HPRT AND GLYCOPHORIN-A MUTATIONS IN FOUNDRY WORKERS - RELATIONSHIP TOPAH EXPOSURE AND TO PAH DNA ADDUCTS

Mutations were evaluated in workers in an iron foundry with exposure t o polycyclic aromatic hydrocarbons (PAHs), measured by personal and ar ea monitoring, ranging from < 5 to 60 ng/m3 of benzo[a]pyrene (B[a]P). Mutation at the hypoxanthine guanine phosphoribosyl transferase (HPRT ) and glycophorin A (GPA) loci (measures of molecular effect in lympho cytes and erythrocytes respectively) were assessed to demonstrate thei r relationship to external exposure at lower levels than previously an alyzed in foundry workers at this plant (< 50-200 ng/m3). The relation ship between mutations and PAH-DNA adducts measured by immunoassay (as a measure of the biologically effective dose) was also investigated. The markers were analyzed for dose-response and interindividual variab ility. Workers were classified into three exposure categories (low, me dium and high). PAH-DNA adduct values for the low, medium and high exp osure groups were 5.19, 6.10 and 9.57 x 10(-8) nucleotides respectivel y (r = 0.28; P = 0.08). HPRT mutant frequencies (adjusted for age and cloning efficiency) for the low, medium and high exposure groups were 1.04, 1.13 and 1.82 x 10(6)cells respectively and demonstrated an upwa rd trend with increasing exposure that was of borderline significance (r = 0.46, P = 0.06). In contrast, HPRT mutations were highly correlat ed with PAH-DNA adducts (r = 0.67; P = 0.004). Interindividual variabi lity in mutant frequencies ranged from 1.5- to 4.5-fold within the thr ee exposure categories. With respect to GPA variants, NN frequency (Vf ) in erythrocytes (which reflects chromosomal loss and duplication, re combination or gene conversion) was not positively correlated with PAH exposure. The level of NO Vf (arising from small-scale structural mut ations in the GPA gene or from larger-scale chromosomal rearrangements or deletions) increased slightly, but not significantly, over the thr ee exposure groups from 8.2 to 10.7 to 11.8/10(6) cells (P = 0.32). In terindividual variation in GPA NN Vf ranged from 2- to 18-fold and in GPA NO from 4- to 5-fold. NN and NO Vf were highly correlated (P = 0.0 01) but no correlation was seen between GPA and HPRT or between GPA an d PAH-DNA adducts. Thus, the most interesting and novel finding is tha t, even at relatively low exposures to PAH, HPRT mutations were increa sed in parallel with PAH-DNA adducts. The observed association between PAH-DNA adducts and HPRT gene mutation in humans is consistent with e xperimental data for PAHs. These results support the use of both biomo nitoring and personal ambient monitoring in further molecular epidemio logy studies.