Two-year intermittent exposure of a multiwalled carbon nanotube by intratracheal instillation induces lung tumors and pleural mesotheliomas in F344 rats

Abstract

Background A mounting number of studies have been documenting the carcinogenic potential of multiwalled carbon nanotubes (MWCNTs); however, only a few studies have evaluated the pulmonary carcinogenicity of MWCNTs in vivo. A 2-year inhalation study demonstrated that MWNT-7, a widely used MWCNT, was a pulmonary carcinogen in rats. In another 2-year study, rats administered MWNT-7 by intratracheal instillation at the beginning of the experimental period developed pleural mesotheliomas but not lung tumors. To obtain data more comparable with rats exposed to MWNT-7 by inhalation, we administered MWNT-7 to F344 rats by intratracheal instillation once every 4-weeks over the course of 2 years at 0, 0.125, and 0.5 mg/kg body weight, allowing lung burdens of MWNT-7 to increase over the entire experimental period, similar to the inhalation study. Results Absolute and relative lung weights were significantly elevated in both MWNT-7-treated groups. Dose- and time-dependent toxic effects in the lung and pleura, such as inflammatory, fibrotic, and hyperplastic lesions, were found in both treated groups. The incidences of lung carcinomas, lung adenomas, and pleural mesotheliomas were significantly increased in the high-dose group compared with the control group. The pleural mesotheliomas developed mainly at the mediastinum. No MWNT-7-related neoplastic lesions were noted in the other organs. Cytological and biochemical parameters of the bronchoalveolar lavage fluid (BALF) were elevated in both treated groups. The lung burden of MWNT-7 was dose- and time-dependent, and at the terminal necropsy, the average value was 0.9 and 3.6 mg/lung in the low-dose and high-dose groups, respectively. The number of fibers in the pleural cavity was also dose- and time-dependent. Conclusions Repeated administration of MWNT-7 by intratracheal instillation over the 2 years indicates that MWNT-7 is carcinogenic to both the lung and pleura of rats, which differs from the results of the 2 carcinogenicity tests by inhalation or intratracheal instillation.

Lung recovery from DNA damage induced by graphene oxide is dependent on size, dose and inflammation profile

“…This similarity allowed in return an accurate evaluation of the impact of GO lateral dimension on lung genotoxicity. In parallel, multi-walled CNTs (MWCNTs, Mitsui-7) were used in both exposure scenarios as a positive control for the intended biological endpoints, based on the extensive number of reports in the literature demonstrating their genotoxicity [16,44,45].…”

“…While some CNTs were not found to cause any toxicity, others were reported to induce a large range of adverse effects, including cytotoxicity, inflammation, genotoxicity and cancer [ 9 , 10 ]. In the lungs, some CNTs were shown to elicit frustrated phagocytosis in macrophages [ 11 ], to have poor biodegradability and high tissue biopersistence [ 11 , 12 ], or to induce fibrosis [ 13 , 14 ], mutagenesis [ 10 ] and carcinogenesis [ 15 , 16 ]. When comparing these effects with those of asbestos fibers, it became apparent that shape and size along with other variables ( i.e ., diameter, rigidity, composition, surface chemistry, or metal impurities) were key drivers of CNT toxicity [ 12 , 17 ].…”

“…Although these different studies demonstrated that GO may have a genotoxic impact on some lung cells after inhalation, they remain limited in their design by the use of single/bolus exposure. Chronic exposure and long-term assessment represent a more realistic scenario to evaluate persistent DNA damages that may lead to carcinogenesis events [ 16 ]. In this respect, we recently demonstrated that a repeated pulmonary exposure to GO via oro-pharyngeal aspiration induced a size, dose and time dependent lung inflammation without tissue remodeling in mice [ 26 ].…”

Assessment of Pristine Carbon Nanotubes Toxicity in Rodent Models

“…Some studies, however, indicate dose-dependent toxicity. Hojo et al indicated in their research that high dosages of MWCNTs significantly increased incidences of lung carcinomas, lung adenomas, and pleural mesotheliomas [ 32 ].…”

Characterization and in vivo toxicological evaluation of multi-walled carbon nanotubes: a low dose repeated intratracheal administrations study

“…The repeated exposures could explain the increased pulmonary toxicity observed, based on the longer time of accumulation in the lungs even after the normal lung clearance pathways to the pleural cavity and lymphatic system. In this context, a recent study (Hojo et al 2022) has suggested that repeated intratracheal exposures to the well-known lung carcinogen MWNT-7 (Mitsui-7) during a two-year exposure carcinogenicity study led to different outcomes as compared to a protocol with only initial exposures. The increased carcinogenicity observed after intermittent repeated exposures could be explained by the accumulation and the higher lung burden achieved.…”