Dose-Response Relationships for Lung Tumor and Pleural Mesothelioma Induction by Repetitive Intratracheal Instillation of a Multiwalled Carbon Nanotube, MWCNT-7, in Rats: Comparison with Inhalation Carcinogenicity Based on Lung Burden.

The multiwalled carbon nanotube, MWCNT-7, is carcinogenic to rat lungs when inhaled over the course of 2 years, but does not induce pleural mesothelioma. In contrast, intratracheal instillation of MWCNT-7 causes both lung tumors and pleural mesotheliomas. To explore the possibility of the use of the intratracheal instillation technique in risk characterization, we administered this widely used reference material using instillation to male F344 rats at doses of 0.0175, 0.07, 0.28, or 0.42 mg/kg once per week for 13 weeks, followed by an observation period of 91 weeks and compared the dose-response toxicological data with the 2-year inhalation study. Lung tumors and pleural mesotheliomas were induced in a dose-dependent manner (the 0.42 mg/kg group was excluded from analysis of lung tumor formation). The lung burden of MWCNT-7 at week 13 was dose-dependent: 0.0302, 0.191, 0.98, and 1.369 mg/lung in the 0.0175, 0.07, 0.28, and 0.42 mg/kg groups, respectively. The number of fibers in the pleural lavage fluid was also dose-dependent. The no-observed-adverse-effect-level (NOAEL) of MWCNT-7's carcinogenicity was 0.0302 mg/lung based on no significant lung tumor induction and no mesothelioma induction in the 0.0175 mg/kg group. When compared based on lung burden, the dose-response relationship and NOAEL of lung tumor induction resembled those in the 2-year inhalation study, offering the possibility of the application of this protocol for risk characterization.