Chronic inhalation toxicity and carcinogenicity study on potassium octatitanate fibers (TISMO) in rats

A chronic inhalation toxicity/carcinogenicity study of potassium octatitanate fibers (TISMO) was conducted in male Fischer 344 rats. Groups of 135 rats were exposed via whole-body inhalation to 0, 20, 60, or 200 WHO fibers/cc of TISMO, 6 h/day, 5 days/w for 24 mo. Six of 30 subgroup rats were killed after 3, 6, 12, 18, and 24 mo of exposure for lung burden evaluations. Another 30 subgroup rats were removed from the exposure chambers after 6 mo of exposure, placed in clean air, and from this group 6 rats were killed at 3, 6, 9, 12, and 18 mo later to study lung clearance. The remaining 75 rats in each group were subjected to 24 mo of exposure for chronic toxicity and carcinogenicity study. Rats exposed to HEPA-filtered air (chamber control) were used as a negative control in each study. The lung burden results indicated that a time point of equilibrium between lung burden and lung clearance at 20 WHO fibers/cc exposure was attained after approximately 18 mo of exposure. There was no difference in the number of WHO fiber from the lungs between 18 and 24 mo at 20 WHO fibers/cc exposure. But disproportional rapid increase in lung burden at 200 WHO fibers/cc exposure appeared to be saturation of lung clearance mechanism resulting from lung overloading. At 200 WHO fibers/cc exposure, approximately 22.9 and 70.5 million WHO fibers were retained in the lung after 3 and 6 mo of exposure, respectively, but lungs revealed normal in appearance. However, alveolar walls enclosing aggregated TISMO-laden alveolar macrophages (AMs) showed fibrotic thickening and approximately 197.3 million WHO fibers were retained in the lungs after 18 mo of exposure. Inhaled fibers were rapidly cleared during 3- and 6-mo recovery periods, and thereafter gradually progressive fiber reduction was observed throughout 18 mo of recovery. The number of WHO fibers decreased by approximately 72%, 74%, and 79% in the 200, 60, and 20 WHO fibers/cc groups, respectively, at the end of the 18-mo recovery period following 6 mo of exposure. Although inhaled TISMO fibers in the 20 WHO fibers/cc exposure group were phagocytized by alveolar macrophages (AMs) the lung morphology appeared normal throughout 24 mo of exposure. At 60 WHO fibers/cc exposure, a slight dose- and time-dependent increase in TISMO-laden AMs was observed throughout 3, 6, and 12 mo of exposure and some alveoli containing aggregated TISMO-laden AMs showed alveolar wall thickening at 18 mo of exposure and minimal alveolar fibrosis at 24 mo of exposure. The exposure concentration is interpreted as a borderline effect level. At 200 WHO fibers/cc exposure, lungs preserved normal architecture at 3 and 6 mo of exposure. Some alveolar walls enclosing aggregates of TISMO-laden AMs were slightly thickened after 12 mo of exposure and revealed slight alveolar fibrosis after 18 and 24 mo of exposure. Neither exposure related-pulmonary neoplasm nor mesothelioma was observed in 24 mo of exposure. The 20 WHO fibers/cc exposure concentration is considered to be a no-observable-adverse-effect level (NOAEL). TISMO exposure limits of 1 WHO fiber/cc would not impose a significant health hazard to humans in the workplace based on the animal experiments and medical surveys on workers.