Review of alternative methods of carcinogenicity testing and evaluation of human pharmaceuticals.

Hundreds of pharmaceuticals have been reported to give a positive result in the standard "Chronic Bioassay", which consists of an 18 to 24 month daily administration of the test compound in mice and rats. This is in contrast with 20 pharmaceuticals, which are known to be carcinogenic to humans. The high incidence of apparently false-positive results in the Chronic Bioassay may be related to differences in mechanism of pharmacological action between rodents and humans, but also to the very high dose levels that have to be administered to rodents in accordance to regulatory guidelines. Lack of relevance to man therefore often has to be demonstrated by additional mechanistic studies. Based upon the deficiencies of the Chronic Bioassay and on the increased knowledge on cellular and molecular mechanisms involved in carcinogenicity, extensive discussions have recently taken place between regulatory agencies and industry associations at the occasion of International Conferences on Harmonization (ICH). These discussions have resulted in the possibility to use alternative short-to-medium-term carcinogenicity models in combination with a single two-year carcinogenicity study for evaluation of carcinogenicity. A description of these models is provided in this review as well as possible strategies for carcinogenicity testing and evaluation in the future.