Relationship of DNA adducts derived from 2-acetylaminofluorene to cell proliferation and the induction of rodent liver and bladder tumors

Pharmacokinetic models have been developed to assist in extrapolating results from rodent bioassays. However, in numerous circumstances, it is necessary to combine such models with cellular response models to fully define interspecies and dose extrapolations. Interactions between pharmacokinetic target tissue end points (DNA adduct formation) and cellular proliferation in liver and urinary bladder carcinogenesis is illustrated with the results from the ED₀₁ study involving 2-acetylaminofluorene administered to female mice. The interaction of genotoxic and cell proliferative effects are also illustrated in a co-carcinogenesis study with low doses of N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide and high doses of sodium saccharin. The application of such interactions to humans is illustrated for the case of cigarette smoke-induced bladder cancer.