asbestos--amosite and silicon-carbide

A range of respirable man-made mineral fibres were tested for evidence of carcinogenicity by injection into the peritoneal cavity of male SPF Wistar rats; and differences in carcinogenicity were related to the dimensions and biopersistence of the injected fibres. The fibres tested included an amosite asbestos, a silicon carbide whisker, a special purpose glass microfibre, and a range of other man-made vitreous fibres (MMVFs) and refractory ceramic fibres (RCFs) from the TIMA fibre repository. The injected dose of each was designed as the estimated mass required to contain 10(9) fibres > 5 microns in length, as determined by optical microscopy. The numbers of long fibres (> 15 microns) contained in these doses ranged across fibres from 0.1 x 10(9) to 0.8 x 10(9) fibres; the number of long fibres thinner than 0.95 micron ranged from 0.015 x 10(9) to 0.4 x 10(9). The treatment groups contained between 18 and 24 animals. Animals were killed when they showed signs of debilitation. At autopsy, the diagnosis of mesothelioma was usually obvious macroscopically. Otherwise, histological examination of peritoneal organs was used to search for early tumour development. Judged by median survival time, four of the fibre types, in the doses administered, presented higher mesothelioma activity than amosite asbestos. The other fibres tested were less carcinogenic than the amosite. Only a ceramic material derived by extreme heating to simulate the effect of furnace or oven conditions, produced no mesotheliomas. Attempts were made, using regression models, to relate these differences to fibre dimensions and to measures of durability from separate experiments. The results pointed principally to a link with the injected numbers of fibres > 20 microns in length and with biopersistence in the rat lung of fibres longer than 5 microns. Improved quantification of the relative importance of fibre dimensions and biopersistence indices requires experimentation with a range of doses.

Topics: Animals; Asbestos, Amosite; Biodegradation, Environmental; Carbon Compounds, Inorganic; Carcinogenicity Tests; Disease Models, Animal; Dose-Response Relationship, Drug; Glass; Male; Mesothelioma; Mineral Fibers; Neoplasms, Experimental; Peritoneal Neoplasms; Rats; Rats, Wistar; Silicon Compounds; Survival Analysis; Time Factors

A wide range of fiber types was tested in two in vitro assays: toxicity to A549 epithelial cells, as detachment from substrate, and the production of the proinflammatory cytokine tumor necrosis factor (TNF) by rat alveolar macrophages. Three of the fibers were also studied in vivo, using short-term inhalation followed by a) bronchoalveolar lavage to assess the inflammatory response and b) measurement of cell proliferation in terminal bronchioles and alveolar ducts, using incorporation of bromodeoxyuridine (BrdU). The amount of TNF produced by macrophages in vitro depended on the fiber type, with the man-made vitreous fibers, and refractory ceramic fibers being least stimulatory and silicon carbide (SiC) whiskers providing the greatest stimulation. In the epithelial detachment assay there were dose-dependent differences in the toxicity of the various fibers, with long amosite being the most toxic. However, there was no clear relationship to known chronic pathogenicity. Fibers studied by short-term inhalation produced some inflammation, but there was no clear discrimination between the responses to code 100/475 glass fibers and the more pathogenic amosite and SiC. However, measurements of BrdU uptake into lung cells showed that amosite and SiC produced a greater reaction than code 100/475, which itself caused no more proliferation than that seen in untreated lungs. These results mirror the pathogenicity ranking of the fibers in long-term experiments. In conclusion, the only test to show potential as a predictive measure of pathogenicity was that of cell proliferation in lungs after brief inhalation exposure (BrdU assay). We believe that this assay should be validated with a wider range of fibers, doses, and time points.

Topics: Administration, Inhalation; Animals; Asbestos, Amosite; Asbestos, Crocidolite; Bromodeoxyuridine; Bronchoalveolar Lavage Fluid; Carbon Compounds, Inorganic; Carcinogens; Cell Division; Cells, Cultured; Ceramics; Epithelial Cells; Glass; Macrophages, Alveolar; Mineral Fibers; Particle Size; Rats; Silicon Compounds; Tumor Necrosis Factor-alpha

Phagocyte-derived free radicals are considered to play a role in fibre-related pathology and the components of the lung lining fluid could modify the surface of fibres. Therefore we examined the ability of long amosite asbestos and a range of man-made fibres to stimulate release of superoxide anion from rat alveolar macrophages when they were in their native form (unopsonised) and opsonised by incubation in rat Immunoglobulin G. We also assessed the specific amount of opsonin adsorbed to each fibre type. In the uncoated form all of the fibres produced modest amounts of superoxide release from macrophages. When they were opsonised however there was an effect on stimulation of release of superoxide that was fibre-specific. Both MMVF21 and RCF 1 were dramatically enhanced in their ability to stimulate release and this was related to a high affinity of their surface for IgG. Code 100/475 and SiC were not substantially affected by opsonisation and this was reflected in their low affinity for IgG. Long amosite had low affinity for IgG but showed dramatic enhancement of capacity to stimulate superoxide release. These fibre-specific differences in the effect of a coating of material that is found in the lung lining points out the problems of interpretation of in vitro data and more work on this important area is warranted.

Topics: Air Pollutants, Occupational; Animals; Asbestos, Amosite; Carbon; Carbon Compounds, Inorganic; Ceramics; Dose-Response Relationship, Drug; Macrophages, Alveolar; Mineral Fibers; Opsonin Proteins; Rats; Silicon Compounds; Superoxides