We have previously investigated the role of polymorphic chemical metabolizing genes in the susceptibility to the development of lung cancer using 110 primary lung cancer patients and 119 matched smoker controls. Together with data from the present study on DNA repair genes, we did not observe significant associations between any single variant genotype for several DNA-repair and chemical-metabolizing genes (XPD [or ERCC2], XRCC1, XRCC3, GSTM1, GSTT1, MPO, and mEH [or EPHX1]) and lung cancer. In the present study, we have further evaluated a nested group of 79 patients and 69 matched controls, and observed that increased chromosome aberrations (CAs) were associated with variant DNA-repair genotypes among both the patient and the control groups, with a significant increase for individuals having the XPD Lys/Gln + Gln/Gln genotypes (P = 0.046). Patients often had significantly increased CAs compared with controls with the same DNA-repair genotype and with similar cigarette smoking habits (< or =40 pack-years or >40 pack-years). Analyses of interactions between the DNA-repair and chemical-metabolizing genes indicated that the most significant interactions were between the repair genotypes and the GSTM1/T1 null genotypes. Significant increases in CA from the interactions were often observed among patients with < or =40 pack-years, but not among those with >40 pack-years. Since some variant DNA-repair genotypes have functional deficits for DNA repair, the association between variant DNA-repair genotypes and increased CAs suggests a risk mechanism for the development of lung cancer, with the DNA-repair genotypes interacting with variant chemical metabolizing genotypes to further increase the risk. The observation that patients had significantly increased CA frequencies compared with controls, irrespective of genotype, suggests that patients have additional factors that contribute to the development of lung cancer.

Exposure to pesticides remains a major environmenal health problem. Health risk from such exposure needs to be more precisely understood. We conducted three different cytogenetic assays to elucidate the biological effects of exposure to mixed pesticides in 20 Costa Rica farnMrs (all nonsmokers) compared with 20 matched controls. The farmers were also exposed to dibromochloropropane during the early employment years, and most of them experienced sterility/fertility problems. Our data show that the famers had consistently higher frequencies of chromosome aberrations, as determined by the standard chromosome aberration assay, and significandy abnormal DNA repair responses (p c 0.05), as determined by the challenge assay, but no statistically significant differences in the tandem-probe fluorescence in situ hybridization (FISH) assay (p > 0.05). Genotype analysis indicates that farmers with certain "unfavorable" versions of polymorphic metabolizing genes (cytochrome P4502El, the glutathione S-transferases mu and theta, and the paraoxonase genes) had significantly more biological effects, as determined by all three cytogenetic assays, than both the farmers with the "favorable" alleles and the matched controls. A unique observation is that, in individuals who had inherited any of the mentioned "unfavorable" alleles, farmers were consistentdy underrepresented. In condusion, the Costa Rican farmers were exposed to genotoxic agents, most likely pesticides, which expressed the induction of biological and adverse health effects. The farmers who had inherited "unfavorable" metabolizing alleles were more susceptible to genotoxic effects than those with "favorable" alleles. Our genotype data suggest that the well-recognized "healthy worker effect" may be influenced by unrecognized occupational selection pressure against genetically susceptible individuals.

Infection with high-risk human papillomavirus (HPV) plays a major role in the etiology of cervical cancer (CC). However, most infected women do not develop cancer. Therefore, exposure to other carcinogenic agents may be a contributing risk factor for CC. We investigated the hypothesis that environmental exposure to cigarette smoke and inheritance of polymorphic chemical metabolizing genes (CYP2E1, GSTM1, and mEH) significantly increase the risk for neoplasia. We selected 76 cases with high-grade cervical neoplasia or with invasive CC and 75 matched healthy controls. The collected data support the well-established observation that infection with high-risk HPV is the major risk factor for CC (OR = 75; 95% CI = 26-220). In addition, our data show that women who smoked more than 15 "pack-year" had a significant 6.9-fold increase in risk (95% CI = 1.2-40.3) after adjustment for HPV infection. The CYP2E1 variant genotype did not significantly increase the risk for neoplasia. A significant increase in risk for neoplasia was observed for the low-activity mEH 113 His allele after adjustment for smoking (OR = 3.0; 95% CI = 1.4-6.3). The GSTM1 null genotype was associated with a significant 3.3-fold increased risk for neoplasia (95% CI = 1.0-11.8) compared to women who were GSTM1-positive after adjustment for smoking and HPV infection. Our study suggests that genetic differences in the metabolism of cigarette smoke, particularly GSTM1, may confer susceptibility to CC. Further studies using larger populations will be needed to confirm our observations and to validate data for disease prevention.

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