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A study on 44 workers exposed to styrene and 44 matched referents was performed in order to examine the influence of genetic polymorphisms in biotransformation and DNA repair enzymes on the levels of N-terminal hemoglobin adducts and genotoxicity biomarkers. Urinary mandelic acid concentration averaged 201.57 mg/g creatinine +/-148.32 in exposed workers, corresponding to a calculated average airborne styrene exposure of 9.5 ppm +/-9.6. Individuals with a high level of N-terminal valine adducts had higher levels of DNA damage, as evaluated by the Comet assay (r = 0.29, P = 0.008). Frequencies of micronucleated mononucleated lymphocytes (MNMC) (0.71 +/- 0.88 vs 0.11 +/- 0.20, P<0.0001), micronucleated binucleated lymphocytes (MNBC) (3.93 +/- 2.75 vs 2.65 +/- 1.94, p = 0.02) and micronucleated nasal epithelial cells (0.52 +/- 0.49 vs 0.23 +/- 0.31, p = 0.04) differed significantly between the exposed and referent groups. In the whole group of 88 individuals, higher frequencies of MNMC were found in individuals possessing the XRCC3 Met(241) allele and those individuals with the XRCC1 Gln( (399) ) allele showed higher frequencies of MNMC and MNCB. In vitro DNA repair capacity, as measured by residual DNA strand breaks in peripheral blood leukocytes after a styrene oxide challenge, was also influenced by styrene exposure, with an apparent induction of early repair mechanisms associated with the intensity of recent exposure and a reduction of late (24 h) repair capacity that was associated with the duration of employment. After 1 h of repair, lower levels of residual DNA damage were found in individuals possessing GSTT1 (P = 0.043). After 24 h of repair, lower residual DNA damage was found in individuals homozygous for XRCC1 Arg(194) (P = 0.013). Multivariate regression analysis indicated that the duration of exposure, smoking habits and polymorphisms of XRCC1 at codon 399 were important variables affecting the genotoxic responses. Our data suggest that DNA damage is formed in workers exposed to low concentrations of styrene, and that genotypes of metabolising and DNA-repair genes are important for the assessment of individual genotoxic risk to styrene. The in vitro DNA repair phenotype assay might be a valuable method to estimate the susceptibility of workers.

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A pooled analysis of five biomonitoring studies was performed to assess the influence of hOGG1 326 , XRCC1 399 and XRCC3 241 gene polymorphisms on micronuclei (MN) frequency in human peripheral blood lymphocytes, as measured by the ex vivo/in vitro cytokinesis-block micronucleus (CBMN) assay. Each study addressed a type of occupational exposure potentially able to induce DNA strand breakage (styrene, ionising radiation, cobalt/hard metal, welding fumes and inorganic arsenite compounds), and therefore MN, as a result of base excision repair and double-strand break repair deficiencies. The effect of genotype, age, exposure to genotoxic agents and smoking habit on MN induction was determined using Poisson regression analysis in 171 occupationally exposed male workers and in 132 non-exposed male referents. The analysis of genotype-genotype, genotype-smoking and genotype-exposure interactions by linear combinations of parameters showed significantly higher MN frequencies in the following subsets: (i) occupationally exposed workers carrying either the Thr/Thr or the Thr/Met XRCC3 241 genotypes compared to their referent counterparts (P < 0.001) and (ii) carriers of the Met/Met XRCC3 241 genotype compared to Thr/Thr XRCC3 241 carriers, as far as they are non-exposed and bear the variant (Ser/Cys or Cys/Cys) hOGG1 326 genotype (P < 0.01). Significantly lower MN frequencies were observed in carriers of the variant hOGG1 326 genotype compared to Ser/Ser hOGG1 326 carriers in the subgroup of non-smokers with Thr/Thr XRCC3 241 genotype (P < 0.01). Stratified analysis by occupational exposure showed a significant MN increase with smoking in occupationally exposed carriers of the Arg/Gln XRCC1 399 genotype (P < 0.001). In contrast, a significant MN decrease with smoking was observed in referents carrying the Ser/Ser hOGG1 326 genotype (P < 0.01). These findings provide evidence that the combination of different DNA repair genes and their interaction with environmental genotoxic agents may modulate MN induction. Understanding the complexity of the relationships between exposure, DNA repair and MN frequencies require larger scale studies and complementary biomarkers.