Multiple-Dose Chronic Inhalation Toxicity Study of Size-Separated Kaolin Refractory Ceramic Fiber in Male Fischer 344 Rats

Abstract

Abstract Refractory ceramic fibers (RCF) are man-made vitreous fibers used primarily in industrial high-temperature applications, especially for insulation of furnaces and kilns. Because of their increasing use and potential for human exposure an in an effort to define the dose-response, as a follow up to a maximum tolerated dose [30 mg/m(3)] study in rats (Mast et al., 1995), a multiple dose chronic toxicity/carcinogenicity inhalation study was conducted in Fischer 344 (F344) rats. Four groups of 140 weanling male F344 rats were exposed via noseonly inhalation to either HEPA-filtered air (chamber controls) or 3, 9, or 16 mg/m(3)(approximately 36, 91, and 162 fibers/cm(3)) of kaolin-based "size-selected" RCF fibers (approximately 1 µm in diameter and approximately 20 µm in length) for 6 h/day, 5 days/wk for 24 mo. They were then held unexposed until approximately 20% survival and sacrificed (30 mo). Croups of 3-6 animals were sacrificed at 3, 6, 12, 18, and 24 mo to follow the progression of pulmonary lesions and to determine fiber lung burdens. Additional groups of 3-6 rats were removed from exposure at 3, 6, 12, and 18 mo and were held until sacrificed at 24 mo (recovery groups) for similar determinations. A dose-related increase in fiber lung burden was observed. Lung burdens at 24 mo ranged from 5.6 × 10(4) to 27.8 × 10(4) fibers/mg dry lung tissue. Significant increases in lung weights and lung to body weight ratios were seen in the high-dose group. Treatment-related lesions were restricted to the lungs. To some extent, all doses of RCF resulted in minimal to mild macrophage infiltration, bronchiolization of proximal alveoli, and microgranuloma formation by 12 mo of exposure. Interstitial fibrosis was observed at 12 mo in the 9 and 16 mg/m(3) groups but not in the low-dose group at any time point. A minimal amount of focal pleural fibrosis was first observed at 12 mo in the 9 and 76 mg/m(3) dose groups and progressed to a mild severity in the high-dose group by the end of the study. The incidence of pulmonary neoplasm's was well within the range typically reported in the male F344 rat. Neoplasm's (bronchoalveolar adenomas and carcinomas) were observed in all groups 10 mg/m(3) (air control), 1 of 129 (0.8%); 3 mg/m(3), 2 of 123 (1.6%); 9 mg/m(3), 5 of 127 (3.9%); 16 mg/m(3), 2 of 124 (1.6%)]. A single pleural mesothelioma was observed in an animal exposed to 9 mg/m(3) of kaolin RCF. The results of this study suggest that the dose response for primary lung neoplasms is steep, while that for mesothelioma may not be.