MULTIPLE-DOSE CHRONIC INHALATION TOXICITY STUDY OF SIZE-SEPARATED KAOLIN REFRACTORY CERAMIC FIBER IN MALE FISCHER-344 RATS

Refractory ceramic fibers (RCF) are man-made vitreous fibers used prim arily in industrial high-temperature applications, especially for insu lation of furnaces and kilns. Because of their increasing use and pote ntial 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 nose-only 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-se lected'' RCF fibers (approximately 1 mu m in diameter and approximatel y 20 mu m 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) . Groups 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 lun g 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 x 10(4 ) to 27.8 x 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 som e extent, all doses of RCF resulted in minimal to mild macrophage infi ltration, bronchiolization of proximal alveoli, and microgranuloma for mation 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 obse rved at 12 mo in the 9 and 16 mg/m(3) dose groups and progressed to a mild severity in the high-dose group by the end of the study. The inci dence of pulmonary neoplasm's was well within the range typically repo rted in the male F344 rat. Neoplasm's (bronchoalveolar adenomas and ca rcinomas) were observed in all groups [0 mg/m(3) (air control), 1 of 1 29 (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 s tudy suggest that the dose response for primary lung neoplasms is stee p, while that for mesothelioma may not be.