Summary of Work: Benzene induces cancer in humans and rodents by an unknown mechanism. Development of a laboratory low dose extrapolation model, especially for the induction of acute myelocytic leukemia, has been cited as a critical research need. Benzene oxidation in vitro may be mediated through cytochrome P450 (CYP) 2E1 in the liver of humans and rodents. Benzene toxicity to hematopoiesis of humans and rodents suggest that rodent models may be developed for investigation of mechanism(s) of tumorigenicity. In the Tg.AC transgenic mouse, insertion of a z-globin promoted v-Ha-ras transgene into the genome introduces a defined genetic lesion, which is critical, but insufficient by itself, to induce tumorigenesis. Mutations in the ras gene family also are frequently observed in human cancers. Benzene applied to the skin induced both skin tumors as well as granulocytic leukemias in Tg.AC mice. Pairwise comparisons were made between mice with a increased burden of benign papillomas and mice with leukemia. There was no significant statistical correlation between papilloma burden and the incidence of leukemia. However, studies in progress have been designed to determine: (1) if this a true leukemia, (2) the dose and dose-rate required for induction of leukemia, (3) if there is a functional relationship between the high burden of benign epidermal papillomas (source of growth factors, e.g. GM- CSF) and the development of leukemia in this mouse line. These mice are relatively free of sporadic tumors until at least 12 months of age, which minimize age related tumors that might confound interpretation and characterizing risk.