The Induction of Hepatocellular Neoplasia by Trichloroacetic Acid Administered in the Drinking Water of the Male B6C3F1 Mouse

Abstract

The prevalence (percent of animals with a tumor) and multiplicity (number of tumors per animal) of hepatocellular neoplasia in the male B6C3F1 mouse exposed to trichloroacetic acid (TCA) in the drinking water were determined. Male mice were exposed to 0.05, 0.5, and 5 g/L TCA for 60 wk (Study 1), to 4.5 g/L TCA for 104 wk (Study 2) and to 0.05 and 0.5 g/L TCA for 104 wk (Study 3). Time-weighted mean daily doses measured for the low, medium, and high dose groups were consistent over the three studies, 6–8, 58–68, and 572–602 mg/kg-d for the 0.05, 0.5, and the 4.5–5 g/L treatment groups, respectively. No significant changes in animal survival were noted across the studies. A significant increase in the prevalence and multiplicity of hepatocellular tumors was found in the 58–68 and 572–602 mg/kg/d TCA dose groups. Nonhepatoproliferative changes (cytoplasmic alterations, inflammation, and necrosis) in mice treated with TCA were mild and dose related. A TCA-induced increase in liver palmitoyl CoA oxidase activity, a marker of peroxisome proliferation, correlated with tumor induction. A linear association was found between peroxisome proliferation and tumor induction. Sporadic increases in the labeling index of nuclei outside of proliferative lesions were observed at carcinogenic doses throughout the studies. Given that there are no compelling data demonstrating genotoxic activity of either TCA or any metabolite, data are consistent with an epigenetic mode of action. The studies provide dose-response data on the development of hepatocellular neoplasia in male mice over a lifetime exposure to TCA. A no-observed-effect-level (NOEL) of 6 mg/kg/d was calculated for neoplastic and nonproliferative liver pathology.

The authors thank Drs. Pedro Ortiz Andrew Kligerman of the National Health and Environmental Effects Research Laboratory and Dr. Michael Plewa from the University of Illinois, Urbana–Champaign, for their thorough review of the article. In addition, they thank Dr. Chris Corton, of the National Health and Environmental Effects Research Laboratory, for his helpful discussions on the role of PPAR-alpha in carcinogenesis. Portions of this work were carried out under U.S. EPA contracts 68-03-3526 and 68-C8-0082 to Pathology Associates, Inc., Frederick, MD, and U.S. EPA contract 68-D2-0056 to ManTech Environmental Technology, Inc., Research Triangle Park, NC. This article has been reviewed by the U.S. Environmental Protection Agency and approved for publication. Mention of trade names or commercial products does not constitute endorsements or recommendations.