Employees in the footwear manufacturing industry are routinely exposed to complex mixtures of solvents used in cleaning and as diluents in glues, primers, and degreasers. The objective of this study was to determine the genotoxic effects in a group of footwear-workers occupationally exposed to solvent-based adhesive and solutions containing organic solvents, mainly toluene. Peripheral blood and buccal cells samples were collected from 39 footwear-workers (31 males and 8 females) and 55 controls (44 males and 11 females). As biomarker of exposure, we obtained data on hippuric acid (HA), the main metabolite of toluene in urine, and DNA damage detected by the Comet assay in blood cells. Micronucleus frequencies in binucleated lymphocytes (BNMN) and in epithelial buccal cells (EBCMN) were analyzed as biomarkers of effect, while polymorphisms in genes GSTT1, GSTM1, GSTP1, CYP1A1, and CYP2E1 were used as susceptibility biomarkers. Results of HA and Comet assay showed statistical increased values amongst footwear-workers relative to controls (P < or = 0.001). No differences were observed in BNMN and EBCMN frequencies between the groups, but a correlation test revealed that age was significantly associated with BNMN frequency in both control (r(s)=0.290; P < or = 0.05) and exposed groups (r(s)=0.674; P < or = 0.001). Regarding the results on genetic polymorphisms, GSTM1 null subjects from the control group showed a significant increase in EBCMN frequency relative to GSTM1 non-null subjects (P < or = 0.05). A significant increase in DNA damage detected by Comet assay in leukocytes was obtained for GSTP1 Ile/Val or Val/Val individuals from the exposed group relative to those with GSTP1 Ile/Ile (P < or = 0.05), especially in younger subjects (P < or = 0.01), and a suggestion of interaction with CYP2E1 polymorphism was found. In confirmation of these data, stepwise multiple regression analyses for selecting between the different independent variables showed that about 25% of levels of the DNA damage in footwear-worker can be associated with genetic polymorphisms in GSTP1 and CYP2E1 (P=0.006, F=5.876).