MECHANISMS OF CHEMICALLY-INDUCED RENAL CARCINOGENESIS IN THE LABORATORY RODENT

Laboratory studies with classical renal carcinogens in the rat and mou se, as well as research investigation with some of the chemicals provi ng positive for the kidney in National Toxicology Program carcinogenic ity bioassays, have demonstrated the existence of a range of diverse m echanisms underlying rodent kidney carcinogenesis. The classical carci nogens used as experimental models for studying renal tumor pathogenes is, such as the nitrosamines, are genotoxic and interact directly with DNA, forming DNA adducts with mutagenic potential. In contrast, potas sium bromate and ferric nitrilotriacetate (Fe-NTA), also effective ren al carcinogens, appear to cause indirect damage to DNA mediated by oxi dative stress. A number of nongenotoxic chemicals are associated with epigenetic renal tumor induction in rodents, and the activity of these tends to involve prolonged stimulation of cell proliferation througho ut the duration of exposure. This mode of action reflects a sustained regenerative response, either due to direct chemical toxicity to the t ubule cells, as with chloroform, or to indirect cytotoxicity associate d with lysosomal overload, as in alpha(2u)-globulin accumulation in ma le rats resulting from the administration of such chemicals as d-limon ene and tetrachloroethylene. The histopathologic nature of hydroquinon e renal carcinogenesis suggests that an additional epigenetic pathway to renal tubule tumor formation in rats may be through chemical-mediat ed exacerbation of, and interaction with, the age-related spontaneous renal disease, chronic progressive nephropathy. These various mechanis tic pathways have implications for the nature of the induced cancer pr ocess with respect to tumor incidence, latency, malignancy, and sex pr edisposition.