Hepatotoxicity of agents that enhance formation of focal hepatocellular proliferative lesions (putative preneoplastic foci) in a rapid rat liver bioassay

Abstract

The histopathology of hepatic toxicity for 58 chemicals previously tested in a rapid rat liver bioassay for demonstrating potential hepatocellular carcinogens and/or tumor promoters was reviewed. Rats received the test diet for 1 week prior to partial hepatectomy and for an additional 5 weeks thereafter at doses near the estimated maximally tolerated dose. These rats served as controls for others receiving initiation by N-nitrosodiethylamine (DEN) and the test diets. Twenty-two of these chemicals were previously found to enhance the formation of glutathione S-transferase, placental form (GST-P)-positive putative preneoplastic hepatocellular foci (promoters) following DEN initiation in this rapid bioassay, whereas 36 chemicals did not. Of the agents that promoted GST-P-positive foci, 14 22 (63.6%) produced toxic hepatocyte lesions while only 4 36 (11.1%) of the nonpromoters did so at the doses used. Biliary toxicity was found for 7 22 (31.8%) of the promoters and 6 36 (16.7%) of the nonpromoters. Only 2 13 (15%) chemicals that inhibited GST-P-positive foci produced hepatic toxicity. Thus, agents that were presumed hepatic tumor promoters characteristically were hepatotoxins while nonpromoters of carcinogenesis were not hepatotoxins in this rapid rat liver bioassay.