TUMORIGENICITY IN NEWBORN MICE OF FJORD REGION AND OTHER STERICALLY HINDERED DIOL EPOXIDES OF BENZO[G]CHRYSENE, DIBENZO[A,L]PYRENE (DIBENZO[DEF,P]CHRYSENE), 4H-CYCLOPENTA[DEF]CHRYSENE AND FLUORANTHENE

Diol epoxides of benzo[g]chrysene, dibenzo[a,l]pyrene (dibenzo[def,p]c hrysene), 4H-cyclopenta[def]chrysene and fluoranthene were tested for tumorigenicity in newborn mice. The compounds tested were racemic 13,1 4-epoxy-11,12,13,14-tetrahydrobenzo[g]chrysene (BgCDE), oxy-anti-13,14 -epoxy-11,12,13,14-tetrahydrodibenzo [a,l] pyrene (DB[a,l]PDE), oxy-1, 2,3,3a-tetrahydro-4H-cyclopenta[def]chrysene (C[def]C-1-3a-DE), poxy-6 ,7,8,9-tetrahydro-4H-cyclopenta[def]chrysene (C[def]C-6-9-DE) and -ant i-1,10b-epoxy-10b,1,2,3-tetrahydrofluoranthene (FDE). BgCDE and DB[a,l ]PDE are fjord region diol epoxides and their tumorigenic activities w ere compared to those of trans-3,4-dihydroxy-anti-1,2-epoxy-1, 2,3,4-t etrahydrobenzo[c]phenanthrene (BcPDE), a fjord region diol epoxide wit h known high tumorigenicity and trans-7,8 anti-9,10-epoxy-7,8,9,10-tet rahydrobenzo[a]-pyrene (BPDE), a highly tumorigenic bay region diol ep oxide. The protocol called for testing of each compound at a total dos e of 25 nmol per mouse, administered on days 1, 7 and 15 of life, with killing at age 35 weeks. BgCDE had similar activity as BcPDE for indu ction of lung tumors and was more active than BcPDE for induction of l iver tumors in male mice. Both compounds were significantly more tumor igenic than BPDE. DB[a,l]PDE was highly toxic. All mice died within 1 week of the first dose. It was then tested in a second study using tot al doses of 5 and 1 nmol per mouse. Only the first dose of the intende d 5 nmol total dose was given due to toxicity. The full course of dose s with a total of 1 nmol per mouse was administered; DB[a,l]PDE induce d a significant incidence and multiplicity of lung tumors and, in male mice, liver tumors at both doses. These results demonstrate that fjor d region diol epoxides are highly active tumorigens in newborn mice, w ith activity greater than that of the most active unsubstituted bay re gion diol epoxide, BPDE. C[def]C-1-3a-DE and C[def]-6-9-DE were compar ed to ihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydrochrysene (CDE), at a t otal dose of 500 nmol per mouse. FDE was also tested at this dose. The most active compound among the chrysene derivatives was C[def]C-1-3a- DE, followed by C[def]C-6-9-DE and CDE. C[def]C-1-3a-DE has a sterical ly constrained bay region, in which the benzylic carbon of the tri-sub stituted epoxide ring is part of a fused ring system. This feature is also present in FDE, which had considerable tumorigenic activity, grea ter than that of CDE in lung and greater than any of the chrysene deri vatives in liver. These results demonstrate that the tumorigenicity of diol epoxides in newborn mice is enhanced by steric constraints prese nt when the epoxide ring is part of a fjord region or is attached to a fused ring system. The tumorigenic activity of FDE may be relevant to human risk since it is a stable metabolite of the widely distributed environmental pollutant fluoranthene.