The Science of the Total Environment, 104 (1991) 73-86 Elsevier Science Publishers B.V., Amsterdam
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Toxicity equivalents and EPA's risk assessment of 2,3,7,8-TCDD Donald G. Barnes United States Environmental Protection Agency, 401 M St. SW, Washington, DC 20460, USA
ABSTRACT Toxicity equivalent factors (TEFs) have proved useful in estimating the toxicity of complex mixtures of chlorinated dibenzo-p-dioxins and dibenzofurans (CDDs/CDFs). An international consensus has formed around a specific set of T E F values as interim solution for addressing environmental contamination by CDDs/CDFs. This procedure capitalizes on the congenerspecific analytical results that are more routinely available in recent years. The TEF approach should be updated as necessary and replaced by more definitive bioassay approaches as soon as practicable. In an independent activity, the USEPA considered a proposal to change (reduce) the cancer potency ascribed to 2,3,7,8-TCDD by a factor of 16. The recommendation was based upon an analysis of the literature and the Agency's earlier risk assessment. The proposal was reviewed by the Science Advisory Board, a group of outside scientific advisors. Subsequently, the Agency decided against making any changes in its assessment at this time. However, it is likely that a reassessment will be conducted shortly that will incorporate new data and a new approach to estimating of cancer risks posed by 2,3,7,8-TCDD.
INTRODUCTION
During 1988-89 there were two significant activities at the United States Environmental Protection Agency (USEPA or Agency) related to the risk assessment for chlorinated dibenzo-p-dioxins and dibenzofurans (CDDs/ CDFs). First, the USEPA, working in conjunction with a special committee of the North Atlantic Treaty Organization (NATO), adopted an updated set of toxicity equivalency factors (TEFs) which guide the Agency's efforts to assess the risks posed by CDDs/CDFs other than 2,3,7,8-tetrachlorodibenzop-dioxin (2,3,7,8-TCDD). Second, the Agency's Science Advisory Board (SAB), a group of distinguished non-governmental scientists and engineers, reviewed a USEPA staff proposal to reassess the cancer risk assessment of 2,3,7,8-TCDD, the effect of which would be to bring USEPA's assessment more in line with that of other risk assessors around the world. This paper summarizes these recent events. In doing so, the author provides
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his interpretation of these developments, which is not necessarily that of USEPA. TOXICITY EQUIVALENTS (TEQs)
Since 1970, when 2,3,7,8-TCDD was first discovered to be an environmental problem, more than $1 billion has been spent on researching the toxicity of this, the most prominent and probably most potent, member of the 210member family of CDDs/CDFs. Despite tremendous gains in our knowledge of the properties and mechanisms-of-action of 2,3,7,8-TCDD, the holding of this conference is clear testimony to the fact that there is no universal agreement on the risks posed by this substance. The data base of toxicological information on any of the other 209 compounds in the CDD/CDF family is much smaller. And yet, over the past decade we have learned that the CDDs/CDFs other than 2,3,7,8-TCDD are more prevalent in the environment; i.e. there are more sources of these compounds and they appear in greater quantities (e.g., Rappe et al., 1987). Consequently, risk assessors and regulators are continually challenged to interpret the significance of environmental levels of these substances. In the late 1970s, Dr Donald Grant, a toxicologist with Health and Welfare Canada, suggested a simplistic approach to this problem (Grant, 1977). He noted that the mechanism-of-action of 2,3,7,8-TCDD appeared to be associated with its interaction with a specific receptor in the cytosolic portion of the cell (e.g., Poland and Knutson, 1982). The other CDDs/CDFs also interact with the same receptor, only at higher doses, and elicit similar toxic properties, but again at higher doses (Poland et al., 1979). Grant hypothesized that the potency of the other CDDs/CDFs would be inversely related to the ECs0 for their interaction with the receptor and early sequela; e.g., enzyme induction. These relative potencies could be expressed as toxicity equivalency factors (TEFs) and used to convert concentrations of CDDs/CDFs found in environmental samples into equivalent concentrations of 2,3,7,8-TCDD. Thus, Estimated 2,3,7,8-TCDD-like toxicity of a mixture of CDDs/CDFs = Concentration of toxicity equivalents = [TEQs] = = Z (TEF)~ x [CDD/CDF]~ i
where (TEF)i is the relative potency of the ith CDD/CDF compared with 2,3,7,8-TCDD, i.e. (TEF)i = (potency of ith CDD/CDF)/(potency of 2,3,7,8-TCDD)
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TABLE 1
Toxicity equivalency factors Compound
EPA-TEFs/87
I-TEFs/88
Mono-, di-, and triCDDs 2,3,7,8-TCDD Other TCDDs 2,3,7,8-PeCDD Other PeCDDs 2,3,7,8-HxCDD Other HxCDDs 2,3,7,8-HpCDD Other HpCDDs OCDD Mono-, di-, and triCDFs 2,3,7,8-TCDF Other TCDFs 1,2,3,7,8-PeCDF 2,3,4,7,8-PeCDF Other PeCDFs 2,3,7,8-HxCDF Other HxCDFs 2,3,7,8-HpCDF Other H p C D F s OCDF
0 1 0.01 0.5 0.005 0.04 0.0004 0.001 0.00001 0 0 0.1 0.001 0.1 0.1 0.001 0.01 0.0001 0.001 0.00001 0
0 I 0 0.5 0 0.1 0 0.01 0 0.001 0 0. ! 0 0.05 0.5 0 0.1 0 0.01 0 0.001
NATO/CCMS, 1988a.
During the 1980s, a number of different groups proposed separate schemes for TEFs (e.g., Grant, 1977; Eadon et al., 1986; Ontario Government, 1982; Gravitz et al., 1983; Olie et al., 1983; USDHHS, 1983; Commoner et al., 1984). In 1987, the USEPA adopted, as a matter of interim science policy, its own set of TEFs (since called "EPA-TEFs/87", see Table 1) after examining the relative potency of different C D D s / C D F s for a variety of in vivo and in vitro endpoints; e.g., cancer, re.productive effects, body weight loss, cell transformation, and immunotoxicity (USEPA, 1987). A clear distinction is made between the laterally substituted congeners ("2,3,7,8-substituted") and those that are not ("non-2,3,7,8-substituted"). Figure 1 and Table 2 show how the TEFs can be used to convert concentrations of C D D s / C D F s in environmental samples into equivalent concentrations of 2,3,7,8-TCDD (USEPA, 1989). The expressed intent of the Agency was, and remains, to replace the TEF approach with a more direct measurement of the biological activity of a C D D / C D F mixture as soon as possible. However, it is interesting to note that, in most instances, the TEQs calculated by the different TEF schemes differ by
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0.8
PCDFs
0.6
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g g
o.c 0.3
= o u
0.2
i
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i
I-TEOs I 88
Fig. 1. Toxicity equivalents in human milk sample (Lindstrom and Rappe, 1986).
TABLE 2 Converting congener-specific data to toxicity equivalents by two TEF schemes (see Fig. 1) TEF scheme
Congener
Source data (ppt)
EPA-TEF/87
I-TEF/88
2,3,7,8-TCDD 1,2,3,7,8-PeCDD 1,2,3,4,7,8-HxCDD 1,2,3,6,7,8-HxCDD 1,2,3,7,8,9-HxCDD 1,2,3,4,6,7,8-HpCDD OCDD Total CDDs
0. i I 0.18 0.08 0.73 0.15 I. 3 5.7
0. I 1 0.09 0.0032 0.029 0.006 0.0013 0 0.24
0.11 0.09 0.008 0.073 0.015 0.013 0.0057 0.31
2,3,7,8-TCDF 1,2,3,7,8-PeCDF 2,3,4,7,8-PeCDF 1,2,3,4,7,8-HxCDF 1,2,3,6,7,8-HxCDF 2,3,4,6,7,8-HxCDF 1,2,3,4,6,7,8-HpCDF OCDF Total CDFs
0.12 0.022 0.51 0.097 0.078 0.04 0.19 0.062
0.012 0.0022 0.051 0.00097 0.00078 0.0004 0.00019 0 0.068
0.012 0.001 I 0.26 0.0097 0.0078 0.004 0.0019 0.000052 0.30
EPA-TEQs/87 = 0.3
I-TEQs/88 = 0.6
37% contributed by 2,3,7,8-TCDD
18% contributed by 2,3,7,8-TCDD
Total TEQs
TOXICITY EQUIVALENTS AND EPA'S RISK ASSESSMENT FOR 2,3.7,8-TCDD
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a factor of < 4. Even more encouraging are the cases in which the TEQ-estimated toxicity of a mixture of CDDs/CDFs has been shown to be remarkably consistent with the demonstrated toxicity obtained from in vivo measures using in toto mixtures (e.g., Sawyer et al., 1983; Safe, 1987; Safe et al., 1989). In 1985, the Committee on the Challenges of Modern Science (CCMS) of NATO formed an information exchange group to examine a multitude of issues surrounding CDDs/CDFs, among them the scientific credibility and regulatory utility of the TEQ concept. A subcommittee examined the problems and promises posed by the TEQ approach. They agreed that the preferred method of toxicological assessment would be to have some effective short-term assay that could measure the toxicity of a C D D / C D F mixture directly. However, in the interim, they recommended the use of TEFs. The subcommittee went further. Following proposals set forth by the Nordic countries, the NATO CCMS group recommended that the member countries adopt a common set of TEFs, which were called "1988 International Toxicity Equivalency Factors (I-TEFs/88)" (See Table 1) (NATO/CCMS, 1988a,b). The more significant changes from the EPA-TEF/87 scheme relate to: (i) focusing solely on 2,3,7,8-substituted congeners; to simplify the scheme and acknowledge that those are the congeners that contribute the majority of the TEQs in most environmental samples, particularly those involving biological tissue; (ii) recognizing the greater potency of 2,3,4,7,8-PeCDF (NATO/CCMS, 1988b); (iii) assigning a non-zero value to OCDD and OCDF, based upon new information (Couture et al., 1988). The I-TEFs/88 have now been adopted by several countries; e.g., the United States (USEPA), Canada, Federal Republic of Germany, Finland, Great Britain, Italy, The Netherlands, Norway, and Sweden. In closing this introduction to TEQs, let me emphasize three points. (i) The use of TEFs is an interim procedure. (a) Research should be conducted to replace the TEF procedure as soon as possible with a short-term assay that measures the combined toxicity of the C D D / C D F mixture. We know, for example, that significant antagonisms can occur in certain mixtures in which the "non-toxic, non-2,3,7,8-substituted" CDDs/CDFs mitigate the biological response invoked by the "toxic, 2,3,7,8substituted" CDDs/CDFs. These non-additive effects are not accounted for in a simple TEF approach. (b) The TEFs should be changed whenever new scientific data indicate that changes are warranted. The USEPA assured its Science Advisory Board that the TEFs would be updated on a regular basis; e.g., every other year. (ii) Analytical chemists should continue to strive toward complete reporting of a congener-specific analysis of an environmental sample, while
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summarizing its toxicological significance in terms of TEQs. Of course, the detailed congener-specific information is needed to calculate TEQs. In addition, congener-specific analyses can sometimes provide information useful in linking a particular CDD/CDF source to the residues found in a particular sample. (iii) Toxicity equivalents should be expressed in such a way that the percentage of total TEQs due to 2,3,7,8-TCDD is clear (Fig. 1). Since a principal concern for CDDs/CDFs risk assessment is cancer, the risk manager should be aware of the proportion of TEQs which are due to the validated animal carcinogen, 2,3,7,8-TCDD (Kociba et al., 1978; NTP, 1982). The remainder of the TEQs are derived from CDDs/CDFs whose carcinogenic properties are less well-demonstrated. Among the limited number of CDDs/ CDFs which have been studied for carcinogenicity, only a mixture of 1,2,3,7,8,9- and 1,2,3,6,7,8-HxCDD has been shown to be carcinogenic in animals. EPA's PROPOSED REASSESSMENT OF THE CARCINOGENIC POTENCY OF 2,3,7,8TCDD
The USEPA proposal During the 1980s a number of regulatory bodies throughout the world generated separate assessments of the cancer risks posed by 2,3,7,8-TCDD. While all of these assessments relied on essentially the same experimental data, they differed in some of their fundamental assumptions; e.g., the mechanismof-action and the methods for extrapolating animal data to humans. The result was a 1000-fold difference in the "level of concern" resulting from these various approaches (see Fig. 2, taken from USEPA, 1988a). The USEPA result is at one extreme of this range. The Agency's estimate of the carcinogenic risk posed by 2,3,7,8-TCDD (USEPA, 1985) was derived using the approach outlined in the 1986 USEPA Cancer Risk Assessment Guidelines (Federal Register, 1986). These Guidelines give prominence to the application of the linearized multi-stage (LMS) mathematical model. Further, the Guidelines call for extrapolating from animal data to humans through the use of a body surface area correction (i.e., dose rate/body surface area), rather than the more traditional body weight correction (i.e., dose rate/body weight). This is a fundamental difference between the USEPA approach and that used by the US Food and Drug Administration (USFDA). In 1987, the USEPA Administrator asked an intra-Agency workgroup to consider carefully all of the data on the carcinogenicity of 2,3,7,8-TCDD and advise him on whether the USEPA assessment should be changed. The
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TOXICITY EQUIVALENTS AND EPA'S RISK ASSESSMENT FOR 2,3,7,8-TCDD
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Fig. 2. Some examples of risk specific doses (10 -6 ) and reference doses calculated by individual scientists, scientific organizations, and regulatory agencies for 2,3,7,8-TCDD. ( ) Conclusions reached by regulatory agencies or scientific organizations; (. . . . ) conclusions reached by research efforts.
workgroup was supported by the efforts of Agency technical experts in a number of different areas. After a year of study and discussion, the group produced a report (USEPA, 1988a), buttressed by a series of appendices dealing with specific issues (USEPA, 1988b). In a companion effort, the Agency produced a report on exposure characteristics of 2,3,7,8-TCDD (USEPA, 1988c). The workgroup reached several conclusions concerning the mechanism-ofaction: (i) 2,3,7,8-TCDD is a potent promoter of carcinogenesis; (ii) the possibility that 2,3,7,8-TCDD acts as a direct-acting, complete carcinogen cannot be eliminated; (iii) 2,3,7,8-TCDD may act through a secondary mechanism(s) which may affect the carcinogenic process at different stages; (iv) 2,3,7,8-TCDD may act through a number of different mechanisms so that the observed effects represent an integrated composite of several mechanisms in operation. After reviewing all of the data, the group concluded that the "promoter" vs "complete carcinogen" characterization of 2,3,7,8-TCDD is probably an oversimplification. While the compound conforms to the operational definition of a complete carcinogen (i.e., tumors are generated in treated animals in a dose-related manner), it does not exhibit other properties often associated with "classical complete carcinogens" (e.g., mutagenicity and binding to DNA). Likewise; while exhibiting promoter behavior in certain bioassays, the chemical differs from the "classical promoter" by acting at very
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D.G. BARNES
M S
(1985)
DOSE Fig. 3. "Multiple mechanism" hypothesis for 2,3,7,8-TCDD carcinogenesis.
low doses. In addition, arguments about the "reversible" aspect of promoters are mitigated in the case of 2,3,7,8-TCDD by the long half-life in the body, i.e. about 7 years (Wolfe et al., 1988). There is a good deal of evidence that 2,3,7,8-TCDD may be exerting its effect through an indirect, receptor-mediated mechanism (e.g., Poland and Knutson, 1982). While some of these indirect routes may behave in a typical "threshold" fashion, it is possible that others also behave in a linear fashion down to zero dose. The various possibilities are displayed conceptually in Fig. 3. The "UCL-LMS (1985)" line (the "upper confidence limit generated from the LMS model") is designed to be an upper limit of what the risk is likely to be. That is, this estimate is not likely to be exceeded in reality; the actual risk could be considerably lower, even zero. The UCL-LMS assumes that all of the tumors observed in the experimental range are related to processes that are also operative in the low-dose region. The "Composite (1988)" line is a conceptual representation of the low-dose behavior where only some of the tumors observed in the experimental range are related to processes that are operative in the low-dose region. In such a situation, it is likely that the low-dose risks would be less than those estimated by the UCL-LMS method. However, the magnitude of that reduction remains unknown without additional data and/or modeling. In my view, another line should be considered: an "Anti-carcinogen" line. In the two long-term bioassays conducted on 2,3,7,8-TCDD (Kociba et al.,
TOXICITY EQUIVALENTSAND EPA'S RISK ASSESSMENT FOR 2,3,7,8-TCDD
8l
1978; NTP, 1982), the animals treated with the lowest doses (,-~ 1 ng kg -~ day -t) exhibited a somewhat reduced tumor response when compared with the controls. While the data are not strong enough to be statistically definitive, they do suggest the possibility of an anti-carcinogenic effect at the lowest doses (c.f., Davis, 1989). If this were the case, then the dose-response line would, at some point, fall below the background risk at some dose greater than zero; i.e., an effective "threshold". However, without additional data, this possibility remains an hypothesis. In summary, the workgroup reached several conclusions concerning risk assessment. (i) Despite evidence that 2,3,7,8-TCDD acts as a promoter, it is inadvisable to adopt a threshold approach for the compound given the unique character of the chemical. (ii) New mathematical extrapolation approaches [e.g., Moolgavkar and Knudson, 1981; Sielken, 1987; Thorslund (in USEPA, 1988b)] are interesting, but, as yet, untested. (iii) The available evidence suggests that reliance on the LMS model may be less appropriate for 2,3,7,8-TCDD than for many ~ther chemicals, and that the Agency's 1985 assessment based on the LMS model may overestimate the upper bound on the risk by some unknown amount. (iv) A new approach to risk extrapolation for 2,3,7,8-TCDD should be undertaken that incorporates the biological information on the receptor-mediated activity of the compound. Thus, while suggesting that the current LMS estimate is likely to "overcall" the risk and favoring the Composite line in Fig. 3, the group could not distinguish between a number of linear-at-low-dose models which seek to describe the cancer risk posed by 2,3,7,8-TCDD. Therefore, the workgroup recommended that, in the absence of scientific data that would distinguish between the different linear-at-low-dose models, the Agency should decide upon a potency value for 2,3,7,8-TCDD on the basis of a science policy decision. The 1985 UCL-LMS risk assessment approach associated a dose of 0.006pg kg -I day -t with a UCL lifetime risk of cancer of 1 × 10-6; i.e., the risk-specific dose [RsD(10-6)] = 0.006pg kg t day-~ (USEPA, 1985). The workgroup recommended that, as a matter of policy, the Agency change the RsD(10 -6) to a value of 0.1pg kg -t day -t, which, they felt, would be consistent with, but not dictated by, the scientific evidence available today. The workgroup's explicit reasoning was as follows. (i) The scientific data indicate that the Agency's current upper bound for 2,3,7,8-TCDD may be an overestimate.
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(ii) The scientific data do not permit an estimate of the extent of the overestimate. (iii) The UCL-LMS RsD(10 -6) estimates generated by US Federal agencies, all based on linear-at-low-dose extrapolation approaches, are arguably of equal scientific merit at this time. (iv) For strictly policy purposes, there is great benefit in Federal agencies adopting more consistent positions in the absence of compelling scientific information. (v) An order of magnitude estimate of the RsD(10-6), as opposed to some more precise estimate, helps to convey the notion that the numerical expression is only a rough estimate, science permitting no greater accuracy. During the summer of 1988, this position was made available for public comment. In the fall, the workgroup's position and the public comments were sent to the USEPA's Science Advisory Board for their consideration.
The Science Advisory Board (SAB) review The SAB is a group of non-governmental scientists and engineers, established by an Act of Congress in 1978 [Environmental Research, Development and Demonstration Authorization Act (42 U.S.C 4365)] to advise the Administrator of USEPA on the strength of the Agency's technical arguments used to support its regulatory positions. Over the past 10 years, the SAB has released more than 200 reports on subjects ranging from risk assessment guidelines to a strategy for environmental research in the 1990s (USEPA, 1990). In this case, the SAB convened a special panel of more than a dozen experts to review the USEPA's proposal for a reassessment of the carcinogenicity of 2,3,7,8-TCDD. The committee met in public session in November 1988. During much of the following year, the committee drafted its report, conferred by phone, and prepared for its presentation to the Administrator. In November 1989 the SAB's report was released and Dr Bernard Goldstein, Co-Chair of the review committee, presented the group's findings to the Administrator, Deputy Administrator, and several other members of senior Agency management. The SAB found much in the USEPA proposal with which to agree. (i) They agreed with the workgroup's criticism of the LMS model. (ii) They agreed that no new information had appeared in the past 3 years that would permit reevaluation of the RsD(10 -6) through the use of the standard LMS approach. (iii) They agreed that while there are promising alternative models that may be expected to reflect more accurately the biological basis of 2,3,7,8TCDD carcinogenesis, such newer models need to be further developed and validated.
TOXICITY EQUIVALENTS AND EPA'S RISK ASSESSMENT FOR 2,3,7,8-TCDD
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(iv) They agreed that new studies have provided much new insight into the toxicological effects of 2,3,7,8-TCDD, and that such information is likely to be of major significance to the regulatory decisions concerning 2,3,7,8-TCDD. (v) They agreed that there is no specific scientific pathway by which one could currently generate a new RsD(10-6). [They did not comment on the validity Of the 1985 RsD(10-6).] However, the Board did not concur with the proposal's recommendation to change the RsD(10-6). Specifically, they stated that: (i) they did not agree with the proposal's contention that the new scientific information concerning 2,3,7,8-TCDD "mandates a change" in the RsD(10-6); (ii) there is no reason to believe that a new model, based on a receptormediated model, would necessarily lead to a relaxation of the RsD(10-6). They concluded by saying "The Panel thus concluded that at the present time the important new scientific evidence about 2,3,7,8-TCDD does not compel a change in the current assessment of the carcinogenic risk for 2,3,7,8T C D D to humans. EPA may, for policy reasons, set a different RsD . . . , but the Panel finds no scientific basis for such a change at this time". As a preferred move at this time, the Board recommended that the Agency " . . . build upon their excellent review of the new scientific data relevant to 2,3,7,8-TCDD carcinogenesis by moving rapidly to develop and validate a new risk model capable of more accurately estimating the risk of human cancer caused by the dioxins and related compounds". What happens now?
In my view, the SAB report supports the USEPA workgroup's position in large measure. Contrary to the implication of the language in the SAB report, the workgroup explicitly stated that the available scientific information does not lead one to select one linear-at-low-dose-derived RsD(10 -6) versus another. That is, the information neither "compels" nor "mandates" a change. Therefore, both the Agency workgroup and the SAB felt that any change would be based on "policy", not "science". However, the SAB did differ with the workgroup in at least one important respect. That is, while the Agency's proposal argued that use of a more appropriate model would most likely lead to a lowering of the risk [raising of the RsD(10-6)] by an unknown magnitude, the SAB argued that neither the direction nor the magnitude could be accurately predicted at this time. During 1989, a committee chaired by the Deputy Administrator of USEPA reviewed the change proposed by the workgroup and the SAB's reaction to it. The committee considered a number of aspects, including the fact that some
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regulatory decisions had already been made by States (e.g., Oregon) and that technical issues had been raised about other parts of the risk assessment, particularly the bioaccumulation of 2,3,7,8-TCDD by fish and the estimated amount of fish consumed by fish-eating populations. Considering this information in toto the committee decided not to adopt the workgroup's proposal at this time. It now appears that the USEPA will mount an effort to reassess the risks posed by 2,3,7,8-TCDD, based upon new data (e.g., Fingerhut et al., 1991) and alternative risk assessment approaches. This work is likely to commence during 1991. CONCLUSIONS
The Agency, in working with the international scientific community, has adopted the I-TEFs/88, as an interim procedure, useful in considering the risks posed by CDDs and CDFs other than 2,3,7,8-TCDD. The Agency is likely to review and update these factors, as needed. At the same time, the Agency will be pushing to replace the TEF approach with a bioassay system that measures directly the toxic potential for these complex mixtures. The official Agency position on the toxicity of 2,3,7,8-TCDD is unchanged from that articulated in 1985 (USEPA, 1985). However, the Agency is likely to initiate soon a reassessment of the carcinogenic risk of 2,3,7,8-TCDD. This activity would involve recent animal and human toxicity data, as well as a number of important exposure factors; e.g., bioaccumulation potential and fish consumption patterns of various human populations. In any event, it is clear that 'dioxin' continues to be a driving issue in many topics before the Agency; e.g., combustion of municipal waste, bleached pulp and paper products, disposal of sewage sludge, and contaminants in commercial chemicals. Therefore, CDD/CDF issues are likely to occupy the attention of USEPA for several more years. REFERENCES Commoner, B., K. Shapiro and T. Webster, 1984. Environmental and economic analysis of alternative municipal solid waste disposal technologies. I. An assessment of the risks due to emissions of chlorinated dioxins and dibenzofurans from proposed New York City incinerators. Queens College, New York, NY. Couture, L.A., M.R. Elwell and L.S. Birnbaum, 1988. Dioxin-like effects observed in male rats following exposure to octachlorodibcnzo-p-dioxin (OCDD) during a 13 week study. Toxicol. Appl. Pharmacol., 93: 31-46. Davis, D.L., 1989. Natural anti-carcinogens, carcinogens and changing patterns in cancer: some speculations. Environ. Res., 50: 322-340. Eadon, G., L. Kaminsky, J. Silkworth, K. Aldous, D. Hiker, P. O'Keefe, R. Smith, J. Gierthy, J. Hawley, N. Kim and A. Decaprio, 1986. Calculation of 2,3,7,8-TCDD equivalent
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concentrations of complex environmental contaminant mixtures. Environ. Health Perspect., 70: 221-227. Federal Register, 1986. Cancer Risk Assessment Guidelines. 51: 33992-34003. Fingerhut, M., W.E. Halperin, D. Marlow, L.A. Piacitelli, P.A. Honchar, M.H. Sweeney, A.L. Greife, P.A. Dill, K. Steenland and A.J. Suruda, 1991. Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. N. Engl. J. Med., 324: 212-218. Gravitz et al., 1983. Interim guidelines for acceptable exposure levels in office settings contaminated with PCB and PCB combustion products. Epidemiological Studies Section, California Department of Health Services, Berkeley, CA. Kociba, R.J., D.G. Keyes, J.E. Beyer, R.M. Carreson, E.E. Wade, D.A. Henbar, P.O. Kalmins, L.F. Franson, P.N. Park, S.D. Barnard, P.A. Hummel and C.G. Humiston, 1978. Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin rates. Toxicol. Appl. Pharmacol., 46(2): 279-303. Lindstrom, G. and C. Rappe, 1986. Analytical method for analysis of polychlorinated dibenzop-dioxins and dibenzofurans in milk. Chemosphere, 17: 921-935. Moolgavkar, S.H. and A.G. Knudson, 1981. Mutation and cancer: a model for human carcinogenesis. J. Natl Cancer Inst., 66: 1037-1052. NATO/CCMS (North Atlantic Treaty Organization, Committee on the Challenges of Modern Society), 1988a. International toxicity equivalency factor (I-TEF) method of risk assessment for complex mixtures of dioxins and related compounds. Rep. No. 176, Brussels, Belgium. NATO/CCMS (North Atlantic Treaty Organization, Committee on the Challenges of Modern Society), 1988b. Scientific basis for the development of international toxicity equivalency (I-TEF) factor method for risk assessment for complex mixtures of dioxins and related compounds. Rep. No. 178, Brussels, Belgium. NTP (National Toxicology Program), 1982. Carcinogenesis bioassay of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Osborne-Mendel rats and B6C3FI mice. Tech. Rep. No. 209. Research Triangle Park, NC. Olie, K., M.V.D. Berg and O. Hutzinger, 1983. Formation rate of PCDD and PCDF from combustion processes. Chemosphere, 12: 627-636. Ontario Government, 1982. Scientific criteria document for standard development. Polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). Ministry of the Environment. No. 4-84, December. Poland, A. and J.C. Knutson, 1982. 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: an examination of mechanism of toxicity. Annu. Rev. Pharmacol. Toxicol., 22: 514-554. Poland, A., W.F. Greenlee and A.S. Kende, 1979. Studies on the mechanisms of action of chlorinated dibenzo-p-dioxins and related compounds. Ann. N.Y. Acad. Sci., 320: 214-230. Rappe, C., R. Anderson, P.A. Berqquist, C. Brohede, M. Hansson, L.O. Keller, G. Lindstrom, S. Marklund, M. Nygren, S.E. Swanson, M. Tysklind and K. Wiberr, 1987. Overview on environmental fate of chlorinated dioxins and dibenzofurans; sources, levels and isomeric patterns in various matrices. Chemosphere, 16:1603-1618. Safe, S.H., 1987. Determination of the 2,3,7,8-TCDD toxic equivalent factors: support for use of the in vitro AHH induction assay. Chemosphere, 16: 791-802. Safe, S.H., G. Mason, T. Sawyer, T. Zacharewski, M. Harris, C. Yao, B. Keyes, K. Farrell, M. Holcomb, D. Davies, L. Safe, J. Piskorska-Pliszczynska, B. Leece, M.A. Denomme, O. Hutzinger, H. Thoma, B. Chittim and J. Madge, 1989. Development and validation of in vitro bioassays for 2,3,7,8-TCDD equivalents. Toxicol. Ind. Health, 5: 757-775. Sawyer, T., S. Bandiera, S. Safe, O. Hutzinger and K. Olie, 1983. Bioanalysis of polychlorinated dibenzofuran and dibenzo-p-dioxin mixtures in fly ash. Chemosphere, 12: 529-534.
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Sielken, R.L., 1987. Quantitative cancer risk assessments for TCDD. Food Chem. Toxciol., 25(3): 257-267. USDHHS, 1983. Levels of concern for hexa- (HCDD), hepta- (HpCDD), and octachlorodibenzo-p-dioxins (OCCD) in chickens and eggs. Memorandum. USEPA (U.S. Environmental Protection Agency), 1985. Health assessment document for polychlorinated dibenzo-p-dioxins. EPA-600/8-84-014F. National Technical Information Service, Springfield, VA, PB86-122546/AS. USEPA, 1987. Interim procedures for estimating risks associated with exposure to mixtures of chlorinated dibenzo-p-dioxins and -dibenzofurans (CDDs/CDFs). Risk Assessment Forum. EPA/625/3-87/012. Principal authors J. Bellin and D. Barnes. National Technical Information Service, Springfield, VA, PB89-125041. USEPA, 1988a. A cancer risk-specific dose estimate for 2,3,7,8-TCDD. External Review Draft. EPA/600/6-88/007Aa. Workgroup and principal authors P. Preuss, Chair; D. Barnes, D. Patton, P. Roberts, H. Spitzer, D. Taylor. National Technical Information Service, Springfield, VA, PB88-231204. USEPA, 1988b. A cancer risk-specific dose estimate for 2,3,7,8-TCDD. Appendices A-F. EPA/60016-88[OO7Ab. Cancer risk modeling, S. Bayard/T. Thorslund; Cancer epidemiology, D. Bayliss; Reproductive and developmental toxicity, G. Kimmel; Epidemiologic data on reproduction, S. Selevan; Immunotoxicity, B. Sonawane; Mechanism of action, M. Gallo. National Technical Information Service, Springfield, VA. USEPA 1988c. Estimating exposures to 2,3,7,8-TCDD. EPA[60016-88/OO5A. USEPA, 1989. Interim procedures for estimating risks associated with exposure to mixtures of chlorinated dibenzo-p-dioxins and -dibenzofurans and 1989 update. Risk Assessment Forum. EPA/625/3-89/016. Principal authors D. Barnes, F. Kutz and D. Bottimore. National Technical Information Service, Springfield, VA. USEPA, 1990. FY88 Report of the Staff Director of the Science Advisory Board. USEPA, Washington, DC. Wolfe, W.H., J.E. Michalek, J.C. Miner and M.R. Peterson, 1988. Serum 2,3,7,8-tetrachlorodibenzo-p-dioxin levels in Air Force health study participants: preliminary report. Mortality and Morbidity Weekly Report, 37: 309-310.
73
Toxicity equivalents and EPA's risk assessment of 2,3,7,8-TCDD Donald G. Barnes United States Environmental Protection Agency, 401 M St. SW, Washington, DC 20460, USA
ABSTRACT Toxicity equivalent factors (TEFs) have proved useful in estimating the toxicity of complex mixtures of chlorinated dibenzo-p-dioxins and dibenzofurans (CDDs/CDFs). An international consensus has formed around a specific set of T E F values as interim solution for addressing environmental contamination by CDDs/CDFs. This procedure capitalizes on the congenerspecific analytical results that are more routinely available in recent years. The TEF approach should be updated as necessary and replaced by more definitive bioassay approaches as soon as practicable. In an independent activity, the USEPA considered a proposal to change (reduce) the cancer potency ascribed to 2,3,7,8-TCDD by a factor of 16. The recommendation was based upon an analysis of the literature and the Agency's earlier risk assessment. The proposal was reviewed by the Science Advisory Board, a group of outside scientific advisors. Subsequently, the Agency decided against making any changes in its assessment at this time. However, it is likely that a reassessment will be conducted shortly that will incorporate new data and a new approach to estimating of cancer risks posed by 2,3,7,8-TCDD.
INTRODUCTION
During 1988-89 there were two significant activities at the United States Environmental Protection Agency (USEPA or Agency) related to the risk assessment for chlorinated dibenzo-p-dioxins and dibenzofurans (CDDs/ CDFs). First, the USEPA, working in conjunction with a special committee of the North Atlantic Treaty Organization (NATO), adopted an updated set of toxicity equivalency factors (TEFs) which guide the Agency's efforts to assess the risks posed by CDDs/CDFs other than 2,3,7,8-tetrachlorodibenzop-dioxin (2,3,7,8-TCDD). Second, the Agency's Science Advisory Board (SAB), a group of distinguished non-governmental scientists and engineers, reviewed a USEPA staff proposal to reassess the cancer risk assessment of 2,3,7,8-TCDD, the effect of which would be to bring USEPA's assessment more in line with that of other risk assessors around the world. This paper summarizes these recent events. In doing so, the author provides
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his interpretation of these developments, which is not necessarily that of USEPA. TOXICITY EQUIVALENTS (TEQs)
Since 1970, when 2,3,7,8-TCDD was first discovered to be an environmental problem, more than $1 billion has been spent on researching the toxicity of this, the most prominent and probably most potent, member of the 210member family of CDDs/CDFs. Despite tremendous gains in our knowledge of the properties and mechanisms-of-action of 2,3,7,8-TCDD, the holding of this conference is clear testimony to the fact that there is no universal agreement on the risks posed by this substance. The data base of toxicological information on any of the other 209 compounds in the CDD/CDF family is much smaller. And yet, over the past decade we have learned that the CDDs/CDFs other than 2,3,7,8-TCDD are more prevalent in the environment; i.e. there are more sources of these compounds and they appear in greater quantities (e.g., Rappe et al., 1987). Consequently, risk assessors and regulators are continually challenged to interpret the significance of environmental levels of these substances. In the late 1970s, Dr Donald Grant, a toxicologist with Health and Welfare Canada, suggested a simplistic approach to this problem (Grant, 1977). He noted that the mechanism-of-action of 2,3,7,8-TCDD appeared to be associated with its interaction with a specific receptor in the cytosolic portion of the cell (e.g., Poland and Knutson, 1982). The other CDDs/CDFs also interact with the same receptor, only at higher doses, and elicit similar toxic properties, but again at higher doses (Poland et al., 1979). Grant hypothesized that the potency of the other CDDs/CDFs would be inversely related to the ECs0 for their interaction with the receptor and early sequela; e.g., enzyme induction. These relative potencies could be expressed as toxicity equivalency factors (TEFs) and used to convert concentrations of CDDs/CDFs found in environmental samples into equivalent concentrations of 2,3,7,8-TCDD. Thus, Estimated 2,3,7,8-TCDD-like toxicity of a mixture of CDDs/CDFs = Concentration of toxicity equivalents = [TEQs] = = Z (TEF)~ x [CDD/CDF]~ i
where (TEF)i is the relative potency of the ith CDD/CDF compared with 2,3,7,8-TCDD, i.e. (TEF)i = (potency of ith CDD/CDF)/(potency of 2,3,7,8-TCDD)
75
TOXICITY EQUIVALENTS AND EPA'S RISK ASSESSMENT FOR 2,3,7,8-TCDD
TABLE 1
Toxicity equivalency factors Compound
EPA-TEFs/87
I-TEFs/88
Mono-, di-, and triCDDs 2,3,7,8-TCDD Other TCDDs 2,3,7,8-PeCDD Other PeCDDs 2,3,7,8-HxCDD Other HxCDDs 2,3,7,8-HpCDD Other HpCDDs OCDD Mono-, di-, and triCDFs 2,3,7,8-TCDF Other TCDFs 1,2,3,7,8-PeCDF 2,3,4,7,8-PeCDF Other PeCDFs 2,3,7,8-HxCDF Other HxCDFs 2,3,7,8-HpCDF Other H p C D F s OCDF
0 1 0.01 0.5 0.005 0.04 0.0004 0.001 0.00001 0 0 0.1 0.001 0.1 0.1 0.001 0.01 0.0001 0.001 0.00001 0
0 I 0 0.5 0 0.1 0 0.01 0 0.001 0 0. ! 0 0.05 0.5 0 0.1 0 0.01 0 0.001
NATO/CCMS, 1988a.
During the 1980s, a number of different groups proposed separate schemes for TEFs (e.g., Grant, 1977; Eadon et al., 1986; Ontario Government, 1982; Gravitz et al., 1983; Olie et al., 1983; USDHHS, 1983; Commoner et al., 1984). In 1987, the USEPA adopted, as a matter of interim science policy, its own set of TEFs (since called "EPA-TEFs/87", see Table 1) after examining the relative potency of different C D D s / C D F s for a variety of in vivo and in vitro endpoints; e.g., cancer, re.productive effects, body weight loss, cell transformation, and immunotoxicity (USEPA, 1987). A clear distinction is made between the laterally substituted congeners ("2,3,7,8-substituted") and those that are not ("non-2,3,7,8-substituted"). Figure 1 and Table 2 show how the TEFs can be used to convert concentrations of C D D s / C D F s in environmental samples into equivalent concentrations of 2,3,7,8-TCDD (USEPA, 1989). The expressed intent of the Agency was, and remains, to replace the TEF approach with a more direct measurement of the biological activity of a C D D / C D F mixture as soon as possible. However, it is interesting to note that, in most instances, the TEQs calculated by the different TEF schemes differ by
76
D.G. BARNES
0.8
PCDFs
0.6
o. o_ 0.6 v
g g
o.c 0.3
= o u
0.2
i
FPA-TE Os/B7
i
I-TEOs I 88
Fig. 1. Toxicity equivalents in human milk sample (Lindstrom and Rappe, 1986).
TABLE 2 Converting congener-specific data to toxicity equivalents by two TEF schemes (see Fig. 1) TEF scheme
Congener
Source data (ppt)
EPA-TEF/87
I-TEF/88
2,3,7,8-TCDD 1,2,3,7,8-PeCDD 1,2,3,4,7,8-HxCDD 1,2,3,6,7,8-HxCDD 1,2,3,7,8,9-HxCDD 1,2,3,4,6,7,8-HpCDD OCDD Total CDDs
0. i I 0.18 0.08 0.73 0.15 I. 3 5.7
0. I 1 0.09 0.0032 0.029 0.006 0.0013 0 0.24
0.11 0.09 0.008 0.073 0.015 0.013 0.0057 0.31
2,3,7,8-TCDF 1,2,3,7,8-PeCDF 2,3,4,7,8-PeCDF 1,2,3,4,7,8-HxCDF 1,2,3,6,7,8-HxCDF 2,3,4,6,7,8-HxCDF 1,2,3,4,6,7,8-HpCDF OCDF Total CDFs
0.12 0.022 0.51 0.097 0.078 0.04 0.19 0.062
0.012 0.0022 0.051 0.00097 0.00078 0.0004 0.00019 0 0.068
0.012 0.001 I 0.26 0.0097 0.0078 0.004 0.0019 0.000052 0.30
EPA-TEQs/87 = 0.3
I-TEQs/88 = 0.6
37% contributed by 2,3,7,8-TCDD
18% contributed by 2,3,7,8-TCDD
Total TEQs
TOXICITY EQUIVALENTS AND EPA'S RISK ASSESSMENT FOR 2,3.7,8-TCDD
77
a factor of < 4. Even more encouraging are the cases in which the TEQ-estimated toxicity of a mixture of CDDs/CDFs has been shown to be remarkably consistent with the demonstrated toxicity obtained from in vivo measures using in toto mixtures (e.g., Sawyer et al., 1983; Safe, 1987; Safe et al., 1989). In 1985, the Committee on the Challenges of Modern Science (CCMS) of NATO formed an information exchange group to examine a multitude of issues surrounding CDDs/CDFs, among them the scientific credibility and regulatory utility of the TEQ concept. A subcommittee examined the problems and promises posed by the TEQ approach. They agreed that the preferred method of toxicological assessment would be to have some effective short-term assay that could measure the toxicity of a C D D / C D F mixture directly. However, in the interim, they recommended the use of TEFs. The subcommittee went further. Following proposals set forth by the Nordic countries, the NATO CCMS group recommended that the member countries adopt a common set of TEFs, which were called "1988 International Toxicity Equivalency Factors (I-TEFs/88)" (See Table 1) (NATO/CCMS, 1988a,b). The more significant changes from the EPA-TEF/87 scheme relate to: (i) focusing solely on 2,3,7,8-substituted congeners; to simplify the scheme and acknowledge that those are the congeners that contribute the majority of the TEQs in most environmental samples, particularly those involving biological tissue; (ii) recognizing the greater potency of 2,3,4,7,8-PeCDF (NATO/CCMS, 1988b); (iii) assigning a non-zero value to OCDD and OCDF, based upon new information (Couture et al., 1988). The I-TEFs/88 have now been adopted by several countries; e.g., the United States (USEPA), Canada, Federal Republic of Germany, Finland, Great Britain, Italy, The Netherlands, Norway, and Sweden. In closing this introduction to TEQs, let me emphasize three points. (i) The use of TEFs is an interim procedure. (a) Research should be conducted to replace the TEF procedure as soon as possible with a short-term assay that measures the combined toxicity of the C D D / C D F mixture. We know, for example, that significant antagonisms can occur in certain mixtures in which the "non-toxic, non-2,3,7,8-substituted" CDDs/CDFs mitigate the biological response invoked by the "toxic, 2,3,7,8substituted" CDDs/CDFs. These non-additive effects are not accounted for in a simple TEF approach. (b) The TEFs should be changed whenever new scientific data indicate that changes are warranted. The USEPA assured its Science Advisory Board that the TEFs would be updated on a regular basis; e.g., every other year. (ii) Analytical chemists should continue to strive toward complete reporting of a congener-specific analysis of an environmental sample, while
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D.G. BARNES
summarizing its toxicological significance in terms of TEQs. Of course, the detailed congener-specific information is needed to calculate TEQs. In addition, congener-specific analyses can sometimes provide information useful in linking a particular CDD/CDF source to the residues found in a particular sample. (iii) Toxicity equivalents should be expressed in such a way that the percentage of total TEQs due to 2,3,7,8-TCDD is clear (Fig. 1). Since a principal concern for CDDs/CDFs risk assessment is cancer, the risk manager should be aware of the proportion of TEQs which are due to the validated animal carcinogen, 2,3,7,8-TCDD (Kociba et al., 1978; NTP, 1982). The remainder of the TEQs are derived from CDDs/CDFs whose carcinogenic properties are less well-demonstrated. Among the limited number of CDDs/ CDFs which have been studied for carcinogenicity, only a mixture of 1,2,3,7,8,9- and 1,2,3,6,7,8-HxCDD has been shown to be carcinogenic in animals. EPA's PROPOSED REASSESSMENT OF THE CARCINOGENIC POTENCY OF 2,3,7,8TCDD
The USEPA proposal During the 1980s a number of regulatory bodies throughout the world generated separate assessments of the cancer risks posed by 2,3,7,8-TCDD. While all of these assessments relied on essentially the same experimental data, they differed in some of their fundamental assumptions; e.g., the mechanismof-action and the methods for extrapolating animal data to humans. The result was a 1000-fold difference in the "level of concern" resulting from these various approaches (see Fig. 2, taken from USEPA, 1988a). The USEPA result is at one extreme of this range. The Agency's estimate of the carcinogenic risk posed by 2,3,7,8-TCDD (USEPA, 1985) was derived using the approach outlined in the 1986 USEPA Cancer Risk Assessment Guidelines (Federal Register, 1986). These Guidelines give prominence to the application of the linearized multi-stage (LMS) mathematical model. Further, the Guidelines call for extrapolating from animal data to humans through the use of a body surface area correction (i.e., dose rate/body surface area), rather than the more traditional body weight correction (i.e., dose rate/body weight). This is a fundamental difference between the USEPA approach and that used by the US Food and Drug Administration (USFDA). In 1987, the USEPA Administrator asked an intra-Agency workgroup to consider carefully all of the data on the carcinogenicity of 2,3,7,8-TCDD and advise him on whether the USEPA assessment should be changed. The
79
TOXICITY EQUIVALENTS AND EPA'S RISK ASSESSMENT FOR 2,3,7,8-TCDD
California
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Fig. 2. Some examples of risk specific doses (10 -6 ) and reference doses calculated by individual scientists, scientific organizations, and regulatory agencies for 2,3,7,8-TCDD. ( ) Conclusions reached by regulatory agencies or scientific organizations; (. . . . ) conclusions reached by research efforts.
workgroup was supported by the efforts of Agency technical experts in a number of different areas. After a year of study and discussion, the group produced a report (USEPA, 1988a), buttressed by a series of appendices dealing with specific issues (USEPA, 1988b). In a companion effort, the Agency produced a report on exposure characteristics of 2,3,7,8-TCDD (USEPA, 1988c). The workgroup reached several conclusions concerning the mechanism-ofaction: (i) 2,3,7,8-TCDD is a potent promoter of carcinogenesis; (ii) the possibility that 2,3,7,8-TCDD acts as a direct-acting, complete carcinogen cannot be eliminated; (iii) 2,3,7,8-TCDD may act through a secondary mechanism(s) which may affect the carcinogenic process at different stages; (iv) 2,3,7,8-TCDD may act through a number of different mechanisms so that the observed effects represent an integrated composite of several mechanisms in operation. After reviewing all of the data, the group concluded that the "promoter" vs "complete carcinogen" characterization of 2,3,7,8-TCDD is probably an oversimplification. While the compound conforms to the operational definition of a complete carcinogen (i.e., tumors are generated in treated animals in a dose-related manner), it does not exhibit other properties often associated with "classical complete carcinogens" (e.g., mutagenicity and binding to DNA). Likewise; while exhibiting promoter behavior in certain bioassays, the chemical differs from the "classical promoter" by acting at very
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D.G. BARNES
M S
(1985)
DOSE Fig. 3. "Multiple mechanism" hypothesis for 2,3,7,8-TCDD carcinogenesis.
low doses. In addition, arguments about the "reversible" aspect of promoters are mitigated in the case of 2,3,7,8-TCDD by the long half-life in the body, i.e. about 7 years (Wolfe et al., 1988). There is a good deal of evidence that 2,3,7,8-TCDD may be exerting its effect through an indirect, receptor-mediated mechanism (e.g., Poland and Knutson, 1982). While some of these indirect routes may behave in a typical "threshold" fashion, it is possible that others also behave in a linear fashion down to zero dose. The various possibilities are displayed conceptually in Fig. 3. The "UCL-LMS (1985)" line (the "upper confidence limit generated from the LMS model") is designed to be an upper limit of what the risk is likely to be. That is, this estimate is not likely to be exceeded in reality; the actual risk could be considerably lower, even zero. The UCL-LMS assumes that all of the tumors observed in the experimental range are related to processes that are also operative in the low-dose region. The "Composite (1988)" line is a conceptual representation of the low-dose behavior where only some of the tumors observed in the experimental range are related to processes that are operative in the low-dose region. In such a situation, it is likely that the low-dose risks would be less than those estimated by the UCL-LMS method. However, the magnitude of that reduction remains unknown without additional data and/or modeling. In my view, another line should be considered: an "Anti-carcinogen" line. In the two long-term bioassays conducted on 2,3,7,8-TCDD (Kociba et al.,
TOXICITY EQUIVALENTSAND EPA'S RISK ASSESSMENT FOR 2,3,7,8-TCDD
8l
1978; NTP, 1982), the animals treated with the lowest doses (,-~ 1 ng kg -~ day -t) exhibited a somewhat reduced tumor response when compared with the controls. While the data are not strong enough to be statistically definitive, they do suggest the possibility of an anti-carcinogenic effect at the lowest doses (c.f., Davis, 1989). If this were the case, then the dose-response line would, at some point, fall below the background risk at some dose greater than zero; i.e., an effective "threshold". However, without additional data, this possibility remains an hypothesis. In summary, the workgroup reached several conclusions concerning risk assessment. (i) Despite evidence that 2,3,7,8-TCDD acts as a promoter, it is inadvisable to adopt a threshold approach for the compound given the unique character of the chemical. (ii) New mathematical extrapolation approaches [e.g., Moolgavkar and Knudson, 1981; Sielken, 1987; Thorslund (in USEPA, 1988b)] are interesting, but, as yet, untested. (iii) The available evidence suggests that reliance on the LMS model may be less appropriate for 2,3,7,8-TCDD than for many ~ther chemicals, and that the Agency's 1985 assessment based on the LMS model may overestimate the upper bound on the risk by some unknown amount. (iv) A new approach to risk extrapolation for 2,3,7,8-TCDD should be undertaken that incorporates the biological information on the receptor-mediated activity of the compound. Thus, while suggesting that the current LMS estimate is likely to "overcall" the risk and favoring the Composite line in Fig. 3, the group could not distinguish between a number of linear-at-low-dose models which seek to describe the cancer risk posed by 2,3,7,8-TCDD. Therefore, the workgroup recommended that, in the absence of scientific data that would distinguish between the different linear-at-low-dose models, the Agency should decide upon a potency value for 2,3,7,8-TCDD on the basis of a science policy decision. The 1985 UCL-LMS risk assessment approach associated a dose of 0.006pg kg -I day -t with a UCL lifetime risk of cancer of 1 × 10-6; i.e., the risk-specific dose [RsD(10-6)] = 0.006pg kg t day-~ (USEPA, 1985). The workgroup recommended that, as a matter of policy, the Agency change the RsD(10 -6) to a value of 0.1pg kg -t day -t, which, they felt, would be consistent with, but not dictated by, the scientific evidence available today. The workgroup's explicit reasoning was as follows. (i) The scientific data indicate that the Agency's current upper bound for 2,3,7,8-TCDD may be an overestimate.
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D.G. BARNES
(ii) The scientific data do not permit an estimate of the extent of the overestimate. (iii) The UCL-LMS RsD(10 -6) estimates generated by US Federal agencies, all based on linear-at-low-dose extrapolation approaches, are arguably of equal scientific merit at this time. (iv) For strictly policy purposes, there is great benefit in Federal agencies adopting more consistent positions in the absence of compelling scientific information. (v) An order of magnitude estimate of the RsD(10-6), as opposed to some more precise estimate, helps to convey the notion that the numerical expression is only a rough estimate, science permitting no greater accuracy. During the summer of 1988, this position was made available for public comment. In the fall, the workgroup's position and the public comments were sent to the USEPA's Science Advisory Board for their consideration.
The Science Advisory Board (SAB) review The SAB is a group of non-governmental scientists and engineers, established by an Act of Congress in 1978 [Environmental Research, Development and Demonstration Authorization Act (42 U.S.C 4365)] to advise the Administrator of USEPA on the strength of the Agency's technical arguments used to support its regulatory positions. Over the past 10 years, the SAB has released more than 200 reports on subjects ranging from risk assessment guidelines to a strategy for environmental research in the 1990s (USEPA, 1990). In this case, the SAB convened a special panel of more than a dozen experts to review the USEPA's proposal for a reassessment of the carcinogenicity of 2,3,7,8-TCDD. The committee met in public session in November 1988. During much of the following year, the committee drafted its report, conferred by phone, and prepared for its presentation to the Administrator. In November 1989 the SAB's report was released and Dr Bernard Goldstein, Co-Chair of the review committee, presented the group's findings to the Administrator, Deputy Administrator, and several other members of senior Agency management. The SAB found much in the USEPA proposal with which to agree. (i) They agreed with the workgroup's criticism of the LMS model. (ii) They agreed that no new information had appeared in the past 3 years that would permit reevaluation of the RsD(10 -6) through the use of the standard LMS approach. (iii) They agreed that while there are promising alternative models that may be expected to reflect more accurately the biological basis of 2,3,7,8TCDD carcinogenesis, such newer models need to be further developed and validated.
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(iv) They agreed that new studies have provided much new insight into the toxicological effects of 2,3,7,8-TCDD, and that such information is likely to be of major significance to the regulatory decisions concerning 2,3,7,8-TCDD. (v) They agreed that there is no specific scientific pathway by which one could currently generate a new RsD(10-6). [They did not comment on the validity Of the 1985 RsD(10-6).] However, the Board did not concur with the proposal's recommendation to change the RsD(10-6). Specifically, they stated that: (i) they did not agree with the proposal's contention that the new scientific information concerning 2,3,7,8-TCDD "mandates a change" in the RsD(10-6); (ii) there is no reason to believe that a new model, based on a receptormediated model, would necessarily lead to a relaxation of the RsD(10-6). They concluded by saying "The Panel thus concluded that at the present time the important new scientific evidence about 2,3,7,8-TCDD does not compel a change in the current assessment of the carcinogenic risk for 2,3,7,8T C D D to humans. EPA may, for policy reasons, set a different RsD . . . , but the Panel finds no scientific basis for such a change at this time". As a preferred move at this time, the Board recommended that the Agency " . . . build upon their excellent review of the new scientific data relevant to 2,3,7,8-TCDD carcinogenesis by moving rapidly to develop and validate a new risk model capable of more accurately estimating the risk of human cancer caused by the dioxins and related compounds". What happens now?
In my view, the SAB report supports the USEPA workgroup's position in large measure. Contrary to the implication of the language in the SAB report, the workgroup explicitly stated that the available scientific information does not lead one to select one linear-at-low-dose-derived RsD(10 -6) versus another. That is, the information neither "compels" nor "mandates" a change. Therefore, both the Agency workgroup and the SAB felt that any change would be based on "policy", not "science". However, the SAB did differ with the workgroup in at least one important respect. That is, while the Agency's proposal argued that use of a more appropriate model would most likely lead to a lowering of the risk [raising of the RsD(10-6)] by an unknown magnitude, the SAB argued that neither the direction nor the magnitude could be accurately predicted at this time. During 1989, a committee chaired by the Deputy Administrator of USEPA reviewed the change proposed by the workgroup and the SAB's reaction to it. The committee considered a number of aspects, including the fact that some
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regulatory decisions had already been made by States (e.g., Oregon) and that technical issues had been raised about other parts of the risk assessment, particularly the bioaccumulation of 2,3,7,8-TCDD by fish and the estimated amount of fish consumed by fish-eating populations. Considering this information in toto the committee decided not to adopt the workgroup's proposal at this time. It now appears that the USEPA will mount an effort to reassess the risks posed by 2,3,7,8-TCDD, based upon new data (e.g., Fingerhut et al., 1991) and alternative risk assessment approaches. This work is likely to commence during 1991. CONCLUSIONS
The Agency, in working with the international scientific community, has adopted the I-TEFs/88, as an interim procedure, useful in considering the risks posed by CDDs and CDFs other than 2,3,7,8-TCDD. The Agency is likely to review and update these factors, as needed. At the same time, the Agency will be pushing to replace the TEF approach with a bioassay system that measures directly the toxic potential for these complex mixtures. The official Agency position on the toxicity of 2,3,7,8-TCDD is unchanged from that articulated in 1985 (USEPA, 1985). However, the Agency is likely to initiate soon a reassessment of the carcinogenic risk of 2,3,7,8-TCDD. This activity would involve recent animal and human toxicity data, as well as a number of important exposure factors; e.g., bioaccumulation potential and fish consumption patterns of various human populations. In any event, it is clear that 'dioxin' continues to be a driving issue in many topics before the Agency; e.g., combustion of municipal waste, bleached pulp and paper products, disposal of sewage sludge, and contaminants in commercial chemicals. Therefore, CDD/CDF issues are likely to occupy the attention of USEPA for several more years. REFERENCES Commoner, B., K. Shapiro and T. Webster, 1984. Environmental and economic analysis of alternative municipal solid waste disposal technologies. I. An assessment of the risks due to emissions of chlorinated dioxins and dibenzofurans from proposed New York City incinerators. Queens College, New York, NY. Couture, L.A., M.R. Elwell and L.S. Birnbaum, 1988. Dioxin-like effects observed in male rats following exposure to octachlorodibcnzo-p-dioxin (OCDD) during a 13 week study. Toxicol. Appl. Pharmacol., 93: 31-46. Davis, D.L., 1989. Natural anti-carcinogens, carcinogens and changing patterns in cancer: some speculations. Environ. Res., 50: 322-340. Eadon, G., L. Kaminsky, J. Silkworth, K. Aldous, D. Hiker, P. O'Keefe, R. Smith, J. Gierthy, J. Hawley, N. Kim and A. Decaprio, 1986. Calculation of 2,3,7,8-TCDD equivalent
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concentrations of complex environmental contaminant mixtures. Environ. Health Perspect., 70: 221-227. Federal Register, 1986. Cancer Risk Assessment Guidelines. 51: 33992-34003. Fingerhut, M., W.E. Halperin, D. Marlow, L.A. Piacitelli, P.A. Honchar, M.H. Sweeney, A.L. Greife, P.A. Dill, K. Steenland and A.J. Suruda, 1991. Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. N. Engl. J. Med., 324: 212-218. Gravitz et al., 1983. Interim guidelines for acceptable exposure levels in office settings contaminated with PCB and PCB combustion products. Epidemiological Studies Section, California Department of Health Services, Berkeley, CA. Kociba, R.J., D.G. Keyes, J.E. Beyer, R.M. Carreson, E.E. Wade, D.A. Henbar, P.O. Kalmins, L.F. Franson, P.N. Park, S.D. Barnard, P.A. Hummel and C.G. Humiston, 1978. Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin rates. Toxicol. Appl. Pharmacol., 46(2): 279-303. Lindstrom, G. and C. Rappe, 1986. Analytical method for analysis of polychlorinated dibenzop-dioxins and dibenzofurans in milk. Chemosphere, 17: 921-935. Moolgavkar, S.H. and A.G. Knudson, 1981. Mutation and cancer: a model for human carcinogenesis. J. Natl Cancer Inst., 66: 1037-1052. NATO/CCMS (North Atlantic Treaty Organization, Committee on the Challenges of Modern Society), 1988a. International toxicity equivalency factor (I-TEF) method of risk assessment for complex mixtures of dioxins and related compounds. Rep. No. 176, Brussels, Belgium. NATO/CCMS (North Atlantic Treaty Organization, Committee on the Challenges of Modern Society), 1988b. Scientific basis for the development of international toxicity equivalency (I-TEF) factor method for risk assessment for complex mixtures of dioxins and related compounds. Rep. No. 178, Brussels, Belgium. NTP (National Toxicology Program), 1982. Carcinogenesis bioassay of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Osborne-Mendel rats and B6C3FI mice. Tech. Rep. No. 209. Research Triangle Park, NC. Olie, K., M.V.D. Berg and O. Hutzinger, 1983. Formation rate of PCDD and PCDF from combustion processes. Chemosphere, 12: 627-636. Ontario Government, 1982. Scientific criteria document for standard development. Polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). Ministry of the Environment. No. 4-84, December. Poland, A. and J.C. Knutson, 1982. 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: an examination of mechanism of toxicity. Annu. Rev. Pharmacol. Toxicol., 22: 514-554. Poland, A., W.F. Greenlee and A.S. Kende, 1979. Studies on the mechanisms of action of chlorinated dibenzo-p-dioxins and related compounds. Ann. N.Y. Acad. Sci., 320: 214-230. Rappe, C., R. Anderson, P.A. Berqquist, C. Brohede, M. Hansson, L.O. Keller, G. Lindstrom, S. Marklund, M. Nygren, S.E. Swanson, M. Tysklind and K. Wiberr, 1987. Overview on environmental fate of chlorinated dioxins and dibenzofurans; sources, levels and isomeric patterns in various matrices. Chemosphere, 16:1603-1618. Safe, S.H., 1987. Determination of the 2,3,7,8-TCDD toxic equivalent factors: support for use of the in vitro AHH induction assay. Chemosphere, 16: 791-802. Safe, S.H., G. Mason, T. Sawyer, T. Zacharewski, M. Harris, C. Yao, B. Keyes, K. Farrell, M. Holcomb, D. Davies, L. Safe, J. Piskorska-Pliszczynska, B. Leece, M.A. Denomme, O. Hutzinger, H. Thoma, B. Chittim and J. Madge, 1989. Development and validation of in vitro bioassays for 2,3,7,8-TCDD equivalents. Toxicol. Ind. Health, 5: 757-775. Sawyer, T., S. Bandiera, S. Safe, O. Hutzinger and K. Olie, 1983. Bioanalysis of polychlorinated dibenzofuran and dibenzo-p-dioxin mixtures in fly ash. Chemosphere, 12: 529-534.
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Sielken, R.L., 1987. Quantitative cancer risk assessments for TCDD. Food Chem. Toxciol., 25(3): 257-267. USDHHS, 1983. Levels of concern for hexa- (HCDD), hepta- (HpCDD), and octachlorodibenzo-p-dioxins (OCCD) in chickens and eggs. Memorandum. USEPA (U.S. Environmental Protection Agency), 1985. Health assessment document for polychlorinated dibenzo-p-dioxins. EPA-600/8-84-014F. National Technical Information Service, Springfield, VA, PB86-122546/AS. USEPA, 1987. Interim procedures for estimating risks associated with exposure to mixtures of chlorinated dibenzo-p-dioxins and -dibenzofurans (CDDs/CDFs). Risk Assessment Forum. EPA/625/3-87/012. Principal authors J. Bellin and D. Barnes. National Technical Information Service, Springfield, VA, PB89-125041. USEPA, 1988a. A cancer risk-specific dose estimate for 2,3,7,8-TCDD. External Review Draft. EPA/600/6-88/007Aa. Workgroup and principal authors P. Preuss, Chair; D. Barnes, D. Patton, P. Roberts, H. Spitzer, D. Taylor. National Technical Information Service, Springfield, VA, PB88-231204. USEPA, 1988b. A cancer risk-specific dose estimate for 2,3,7,8-TCDD. Appendices A-F. EPA/60016-88[OO7Ab. Cancer risk modeling, S. Bayard/T. Thorslund; Cancer epidemiology, D. Bayliss; Reproductive and developmental toxicity, G. Kimmel; Epidemiologic data on reproduction, S. Selevan; Immunotoxicity, B. Sonawane; Mechanism of action, M. Gallo. National Technical Information Service, Springfield, VA. USEPA 1988c. Estimating exposures to 2,3,7,8-TCDD. EPA[60016-88/OO5A. USEPA, 1989. Interim procedures for estimating risks associated with exposure to mixtures of chlorinated dibenzo-p-dioxins and -dibenzofurans and 1989 update. Risk Assessment Forum. EPA/625/3-89/016. Principal authors D. Barnes, F. Kutz and D. Bottimore. National Technical Information Service, Springfield, VA. USEPA, 1990. FY88 Report of the Staff Director of the Science Advisory Board. USEPA, Washington, DC. Wolfe, W.H., J.E. Michalek, J.C. Miner and M.R. Peterson, 1988. Serum 2,3,7,8-tetrachlorodibenzo-p-dioxin levels in Air Force health study participants: preliminary report. Mortality and Morbidity Weekly Report, 37: 309-310.
