FORMATION OF DNA-ADDUCTS AND INDUCTION OF MUTATIONS IN RATS TREATED WITH TUMORIGENIC DOSES OF 1,6-DINITROPYRENE

1,6-Dinitropyrene, a component of diesel exhaust, is a lung carcinogen in male F344 rats following a single intrapulmonary;administration. I n this study, rats were treated with tumorigenic doses of 1,6-dinitrop yrene to establish dose-response relationships for the formation of DN A adducts in target (lung) and nontarget (liver) tissues and for the i nduction of 6-thioguanine-resistant mutations in spleen T-lymphocytes. One week after treatment with 0.3, 1, 3, 10, 30, 100, or 150 mu g of 1,6-dinitropyrene, dose-responsive DNA binding was measured in lung an d liver with binding in the lung being 10-fold higher than in the live r. In the lung, a 2-fold increase in dose resulted in a 1.8-fold incre ase in DNA binding at treatments up to 30 mu g of 1,6-dinitropyrene, w hile in the liver, a 2 fold increase in 1,6-dinitropyrene produced a 2 -fold increase in DNA binding at doses up to the 10 mu g treatment. Hi gher doses of 1,6-dinitropyrene resulted in proportionally smaller inc reases in adduct formation in the two tissues. When measured 21 weeks after treatment, mutations in T-lymphocytes increased with doses up to 100 mu g of 1,6-dinitropyrene, but the response was nonlinear through out the dose range. These findings indicate that concentrations of 1,6 -dinitropyrene that produce a dose-dependent induction of lung tumors also result in a dose-dependent formation of DNA adducts and induction of lymphocyte mutations but that the dose-response curves for DNA bin ding and mutations are different.