Objective: We reviewed studies on pulmonary, reproductive, and developmental toxicity caused by carbon nanotubes (CNTs). In paricular, we analyzed how CNT exposure affects the several processes of pulmonary toxicity, including inflammation, injury, fibrosis, and pulmonary tumors. Methods: In pulmonary toxicity, there are various processes, including inflammation, injury, fibrosis, respiratory tumor in the lungs, and biopersistence of CNTs and genotoxicity as tumor-related factors, to develop the respiratory tumor. We evaluated the evidence for the carcinogenicity of CNTs in each process. In the fields of reproductive and developmental toxicity, studies of CNTs have been conducted mainly with mice. We summarized the findings of reproductive and developmental toxicity studies of CNTs. Results: In animal studies, exposure to CNTs induced sustained inflammation, fibrosis, lung cancer following long-term inhalation, and gene damage in the lung. CNTs also showed high biopersistence in animal studies. Fetal malformations after intravenous and intraperitoneal injections and intratracheal instillation, fetal loss after intravenous injection, behavioral changes in offsprings after intraperitoneal injection, and a delay in the delivery of the first litter after intratracheal instillation were reported in mice-administered multi-walled carbon nanotubes (MWCNTs). Single-walled carbon nanotubes (SWCNTs) appeared to be embryolethal and teratogenic in mice when given by intravenous injection; moreover, the tubes induced death and growth retardation in chicken embryos. Conclusion: CNTs are considered to have carcinogenicity and can cause lung tumors. However, the carcinogenicity of CNTs may attenuate if the fiber length is shorter. The available data provide initial information on the potential reproductive and developmental toxicity of CNTs.

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Multi-walled carbon nanotubes (MWCNTs), dispersed in suspensions consisting mainly of individual tubes, were used for intratracheal instillation and inhalation studies. Rats intratracheally received a dose of 0.2 mg, or 1 mg of MWCNTs and were sacrificed from 3 days to 6 months. MWCNTs induced a pulmonary inflammation, as evidenced by a transient neutrophil response in the low-dose groups, and presence of small granulomatous lesion and persistent neutrophil infiltration in the high-dose groups. In the inhalation study, rats were exposed to 0.37 mg/m(3) aerosols of well-dispersed MWCNTs (>70% of MWCNTs were individual fibers) for 4 weeks, and were sacrificed at 3 days, 1 month, and 3 months after the end of exposure. The inhalation exposures delivered less amounts of MWCNTs into the lungs, and therefore less pulmonary inflammation responses was observed, as compared to intratracheal instillation. The results of our study show that well-dispersed MWCNT can produce pulmonary lesions, including inflammation.

In an evaluation of carbon nanotubes (CNTs) for the IARC Monograph 111, the Mechanisms Subgroup was tasked with assessing the strength of evidence on the potential carcinogenicity of CNTs in humans. The mechanistic evidence was considered to be not strong enough to alter the evaluations based on the animal data. In this paper, we provide an extended, in-depth examination of the in vivo and in vitro experimental studies according to current hypotheses on the carcinogenicity of inhaled particles and fibers. We cite additional studies of CNTs that were not available at the time of the IARC meeting in October 2014, and extend our evaluation to include carbon nanofibers (CNFs). Finally, we identify key data gaps and suggest research needs to reduce uncertainty. The focus of this review is on the cancer risk to workers exposed to airborne CNT or CNF during the production and use of these materials. The findings of this review, in general, affirm those of the original evaluation on the inadequate or limited evidence of carcinogenicity for most types of CNTs and CNFs at this time, and possible carcinogenicity of one type of CNT (MWCNT-7). The key evidence gaps to be filled by research include: investigation of possible associations between in vitro and early-stage in vivo events that may be predictive of lung cancer or mesothelioma, and systematic analysis of dose–response relationships across materials, including evaluation of the influence of physico-chemical properties and experimental factors on the observation of nonmalignant and malignant endpoints.

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 concentrati...

Biological responses of multi-wall carbon nanotubes (MWCNTs) were assessed after a single intratracheal instillation in rats. The diameter and median length of the MWCNTs used in this study were approximately 60 nm and 1.5 μm, respectively. Groups of male Sprague-Dawley rats were intratracheally instilled with 0.04, 0.2, or 1 mg/kg of the individually dispersed MWCNT suspension. After instillation, the bronchoalveolar lavage fluid was assessed for inflammatory cells and markers, and the lung, liver, kidney, spleen, and cerebrum were histopathologically evaluated at 3-day, 1-week, 1-month, 3-month, and 6-month post-exposure. Transient pulmonary inflammatory responses were observed only in the lungs of the group of rats exposed to 1 mg/kg of MWCNTs. Morphology of the instilled MWCNTs in the lungs of rats was assessed using light microscopy and transmission electron microscopy (TEM). Light microscopy examination revealed that MWCNTs deposited in the lungs of the rats were typically phagocytosed by the alveolar macrophages and these macrophages were consequently accumulated in the alveoli until 6-month post-exposure. The 400 TEM images obtained showed that all MWCNTs were located in the alveolar macrophages or macrophages in the interstitial tissues, and MWCNTs were not located in the cells of the interstitial tissues. There was no evidence of chronic inflammation, such as angiogenesis or fibrosis, induced by MWCNT instillation. These results suggest that MWCNTs were being processed and cleared by alveolar macrophages.

The objective of this study was to examine what kinds of cytokines are related to lung disorder by well-dispersed nanoparticles. The mass median diameter of nickel oxide in distilled water was 26 nm. Rats intratracheally received 0.2 mg of nickel oxide suspended in distilled water, and were sacrificed from three days to six months. The concentrations of 21 cytokines including inflammation, fibrosis and allergy-related ones were measured in the lung. Infiltration of alveolar macrophages was observed persistently in the nickel oxide-exposed group. Expression of macrophage inflammatory protein-1alpha showed a continued increase in lung tissue and broncho-alveolar lavage fluid (BALF) while interleukin-1alpha (IL-1alpha), IL-1beta in lung tissue and monocyte chemotactic protein-1 in BALF showed transient increases. Taken together, it was suggested that nano-agglomerates of nickel oxide nanoparticles have a persistent inflammatory effect, and the transient increase in cytokine expression and persistent increases in CC chemokine were involved in the persistent pulmonary inflammation.