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A MULTISTAGE BIOLOGICALLY BASED MODEL FOR MOUSE LIVER TUMORS RESULTING FROM EXPOSURE TO DICHLOROACETIC ACID
Citation:
Rabinowitz, J. R., M. Schonwalder, A B. DeAngelo, M J. Mass, J A. Ross, H. W. Carter, J. H. Carter, AND S Nesnow. A MULTISTAGE BIOLOGICALLY BASED MODEL FOR MOUSE LIVER TUMORS RESULTING FROM EXPOSURE TO DICHLOROACETIC ACID. Presented at Society of Toxicology Annual Meeting, Philadelphia, Pennsylvania, March 19-23, 2000.
Description:
Dichloroacetic Acid (DCA) is a major byproduct of the chlorine disinfection of humic acid containing drinking water sources. It is a hepatocarcinogen in mice and rats at exposure concentrations in drinking water that are at least 4 orders of magnitude above the concentrations in drinking water to which humans are exposed. Under the dosing regime that results in the formation of tumors in B6C3F1 male mice, DCA causes a spectrum of benign, premalignant and malignant lesions of the liver that changes during the lifetime of the subjects. To aid in the extrapolation from these exposure conditions to drinking water exposures a biological based model for DCA carcinogenesis has been developed. Histopathologic analysis of the livers of exposed mice suggests that following chronic exposure to DCA, carcinomas can arise directly from single initiated cells in the liver as well as within hyperplastic nodules and adenomas. Based on these studies, a biologically based model for DCA carcinogenesis that contains at least 3 precancerous stages and 6 transitions was developed. With the large number of parameters in this model, it is clear that any method for numerical parameter estimation would not provide meaningful results. The PCNA and TUNEL assays were used to obtain birth and death rates for cells in each precancerous stage. A general transition rate was obtained from the mutation frequency induced in the livers of lacI B6C3F1 transgenic mice. Many of these parameters were a function of DCA exposure. Using the experimentally determined parameters and the Kolmogorov backwards equations, there is agreement with the time-to-tumor data for mice exposed through their drinking water for two years. It is more difficult to obtain agreement with the experimental determination of the number of tumors/animal as a function of time in that study. Dose related extrapolation of the model may be obtained from extrapolation of the parameters.