In this application, it is proposed to validate a unique transgenic mouse model for identification of genotoxic carcinogens. The mice have been engineered to overexpress the enzyme ornithine decarboxylase (ODC) in skin and other tissues. As a result, the mice are endogenously """"""""promoted"""""""" and thus very sensitive for tumor induction to very low, initiating doses of known skin carcinogens. The model will be further validated by conducting dose-response studies for several carcinogenic and noncarcinogenic compounds. The sensitivity of the upper aerodigestive tract to a known carcinogen will also be evaluated in this model. The potential for technological innovation in this application is the likelihood that, for the first time, a short-term, highly sensitive and inexpensive in vivo model will be available to test suspect chemicals at low doses, more relevant to typical human exposures than the maximum tolerated doses commonly employed in current test systems. In terms of chemical risk assessment, it could be feasible using results from this model to base regulatory decisions on low dose data, rather than have to extrapolate from high dose data as is currently done.
An in vivo model will be developed for testing the carcinogenic potential of drugs, environmental chemicals, and dietary constituents. Because the model is extremely sensitive, chemicals can be tested at low doses, comparable to human exposure levels.
