MECHANISMS OF CARCINOGENESIS BY CRYSTALLINE SILICA IN RELATION TO OXYGEN RADICALS

The carcinogenic effects of crystalline silica in rat lungs were exten sively demonstrated by many experimental long-term studies, showing a marked predominance for adenocarcinomas originating from alveolar type II cells and associated with areas of pulmonary fibrosis (silicosis). In contrast with its effects in rats, silica did not induce alveolar type II hyperplasia and lung tumors in mice and hamsters, pointing to a critical role for host factors. Using these animal models, we are in vestigating the role of cytokines and other cellular mediators on the proliferation of alveolar type II cells. immunohistochemical localizat ion of TGF-beta 1 precursor in alveolar type II cells adjacent to sili cotic granulomas was shown to occur in rats, but not in mice, and hams ters, suggesting a pathogenetic role for this regulatory growth factor . Recent investigations in our laboratory on the biologic mechanisms o f crystalline silica included determination of anionic sites on crysta lline silica surfaces by binding of the cationic dye janus Green B; bi nding of crystalline silica to DNA, demonstrated by infrared spectrome try; production of oxygen radicals by crystalline silica in aqueous me dia; induction of DNA strand breakage and base oxidation in vitro and its potentiation by superoxide dismutase and by hydrogen peroxide; and induction by crystalline silica of neoplastic transformation and chro mosomal damage in cells in culture. On the basis of these in vitro stu dies, we propose that DNA binding to crystalline silica surfaces may b e important in silica carcinogenesis by anchoring DNA close to sites o f oxygen radical production on the silica surface, so that the oxygen radicals are produced within a few Angstrom from their target DNA nucl eotides.