MWCNT‐7 administered to the lung by intratracheal instillation induces development of pleural mesothelioma in F344 rats

Abstract

Multi‐walled carbon nanotube‐7 (MWCNT‐7) fibers are biopersistent and have a structure similar to asbestos. MWCNT‐7 has been shown to induce malignant mesothelioma when administered by intrascrotal or intraperitoneal injection in rats and mice, and an inhalation study demonstrated that rats exposed to respirable MWCNT‐7 developed lung tumors. MWCNT‐N, which is similar to MWCNT‐7, was shown to induce both lung tumors and malignant mesothelioma in rats when administered by trans‐tracheal intrapulmonary spraying (TIPS). The present study was performed to investigate the carcinogenicity of MWCNT‐7 when administered by the TIPS method. Ten‐week‐old male F344/Crj rats were divided into 3 groups and administered 0.5 mL vehicle, 0.250 μg/mL MWCNT‐7 or 0.250 μg/mL crocidolite once a week for 12 weeks (total doses of 1.5 mg/rat) and then observed for up to 104 weeks. Rats in the MWCNT‐7 group began to die from pathologies associated with the development of malignant mesothelioma 35 weeks after the final TIPS administration. Overall, the incidence of malignant mesothelioma in the MWCNT‐7 group was significantly higher than in the vehicle or crocidolite groups.

Comparative carcinogenicity study of a thick, straight-type and a thin, tangled-type multi-walled carbon nanotube administered by intra-tracheal instillation in the rat

“…In these studies, these larger diameter straight-type MWCNTs had less carcinogenic potential than the smaller diameter straight-type MWCNTs [16,17]. Three other studies administered MWCNT-7 or MWCNT-N (both are straight-type MWCNTs) to rats via the airway: Administration of 1.0 mg/rat of MWCNT-N using TIPS resulted in the development of both lung tumors and mesotheliomas [12]; inhalation exposure to MWCNT-7 resulted in the development of lung tumors but not pleural mesotheliomas [8]; administration of 1.5 mg/rat of MWCNT-7 using TIPS resulted in mesothelioma but not lung tumors (the authors argue that the early death of the treated rats due to the rapid development of mesotheliomas precluded the development of lung tumors) [13]. These results are consistent with the intraperitoneal studies: straight-type MWCNTs are potential carcinogens.…”

“…071223 fibers had an average diameter of 83.8 nm and lot No. 080126 fibers had an average diameter of 90.7 nm) for 2 years by whole body inhalation developed lung tumors [8], and rats administered MWCNT-7 by TIPS developed pleural mesotheliomas [13]. These results indicate that rigid straight-type MWCNTs can be carcinogenic to the lung and pleural mesothelium in the rat after administration to the lung.…”

Predictive Biomarkers for the Ranking of Pulmonary Toxicity of Nanomaterials

“…The pulmonary toxicity of nanomaterials needs to be fully assessed before the industrial nanomaterials are handled by humans. It is necessary to develop biomarkers in order to predict the hazard level of industrial nanomaterials, because multi-wall carbon nanotubes (MWCNTs), a representative nanomaterial, are known to be carcinogenic: the development of lung tumors or malignant pleural mesothelioma was confirmed in intratracheal instillation [ 3 , 4 ] and in inhalation studies [ 5 ].…”

Frequent homozygous deletion of Cdkn2a/2b in tremolite‐induced malignant mesothelioma in rats

“…For the assessment of the carcinogenicity of fibrous materials, intratracheal instillation of 1 mg each of 2 MWCNTs, with a length of 4.2 ± 2.9 μm or 2.6 ± 1.6 μm, induced MM (3/12 and 3/12) and lung tumor (4/12 and 3/12), respectively, in F344 rats 31 . Further, intratracheal instillation of 1.5 mg MWCNT, with a length of 4.8 ± 2.8 μm, induced a high incidence of MM (18/19) and lung tumors (1/19) in F344 rats 32 . Taken together, these findings indicate that length of carcinogenic fiber might start from less than 4 μm, because Stanton’s hypothesis was established on the basis of the correlation coefficients of tumor probability and the following 5 fiber length categories: 0.1‐1, 1‐4, 4‐8, 8‐64, and longer than 64 μm 21 .…”