Graphene is a 2D nanomaterial with unique physicochemical properties making it highly marketable for applications in numerous industries. Our previous studies have shown that toxicity varies depending on size and oxidative form of graphene following a single bolus-dose aspiration in mice, with exposure to reduced graphene oxide (rGO) resulting in the greatest degree of lung injury and inflammation. The goal of this study was to characterize pulmonary toxicity following subacute inhalation of rGO. C57BL/6J mice were exposed to rGO (2.41 microm MMAD, 2.69 GSD) by whole body inhalation at 5.0 mg/m3 for 5 h/d for 19 d, 0.5 mg/m3 for 5 h/d for 19 d, or 0.5 mg/m3 for 0.5 h/d for 19 d to achieve depositions with a two order of magnitude range. Controls were exposed to filtered air. Lung burden of rGO, parameters of lung toxicity and inflammation, and histopathology was analyzed 0 d, 3 d, 1 m, and 3 m post-exposure. Lung burden at 0 d was 0.78, 6.47, and 34.4 microg per lung for the low, middle and high dose. Following high dose exposure, lactate dehydrogenase (LDH) in lung lavage fluid (LLF, lung injury) and total lavage cells (inflammation) were increased up to 1 m compared to control. The cellular increase was due primarily to macrophage influx. Neutrophils were also significantly increased; however, this cell population accounted for less than 1% of the total cells. Inflammation and injury resolved by 3 m. Inflammatory and tissue remodeling proteins in LLF followed a similar pattern. Pathologic analysis indicated increased macrophages in the lungs at 0 and 3 d scored as minimal, resolving over time. Particle burden in macrophages was also observed to decrease over time. Following middle dose exposure, total lavage cells increased at 3 d, due primarily to macrophage influx, and resolved by 1 mo. Significantly fewer inflammatory proteins were elevated in LLF following exposure to the middle dose compared to the high dose, with resolution by 1 m. There was no difference in lung cellularity following low dose exposure. No lung pathology or increased LDH in LLF were observed following middle or low dose exposures. Exposure to rGO led to an acute dose-dependent increase in lung injury and inflammation, which resolved over time, with 0.5 mg/m3 causing a minimal degree of inflammation representing the low observable effect level.
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