Development of Intratracheal Intrapulmonary Spraying (TIPS) Administration as a Feasible Assay Method for Testing the Toxicity and Carcinogenic Potential of Multiwall Carbon Nanotubes

Abstract

Multiwall carbon nanotubes (MWCNTs) are composed of multiple concentric one-atom thick graphene cylinders. The carbon-carbon bonds of graphene are exclusively sp2, which gives MWCNT fibers their extraordinary properties. Production of MWCNTs is rapidly increasing because of their superiority over other materials. However, similarly to asbestos, MWCNTs are highly biopersistent in human tissues when inhaled and deposition in tissues causes sustained inflammatory reactions with the potential of inducing carcinogenesis. Several species of MWCNTs, including MWCNT-7, were shown to induce malignant peritoneal mesotheliomas after intraperitoneal administration in rats and mice; inhalation exposure to MWCNT-7 also induces bronchiolo-alveolar tumors in rats; and MWCNT-N, another type of MWCNT, was shown to induce both bronchiolo-alveolar tumor and pleural malignant mesothelioma in rats after administration by intratracheal intrapulmonary spraying (TIPS). Using the TIPS method, we recently found that another MWCNT, MWCNT-B, was carcinogenic to the lung, and that MWCNT-7 induced malignant pleural mesotheliomas as well as bronchiolo-alveolar tumors. Notably, despite the fact that the intraperitoneal injection studies that established the potential carcinogenicity of MWCNTs were published in 2008–2009, at the time of this writing only a single whole-body inhalation study of the toxicity of respirable MWCNTs has been reported. The lack of testing of these economically important, widely used, and potentially dangerous materials is due to the enormous expense of whole-body inhalation administration and to the very few facilities that are equipped to perform such studies. In contrast to whole-body inhalation testing that requires specialized inhalation facilities, the TIPS method uses commonly available equipment and techniques. Consequently, TIPS administration can be widely used to test the carcinogenicity of respirable materials, promoting evaluation of the toxicity and carcinogenic potential of the numerous types of MWCNTs now being produced. For example, we are currently conducting further testing of MWCNTs using the TIPS method to assess the effect of the shape and physical properties of MWCNTs on their toxicity in the lung and pleura.