Comparative Mutagenicity, Tumor-Initiating Activity, Carcinogenicity, and in Vitro Metabolism of Fluorinated 5-Methylchrysenes23

The comparative mutagenicity toward Salmonella typhlmurlum TA 100, tumor-initiating and complete carcinogenic activity on mouse skin, and in vitro metabolism of fluorinated derivatives of the carcinogen 5-methylchrysene (5-MeC) were studied. The compounds studied were 1-fluoro-5-methylchrysene (1-F-5-MeC), 3-fluoro-5-methylchrysene (3-F-5-MeC), 6-fluoro-5-methylchrysene (6-F-5-MeC), 7-fluoro-5-methylchrysene (7-F-5-MeC), 9-f1uoro-5-methylchrysene (9-F-5-MeC), 11-fluoro-5-methylchrysene (11-F-5-MeC), and 12-fluoro-5-methylchrysene (12-F-5-MeC). All seven fluoro compounds and 5-MeC were mutagenic toward S. typhlmurlum TA 100 when tested in the presence of liver homogenates from F344 rats treated with Aroclor 1254; the most mutagenic compound was 7-F-5-MeC. In the assays for tumor-initiating activity on skin of Swiss mice, 1-F-S-MeC and 3-F-5-MeC were significantly less active than was 5-MeC at both doses studied (30 and 100 μg), whereas 12-F-5-MeC was less tumorigenic than was 5-MeC at the 30-μg dose only. The other fluorinated compounds were as active as 5-MeC as tumor initiators. In agreement with these results, both 1-F-5-MeC and 3-F-5-MeC were inactive as complete carcinogens; 12-F-5-MeC was also significantly less carcinogenic than was 5-MeC. 6-F-5-MeC was more carcinogenic than was 5-MeC, whereas 7-F-5-MeC, 9-F-5-MeC, and H-F-5-MeC were as active as was 5-MeC. Examination of the in vitro metabolism of the fluorinated compounds by liver homogenates from Aroclor 1254-treated rats indicated that fluorine substitution inhibited the oxidative metabolism at the position of attachment and at neighboring positions. Thus in 1-F-5-MeC and 3-F-5-MeC, formation of the 1,2-dihydrodiol was inhibited and in 7-F-5-MeC, formation of the 7,8-dihydrodiol and chrysenols was reduced. In the metabolism of 12-F-5-MeC, the concentration of the 1,2-dihydrodiol was reduced compared to that of 5-MeC, whereas in 6-F-5-MeC, formation of the 7,8-dihydrodiol and chrysenols was inhibited.