The present proposal is focused on the interaction of the long lived polyhalogenated hydrocarbons with two specific environmentally relevant compounds, chloroform and benzidine. Among the effects produced by these compounds are toxicity and carcinogenicity in the kidney and urinary tract, organs with which we have considerable expertise. It is our contention that exposure to polyhalogenated aromatic hydrocarbons does not produce any overt toxicity, but alters the renal biochemical pathways responsible for the metabolic activation of a variety of nephrotoxicants and, therefore, renders an individual hypersusceptible to renal damage by nephrotoxicants.
The specific aims of this proposal are two-fold: 1) to characterize the interaction of two environmental contaminants, polybrominated biphenyls (PBBs) and polychlorinated biphenyls (PCBs) and the nephrotoxic effects of chloroform. It has previously been shown by us that pretreatment with PBBs will potentiate chloroform nephrotoxicity while PCBs will protect from chloroform nephrotoxicity. The present proposal is concerned with the renal metabolism of chloroform. Renal chloroform metabolism will be measured both in vivo and in vitro by trapping phosgene, a suspected reactive intermediate of chloroform, by measuring CO2 liberation and by measuring covalent binding to tissue macromolecules. The effect of exposure to PBBs and PCBs on renal chloroform metabolism will then be quantified. These data should elucidate the mechanism of the diametrically opposed effects of PBBs and PCBs on chloroform nephrotoxicity. 2) This proposal also includes experiments designed to evaluate the renal metabolism of benzidine both in vivo and in vitro and the influence of prior exposure to polyhalogenated aromatic compounds. Unlike the proposed chloroform experiments which focuses primarily on Phase I reactions, this section includes both Phase I and Phase II metabolism of benzidine since metabolic activation of benzidine has been suggested to proceed via a Phase II reaction. Measurements of benzidine metabolism and covalent binding will be performed in isolated cell fractions and in the isolated perfused kidney. The effects of prior exposure to PBBs, PCBs and hexachlorobenzene on renal toxicity and metabolism of benzidine will then be evaluated. Experiments described in this proposal are highly mechanistic in nature and to our knowledge, this is the first substantial research project specifically designed to evaluate the concept that the kidney can generate nephrotoxic metabolites by metabolic pathways which may be targets of other chemicals, particularly the halogenated aromatic hydrocarbons.
