Effects of physicochemical properties of TiO₂ nanomaterials for pulmonary inflammation, acute phase response and alveolar proteinosis in intratracheally exposed mice

Nanomaterial (NM) characteristics may affect the pulmonary toxicity and inflammatory response, including specific surface area, size, shape, crystal phase or other surface characteristics. Grouping of TiO₂ in hazard assessment might be challenging because of variation in physicochemical properties. We exposed C57BL/6 J mice to a single dose of four anatase TiO₂ NMs with various sizes and shapes by intratracheal instillation and assessed the pulmonary toxicity 1, 3, 28, 90 or 180 days post-exposure. The quartz DQ12 was included as benchmark particle. Pulmonary responses were evaluated by histopathology, electron microscopy, bronchoalveolar lavage (BAL) fluid cell composition and acute phase response. Genotoxicity was evaluated by DNA strand break levels in BAL cells, lung and liver in the comet assay. Multiple regression analyses were applied to identify specific TiO₂ NMs properties important for the pulmonary inflammation and acute phase response. The TiO₂ NMs induced similar inflammatory responses when surface area was used as dose metrics, although inflammatory and acute phase response was greatest and more persistent for the TiO₂ tube. Similar histopathological changes were observed for the TiO₂ tube and DQ12 including pulmonary alveolar proteinosis indicating profound effects related to the tube shape. Comparison with previously published data on rutile TiO₂ NMs indicated that rutile TiO₂ NMs were more inflammogenic in terms of neutrophil influx than anatase TiO₂ NMs when normalized to total deposited surface area. Overall, the results suggest that specific surface area, crystal phase and shape of TiO₂ NMs are important predictors for the observed pulmonary effects of TiO₂ NMs.