Long-Term Pulmonary Responses of Three Laboratory Rodent Species to Subchronic Inhalation of Pigmentary Titanium Dioxide Particles

Female mice, rats, and hamsters were exposed to 10, 50, or 250 mg/m(3) pigmentary titanium dioxide (p-TiO(2)) particles for 6 h per day and 5 days per week for 13 weeks with recovery groups held for an additional 4, 13, 26, or 52 weeks postexposure (46 weeks for the p-TiO(2)-exposed hamsters). At each time point p-TiO(2) burdens in the lung and lymph nodes and selected lung responses were examined. The responses studied were chosen to assess a variety of pulmonary parameters, including inflammation, cytotoxicity, lung cell proliferation, and histopathologic alterations. Burdens of p-TiO(2) in the lungs and in the lung-associated lymph nodes increased in a concentration-dependent manner. Retained lung burdens following exposure were greatest in mice. Rats and hamsters had similar lung burdens immediately postexposure when assessed as milligrams of p-TiO(2) per gram of dried lung. Particle retention data suggested that pulmonary overload was achieved in both rats and mice at the exposure levels of 50 and 250 mg/m(3). Under the conditions of the present study, hamsters were better able to clear p-TiO(2) particles than were similarly exposed mice and rats. Pulmonary histopathology revealed both species and concentration-dependent differences in p-TiO(2) particle retention patterns. Inflammation was noted in all three species at 50 and 250 mg/m(3), as evidenced by increases in macrophage and neutrophil numbers and in soluble indices of inflammation in bronchoalveolar lavage fluid (BALF; rats > mice, hamsters). In mice and rats, the BALF inflammatory responses remained elevated relative to controls throughout the entire postexposure recovery period in the most highly exposed animals. In comparison, inflammation in hamsters eventually disappeared, even at the highest exposure dose, due to the more rapid clearance of particles from the lung. Pulmonary lesions were most severe in rats, where progressive epithelial- and fibroproliferative changes were observed in the 250 mg/m(3) group. These epithelial proliferative changes were also manifested in rats as an increase in alveolar epithelial cell labeling in cell proliferation studies. Associated with these foci of epithelial proliferation were interstitial particle accumulation and alveolar septal fibrosis. In summary, there were significant species differences in pulmonary responses to inhaled p-TiO(2) particles. Under conditions in which the lung p-TiO(2) burdens were similar and likely to induce pulmonary overload, rats developed a more severe and persistent pulmonary inflammatory response than either mice or hamsters. Rats also were unique in the development of progressive fibroproliferative lesions and alveolar epithelial metaplasia in response to 90 days of exposure to a high concentration of p-TiO(2) particles.