Tumorigenicity and liver tumor ras-protooncogene mutations in CD-1 mice treated neonatally with 1-and 3-nitrobenzo[a]pyrene and their trans-7,8-dihydrodiol and aminobenzo[a]pyrene metabolites

The environmental pollutants 1- and 3-nitrobenzo[a]pyrene (1- and 3-NBaP) a re metabolized by mammalian microsomes through ring oxidation to 1-NBaP tra ns-7,8-dihydrodiol and 3-NBaP trans-7,8-dihydrodiol, and by nitroreduction to 1- and 3-aminobenzo[a]pyrene. To determine if these compounds are tumori genic, 1- and 3-NBaP, along with several of their metabolites and the paren t benzo[a]pyrene (BaP) and its trans-7,8-dihydrodiol metabolite, were teste d in the neonatal CD-I mouse bioassay. Male mice were administered i.p, inj ections at a total dose of 100 or 400 nmol per mouse on 1, 8 and 15 days af ter birth. While the liver tumor incidences for BaP, BaP trans-7,8-dihydrod iol, and the positive control 6-nitrochrysene (6-NC) were significantly hig her than in the solvent control animals, all the other tested compounds exh ibited no tumorigenicity. The frequency of Ha- and Ki-ras mutations in live r tumors of mice treated with BaP, BaP trans-7,8-dihydrodiol, and 6-NC were higher than in the few liver tumors isolated from control mice or mice tre ated with the NBaPs or their metabolites. Since 1- and 3-NBaP and their met abolites are potent mutagens in the Salmonella assay and moderate mutagens in the Chinese hamster ovary (CHO) mammalian mutagenicity assay, our result s indicate that the in vitro mutagenicity of these compounds does not corre late with their tumorigenicity. (C) 1999 Published by Elsevier Science Ltd. AU rights reserved.