Trichloroacetate Tissue Dosimetry and PPAR alpha-Mediated Liver Cancer Induction by Trichioroethylene and Perchioroethylene

摘要

A biologically-motivated dose-response analysis was undertaken for liver cancer induction in mice by trichloroethylene (TCE) and perchloroethylene (PERC). The mechanistic hypothesis evaluated was whether tumors resulted from a peroxisome proliferator-activated receptor-alpha (PPARa)-mediated process initiated by formation of trichloroacetate (TCA) from the two volatile organics. Available mechanistic data for TCE, PERC, and TCA were compared with those for prototypical PPARa-ligands. Several early and late events were consistent: increased liver to body weight ratio (LW/BW) due to induction of peroxisomes, hypertrophy, and cell proliferation; the phenotype of induced foci; and reversibility of tumor response with cessation of exposure. One difference was hepatic accumulation of lipid with PERC, but not the other compounds. Use of precursor events for analyzing cancer dose response was evaluated; increased LW/ BW was suggested as a useful indicator of the pleiotropic response necessary for PPARa-mediated liver carcinogenesis. Physiologically based pharmacokinetic models provided estimates of internal dose metrics for TCA. Oral and inhalation studies for LW/BW and cancer were evaluated to obtain points of departure. Low dose extrapolation used a margin of exposure approach for TCE; TCA and PERC were not evaluated. While there are difficulties in analyzing the hypothesis due to the variety of exposure protocols used in the studies with TCE, PERC, and TCA, this analysis indicated substantial consistencies in the database supporting a PPARa-mediated process for TCE- and TCA-induced liver carcinogenesis as a major causative process.