Subchronic, 90-day inhalation exposures of rats, mice, and hamsters to either pigmentary or ultrafine TiO2 particles at concentrations likely to induce particle overload resulted in a more severe and persistent pulmonary inflammatory response in rats, when compared with either similarly-exposed mice or hamsters. Rats were unique among these three rodent species in the development of progressive fibroproliferative lesions and alveolar epithelial metaplasia (Bermudez et al, 2002 and 2004). Female rats, mice or hamsters were exposed to 10, 50 or 250 mg/m3 concentrations of pigmentary (rutile type) TiO2 particles for 6 hours/day, 5 days/week for 13 weeks followed by 4, 13, 26 or 52 weeks of post exposure (46 weeks for hamsters)(Bermudez et al, 2002). Lung and associated lymph node loads of TiO2 increased in a concentration-related manner. It is important to note that retained lung burdens were greatest in mice following exposure, with rats and hamsters demonstrating similar lung burdens immediately following 90-day exposures. Particle retention data indicated that particle overload in the lungs was reached in both rats and mice at the 50 and 250 mg/m3 concentrations. Inflammation was observed in all three species at the two highest concentrations. This inflammation persisted in rats and mice throughout the post exposure recovery period at the highest exposure concentration. In hamsters, inflammatory responses were eventually resolved due to the more rapid clearance of particles from the lung. In rats exposed to the highest concentration (250 mg/m3), pulmonary lesions consisted of epithelial proliferative changes manifested by increased alveolar epithelial cell labelling indices, as evidenced by the results of cell proliferation studies. Associated with these proliferative changes in the rat were enhanced interstitial accumulations of particles along with alveolar septal fibrosis. Although rats exposed to 50 mg/m3 developed minimal alveolar cell hypertrophy, accumulation of particle-laden macrophages, and inflammation, no alveolar septal fibrosis or relevant cell turnover at alveolar sites were observed at this lower exposure concentration. Similar changes to those seen in rats were not observed in either mice or hamsters. The study clearly demonstrated the uniqueness of the rat pulmonary response to particle overload concentrations.