Proliferative and genotoxic cellular effects in 2-acetylaminofluorene bladder and liver carcinogenesis: biological modeling of the ED01 study.

The development of tumors in relationship to 2-acetylaminofluorene (AAF) dose and time on study has been evaluated in an experiment conducted by the National Center for Toxicological Research (NCTR) using more than 24,000 female BALB/c mice. By using a biologically based model of two-event carcinogenesis accounting explicitly for both genotoxic and nongenotoxic proliferative effects at the cellular level, we provide a unifying explanation for the apparently disparate dose-response results observed in the urinary bladder and liver. Experimental observations of dose-related DNA adduct levels in both tissues and hyperplasia in the bladder were utilized in estimation of model parameters. Analyses demonstrate that tumor prevalence in the liver can be explained entirely by the influence of AAF on the first of two genetic events, and in the bladder by the synergy between AAF genotoxicity affecting both genetic events and cellular proliferation at higher doses. These results are consistent across the entire ED01 data set.