Dose-dependent pulmonary response of well-dispersed titanium dioxide nanoparticles following intratracheal instillation

In order to investigate the relationship between pulmonary inflammation and particle clearance of nanoparticles, and also their dose dependency, we performed an instillation study of well-dispersed TiO₂ nanoparticles and examined the pulmonary inflammations, the particle clearance rate and histopathological changes. Wistar rats were intratracheally administered 0.1 mg (0.33 mg/kg), 0.2 mg (0.66 mg/kg), 1 mg (3.3 mg/kg), and 3 mg (10 mg/kg) of well-dispersed TiO₂ nanoparticles (diameter of agglomerates: 25 nm), and the pulmonary inflammation response and the amount of TiO₂ in the lung were determined from 3 days up to 12 months sequentially after the instillation. There were no increases of total cell or neutrophil counts in bronchoalveolar lavage fluid (BALF) in the 0.1 and the 0.2 mg-administered groups. On the other hand, mild infiltration of neutrophils was observed in the 1 and 3 mg-administered groups. Histopathological findings showed infiltration of neutrophils in the 1 and 3 mg-administered groups. Of special note, a granulomatous lesion including a local accumulation of TiO₂ was observed in the bronchioli-alveolar space in the 3 mg-administered group. The biological half times of the TiO₂ in the lung were 4.2, 4.4, 6.7, and 10.8 months in the 0.1, 0.2, 1, and 3 mg-administered groups, respectively. Neutrophil infiltration was observed as the particle clearance was delayed, suggesting that an excessive dose of TiO₂ nanoparticles may induce pulmonary inflammation and clearance delay.