The frequency of thioguanine-resistant, hypoxanthine phosphoribosyltransferase-deficient lymphocytes in the peripheral blood of human subjects was used to study the genotoxic effects of smoking. Sixty-two nonsmokers and 58 smokers, aged 19 to 45 years with average ages of 30 and 32 years, respectively, and with no other known exposures, were studied using an in vitro assay of the frequency of mutant lymphocyte clones. Analysis of variance explained 68% of the variation in the mutant frequencies. Mutant frequency was dependent upon lymphocyte cloning efficiency, length of smoking history, age, and interactions between these variables. Four nonsmokers and three smokers had high mutant frequencies that were not explained by these variables. Mutant frequencies were inversely related to lymphocyte cloning efficiencies; the effect was twice as great for smokers as for nonsmokers. The time-dependent effect of smoking dominated, with mutant frequency increasing 10%/year of smoking as compared with an independent 1%/year of age. Smoking had a greater effect on young smokers' lymphocytes. Heterogeneity of mutant frequency among both smokers and nonsmokers and its implications for use of lymphocyte mutation assays as biomarkers are discussed.

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