An enhanced 13-week bioassay: an alternative to the 2-year bioassay to screen for human carcinogenesis.

The 2-year rodent bioassay has become the standard carcinogenicity screen for chemicals, despite concerns of costs, time, and excessive doses. More importantly, there are increasing concerns regarding its relevance to human carcinogenic risk, especially for non-DNA reactive chemicals. Cancer risk can be increased either by direct damage to DNA (DNA reactivity) or by increased cell proliferation. Utilizing the scientific basis for mode of action analysis in the framework that has been developed for extrapolating to human relevance, a short-term screen is proposed as a replacement for the 2-year bioassay. Chemicals are evaluated for DNA reactivity, immunosuppression, and estrogenic activity, known mechanisms of human carcinogenesis, by in vitro and/or in vivo tests. The chemical can then be evaluated for toxicity and/or increased cell proliferation in target tissues. This relies primarily on evaluation of organ weights and histopathology, and also utilizes data from blood and urine chemistries and DNA-labeling indices. Significant concern is raised regarding the relevance of evaluation of tissues that are present in rats or mice but not humans, and the relevance of proliferative responses in rodent endocrine tissues. In developing alternative procedures to evaluate chemicals for possible carcinogenic activity in humans, it is important not to rely on the 2-year rodent bioassay for validation of the new procedure. It is time to discontinue the performance of the 2-year rodent bioassay.