Inhalation toxicity assessment of carbon-based nanoparticles.

Although the demand for nanomaterials has grown, researchers have not conclusively determined the effects of nanomaterials on the human body. To understand the effects of nanomaterials on occupational health, we need to estimate the respiratory toxicity of nanomaterials through inhalation studies, intratracheal instillation studies, and pharyngeal aspiration studies. The discrepancies observed among these studies tend to result from differences in the physiochemical properties of nanomaterials, such as aggregation and dispersion. Therefore, in all toxicity studies, identification of the physicochemical properties of nanomaterials is essential. This Account reviews the inhalation toxicity of manufactured nanomaterials and compares them with inhalation and intratracheal instillation studies of well-characterized fullerene and carbon nanotubes. In many reports, pulmonary inflammation and injury served as pulmonary endpoints for the inhalation toxicity. To assess pulmonary inflammation, we examined neutrophil and macrophage infiltration in the alveolar and/or interstitial space, and the expression of the neutrophil and/or monocyte chemokines. We also reported the release of lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) in the bronchoalveolar lavage fluid (BALF), the expression of oxidative stress-related genes characteristic of lung injury, and the presence of granulomatous lesion and pulmonary fibrosis. In the inhalation and intratracheal instillation studies of well-characterized fullerenes, exposure to fullerene did not induce pulmonary inflammation or transient inflammation. By contrast, in an inhalation study, a high concentration of multiwall carbon nanotubes (MWCNTs) and single-wall carbon nanotubes (SWCNTs) induced neutrophil inflammation or granulomatous formations in the lung, and intratracheal instillation of MWCNTs and SWCNTs induced persistent inflammation in the lung. Among the physicochemical properties of carbon nanotubes, the increased surface area is associated with inflammatory activity as measured by the increase in the rate of neutrophils measured in bronchoalveolar lavage fluid. Metal impurities such as iron and nickel enhanced the pulmonary toxicity of carbon nanotubes, and SWCNTs that included an amorphous carbon induced multifocal granulomas in the lung while purer SWCNTs did not. The aggregation state also affects pulmonary response: Exposure to well-dispersed carbon nanotubes led to the thickening of the alveolar wall and fewer granulomatous lesions in the lung, while agglomerated carbon nanotubes produced granulomatous inflammation. The values of the acceptable exposure concentration in some countries were based on the data of subacute and subchronic inhalation and intratracheal instillation studies of well-characterized fullerene and carbon nanotubes. In Japan, the acceptable exposure concentration of fullerene is 0.39 mg/m³. In Europe, the proposal concentration is 44.4 μg/m³ for acute toxicity and 0.27 μg/m³ for chronic toxicity. The proposal acceptable exposure concentrations of carbon nanotubes are 0.03, 0.05, and 0.007 mg/m³ in Japan, Europe, and the United States, respectively.