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A Scientific Limitations to Extrapolating Data on Cancer Risk from Animals to Humans As noted in Chapter 4, CAG is directed by Agency guidelines (U.S. EPA 1976) to determine the carcinogenicity of chemicals and to provide numerical estimates of excess cancers in the human population that would result from current use of the compounds under scrutiny. The question of how or even whether to quantify human cancer risks has been the object of considerable controversy within both the scientific and federal regulatory communities for several years (Carter 1979~. If relevant data were available, numerical estimates would contain less error, and less controversy would surround the issue. Few would doubt the scientific validity and precision of estimates of the human risk of cancer if the estimates were based on sound epidemiologic evidence, but such evidence is rarely available. Most commonly, only carcinogenicity test data derived from studies conducted with experimental animals are available and it is from such data that CAG generally determines whether and to what extent a compound appears to be a potential carcinogen to humans. There is general agreement in the scientific community about a reasonable basis for qualitatively determining that a substance is a potential human carcinogen GREG 1979~. The I~G report, currently under review as federal guidelines to cancer risk assessment, provides a detailed consideration of this type of qualitative determination. The reader is referred to this source for additional information. The opinion is widely held that if a substance is demonstrated to be a carcinogen for any mammalian species in an appropriately designed and performed 239
240 Appendix A carcinogenesis bioassay, then the substance is likely to pose a potential cancer risk to humans (Upton 1979~. However, as we have noted, the qualitative evaluation is only half the charge given to CAG. They are also expected to estimate the impact of the carcinogenic compound in terms of quantitative tumor response in the human population by extrapolating from observed responses in animal test systems. It is this issue that is the source of so much debate. It is the opinion of the Committee that the current state of scientific knowledge does not permit meaningful and safe quantification of cancer risks in humans, and for that reason EPA'S current practice should be abandoned or greatly modified. The error in EPA'S risk estimates could be as much as 5 or 6 orders of magnitude, while benefit estimates can be trusted within 1 order of magnitude. (See Chapter 4.) The scientific considerations that lead us to this opinion are discussed briefly in this appendix. SOURCES OF ERROR Potential sources of error in making both qualitative and quantitative evaluations of carcinogenesis bioassay data are numerous. The determi- nation that a chemical is carcinogenic rests upon demonstrating a statistically significant excess of tumors in experimental groups as compared to control groups. Inherent in this determination is an assessment of how adequately a study was performed, including the adequacy of the evaluation of the pathology of the tumors. Since the number of excess tumors ascertained will be used for determining quantitative risk, the ascertained and any error inherent in the evaluation propagated to yield the final error. Furthermore, in order to determine a meaningful excess incidence of tumors, statistical evaluation of tumor results must consider all the experimental and control animals, including premature deaths with or without tumors. Next, the quantitative data from the bioassay must be extrapolated to conditions that apply to the induction of tumors in humans. There are several important differences to consider in comparing the conditions of experimental studies in animals and those of human exposure to presumed carcinogens. First, experimental studies are conducted in a species other than humans, most commonly rodents. Second, differences often exist between the route of administration of the carcinogenic compound to experimental animals and the typical route of exposure observed in human populations. Finally, practical considerations posed by the limited life spans of the experimental animals used in the studies and the limited sizes of experimental groups dictated by costs generally require that large doses of the compound be administered to the
Appendix A 241 experimental animals. In contrast, estimated levels of exposure in the human population may be considerably smaller, often by several orders of magnitude. Several other factors must also be considered, and any errors inherent in these processes quantified and included in the risk estimates. Such factors include the additive or synergistic ejects of interactions between other carcinogens and the test compound in the human population, the biological and genetic diversity of the human population as compared to the experimental animals studied, and the effects of intercurrent disease in the human population. These factors would have to be combined Lath appropriate quantitative data concerning exposure to the compound in question within the human population. PERFORMANCE OF CARCINOGENESIS BIOASSAYS Before the recent effort to describe and adopt standard protocols, carcinogenesis bioassays varied widely in the manner in which they were performed. Factors such as the choice of experimental animal, the number of animals per experimental group, the dose of the test compound employed, the schedule for administering the compound, the conditions of housing and maintenance of the animals, and the duration of the experiment and procedure for terminating it (e.g., serial or terminal sacrifices, or lifetime holding) were all variables determined by the investigator. They frequently differed between individual investiga- tors and even between individual studies by the same investigator. In the reports stemming from these studies, details of experimental technique are frequently omitted with the result that specific techniques are not definable. Frequently the chemical tested is not thoroughly evaluated in terms of purity and composition. Similarly, diets that were obtained from commercial sources may have changed in unknown respects between the interval in which the study was performed and the present. In cases where several chemicals were evaluated for carcinogenicity at the sane time, it is rarely if ever evident whether animals exposed to more than one compound were held in the same room and in proximity to one another. It is also often unclear whether animals treated with known strong carcinogens as positive controls were housed together with the experimental animals. Many of these uncertainties have been corrected or clarified in more recent studies, but the results of earlier investigations remain in the literature often without information vital to their thorough evaluation. When a compound is being considered for regulation, the early studies must be part of the evaluation. In its risk assessments, CAG iS responsible
242 Appendix A for evaluating the results of every study available for a given compound and deciding whether and how to use them. CAG'S assessment is subject to comment by all interested parties, any one of whom may challenge or attempt to revise CAG'S evaluation of the adequacy of the relevant studies. EVALUATION OF TUMOR PATHOLOGY The basic data in a carcinogenesis bioassay are tumors observed in the experimental and control groups. The evaluation of the pathologic lesions in experimental and control animals of a bioassay is basically a subjective process. Morphologic lesions, both gross and microscopic, that may fall anywhere on a continuum of biologic diversity are assigned to discontinuous categories. The adequacy of the categorization depends on the insight into the morphologic manifestations of the natural history of the disease and the thoroughness with which individual categories are characterized and distinguished. Lesions may fall between clearly defined categories, and more than one type of lesion can occur concurrently in a given tissue. Furthermore, the natural histories of some disease processes in experimental animals are less well characterized than comparable lesions in humans. In such cases, it is more difficult to morphologically characterize and define lesions, and pathologists have less insight into the biological significance of the lesions. These factors influence the precision of categorization of pathology. Diagnostic precision is also influenced by personal insights, skill, and experience. Although pathologic evaluations are admittedly subjective, rarely, if ever, is an attempt made to place a measure on the precision or accuracy of these diagnoses, that is, to determine precisely how the categorization or description of lesions characterize the pathology in that organism, or how well individual pathologists rate in their assignment of given lesions to appropriate categories. It is unclear in most cases whether this error is 20 percent, 10 percent, 5 percent, or 1 percent, and so on. As a consequence, the diagnoses are generally used as numerical data without error tolerances. Thus, a major potential source of error in the risk quantification never enters into a determination of error tolerances in the risk estimate. The problem is compounded in older studies in which diagnostic material may be unavailable for subsequent reevaluation. Furthermore, diagnostic criteria and pathologic categorization may have changed during the interval between initial pathologic review and subsequent publication of a paper. For more recent studies, particularly those sponsored by the federal government, external review of pathologic
Appendix A 243 evaluations has been instituted. This policy should presumably reduce error, but the extent of imprecision remains unclear. EVALUATION OF RESULTS Bioassay results may be evaluated according to incidence of tumors of all types within animal groups, incidences of tumors in specific locations, multiplicity of tumors, incidences of tumors of grouped organ sites, and so on. Methods for evaluating results vary both with the result observed and the procedures used for performing the bioassay. For example, different procedures may be used to evaluate studies in which whole animals survived to a terminal sacrifice as compared to studies in which excess early mortality occurred or animals were held until they died spontaneously. The availability of dose-response data provides addition- al bases for evaluating results. Lee difficulty involved in assessing excess tumors, therefore, varies with the results of a study. In cases in which there is a large excess incidence of tumors in the test group, no comparable tumors in the control group, and both control and test groups are large, simple comparisons of the difference in tumor incidence may suffice. If the groups are not large, comparisons of tumor incidence must be supplemented with estimates of the imprecision of the experiment. Preferably, such error estimates should measure inherent inconsistencies or variances between studies in the ejects of a given dose of a compound. Generally, however, there is only one test group in a study, or certainly only one group at a given dose level, making such estimates impossible. Thus, error estimates are generally based upon the size of the group used to make the comparison between test and control animals. When tumor responses are small or when there is a significant incidence of tumors in the control animals, the issue of experimental error becomes more critical, particularly when experimental groups are small and reliable estimates of biologic variability and response to the test compound are not available. For example, if, for a given site, tumors occur in the control animals, but a greater number of tumors is detected at this site in the one tested group, is this a real property of the test compound? Without knowing the variation of tumors in control animals at the given site, an excess of tumors in the test over the control group may only lie within the range of biologic variability of the test animals. For studies in which animals are allowed to live until they die spontaneously, or studies that involve a terminal sacrifice but in which a large proportion die before termination, alternative methods for evaluat- ing tumor responses are necessary. The general approach is an actuarial or life-table analysis. Specification of a defined end point in the study is
244 Appendix A critical to this approach. For example, the presence of a tumor that is uniformly lethal to the host is a defined end point. Similarly, tumors that are uniformly nonlethal and are found incidentally at death also present a defined end point. In contrast, tumors that may cause the death of an animal but do not necessarily do so, and may be found as incidental microscopic lesions, are less clearly defined as end points and pose difficulties in statistical analysis. Quantitative estimates of differences between control and test groups are difficult to make, and lack of precision here poses an even greater problem for quantification. To summarize, the degree of difficulty in estimating excess tumor incidence relates in part to the magnitude of tumor excess in the test animals over the controls and in part to the number of premature deaths occurring in the test group as compared to the controls. The preceding considerations apply to the qualitative determination of the carcinogenicity of a compound. All these factors also apply to the quantitative determination of the magnitude of carcinogenic response to a given mode of treatment with a test compound. In addition, as noted, several other factors must be considered in achieving a quantitative extrapolation to human cancer risks, and these factors are considered briefly below. Methods for determining human exposure have been considered in Chapter 4 and will not be reiterated here. It should be evident, however, that the error and imprecision inherent in estimates of human exposure must be propagated to yield the final estimate of tumor response in the human population and the error in the estimate offered. EXTRAPOLATION TO LOW DOSES Typically, constraints of time and money require that carcinogenesis bioassays be performed in rodents. Because of expense, control and experimental groups are limited generally to fewer than 100 animals and, frequently, to even fewer than 20. Consequently, to maximize the probability of detecting a postive tumor response, very high doses of test compounds are used. The doses are generally based upon the maximum tolerated dose that yields no excess subacute toxicity in the test group. Such doses are generally much higher than the typical dose to which humans are exposed frequently by several orders of magnitude (on a milligram per kilogram body weight per lifetime basis). The choice of these high doses is a pragmatic one, but it poses the problem of extrapolating from ejects at high doses to tumor responses anticipated at the extremely low doses typical of human exposure. Since we do not have a comprehensive, detailed theory of carcinogenesis, we do not have a method for calculating the real number of tumors that will
Appendix A 245 develop in experimental animals at a projected lower dose based upon observations at higher doses. However, numerous models have been proposed that make a variety of assumptions about the nature of carcinogenesis and over a wide range of estimated tumor responses in a low-dose range. As has recently been reported for saccharin, depending upon which assumptions are made and consequently which extrapola- tion procedures are used, the errors in the predicted tumor incidence at low doses may range over 6 orders of magnitude in this case and could conceivably be higher in other circumstances (NRC/TOM 1978~. Again, the estimates are based in science but rest on unproven assumptions, and the precision of the resulting estimates is unclear. Because of the uncertainties inherent in extrapolation models, CAG generally uses the extrapolation that gives the highest reasonable estimate of cancer incidence within the dose range of human exposure. The linear nonthreshold model, although not likely to be close to reality for most compounds, is generally presumed to represent an upper bound on risk extrapolation in most cases. If, however, only one dose level is tested, and if the dose is in a saturation plateau of carcinogenic elect, then a linear nonthreshold extrapolation may underestimate the carcino- genic potential of the compound for a portion of the dose-response curve. Thus, under certain circumstances, even this rather "conservative" extrapolation procedure may provide an underestimate of erect. None- theless, the estimates are crude, and the extent of propagation of error in resulting human risk estimates is, again, unclear. CORRECTION FOR DIFFERENT ROUTES OF ADMINISTRATION Carcinogenesis bioassays are most typically performed by feeding the test compound to experimental animals. Less frequently, compounds are tested by application to the skin, by inhalation, or by subcutaneous or other routes of injection into the experimental animal. Although people are frequently exposed via ingestion, other routes of exposure may be important. Consequently, corrections must be made when the experi- mental route of exposure diners from the human. These corrections are generally not based on theory that is as well formulated as that on which the extrapolation from high to low doses is based. The technique that CAG generally uses employs an analogy between the compound in question and a carcinogen that is chemically similar to the test compound and has been tested by a variety of routes. Short-term metabolic studies can indicate similarities or differences between the distribution of the comparison compound and the test compound and thus provide, by analogy, more insight into the validity of the
246 Appendix A comparison. The efficacy of tumor induction at various sites depending upon the route of administration can be determined for the comparison compound, and in this manner an analogy can be constructed. Unfortunately, there is a long history of peculiarities of individual chemicals; even chemicals that are structurally quite similar may manifest very different properties of distribution in the body and activation to carcinogenic forms. Thus, the precision of the comparisons is largely unmeasured. Again, in practice, comparisons are generally made so as to maximize the estimated eject. Nonetheless, the estimates are crude and the extent of propagation of error in the resulting human risk estimate is unclear. EXTRAPOLATION BETWEEN SPECIES In making extrapolations between ejects noted in rodents and those anticipated in humans, the extrapolator generally chooses the test species in which the largest tumor response per unit dose is observed. This is then considered the most sensitive test species, and it is generally assumed that the human population will be less sensitive. This assump- tion is largely based on the evaluation of six compounds for which quantitative exposure-tumor response data are available for both experimental animals and human populations. In these six cases, a reasonable comparability was determined between the extrapolated human tumor incidences and the animal dose-response data (NRC 1975~. In each case where the most sensitive animal strain was selected, the anticipated or calculated human cancer risk was greater than that observed epidemiologically in the human population. However, such evidence for only six compounds does not prove the validity of the assumption, and there may indeed be compounds for which the extrapolation is not appropriate. For example, epidemiological studies indicated that benzene and arsenic are carcinogenic in humans, but experimental studies with these compounds have yet to prove conclusive- ly that they are carcinogenic in animal bioassays. It is conceivable that in these two cases, the discrepancy arises from the fact that the human is the more sensitive species. Thus, in attempting to extrapolate between species, to make the assumption that the human is less sensitive than the most sensitive of the test species is not necessarily correct. OTHER CONSIDERATIONS Without a well-formulated, comprehensive theory and explanation for all or most facets of the development of human cancer, several critical
Appendix A 247 determinants of risk in the human population may be omitted from the extrapolation procedures as currently performed. Factors not now considered include individual variability in the human population in response to exposure to carcinogens, erects of intercurrent diseases, and various forms of interactions between carcinogens, co-carcinogens, promoters, and other factors. CAG PRACTICES In determining whether or not a compound is a potential carcinogen, CAG iS directed by the EPA guidelines to use a "weight-of-evidence" approach. The guidelines indicate the relative weight to be given to epidemiological studies, carcinogenesis bioassays, and short-term tests, but, as noted in Chapter 4, neither the guidelines nor CAG provide written criteria for following the approach. In fact there is uncertainty about how the approach is to be applied, particularly in cases where studies of the same type come to different conclusions regarding carcinogenicity or where the quality of studies compared diners substantially. It is unclear whether CAG adheres to a neutral or objective "weight-of-evidence" approach or whether it places greater weight on data suggesting carcinogenicity in an effort to avoid underestimating the potential for human cancer risk. In making quantitative estimates, CAG'S philosophy is to maximize each of the individual components employed in the extrapolation to estimate excess human cancer deaths, so that the real risk to which the human population may be subject will always be less than the estimated risk. This is a practical attempt to deal with the problem of limitations of current scientific knowledge. Since CAG recognizes that actual human risk is difficult or impossible to determine precisely, it attempts to estimate an upper bound of probable human risk. For each of the three extrapolations discussed above high to low dose, test animal to human, and route of administration CAG uses those assumptions and estimates that tend to maximize risI;. Even human exposure estimates, not CAG'S responsibility, are "upper-limit" estimates. The end result is that CAG propagates through the calculations those error tolerances that can be estimated, and the final estimate of excess human cancer incidence is reported as a range. The principal error arises in calculating the excess proportion of tumors occurring in the test group as compared to those arising in the control group and in correcting for the size of the experimental group, a factor that relates to the precision of the result. CAG results thus show an estimated number of excess cancer incidences
248 Appendix A with a range of confidence although, as noted above, all sources of error are not considered. CAG informally urges caution in interpretation of its estimates. For example, if each of two estimates-say, 410 and 380 incidences falls within the error tolerance of the other (the usual case), the two figures are not to be interpreted as significantly different. Nor are they to be interpreted as an actual excess of human cancer incidence of this precise magnitude. Instead, CAG'S estimate is to be interpreted as an upper bound, and, presumably, the actual excess of human cancer incidence will be less than this number or less than the upper limit of the variability of this value. What CAG appears to believe is most important, however, is an extrapolated risk estimate (or better yet, its upper confidence limit) that falls below an incidence of one excess cancer; CAG tends to view this type of result as an indication that the compound in question is not a significant human cancer risk. But CAG'S estimates would be more valuable if they were accompanied by these informal interpretations. Currently, the estimates stand as values with tolerance ranges that, contrary to the "warning-signal" stature recommended in the Agency guidelines, appear as actual numerical estimates of excess human cancer incidence attributable to use of the compound in question. If CAG'S risk estimates are to be used as intended two conditions must be met: (1) the estimates must be interpreted correctly by the Adminis- trator, who is required to judge the balance between risks and benefits; and (2) the estimates must in fact be an upper bound on the real excess of human cancer incidence attributable to the compound. By presenting estimates of excess risk as numerical values, even with error tolerances, CAG provides values that appear to have tangibility and scientific validity. Although CAG members have attempted to provide Administra- tors with insight into the usefulness and limitations of the CAG estimates, it is difficult to judge how well they have succeeded. The estimates become a matter of record subject to evaluation and interpretation by individuals who do not have the benefit of CAG'S informal interpretation of its own results. Thus, the presentation of the estimates without verbal explanation of how they might best be used exposes the figures to misinterpretation and misuse. In fact, the values are often erroneously accepted quite literally as sound scientific estimates with well-defined error limits. The second point mentioned above concerns the adequacy of CAG estimates as an upper bound on real risk. As we have already seen, CAG has attempted to validate its extrapolation procedures on the basis of an NRC (1975) report that compares the results of animal studies and human epidemiologic investigations for six compounds-benzidine, chlornapha
Appendix A 249 zinc, DES, aflatoxin B., vinyl chloride, and cigarette smoking for which dose-response data exist for both human exposure and animal experi- mentation. The NRC report concluded that, in at least four of the six cases, there is substantial agreement between the epidemiologically estimated excess of cancer deaths and the estimates extrapolated from animal studies. The translation of this limited conclusion, however, into a working hypothesis that human lifetime cancer incidence in general can be approximated by extrapolating from the lifetime incidence induced by similar exposure in laboratory animals is open to question. For example, CAG'S estimates from human and animal data of the incremental risk per unit of inspired benzo~a~pyrene varied over 21/2 orders of magnitude. One of the values determined from the animal studies was 2 orders of magnitude lower than that determined from epidemiological estimates, and another value was one twentieth of that estimated from the human studies (CAG 1978~. In addition to orders of magnitude disagreement between estimates from animal and human data, epidemiological estimates themselves are subject to error. These errors arise not only from imprecisions in the determination of excess cancers, but from difficulty in estimating actual human exposures. Epidemiological studies of vinyl chloride exposures and the related cancer risks are cited as a source of reliable dose- response data in the human population (NRC 19754. Yet, in this example, where efforts have been made to quantify exposure of the working population, the estimates are derived and not the product of precise measurement of doses. Exposures were estimated retrospectively on the basis of duration of employment and the specific job of individuals exposed during that period. The majority of the exposure estimates were derived from measurements of current levels of exposure to vinyl chloride in specific jobs, using current equipment and reagent stock. The extent to which these conditions apply to earlier periods of exposure is unknown. Furthermore, unlike the corresponding animal studies, the vinyl chloride workers were probably exposed to a combination of other organic materials that may influence the elects of the vinyl chloride (see below) (Nicholson et al. 1975~. Consequently, even the case of vinyl chloride, considered by some a source of sound epidemiological dose- response data for excess cancer risk, is open to serious question concerning; the precision of its exposure estimates. In most other epidemiological studies exposure estimates are less sound than in the case of vinyl chloride. Even in the case of human exposure to low doses of irradiation, where because of better dosimetry one might expect more precise estimates to be available than for chemical substances, expert opinions on estimated risks vary by 1-2 orders of magnitude (NRC 1979~.
250 Appendix A Furthermore, the six cases with "good" epidem~olog~cal data present- ed in the NRC report (1975) involved strong carcinogens. The majority of compounds that CAG will be required to assess will be weaker carcinogens than those noted above, and epidem~olog~cal evidence will generally not be available for validation of the extrapolated values. Therefore, even if one were to accept the validity of the epidemiolog~- cal/expenmental comparisons of the six tested compounds, one could not be sure that the relationship would still be valid for the more typical compounds CAG iS asked to evaluate. Perhaps most distressing is that for some calculated incremental nsks, benzo~a~pyrene for example, an estimate extrapolated from animal studies was not ~ fact an upper bound on the epidem~olog~cally determined excess risk. One cannot be certain that the 2-order-of-magn~tude discrepancy (underestimate) be- tween one of the animal studies and the human epidem~olog~cal estimates will not be exceeded. This calls into question the fundamental premise that CAG estimates represent upper bounds on human cancer risk attributable to the use of a compound. Thus, not only are there uncertainties in the evaluation of bioassay data, limitations in extrapolation methods, and omissions of factors estimating risk because of lack of scientific knowledge, but CAG'S assumption that their estimates are upper bounds can also be questioned. Within CAG these problems may be understood and recognized as part of the estimation process. Of greater concern, however, is the fact that once out of the hands of CAG, the estimates themselves are subject to misinterpretation. CONCLUSIONS The goal of quantifying assessments of human risk of cancer is attractive in theory. It could provide a comprehensible, quantitative measure against which to balance benefits and thereby make administrative decision making easier. It might also lead to some consistency among regulatory decisions, if the current attempt by federal agencies to agree on a uniform method of quantifying cancer risks is successful. Despite these advantages, the Committee concurs with this recent statement by Arthur Upton (1979), Director of NCI: Although an attractive idea, quantitative risk assessment involving extrapolation from animal data is not yet sufficiently developed to be used as a primary basis for regulating human exposure to carcinogens. Although we are correct in concluding qualitatively that animal carcinogens are potential human carcino
Appendix A 251 gene, quantitative extrapolations involve potentially large errors, some of which could underestimate the actual human risk from exposure. Scientific knowledge is currently insufficient to lend precision to this process. The attempt to precisely estimate quantitative cancer risks raises controversy because it requires scientific judgments and extrapolations which transcend the limits to our scientific knowledge. Important considerations have been omitted from estimates; this indicates they were either unrecognized (unlikely) or that no method was available for incorporating them. Furthermore, some of the factors integral to current quantification methods may have unquantified errors and thus be potential sources of further errors whose tolerances may be orders of magnitude in scale. Substantial additional research is needed to add to current scientific knowledge before sound quantitative risk estimates can be achieved. Such research should focus on: mathematical modeling of carcinogenesis to learn more about dose extrapolations, synergistic and additive effects, and quantification of the precision and accuracy ranges of pathological evaluations. Support is also needed for development of sources of data and references for pathology, critical reviews of old carcinogenesis data, and development of a bank of well-characterized reference carcinogens with dose ejects, pharmacodynamics, species differences, and other information. The practical value of quantitative risk assessment alluded to above makes the pursuit of valid estimation a worthy goal. However, current methods need to be critically tested and scrutinized before they can become accepted procedure. Clear distinctions should be made between scientifically supportable components and those that are only best-guess extrapolations. The possibility of gross error, particularly underesti- mates, must be indicated. Overestimates involve the monetary costs of overregulating a compound; but underestimates are detected years later and are paid for in human deaths from cancer. In closing, we repeat the theme of this appendix: until the scientific limitations to extrapolating numerical estimates of human cancer incidences from animal data are reduced, the Committee recommends that the practice be abandoned. EPA currently uses such estimates as a primary basis for regulating human exposure to carcinogens. Although Upton suggests that "regulatory decisions must be based on an evaluation of all the relevant information including the quantitative estimates of risk" (Upton and Nelson 1979), the Committee feels that until quantitative estimates are more sound, cessation of the quantitation of human cancer risk estimates appears to be the most certain method to
252 Appendix A prevent the misuse of such estimates. An alternative method for estimating risk is offered in Chapter 4 and applied in Chapter 7. REFERENCES Carcinogen Assessment Group (1978) Preliminary Report on POM Exposures. External Review Draft. U.S. Environmental Protection Agency, Washington, D.C. 20460. (Unpublished) Carter, L.J. (1979) How to assess cancer risks. Science 204:811~13. Interagency Regulatory Liaison Group (1979) Scientific Bases for Identification of Potential Carcinogens and Estimation of Risks. Report of the BEG, Work Group on Risk Assessment. Journal of the National Cancer Institute 63:241-268. National Research Council (1975) Pest Control: An Assessment of Present and Alternative Technologies. Volume I, Contemporary Pest Control Practices and Prospects: The Report of the Executive Committee, Study on Problems of Pest Control, Environmental Studies Board, Commission on Natural Resources. Washington, D.C.: National Academy of Sciences. National Research Council/Institute of Medicine (1978) Saccharin: Technical Assessment of Risks and Benefits. Committee for Study on Saccharin and Food Safety Policy. Washington, D.C.: National Academy of Sciences. National Research Council (1979) The Effects on Populations of Exposure to Low Levels of Ionizing Radiations. Committee on the Biological Effects of Ionizing Radiation, Division of Medical Sciences, Assembly of Life Sciences. 1974582-412:45. Washington, D.C.: U.S. Government Printing Office. Nicholson, W.J., E.C. Hammond, H. Seidman, and I.J. Selikoff(1975) Mortality experience of a cohort of vinyl chloride-polyvinyl chloride workers. Annals of the New York Academy of Sciences 246:225-230. Upton, A.C. (1979) Quantitative Risk Assessment. Memorandum to Commissioner, U.S. Food and Drug Administration, April 5, 1979, from the Director, National Cancer Institute, National Institutes of Health. (Unpublished) Upton, A.C. and N. Nelson (1979) Cancer Risk Assessment. Joint statement by Upton, Director, NC! and Nelson, ~rector, Institute of Environmental Medicine, New York University Medical Center, Sept. 21. (Unpublished) U.S. Environmental Protection Agency (1976) Health Risk and Economic Impact Assessments of Suspected Carcinogens: Interim Procedures and Guidelines. 41 Federal Register (102)21402-21405.