Nitropolynuclear aromatic hydrocarbons have been detected in various environmental samples. These agents are highly mutagenic in the S. typhimurium assay, but little is known about their carcinogenic activities or metabolic transformations in vivo. The objective of this study is to establish the mechanism of action of 6-nitrochrysene, 3-nitrofluoranthene, and 1-nitropyrene in conventional and axenic (germfree) F-344 rats and to determine whether the observed tumorigenicity, if any, is due primarily to the reduction of the nitro group, to diol epoxide formation, or to a combination of both pathways. The proposed methods will require the synthesis of the above mentioned compounds and the corresponding 14C-radiolabeled compounds. The LD50 will be determined and the compounds will be administered orally in corn oil to bothconventional and germfree F-344 rats to test for carcinogenicity. The metabolism studies in conventional and germfree F-344 rats will utilize the 14C-radiolabeled compounds. The structures of the biliary, fecal, and urinary metabolites derived from each compound will be determined. Independent synthesis of the identified metabolites will be carried out. The potential roles of the identified metabolites in activation or detoxification will be determined by assaying their mutagenic activities in S. typhimurium and their abilities to induce unscheduled DNA synthesis in the rat hepatocyte primary culture/DNA repair assay. The results of this study will provide badly needed information on the tumorigenicity of these environmental compounds. The metabolism studies in both conventional and germfree rats will provide information on the role of the intestinal microflora in the metabolic activation of these nitro compounds. The results of this study are essential in evaluating the actual risks of human exposure to nitropolynuclear aromatic hydrocarbons.
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