The Potential Role of Chemically Induced Hyperplasia in the Carcinogenic Activity of the Hypolipidemic Carcinogens

Abstract

Di(2-ethylhexyl)phthalate (DEHP) is a widely used plasticizing agent resulting in substantial human exposure and environmental contamination. In a chronic bioassay, high doses of DEHP induced hepatocellular carcinomas in female Fischer-344 rats and male and female B6C3F1 mice. Thus, there is considerable concern as to the species specificity, mechanism of action, and human risk assessment of DEHP. DEHP belongs to a class of agents described as hypolipidemic hepatocarcinogens. These chemicals share the ability to induce hepatic peroxisomal proliferation and range from very weak to very potent hepatocarcinogens. Unlike most identified carcinogens, the hypolipidemic carcinogens lack DNA reactivity in sensitive cell culture systems such as the Ames test. It has been proposed that active oxygen radicals, produced as a result of peroxisomal proliferation, induce DNA damage. While this is an attractive hypothesis, no genotoxic activity has been observed in hepatocytes with peroxisomal proliferation in treated animals. Another biological activity shared by this class of compounds is their ability to stimulate liver growth or hyperplasia. This additive hyperplasia results from direct mitogenic stimulation rather than regenerative growth following liver toxicity. This hyperplasia can be dramatic, with liver to body weight ratios from treated animals reaching two to three times normal. The degree of induced hyperplasia correlates well with the carcinogenic potency of these agents, whereas genotoxicity does not correlate at all. Increased cellular growth may result in spontaneous mutational events or proniotional effects. While some feedback mechanism eventually inhibits liver growth, it is possible that key genes related to the regulation of cellular growth and cancer remain stimulated during continued administration of the chemical. Thus, determination of hyperplastic activity represents an attractive first-step approach to the short-term detection and study of the mode of action of nongenotoxic carcinogens.