Mammary carcinogenicity of diol epoxide metabolites of benzo[j]fluoranthene in female CD rats

The mammary carcinogenicity of two diol epoxide metabolites of the commonly occurring environmental carcinogen benzo[j]fluoranthene (BjF) was investigated by direct application to the tissue beneath the mammary glands of female CD rats. The compounds tested were trans-4,5-dihydroxy-anti-6,6a-epoxy-4,5,6,6a-tetrahydroBjF (BjF-4,5-DE) and trans-9,10-diihydroxy-anti-11,12-epoxy-9,10,11,12-tetrahydroBjF (BjF-9,10-DE). The positive control was trans-3,4-dihydroxy-anti-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene (BcPDE). Groups of 20 female CD rats were maintained on AIN-76A-based high fat diet (23.5% corn oil) and at age 30 days were given three injections of 0.2 μmol of each compound in 0.1 ml dimethyl sulfoxide (DMSO), or DMSO alone, in the tissue underlying each of the three left thoracic nipples. The three right nipple areas were injected with DMSO alone. On the next day, each rat received three injections of 0.2 μmol of each compound in 0.1 ml DMSO, or DMSO alone, under each of the three left inguinal nipples, and DMSO alone under the three right nipples. The experiment was terminated after 44 weeks. BjF-9,10-DE, mean latent period 21.0 ± 8.8 weeks, was more active than BjF-4,5-DE, mean latent period 36.2 ± 8.0 weeks. BjF-9,10-DE induced tumors in 70% of the rats; a total of 38 fibroadenomas and eight adenocarcinomas was observed. BjF-4,5-DE induced tumors in 55% of the rats. These included 17 fibroadenomas, seven dysplastic fibroadenomas, and two adenocarcinomas. BcPDE induced tumors rapidly, with a mean latent period of 9.7 ± 4.0 weeks. All BcPDE-treated rats had mammary tumors. A total of 46 adenocarcinomas, as well as other tumors, were observed. In the DMSO-treated rats, mammary tumor incidence was 15%. The results of this study demonstrate that BjF-9,10-DE is more carcinogenic in the rat mammary gland than BjF-4,5-DE and that low doses of both diol epoxide metabolites of BjF are effective mammary tumorigens in female CD rats maintained on a high fat diet.