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A multispecies, subchronic, inhalation study comparing pulmonary responses to ultrafine titanium dioxide (uf-TiO(2)) was performed. Female rats, mice, and hamsters were exposed to aerosol concentrations of 0.5, 2.0, or 10 mg/m(3) uf-TiO(2) particles for 6 h/day, 5 days/week, for 13 weeks. Following the exposure period, animals were held for recovery periods of 4, 13, 26, or 52 weeks (49 weeks for the uf-TiO(2)-exposed hamsters) and, at each time point, uf-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 histopathological alterations. Retained lung burdens increased in a dose-dependent manner in all three species and were at a maximum at the end of exposures. Mice and rats had similar retained lung burdens at the end of the exposures when expressed as mg uf-TiO(2)/mg dry lung, whereas hamsters had retained lung burdens that were significantly lower. Lung burdens in all three species decreased with time after exposure, and, at the end of the recovery period, the percentage of the lung particle burden remaining in the 10 mg/m(3) group was 57, 45, and 3% for rat, mouse, and hamster, respectively. The retardation of particle clearance from the lungs in mice and rats of the 10 mg/m(3) group indicated that pulmonary particle overload had been achieved in these animals. Pulmonary inflammation in rats and mice exposed to 10 mg/m(3) was evidenced by increased numbers of macrophages and neutrophils and increased concentrations of soluble markers in bronchoalveolar lavage fluid (BALF). The initial neutrophil response in rats was greater than in mice, whereas the relative increase of macrophages was less than in mice. The neutrophilic response of rats, but not mice, declined in a time-dependent manner correlating with declining lung burdens; however, the fraction of recovered neutrophils at 52 weeks postexposure was equivalent in the two species. Consistent increases in soluble indicators of toxicity in the BALF (LDH and protein) occurred principally in rats and mice exposed to 10 mg/m(3) and diminished with time postexposure. There were no significant changes in cellular response or with markers indicating toxicity in hamsters, reflecting the capacity of these animals to rapidly clear particles from the lung. Progressive epithelial and fibroproliferative changes were observed in rats of the 10 mg/m(3) group. These lesions consisted of foci of alveolar epithelial proliferation of metaplastic epithelial cells (so-called alveolar bronchiolization) circumscribing aggregated foci of heavily particle-laden macrophages. The observed 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. These lesions became more pronounced with increasing time postexposure. Epithelial, metaplastic, and fibroproliferative changes were not noted in either mice or hamsters. In summary, there were significant species differences in the pulmonary responses to inhaled uf-TiO(2) particles. Under conditions where the lung uf-TiO(2) burdens were equivalent, rats developed a more severe inflammatory response than mice and, subsequently, developed progressive epithelial and fibroproliferative changes. Clearance of particles from the lung was markedly impaired in mice and rats exposed to 10 mg/m(3) uf-TiO(2), whereas clearance in hamsters did not appear to be affected at any of the administered doses. These data are consistent with the results of a companion study using inhaled pigmentary (fine mode) TiO(2) (Bermudez et al., 2002) and demonstrate that the pulmonary responses of rats exposed to ultrafine particulate concentrations likely to induce pulmonary overload are different from similarly exposed mice and hamsters. These differences can be explained both by pulmonary respy response and by particle dosimetry differences among these rodent species.