HUMAN CELL MODELS--LONGTERM LOW DOSE EXPOSURES AND MUTANT RESISTANT STATE

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We have discovered that when our human cell line, AHH-1, which expresses cytochrome P-450 1A1, is exposed continuously to low concentrations of potent airborne mutagens such as benzo(a)pyrene and naphtho(a)pyrene that they switch from a high mutation rate to a low mutation rate after 5 days. This low mutations rate is only some three fold higher than seen for spontaneous mutation in the concurrent untreated controls. Studies with radioactive benzo(a)pyrene show that the rate of DNA adduct formation is unchanged by this phenomenon. The ratio of the rate of mutation relative to the rate of constant DNA adduction is changed by a factor of four suggesting induction of a post-DNA adduction process such as DNA repair is occurring. Because such a phenomenon would, if occurring in vivo, represent a major physiologic response protecting against induction of mutations by airborne toxicants. Our studies so far establish that the induction of the mutation-resistance by benzo(a)pyrene confers cross-resistance to mutation by the potent airborne mutagen, cyclopenta[c,d]pyrene. Secondly, we have found that another potent airborne mutagen naphtho(a)pyrene induces resistance to mutation in a time dependent pattern similar to that of benzo(a)pyrene. Finally, we have found human cell lines derived from AHH-1 which are markedly sensitive to mutation by air sample extract under short term high dose conditions giving use a useful mode for proposed long term dose mimicking conditions of samples, source samples and their extracts and subfractions on these human cells under these long term low dose conditions which more closely approximate the conditions of exposure in the human bronciolar tree, (b) discover it the "mutation resistant state" is induced by exposure to raw air particulates, by particulate extracts and by particulate extract subfractions, and (c.) carry out appropriate studies of the process at the cellular and molecular levels.