GLYCOPHORIN A SOMATIC-CELL MUTATION FREQUENCIES IN FINNISH REINFORCED-PLASTICS WORKERS EXPOSED TO STYRENE

We have used the glycophorin A (GPA) in vivo somatic cell mutation ass ay to assess the genotoxic potential of styrene exposure in 47 reinfor ced plastics workers occupationally exposed to styrene and 47 unexpose d controls matched for age, gender, and active smoking status. GPA var iant erythrocyte frequencies (V-f), reflecting GPA allele loss (O/N) a nd allele loss and duplication (N/N) somatic mutations arising lit viv o in the erythroid progenitor cells of individuals of GPA M/N heterozy gous genotype, were flow cytometrically determined in peripheral blood samples from these subjects, Measurements of styrene exposure of the workers at the time of blood sampling showed a mean 8-h time-weighted average (TWA(8-h)) styrene concentration of 155 mg/m(3) (37 ppm) in th e breathing zone, Mean urinary concentrations of the styrene metabolit es mandelic acid (MA) and mandelic acid plus phenyl glyoxylic acid (MA +PGA) were 4.4 mmol/liter (after workshift) and 2.1 mmol/liter (next m orning), respectively, Multivariate analysis of covariance on log-tran sformed GPA V-f data with models allowing adjustment for age, gender, smoking status, and styrene exposure showed that N/N V-f were nearly s ignificantly increased among an of the exposed workers (adjusted geome tric mean, 6.3 per million versus 5.0 in the controls; P = 0.058) and were statistically significantly elevated (adjusted geometric mean, 6. 8 versus 5.0 in the controls; P = 0.036) among workers classified into a high-exposure group according to personal TWA(8-h) concentration of styrene in the breathing zone of greater than or equal to 85 mg/m(3) (20 ppm; Finnish threshold limit value), Women in this high exposure g roup showed especially elevated N/N V-f (adjusted geometric mean 8.5 v ersus 5.3 in control women; P = 0.020); this elevation was also signif icant if urinary MA+PGA of greater than or equal to 1.2 mmol/liter was used as the basis of classification (adjusted geometric mean, 8.3; P = 0.030), The occupational exposure could not be shown to influence O/ N V-f. Cigarette smoking was associated with significantly elevated GP A V-f among active smokers (P = 0.042 for O/N and P = 0.020 for N/N) a nd among active and ex-smokers combined (P = 0.014 for N/N), Its influ ence on O/N V-f was especially clear among active smokers in the contr ol group (P = 0.005), An effect of smoking, nearly statistically signi ficant, was also observed for the O/N V-f of control ex-smokers (P = 0 .055) and of all active and ex-smokers combined (P = 0.050), Thus, the two characterized chemical exposures experienced by this group of wor kers and controls appear to produce differential effects on the two in dependent classes of GPA variants enumerated in the assay, This result suggests that the genotoxicity of these agents is mediated, at least in part, by different genetic mechanisms, Styrene exposure is associat ed with a specific increase in GPA N/N V-f; these allele loss and dupl ication variants reflect predominantly somatic recombination mechanism s in erythroid progenitor cells, Tobacco smoke exposure in active and ex-smokers is also associated not only with an increase in N/N V-f but also with an increase in O/N V-f, reflecting the induction of GPA gen e-inactivating mutations, including point mutations and deletions, Thi s finding is consistent with a broad mechanistic spectrum of tobacco s moke genotoxicity associated with this complex mixture of chemical mut agens, Finally, there was no detectable effect of age on O/N V-f; howe ver, a highly significant (P = 0. 0002) increase in N/N V-f with age, even after adjustment for other variables, was observed.