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Abstract: Objective: Association between genetic deletion polymorphism of GSTM1 (*0/*0 or active) and levels of anti (±)-r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE)-DNA adducts in the peripheral blood lymphocyte plus monocyte fraction (LMF) of PAH-exposed subjects was investigated. Methods: A total of 94 Caucasian subjects comprised the sample population: 13 coke-oven workers, 19 chimney sweeps, 36 aluminum-anode plant workers, and 26 non-occupationally PAH-exposed subjects (controls). PAH exposure was assessed in each group by means of the urinary excretion of 1-pyrenol (mean group levels 1.2, 0.7, 0.3, and 0.1 μmol/mol creatinine in coke-oven workers, chimney sweeps, aluminum-anode plant workers, and control subjects, respectively). Anti-BPDE-DNA adducts were detected by HPLC/fluorescence analysis of anti-BPDE tetrols (tetrol I-1) released after acid hydrolysis of DNA samples. Results: In coke-oven workers the percentage of cases with adduct levels exceeding the 95th percentile control value (4.4 adducts/108 nucleotides) was significantly higher in the subgroup with the null GSTM1 genotype (*0/*0) (100%) than in that with active GSTM1 (43%; 2 test, P < 0.05). In the other groups with different and lower levels of PAH exposure the percentages of positive samples were always higher in the subgroup with GSTM1 *0/*0 than in the active one, although the differences were not statistically significant. Univariate (odds ratio) and multivariate (relative risk) analyses showed that the risk of having high anti-BPDE-DNA levels increased with occupational exposure to PAH. Such risks, moreover, were further significantly increased by the lack of GSTM1 activity (RR = 5.94; CI = 1.15–30.7; P < 0.05). In coke-oven workers, chimney sweeps, and aluminum workers, respectively, the multiplicative effect of the null genotype with occupational PAH exposure gives risks of 162 (=27.2 × 5.94), 10 (=1.70 × 5.94), and 3 (=0.50 × 5.94) times higher probability (risk) of high BPDE-DNA adduct formation than that of nonexposed subjects with the active GSTM1 genotype. Conclusion: Our results indicate a greater risk of anti-BPDE-DNA adduct formation resulting from occupational high-level PAH-exposure in GSTM1 null (GSTM1 *0/*0) workers.

The influence of the metabolic genotypes GSTM1 and NAT2 on the urinary excretion of mutagens in 46 coke oven workers (27 of them smokers) was studied. Exposure to polycyclic aromatic hydrocarbons (PAH) was estimated from urinary 1-pyrenol levels, which varied from 0.23 to 5.59 micromol/mol creatinine. Fourteen urine samples (30.4%), all but one belonging to smokers, were positive for mutagenic activity (i.e. at least one of the assayed doses was able to double the number of spontaneous revertants). Nine of the urine-positive subjects were both GSTM1-null and NAT2-ss (64.3%), while the same combination of genotypes was found in nine out of 31 urine-negative subjects (29.0%) (P < 0.05). Significantly more smoking workers with the genotype combination GSTM1-null/NAT2-ss showed positive urine mutagenicity than the other subjects (75.0 versus 28.6%, P < 0.05). Smokers with the slow acetylator genotype showed a significantly higher frequency of positive urine samples than smoking fast acetylators (64.7 versus 22.2%, P < 0.05). Our results suggest that smoking coke oven workers with genotypes unfavourable for detoxification of aromatic amines (NAT2-ss) and PAH (GSTM1-null) may have an increased risk of developing bladder cancer.