold” or safe dose of dioxins that would not cause adverse effects The supposition of a response threshold for receptor-mediated effects (such as those associated with dioxins’ binding to the aryl hydrocarbon receptor ) is a subject for scientific debate. The same receptor occupancy assumption of the classic receptor theory is interpreted by different parties as support for and against the existence of a threshold. TCDD does not affect genetic material, and there is a level of exposure below which cancer risk would be negligible. Although TCDD is classified by IARC as a human carcinogen, it is not considered to be a direct acting carcinogen. Therefore, a threshold approach could be used in the hazard assessment approach. Empirical dose-response data from cancer studies do not provide consistent or compelling support for threshold models and are insufficient to move from EPA’s default policy of linear extrapolation (an approach that assumes there is no threshold of exposure without risk). A tolerable intake can be established for TCDD on the basis of the assumption that there is a threshold for all effects, including cancer. Because cancer occurred in animals at higher body burdens than other toxic effects, establishing a tolerable intake on the basis of noncancer effects would also address any carcinogenic risk. Threshold levels of lifetime exposure to dioxins that would cause toxic noncancer effects may be below the current level of background exposure and body burdens, and, therefore, the potential exists for noncancer risk at background exposure. Whether it is useful to set a dose or exposure level that the public could experience for a lifetime without expectation of harm EPA did not calculate reference dose or reference concentration values in this reassessment as it generally does for noncancer effects in other assessments. Instead, EPA chose to characterize the margins of exposure between estimated actual human exposure and the exposure levels at which studies indicated various adverse noncancer effects could occur. The WHO 1998 consultation set daily limits on exposure levels of dioxins for non-cancer effects, a tolerable daily intake. The Joint Expert Committee on Food Additives of the United Nation’s Food and Agriculture Organization and WHO set a provisional tolerable monthly intake limit on exposure levels to dioxins, again focusing on noncancer effects. The Committee participants felt that it was more appropriate to express the tolerable intake on a monthly rather than a daily basis because of the long half-life of dioxins (i.e., the body’s stored dioxins decline slowly, with only half of the accumulated dioxins disappearing over about 7 years). Human exposure to dioxins has occurred through background exposure, contamination of foods, occupational exposure, and exposure associated with industrial accidents. An increased background exposure can result from either a diet that favors consumption of foods high in dioxin content or a diet that is disproportionately high overall in animal fats. Human exposure to dioxins may occur through background (environmental) exposure and accidental and occupational contamination. Over 90 percent of human background exposure is estimated to occur through the diet, with food from animal origin being the predominant source. Most (more than 95 percent) background exposure results from the presence of minute amounts of dioxins in dietary fat, primarily from the commercial food supply. Recent studies show decreasing levels of dioxins in food and consequently a significantly lower dietary intake of these compounds. The average dioxin tissue level for the general U.S. adult population appears to be declining. Five compounds account for most (about 80 percent) of the toxicity in human tissue concentrations. Risks of adverse health effects at the general public’s current levels of exposure to dioxins In general, EPA’s assessments indicated that dioxins pose risks at lower levels of exposure than previously estimated and that the general public’s current levels of exposure are at or near those that have been observed to cause harm. In general, WHO’s assessments also indicated that dioxins pose risks at lower levels of exposure than previously estimated and that the general public’s current levels of exposure are at or near those that have been observed to cause harm. EPA estimates that the upper bound cancer risk at average current background body burdens exceeds 10-3 (i.e., the upper bound on general population lifetime risk for all cancers might be on the order of 1 in 1,000 or more). However, this is an upper bound estimate, so the true risks are likely less than that and may be zero for most people. In 1985, EPA’s estimate of the cancer slope factor based on exposure to TCDD was 1.6 x 10-4 per picogram of TCDD per kilogram of body weight per day (pgTCDD/kgBW/day). In 1990, WHO experts had established a tolerable daily intake for TCDD of 10 picograms per kilogram of body weight. In 1998, the WHO consultation established a tolerable daily intake for dioxins at a range of 1-4 TEQ picograms per kilogram of body weight and noted that subtle effects may already occur in the general population at current background levels of 2 to 6 picograms per kilogram of body weight. The consultation stressed that the ultimate goal is to reduce human intake levels below 1 picogram TEQ per kilogram of body weight per day. EPA’s current upper bound slope factor for estimating human cancer risk on the basis of human data is 1 x 10-3 per pgTCDD/kgBW/day. EPA’s current upper bound slope factor for estimating human cancer risk on the basis of animal data is 1.4 x 10-3 per pgTCDD/kgBW/day. In 2001, Joint Expert Committee on Food Additives of the United Nation’s Food and Agriculture Organization of the United Nations and WHO determined that a monthly tolerable intake level made more sense than a daily level and established a provisional tolerable monthly intake of 70 picograms per kilogram of body weight per month (equivalent to 2.33 picograms per day) for dioxins. EPA estimated that U.S. residents are exposed daily to about 1 picogram of dioxins per kilogram of body weight, which is close to the level that caused biological changes in animals. EPA noted that the margins of exposure between estimated actual human exposure and the exposure levels at which studies indicated adverse noncancer health effects could occur were “considerably less than typically seen for environmental contaminants of toxicologic concern.” The various WHO entities did not calculate quantitative cancer risk estimates for the additional cancer risk that dioxins might pose to the general population. However, WHO did explore the calculation of a cancer “benchmark dose” (the dose or body burden estimated to result in a 1-percent increase in cancer mortality) through various models. On the basis of data from three industrial exposure studies, WHO estimated that the body burden of dioxins associated with a 1-percent excess cancer risk over a lifetime was 3 to 13 nanograms per kilogram of body weight, which is associated with a daily dose of dioxins in the range of 2 to 7 picograms per kilogram of body weight per day. Children’s risks from dioxins and related compounds may be greater than that of adults, but more data are needed to fully address the issue. Certain population subgroups are at greater risk from dioxins. Fetuses are most sensitive to dioxin exposure, and newborns may also be more vulnerable to certain effects. Some individuals or groups of individuals may be exposed to higher levels of dioxins because of their diets or occupations. There may be individuals in the population who might experience a higher cancer risk on the basis of genetic factors or other determinants of cancer risk not accounted for in epidemiologic data or animal studies. In particular, a very small percentage of the population (less than 1 percent) may experience risks that are 2 to 3 times higher than the general population estimate if their individual response is at the upper bound and they are among the most highly exposed based on dietary intake of dioxins. EPA sought expert opinions from both a July 2000 panel of independent peer reviewers and a November 2000 Science Advisory Board expert panel on several key questions that pertain to the content of the documents under review. The questions are classified into 11 general topics. Most of the questions are the same for both panels. However, according to usual Science Advisory Board practice, EPA staff, Board staff, and the chair of the Board’s dioxin reassessment review subcommittee jointly developed additional questions for the Board’s review. Table 6 and table 7 show the topics and questions addressed by the July 2000 panel, and Board panel, respectively. EPA generally addressed the peer review panels’ comments by performing additional analyses, adding or revising text, or identifying comments as related to EPA’s long-term research goals. In some instances, EPA thought that the reassessment already addressed the panel’s comment. The panels classified their recommendations, suggestions, and concerns, and EPA responded to each. Tables 8 and 9 show the comments made by the panels and EPA’s response or action taken. The following are GAO’s comments on EPA’s letter dated April 17, 2002. 1. The discrepancies we identify between the Integrated Summary and supporting chapters appear in the October 2001 reassessment documents that EPA distributed for internal agency review. We identified them primarily to inform readers of our report of the source of the information we cite. For example, a reader of the Integrated Summary would find (outdated) information on 9 food types, whereas we are citing information on 10 food types that is provided in the supporting chapters of EPA’s reassessment documents and that EPA officials told us is correct. 2. Throughout the section of our report on EPA’s estimate of dietary exposure to dioxins, we attribute the identification of the limitations to EPA’s draft reassessment report. 3. Our report did not characterize the significance of the limitations EPA identified in its reassessment documents. We have added to the report EPA’s opinion that these limitations do not represent major weaknesses in its estimates of dietary exposure to dioxins. 4. The statement in our report that that the available studies generally were not designed to estimate national exposures is derived from page 76 of EPA’s October 2001 Integrated Summary draft. In this document EPA says: “The amount and representativeness of the data vary, but in general these data were derived from studies that were not designed to estimate national background means.” In its written comments, EPA says that most of the dietary exposure it estimated was derived from studies specifically designed to estimate national exposures. In support of this point, EPA says that 66 percent of the estimated exposure to dioxins is from eating beef, pork, poultry, milk, and dairy products, and that these studies were designed to estimate national exposures. (We note that these studies cover 5 of the 10 food types on which EPA based its exposure estimates.) Importantly, our draft report stated that the studies on beef, pork, and poultry were based on the first statistically designed national surveys of dioxin levels in these foods and that the milk samples upon which both the milk and dairy estimates were based came from a national survey with samples collected from sampling stations in a majority of the states. However, while our review of EPA’s milk survey design plan indicated the milk samples were intended to assess the levels of dioxins in the general milk supply of the United States, the survey design document also stated that (1) the milk would be collected from dairy plants around the United States that represent approximately 20 percent of the nation’s milk supply and (2) the survey was not designed to be statistically rigorous—that is, it was not intended to randomly sample milk in such a way that the results could be generalized to the full milk supply with a known degree of precision. Thus, we concluded that EPA’s statement in the Integrated Summary—that the studies covering the 10 food types generally were not designed to estimate national exposures—was accurate. In light of EPA’s comments and the fact that the milk samples used to estimate milk and dairy exposures did have national coverage, we have revised the report to indicate that EPA acknowledges that some of the available studies were not designed to estimate national average exposures. 5. We revised the description of the fat samples from “inedible fat samples” to cuts of fat, such as back fat on cattle, that generally are not consumed by the U.S. public. 6. We understand that there is variability associated with measurements at the picogram level. Nonetheless, we continue to believe that the variability identified among the five samples studied indicates that using fat samples not consumed by the public may overstate or understate to some extent dioxin levels in beef, pork, and poultry products sold to the public. 7. In its comments, EPA stated that it believes that sufficient information is available to support a conclusion that, in spite of the emission reduction of the late 1990s, the exposure estimates of the draft reassessment are a reasonable characterization of contemporary exposure. We have revised the report to include EPA’s opinion and the reasons it cited in support of its view that the emission reduction in the late 1990s does not significantly affect the current estimate of general population exposure. However, because EPA does not have data on dioxin emissions after 1995, we cannot evaluate EPA’s conclusion. 8. EPA stated that it plans to delete information on the variability in dairy concentration data from the reassessment report, and we have therefore deleted this point from our report. 9. We understand that the contamination of the two samples eliminated from EPA’s estimate was found to stem from a localized ball clay contamination. However, we continue to believe that because of the lack of information on the incidence of dioxin contamination in animal feeds as well as on the potential sources of such contamination, it is not clear that the poultry samples with high concentrations of dioxins were anomalies. For example, this animal feed contamination problem was identified as a result of the first national survey of only 80 poultry fat samples. We acknowledge that a decision to exclude apparently anomalous information entails professional judgment. However, because the incidence of contamination of animal feed is unknown, we believe that it is important for users of the dioxin reassessment to understand the judgments EPA made in estimating dietary exposure. 10. In the draft report, EPA does not provide information on the assumptions and analyses used to estimate the average fat percentages for pork and poultry. However, EPA does provide some information on how it estimated the fat percentage for beef. The fat percentage estimates affect the exposure estimates, and we believe this information should be included in the reassessment report. In its comments to us, EPA stated that the agency is considering adding information about the pork and poultry estimates to the report. We are therefore deleting references to this point in our report. 11. We deleted the phrase “assembled by EPA” to be consistent with information we provide in the body of the report that the peer review panelists were selected by an independent contractor. 12. We have revised this statement to reflect the fact that most (rather than all) of the other dioxins have TEFs of 0.1 or lower. 13. We clarified that TEFs apply to all effects, not just those for which relative potency data were available. Other key contributors to this report include Timothy Bober, Greg Carroll, Nancy Crothers, Greg Wilmoth, and Carrie Wheeler.

Summary: Dioxins--chemical compounds that share structural and biological characteristics--have been linked to human illnesses, including cancer. Often the byproducts of combustion and industrial processes, complex mixtures of dioxins enter the food chain and human diet through emissions into the air. The Environmental Protection Agency (EPA) and the World Health Organization (WHO) noted the potential human health risks of dioxins in the 1970s when animal studies showed them to be among the most potent cancer-causing chemicals. EPA derived its estimates of human dietary exposure to dioxins in the United States from (1) chemically analyzed samples of 10 food types, (2) toxicity estimates of levels of individual dioxins in these foods, and (3) estimates of the quantities of these foods consumed by Americans. To develop more reliable national estimates of dietary exposure, EPA incorporated into its analysis some food studies that were nationally representative. Although both EPA and the WHO have assessed the human health risks of dioxins during the last decade, some of their objectives and processes have differed. Nonetheless, the analytical methods used and the conclusions reached have much in common. A major difference in the assessments is whether there are threshold levels below which exposure to dioxins would pose a negligible risk of cancer. EPA assumed there is no safe threshold level for cancer effects, but the WHO assumed there is. EPA's draft reassessment report reflects the recommendations and suggestions provided to the agency by the two most recent independent peer review panels. The panels, one consisting of 12 independent reviewers and the other convened by EPA's Science Advisory Board, concurred with many key assumptions and approaches that EPA used.