Hepatotoxicity of Agents That Enhance Formation of Focal Hepatocellular Proliferative Lesions (Putative Preneoplastic Foci) in a Rapid Rat Liver Bioassay

Hepatotoxicity of Agents That Enhance Formation of Focal HepatocellularProliferative Lesions (Putative Preneoplastic Foci) in a RapidRat Liver Bioassay. WARD, J. M., TSUDA, H., TATEMATSU, M., HAGIWARA,A., AND ITO, N. (1989). Fundam Appl Toxicol. 12., 163–171.The histopathology of hepatic toxicity for 58 chemicals previouslytested in a rapid rat liver bioassay for demonstrating potentialhepatocellular carcinogens and/or tumor promoters was reviewed.Rats received the test diet for 1 week prior to partial hepatectomyand for an additional 5 weeks thereafter at doses near the estimatedmaximally tolerated dose. These rats served as controls forothers receiving initiation by N-nitrosodiethylamine (DEN) andthe test diets. Twenty-two of these chemicals were previouslyfound to enhance the formation of glutathione S-transferase,placental form (GST-P)-positive putative preneoplastic hepatocellularfoci (promoters) following DEN initiation in this rapid bioassay,whereas 36 chemicals did not. Of the agents that promoted GST-P-positivefoci, 14/22 (63.6%) produced toxic hepatocyte lesions whileonly 4/36(11.1%) of the nonpromoters did so at the doses used.Biliary toxicity was found for 7/22 (31.8%) of the promotersand 6/36 (16.7%) of the nonpromoters. Only 2/13 (15%) chemicalsthat inhibited GST-P-positive foci produced hepatic toxicity.Thus, agents that were presumed hepatic tumor promoters characteristicallywere hepatotoxins while nonpromoters of carcinogenesis werenot hepatotoxins in this rapid rat liver bioassay.