DCA Dosimetry: Interpreting DCA-Induced Liver Cancer Dose Response and thePotential for DCA to Contribute to TCE-Induced Liver Cancer

摘要

The contribution of TCE-derived DCA to the induction of hepatocellular carcinomain the mouse liver bioassay has been a pivotal issue in assessing the risk associated with oral exposure to TCE. The goal of this study was to investigate the biological plausibility of the hypothesis that TCE-derived DCA contributed significantly to TCE-induced mouse liver cancer. A pharmacokinetic analysis for DCA in naive and DCA-pretreated mice has been conducted in order to interpret the chronic bioassay liver tumorigenicity results for DCA and to evaluate the potential involvement of DCA in liver carcinogenicity induced by TCE. A physiologically motivated two-compartment model with liver and a body compartment was used to estimate the volume of distribution and the kinetic parameters for metabolic clearance by the liver. Analysis of the data confirm that there is a very large first pass metabolic clearance of DCA by the liver and that the metabolism is significantly inhibited by exposure to high doses of DCA. Most chronic drinking water studies with DCA have been conducted at concentrations of 1 to 5 g/L. At these doses inhibition of metabolism occurs rapidly relative to the length of the bioassay. Large increases in tumor incidence that have been observed at these doses correlate with increasing AUCL for the parent compound (DCA) that occurs as a consequence of saturation of its metabolism. The AUCL for TCE-derived DCA is similar to that estimated for the 0.05 g/L DCA drinking water exposure which was not associated with an increase in the prevalence of liver cancer.