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Toxicologic Pathology
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Hypolipidemics Carcinogenicity and Extrapolation of Experimental Results for Human Safety Assessments

Felix A. de la Iglesia, M.D.

Department of Pathology and Experimental Toxicology, Warner-Lambert/Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan and Department of Pathology, Banting Institute, University of Toronto, Toronto, Ontario, Canada

Emmanuel Farber, M.D., Ph.D.

Department of Pathology and Experimental Toxicology, Warner-Lambert/Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan and Department of Pathology, Banting Institute, University of Toronto, Toronto, Ontario, Canada

Dyslipoproteinemias represent a group of disorders closely related to alterations of cholesterol and triglycerides. The alterations of these lipids are considered important risk factors in coronary heart disease and indicate the need for clinically effective and safe drugs.

Hypolipidemic agent therapy, however, does not appear without risk since the administration of these agents is by necessity, on a long-term basis. In the conduct of animal safety studies with some hypolipidemics, hyperplastic nodules or tumors developed in the liver of rodents. Data from the literature seem to indicate that the tumor response in rodents varies with the type of hypolipidemic drug administered. This paper summarizes the studies with the new lipid-regulating agent gemfibrozil. Aside from conventional long-term studies in rodents, the ultrastructural aspects of the liver were analyzed in several species and genotoxicity assays and short-term tests for hepatocarcinogenicity were conducted. Thus, it was possible to obtain an overview of these biological phenomena in order to allow for safety extrapolations. The biological behavior of these liver nodules showed that gemfibrozil and clofibrate-induced hepatocytes had not undergone malignant transformation. Further, the phenomenon of peroxisome proliferation, a characteristic event that follows hypolipidemic administration in rodents, was not confirmed in primate or human liver. Peroxisome proliferation has been linked to the process of hepatocarcinogenesis in rodents, although genotoxicity assays were negative and initiation/promotion tests failed to elicit tumors or nodules in a system where hepatocarcinogens manifest their activity.

Thus, hypolipidemics such as gemfibrozil or clofibrate may possess low tumorigenic potential with low risk due to the lack of correlation between these tests. Nevertheless, these agents are indicated for specific lipoprotein phenotype alteration with the resulting clinical benefits.

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Toxicologic Pathology, Vol. 10, No. 2, 152-170 (1982)
DOI: 10.1177/019262338201000228
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