Long-term, low-dose benzo[a]pyrene-induced mutation in human lymphoblasts competent in xenobiotic metabolism

We have studied the mutagenic effects of benzo[a]pyrene (BP) administered in a long-term, low-dose fashion to metabolically competent human lymphoblastoid cells. A continuous dose as low as 0.02 microM for 20 days produced a significant increase in mutant fraction at the 6TG-resistance (HGPRT) locus. The slope of the mutant fraction over time in the 0.02 microM BP-treated culture was twice that observed in the untreated concurrent control; 0.02 microM therefore represents the doubling dose of BP for gene mutation in this cell line. For higher doses of 0.1, 0.5 or 1 microM BP, the rate (or efficiency) of induced mutation was considerably higher for the first 5 or 6 days of exposure than for the last 14-15. This did not appear to be due to a growth disadvantage against early-arising mutants. Comparison to previously published data in the same cell system (Crespi and Thilly, 1984) revealed that the long-term , low-dose protocol (0-1 microM for up to 20 days) was significantly more efficient at inducing mutations than a short-term, high-dose protocol (0-10 microM for 1 day).