Epidemiologic and experimental studies indicate that particulates and/or chemical carcinogens are important in the development of respiratory disease. Occupational exposure to silica often includes exposure to polycyclic aromatic hydrocarbons (PAH); silica has an enhancing effect on benzo(a)pyrene (BaP) induced lung carcinogenesis. Although the mechanism of cocarcinogenic action is unknown, several investigators have implicated BaP metabolism. An important biological response to inhaled particulates is ingestion by pulmonary alveolar macrophages (AM) and clearance from the lung. Since these cells have the capacity to metabolize BaP, it is possible that altered BaP metabolism leading to an enhanced carcinogenic potential occurs in the AM following phagocytosis of silica particulates and absorbed BaP. The long term objective of this research is to investigate the role that AM play in the particulate-dependent response of the lung to BaP via mechanisms involving BaP metabolism. Male Syrian Golden hamsters (8-9 wk old) are known to be susceptible to the formation of lung tumors by PaP-coated particulates. Using AM derived from these animals, the specific aims are to determine: 1) the ability of AM to phagocytize BaP- coated forms of silica including crystalline and amorphous silica and foundry sands, relative to Fe2O3 and Al2O3 that do and do not enhance BaP carcinogenicity, respectively, 2) the pattern of formation of metabolites derived from BaP-coated particulates incubated with AM, 3) the metabolism of BaP and BaP-binding to DNA and protein from BaP-coated particulates and 4) the mutagenic potential of the mixture of BaP metabolites present in media of AM cultures exposed to BaP-coated particulates. AM will be incubated with noncytotoxic doses of 3H-BaP coated particulates and analyzed at various times for 3H-BaP in the cells and the reduction of cytochrome C as a measure of the metabolic activity of AM. Analyses will be performed using extraction procedures, HPLC, and neutral alumina column chromatography for separation of metabolites and isolation of DNA and protein, liquid scintillation spectrometry, and forward and reverse Salmonella mutagenesis assays. In the evaluation of occupational hazards that may lead to increased susceptibility to lung cancer, the cocarcinogenic potential of an exposure is an important consideration. This research will provide information on particulate modified BaP metabolism and will contribute to our understanding of the involvement of AM in the mechanism of lung disease.
| Warshawsky, D; Reilman, R; Cheu, J et al. (1994) Influence of particle dose on the cytotoxicity of hamster and rat pulmonary alveolar macrophage in vitro. J Toxicol Environ Health 42:407-21 |
