QUANTITATIVE STUDIES ON CONCURRENT FACTORS IN NEOPLASTIC TRANSFORMATION

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Crystalline silica samples in the respirable size (1-5 microns in diameter) were studied for their effects in the BALB/3T3/A31-1-1 mouse embryo cell line. The following samples were used: (A) quartz samples: Min-U-Sil 5 (MQZ, a standard U.S. preparation), hydrofluoric-acid-etched MQZ (HFMQZ, prepared for this laboratory in order to remove impurities from the silica surface by HF-etching), DQ12 and F600 (two standard preparations from Germany) and CSQZ (a standard preparation from China); (B) other crystalline silica forms: cristobalite and tridymite (prepared synthetically for this laboratory); and (C) non-fibrogenic dusts for comparison, usually ferric oxide. Neoplastic transformation was induced by three samples of quartz in the following order of activity: MQZ, HFMQZ and F600. Cells from the transformed foci, all found to be positive for tumorigenicity in nude mice, were cryopreserved and used for karyotyping and for molecular analysis of activated oncogene expression. Cytotoxicity, induced by initial exposure to silica and expressed by decreased colony forming efficiency (CFE), was followed by storage of phagocytosed particles with no further signs of toxicity in the surviving cells. Current results suggest that the mechanisms responsible for cytotoxicity, and possibly for transformation, take place in the time interval between the encounter of the particles with the cell membrane and the completion of phagocytosis. The hypothesis that toxic effects occur only during this initial phase is being tested by treating the cells for selected periods of time with various inhibitors of the mechanisms of toxicity. Decreasing the serum concentrations in the medium progressively decreased the CFE of control cells and of quartz-treated cells, the latter always showing a proportionally lower CFE than control cells. Exposure of cells to media conditioned by incubation with large doses of silica showed no toxicity, suggesting that the effect is not due to soluble factors.