Sulfur dioxide and the carcinogenic hydrocarbon benzo(a)pyrene (BP) are ubiquitous air pollutants and are components of tobacco smoke as well. Environmental exposure to these agents is unavoidable and social exposure remains far too prevalent. Epidemiologic data suggest an enhancing effect of sulfur dioxide on the formation of human respiratory tract cancers. Moreover, tumorigenicity studies in rats and hamsters have demonstrated an increased tumor yield and shortened latency period when BP and sulfur dioxide are administered together relative to those animals treated with BP alone. Sulfur dioxide itself is not carcinogenic. One way to enhance the carcinogenicity of BP would be to increase the formation of bay-region diolepoxides, the presumed ultimate carcinogenic derivatives, and to increase covalent modification of DNA by these activated forms of BP. This proposal describes a mechanistic investigation of the role of sulfur dioxide-derived oxidants on the conversion of 7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene (BP-7,8-diol) to bay-region diolepoxides, i.e., the final activation step for BP as a carcinogen, and on the formation of specific deoxyribonucleoside adducts. The experimental system will be the intact hamster trachea in short-term organ culture, a model system for BP-induced pulmonary carcinogenesis. Sulfur dioxide exists in aqueous systems at neutral pH as its hydrated, ionized form, the sulfite anion. Spontaneous or enzymatic oxidation of sulfite produces peroxyl radical and peracid derivatives, and these highly reactive oxidants may be involved in the effects of sulfur dioxide on BP carcinogenesis. Sulfite-dependent effects on BP-7,8-diol metabolism will be determined, with particular attention paid to the role of sulfite oxidation products in the process. This project examines a likely target for the expression of sulfur dioxide-induced toxic effects in a mechanistic way. As exposure to sulfur dioxide is unavoidable, such an understanding of the mechanism of toxic action provides the only rational basis for intervention in the toxic process.
