You are here:
THE INDUCTION OF HEPATOCELLULAR NEOPLASIA BY TRICHLOROACETIC ACID ADMINISTERED IN THE DRINKING WATER OF THE MALE B6C3F1 MOUSE
Citation:
DEANGELO, A. B., F. B. DANIEL, D. M. WONG, AND M. H. GEORGE. THE INDUCTION OF HEPATOCELLULAR NEOPLASIA BY TRICHLOROACETIC ACID ADMINISTERED IN THE DRINKING WATER OF THE MALE B6C3F1 MOUSE. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. Taylor & Francis, Inc., Philadelphia, PA, 71(16):1056-1068, (2008).
Impact/Purpose:
This study was designed to provide the Agency dose-response data on the development of hepatocellular cancer and non-cancer endpoints in male mice following a two year exposure to trichloroacetic acid, a drinking water disinfection by-product.
Description:
Summary
What is the study?
The study is a chronic bioassay (2 years) of trichloroacetic acid, a drinking water disinfection by-product, in the male B6C3F1 mouse.
What is the impact to the field and the Agency?
The impact of this study will derive from the use of the dose-response data in the calculation of a carcinogenic risk assessment for an updated IRIS document.
Abstract
The prevalence and multiplicity of hepatocellular neoplasia in the male B6C3F1 mouse exposed to trichloroacetic acid (TCA) in the drinking water were determined in an grouping of three studies. Male mice were exposed to 0.05, 0.5, and 5 g/l TCA for 60 weeks (Study 1), to 4.5 g/l TCA for 104 weeks (Study 2) and to 0.05 and 0.5 g/l TCA for 104 weeks (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-day for the 0.05, 0.5, and the 4.5 - 5.0 g/l treatment groups, respectively. No significant differences in animal survival were noted across the studies. A significant trend for an increased prevalence (percent of animals with a lesion) and multiplicity (number of lesions/animal) for hepatocellular adenomas and carcinomas were observed with dose. Significant increases in prevalence or multiplicity of tumors were observed at 58 – 68 and 572 – 602 mg/kg/day TCA. No significant increase above background was noted for hepatic neoplasia in animals receiving 6 - 8 mg/kg/day TCA in any of the studies. Biochemical and non-neoplastic pathological alterations in the liver were similar across studies and appeared to be dose-related. Non-hepatoproliferative alterations (cytoplasmic alterations, inflammation, and necrosis) observed in mice treated with TCA were mild and dose related and correlated with the presence hepatocellular neoplasia. Other than a significant trend in testicular tubular degeneration, no other histopathological alterations out side of the liver exceeded background levels. Liver palmitoyl CoA oxidase (PCOA) activity, a marker of peroxisome proliferation, was dose-related and correlated with tumor induction. The labeling index for nuclei outside of hepatic proliferative lesions was increased at 30, 45, and 60 weeks with no relationship to TCA dose. The observations suggest that an increased hepatocellular neoplasia occurs secondary to epigenetic and non-cancer histopathological alterations. This might be important since there are no compelling data that TCA or a metabolite possess any genotoxic activity.
