Demonstration of the carcinogenicity of a flexible tangled multiwalled carbon nanotube in the rat lung

Carbon nanotubes (CNTs) are composed of one or more one-atom thick graphene cylinders. CNTs have remarkable mechanical, thermal, chemical, and electrical properties, and their tubular structure makes them very lightweight. However, these properties also make CNTs easily airborne and highly biopersistent, and respired CNTs have the potential to induce inflammatory lesions in tissues. Similar to asbestos, several MWCNTs were shown to induce peritoneal malignant mesotheliomas after intraperitoneal administration in rats and mice. MWCNT-N was the first CNT shown to induce lesions in lung and pleural tissue after administration via the airway: in this study, MWCNT-N was administered to rats using intratracheal, intrapulmonary spraying (TIPS). Shortly thereafter, MWCNT-7 was shown to induce bronchioloalveolar tumors in rats after inhalation exposure. These two MWCNTs have walls of more than 40 layers and form rod-shaped aggregates, and consequently have the potential to act similarly to asbestos and induce neoplastic lesions in the lung and/or pleural tissue. To investigate the effects of wall thickness on the carcinogenicity of MWCNTs, we conducted a 2-year study comparing 2 different types of MWCNTs, rigid rod-shaped MWCNT-A (213 layers, 150 nm in diameter, forming rigid rod shape aggregates) and flexible MWCNT-B (15-18 layers, 15 nm in diameter, forming tangled shaped aggregates). Crocidolite asbestos was used as the reference material. The rats were administered MWCNTs and asbestos using TIPS once a week over an 8-week period (total low and high doses of 0.5 and 1.0 mg/rat), followed by 2-year observation without further treatment (Suzui et al., 2016; Xu et al., 2014; Abdelgied and Elgazzar, 2019). In the MWCNT-B group, the combined incidence of bronchioloalveolar tumors was increased in the group administered 1.0 mg MWCNT-B compared to the vehicle control group. Malignant pleural mesothelioma was not induced in any of the groups. MWCNT-A and crocidolite asbestos also induced bronchioloalveolar tumors; however, the incidence was not statistically significant compared to the controls. The results indicate that the carcinogenic potential of inhaled flexible, tangled MWCNT-B is as high or higher than that of rigid, rod-shaped MWCNT-A. This is the first study to show that a thin, flexible MWCNT induces lung tumors after administration via the airway. Further studies are warranted to investigate the association of shape and rigidity with the carcinogenicity of respirable CNTs. Citation Format: Hiroyuki Tsuda, William T. Alexander, Takamasa Numano, Mohamed Ahmed Mahmoud Abdelgied, Ahmed Maher Mahmoud Ibrahim Elgazzar, Hiroshi Takase, Jiegou Xu, Aya Naiki, Satoru Takahashi, Akihiko Hirose, Makoto Ohnishi, Jun Kanno, David B. Alexander. Demonstration of the carcinogenicity of a flexible tangled multiwalled carbon nanotube in the rat lung [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A53.