The phases of development, validation and application of biomarkers for cancer risk requires intensive study for each phase in order to build a reliable foundation for cancer risk assessments. This laboratory has focused upon the development of DNA-adduct detection assays that will serve to validate screening assays. These methods also will allow for the study of adducts as phenotypes of cancer susceptibility. Towards that end, chemically specific methods have been developed for the detection of 7-methyl-dGp, 7-ethyl-dGp and polycyclic aromatic hydrocar- bon-dGp adducts. Separately, improved methods and validation of N- acetyltransferase (NAT) and glutathione-S-transferase M1 (GSTM1) genetic polymorphisms have been developed. These studies have led to the discovery that GSTM1 null genotypes predict the presence of PAH-dGp adducts in human lung in vivo. Cytochrome P450 2E1 and 2D6 predict the presence of 7-methyl-dGp adducts. Determination of the different adduct levels in the same tissues demonstrate the differences in metabolic tendencies for adduct formation. Separately, an analysis of different parts of human lung indicate that interindividual differences in adduct formation is a greater predictor of adduct levels compared to the location in the lung and possible associated factors such as airflow. An interlaboratory study has shown that polychlorinated biphenyl (PCB) congeners are measurable in human lung and this procedure will be used to assess the effects of PCBs on cytochrome P450 induction. This work also has demonstrated the superiority of RFLP method detection for NAT genotypes and that these genotypes correlate with 4-aminobiphenyl hemoglobin adducts. Finally, polychlorinated biphenyl congeners have been reliably detected in human lung tissue and these methods will be used to assess correlations with enzyme induction in vivo.
