| Summary: | Several reports on amorphous silica nanomaterial (aSiO<sub>2</sub> NM) toxicity have been questioning their safety. Herein, we investigated the in vivo pulmonary toxicity of four variants of aSiO<sub>2</sub> NM: SiO<sub>2</sub>_15_Unmod, SiO<sub>2</sub>_15_Amino, SiO<sub>2</sub>_7 and SiO<sub>2</sub>_40. We focused on alterations in lung DNA and protein integrity, and gene expression following single intratracheal instillation in rats. Additionally, a short-term inhalation study (STIS) was carried out for SiO<sub>2</sub>_7, using TiO<sub>2</sub>_NM105 as a benchmark NM. In the instillation study, a significant but slight increase in oxidative DNA damage in rats exposed to the highest instilled dose (0.36 mg/rat) of SiO<sub>2</sub>_15_Amino was observed in the recovery (R) group. Exposure to SiO<sub>2</sub>_7 or SiO<sub>2</sub>_40 markedly increased oxidative DNA lesions in rat lung cells of the exposure (E) group at every tested dose. This damage seems to be repaired, since no changes compared to controls were observed in the R groups. In STIS, a significant increase in DNA strand breaks of the lung cells exposed to 0.5 mg/m<sup>3</sup> of SiO<sub>2</sub>_7 or 50 mg/m<sup>3</sup> of TiO<sub>2</sub>_NM105 was observed in both groups. The detected gene expression changes suggest that oxidative stress and/or inflammation pathways are likely implicated in the induction of (oxidative) DNA damage. Overall, all tested aSiO<sub>2</sub> NM were not associated with marked in vivo toxicity following instillation or STIS. The genotoxicity findings for SiO<sub>2</sub>_7 from instillation and STIS are concordant; however, changes in STIS animals were more permanent/difficult to revert.
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