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 f ully define interspecies and dose extrapolations. Interactions between pharmacokinetic target tissue end points (DNA adduct formation) and c ellular proliferation in liver and urinary bladder carcinogenesis is i llustrated with the results from the ED(01) study involving 2-acetylam inofluorene administered to female mice. The interaction of genotoxic and cell proliferative effects are also illustrated in a co-carcinogen esis study with low doses of N-[4-(5-nitro-2-furyl)-2-thiazolyl]formam ide and high doses of sodium saccharin. The application of such intera ctions to humans is illustrated for the case of cigarette smoke-induce d bladder cancer.