A mechanistic approach to modelling the risk of liver tumours in mice exposed to fumonisin B-1 in the diet

Data from the National Toxicology Program's carcinogenesis study of fumonis in B-1 in B6C3F(1) mice, conducted at the National Center for Toxicological Research, were used to fit the Moolgavkar-Venzon-Knudson (MVK) two-stage, clonal-expansion model of carcinogenesis. In addition to tumour data from t he conventional 2-year bioassay, the study included data on tissue weights, cell proliferation, cell death, and sphingolipid metabolism in primary tar get organs. The model was used to predict 2-year liver tumour rates in fema le and male mice based on differences among dose groups in the effect of fu monisin B-1 on the growth of normal tissue and on the proliferation of pren eoplastic cells as a compensatory response to sphinganine-induced cell deat h. Fumonisin B-1 was assumed to be non-genotoxic, i.e. the model did not in clude any effect of fumonisin B-1 on either of the two mutation rates of th e MVK model. The model was able to reproduce reasonably well the observed t umour rates in both female and male mice, predicting substantially increase d rates above background only at the highest doses of fumonisin B-1 in fema les.