The Toxic Substances Control Act mandates the testing of industrial chemicals for which insufficient evidence of safety exists. One of the more critical areas in chemical carcinogenesis testing is a dependable approach to confirmatory tests (tier 2) of identified positives at a screening level (tier 1). The present work was undertaken as part of a systematic evaluation of a series of short-term in vitro and in vivo tests which possess properties thought desirable for tier 2 testing. Experiments were designed to determine whether the mouse skin responds to initiating doses of carcinogens selected from the major carcinogen classes administered by four routes, oral, IP, Sub Q and topical. Experiments to date include testing of diethylnitrosamine, urethane, benzene, benzo(a)pyrene, DMBA, aflatoxin B1, methylmethane sulfonate, azobenzene, FANFT and lead acetate. Two weeks following application of the initiating doses of each carcinogen a 20 week promotion schedule involving the application of lug of 12-0-tetradecanoyl phorbol-13-acetate (TPA) was initiated. On the basis of preliminary data it is apparent that papilloma development in response to chemical carcinogens varies with route of exposure. For example, it is apparent that the response to urethane administered orally exceeds that observed by the topical route by 3-fold. Conversely, the response of the mouse skin to benzo(a)pyrene is more than 10-fold by the topical vs. systemic routes of exposure. Route specific responses to DMBA, benzene, diethylnitrosamine and aflatoxin B1 are also apparent.