Accession Number:

ADA383432

Title:

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

Descriptive Note:

Final rept. Sep 1998-Mar 2000

Corporate Author:

K S CRUMP GROUP INC RESEARCH TRIANGLE PARK NC ICF KAISER INTERNATIONAL

Report Date:

2000-03-01

Pagination or Media Count:

69.0

Abstract:

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 LWBW 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 LWBW 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 LWBW 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.

Subject Categories:

  • Biochemistry
  • Medicine and Medical Research
  • Organic Chemistry

Distribution Statement:

APPROVED FOR PUBLIC RELEASE