Benzo[b]fluoranthene and 4-, 5-, 6-, and 7-fluorobenzo[b]
fluoranthene were evaluated for
tumor-initiating activity in mouse skin. These fluorinated
benzo[b]fluoranthene derivatives were assayed at doses of 400, 120, 40, and 10 nmol per mouse. Similar tumorigenic activity was observed for
benzo[b]fluoranthene and 5-fluorobenzo[b]
fluoranthene. While 4-fluorobenzo[b]
fluoranthene did produce a significant tumorigenic response at each dose assayed, substantially fewer
tumors per mouse were observed compared to
benzo[b]fluoranthene at initiator doses at or above 120 nmol. Only moderate tumorigenic activity was observed for 6- and 7-fluorobenzo[b]
fluoranthene. Both of these fluorinated derivatives were significantly less tumorigenic (P < 0.05) than 4-fluorobenzo[b]
fluoranthene when administered at initiator doses at or below 120 nmol. These results were unanticipated in view of data which indicate that metabolism of trans-9,10-dihydro-9,10-dihydroxybenzo[b]-
fluoranthene to trans-9,10-dihydro-5,9,10-trihydroxybenzo[b]
fluoranthene represents a principal activation mechanism of
benzo[b]fluoranthene in mouse skin. The potential of
fluorine substitution not only to inhibit metabolism, but also to alter the genotoxic activity of those metabolites which do form could explain the tumorigenic activity observed with these fluorinated derivatives of
benzo[b]fluoranthene. These data suggest caution in the interpretation of results based exclusively upon the assumption that the only influence of
fluorine substitution is inhibition of the formation of specific metabolites.