Tumorigenicity of Bay-Region Epoxides and Other Derivatives of Chrysene and Phenanthrene in Newborn Mice

The tumorigenic activities of several derivatives of chrysene and phenanthrene were tested in newborn Swiss-Webster mice. The compounds were administered i.p. in doses of 0.2, 0.4, and 0.8 µmol on the first, eighth, and 15th days of life. Experiments were terminated when the animals were 38 to 42 weeks old. The only tumors found in control mice were lung adenomas; 15% of the control animals developed these pulmonary tumors with an average of 0.17 tumor/mouse. (±)-1β,2α-Dihydroxy-3α,4α-epoxy-1,2,3,4-tetrahydrochrysene (diol epoxide-2) with the benzylic 1-hydroxyl group trans to the bay-region epoxide oxygen was the most potent chrysene derivative tested. It induced pulmonary tumors in 98% of the mice, with an average of 15.9 tumors/mouse. (±)-1β,2α-Dihydroxy-3β,4β-epoxy-1,2,3,4-tetrahydrochrysene (diol epoxide-1), in which the bay-region epoxide oxygen is cis to the benzylic 1-hydroxyl group, had little if any tumorigenic activity at the dose tested. trans-1,2-Dihydroxy-1,2-dihydrochrysene and 1,2-dihydrochrysene, the immediate metabolic precursors of a bay-region diol-epoxide and a bay-region tetrahydroepoxide, respectively, were the next most active chrysene derivatives tested; they produced pulmonary tumors in 73 to 75% of the mice, with an average of 2.1 to 2.2 tumors/mouse. 3,4-Epoxy-1,2,3,4-tetrahydrochrysene (bay-region epoxide) induced pulmonary tumors in 71% of the mice, with an average of 1.26 tumors/mouse. trans-3,4-Dihydroxy-3,4-dihydrochrysene, 3,4-dihydrochrysene, and trans-5,6-dihydroxy-5,6-dihydrochrysene had little or no tumorigenic activity. Chrysene itself had little or no tumorigenic activity in the lung but produced a 25% incidence of hepatic tumors in male mice, with an average of 0.42 tumor/mouse. Chrysene derivatives which induced a large number of pulmonary tumors also induced some hepatic tumors and lymphomas. Phenanthrene and its derivatives were less tumorigenic than chrysene and its derivatives. Phenanthrene, 1,2-dihydrophenanthrene, and the two diastereomeric bay-region diol-epoxides of phenanthrene had little or no tumorigenic activity, but the bay-region tetrahydroepoxide, 3,4-epoxy-1,2,3,4-tetrahydrophenanthrene, had some activity. This compound induced pulmonary tumors in 45% of the mice, with an average of 0.74 tumor/mouse. It also induced a few hepatic tumors and lymphomas.