Recent efforts have focused on identifying risk factors for the myelodysplastic syndromes, a collection of hematologic disorders of increasing importance among the elderly. About 20-40% of patients with myelodysplasia develop acute myeloid leukemia (AML); others have substantial morbidity even without transformation to AML. In our study of 158 adults with myelodysplasia and population controls, risk factors identified thus far include petroleum distillates, halogenated solvents, welding fumes and other agents. In contrast, these factors were not associated with AML that was not preceded by a myelodysplasia. These results suggest that myelodysplasia may be a marker of chemical exposure in AML and that there may be pathogenetically distinct subsets of leukemia that can be identified by clinical or laboratory parameters. We are continuing to explore the role of genes that affect the metabolism of specific carcinogens. For example, we showed that persons with the null genotype of the glutathione-S-transferase theta gene had four times the odds of developing myelodysplastic syndromes as persons with the gene, although no clear exposure-gene interactions were identified. We have found the paraoxonase gene to be unrelated to risk of myelodysplastic syndromes; although organophosphate pesticides have been associated with risk for hematopoietic cancers, and these are metabolized by the paraoxonase gene, the lack of an effect in our data is consistent with our finding of no clear relationship between myelodysplasia and pesticides. We completed testing for ras mutations in bone marrow of 250 acute myeloid leukemia patients and have begun analyzing our data in an attempt to confirm a previous observation of an association between ras- positive leukemia and solvent exposure. In addition, we will explore a possible link between metabolism gene polymorphisms and leukemia that is characterized by ras mutations. We are planning a new, larger study of genetic and environmental risk factors for myelodysplastic syndromes and AML in collaboration with Cancer and Leukemia Group B member institutions.