Scientific Bases for Identification of Potential Carcinogens and Estimation of Risks

Abstract

Three types of evidence can be used to identify substances that may pose a carcinogenic hazard; these types are designated in Part I of this report as 1) epidemiologic evidence derived from studies of exposed human populations, 2) experimental evidence derived from long-term bloassays on animals, and 3) supportive or suggestive evidence derived from studies of chemical structure or from short-term or other tests that are known to correlate with carcinogenic activity. Part II delineates the scientific bases for accepting evidence from these three sources and describes their relative contributions to the determination that a substance may pose a carcinogenic hazard. Further, It details the factors that should be considered in the evaluation of experimental and epidemiologic data for ascertaining the reliability and scientific merit of each source of evidence. It also specifies how certain types of limitations in data may require qualification of conclusions. Because data on experimental animals are currently the major source of information for assessing carcinogenicity, they receive the greatest emphasis. Features of experimental design and conduct that influence the evaluation of such studies are discussed, as are the criteria for making evaluations. The report is not intended to specify how such studies should be designed and conducted; rather, it discusses how data from experimental animal studies of widely varying content and quality should be evaluated for purposes of identifying carcinogens. Epidemiologic data and some of their limitations are discussed in less detail. Chemical structure and the short-term tests that correlate with carcinogenic activity are briefly described, as are their roles in providing suggestive or—if coupled with positive data on animals or humans-supportive evidence of carcinogenicity. In Part II are presented the criteria used to ascertain the adequacy of evidence purporting to show that a substance does not pose a risk of cancer. Part II also includes discussions of some types of experimental evidence that, if the extent and quality are adequate, may be used to show that certain carcinogenic responses observed in experimental animals may not be predictive of human response. Part III sets forth current methodologies for quantification of risk. Included are discussions of mathematical models available for extrapolation, within a biologic system, of cancer incidence data observed at experimental dose levels to estimate risks at the (usually much lower) levels that are of concern for humans. Also presented are the factors that should be considered in attempts to identify the human population(s) at risk and to define their conditions and levels of carcinogen exposure. Part III also deals with correlation of the magnitude of effects observed in one human population group or in experimental animals (under their conditions and level of exposure) with the magnitude of effects in the human population for which the estimate of risk is being made. Limitations in current risk estimation methodologies are described, as are the problems of ensuring that human risk is not underestimated. The issue of thresholds for carcinogens is discussed in the final section of Part III.