Statistical issues in the design, analysis and interpretation of animal carcinogenicity studies are discussed. In the area of experimental design, issues that must be considered include randomization of animals, sample size considerations, dose selection and allocation of animals to experimental groups, and control of potentially confounding factors. In the analysis of tumor incidence data, survival differences among groups should be taken into account. It is important to try to distinguish between tumors that contribute to the death of the animal and "incidental" tumors discovered at autopsy in an animal dying of an unrelated cause. Life table analyses (appropriate for lethal tumors) and incidental tumor tests (appropriate for nonfatal tumors) are described, and the utilization of these procedures by the National Toxicology Program is discussed. Despite the fact that past interpretations of carcinogenicity data have tended to focus on pairwise comparisons in general and high-dose effects in particular, the importance of trend tests should not be overlooked, since these procedures are more sensitive than pairwise comparisons to the detection of carcinogenic effects. No rigid statistical "decision rule" should be employed in the interpretation of carcinogenicity data. Although the statistical significance of an observed tumor increase is perhaps the single most important piece of evidence used in the evaluation process, a number of biological factors must also be taken into account. The use of historical control data, the false-positive issue and the interpretation of negative trends are also discussed.
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