REVIEW OF ALTERNATIVE METHODS OF CARCINOGENICITY TESTING AND EVALUATION OF HUMAN PHARMACEUTICALS

Hundreds of pharmaceuticals have been reported to give a positive resu lt in the standard ''Chronic Bioassay'', which consists of an 18 to 24 month daily administration of the test compound in mice and rats. Thi s is in contrast with 20 pharmaceuticals, which are known to be carcin ogenic to humans. The high incidence of apparently false-positive resu lts in the Chronic Bioassy 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 accor dance to regulatory guidelines. Lack of relevance to man therefore oft en has to be demonstrated by additional mechanistic studies. Based upo n the deficiencies of the Chronic Bioassay and on the increased knowle dge on cellular and molecular mechanisms involved in carcinogenicity, extensive discussions have recently taken place between regulatory age ncies and industry associations at the occasion of International Confe rences on Harmonization (ICH). These discussions have resulted in the possibility to use alternative short-to-medium-term carcinogenicity mo dels in combination with a single two-year carcinogenicity study for e valuation of carcinogenicity. A description of these models is provide d in this review as well as possible strategies for carcinogenicity te sting and evaluation in the future.