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© 1989 Oxford University Press

research-article

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

JERROLD M. WARD1,*, HIROYUKI TSUDA{dagger}, MASAE TATEMATSU{dagger}, AKIHIRO HAGIWARA*,{dagger} and NOBUYUKI ITO{dagger}

*Tumor Pathology and Pal hogen esis Section, Laboratory of Comparative Carcinogenesis, Division of Cancer Etiology National Cancer Institute, Frederick, Maryland 21701-1013 {dagger}Department of Pathology, Nagoya City University Medical School 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467, Japan

Received April 4, 1988; accepted June 27, 1988

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


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