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Appendix A: Scientific Limitations to Extrapolating Data on Cancer Risk From Animals to Humans
Appendix A: Scientific Limitations to Extrapolating Data on Cancer Risk From Animals to Humans
Pages 239-252
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From page 239... ...
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.
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From page 240... ...
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
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From page 241... ...
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.
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From page 242... ...
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.
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From page 243... ...
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?
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From page 244... ...
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.
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From page 245... ...
Nonetheless, 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.
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From page 246... ...
This assumption 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~.
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From page 247... ...
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.
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From page 248... ...
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.
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From page 249... ...
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 doseresponse data in the human population (NRC 19754.
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From page 250... ...
between 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.
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From page 251... ...
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.
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From page 252... ...
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.
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