Abstract
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.
Highlights
The global increase in production and application of titanium dioxide nanomaterials (TiO2 NMs) in a wide range of industrial and consumer products leads to potential exposure-related adverse health effects for workers
The specimens were prepared by probe sonication of NMs (TiO2 NM-1, TiO2 NM-2 and TiO2 tube) in the suspension used for i.t. instillation while DQ12 and TiO2 cube NMs were dispersed ultrasonically in MeOH for 20 min
Anatase TiO2 NMs, labeled as TiO2 NM-1, TiO2 NM-2, TiO2 tube, TiO2 cube, and DQ12 were investigated with transmission electron microscopy (TEM) to determine particle morphology and size (Table 1)
Summary
The global increase in production and application of titanium dioxide nanomaterials (TiO2 NMs) in a wide range of industrial and consumer products leads to potential exposure-related adverse health effects for workers. Neutrophil influx in BAL fluid has been shown to correlate closely with pulmonary acute phase response in terms of increased serum amyloid A 3 (Saa3) mRNA levels in lung tissue of mice exposed to TiO2 NMs by i.t. instillation and by inhalation (Halappanavar et al, 2011; Saber et al, 2013). The main objectives of the present study was to assess pulmonary toxicity in terms of influx of inflammatory cells into the lung, pulmonary acute phase response, genotoxicity, and lung histopathology in mice exposed to four anatase TiO2 NMs with different physicochemical properties (a large and a small NM, and a cube and a tube shaped NM) by i.t. instillation. We Journal Pre-proof discuss the significance of BET surface area, crystal phase and shape as possible predictors of pulmonary toxicity (neutrophil influx, acute phase response) by using multiple regression analyses
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