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.

Keywords: MWCNT-7; inhalation toxicity; intra-tracheal intra-pulmonary spraying; malignant mesothelioma; rat.

Figure 1

Kaplan‐Meier survival plot of the rats in the vehicle, MWCNT‐7, and crocidolite groups

Figure 2

Deposition of MWCNT‐7 in the lung (A) and a polarized light microscope image (B). Representative histological imagines of malignant mesotheliomas located near the lung (C, D) and heart (E) in MWCNT‐7 administered rats. Several mesotheliomas had sites of ossification (arrow in F). Most mesotheliomas had adherence to the thoracic wall (G) or diaphragm (H)

Figure 3

Representative histopathological images of the lung adenocarcinoma in the vehicle‐treated rat (A) and mesotheliomas that developed in the MWCNT‐7 treated rats (C, E, and G). Immunohistochemical staining of TTF‐1 (B, D, F and H). Nuclei in the adenocarcinoma are positive for TTF‐1 (B). The malignant mesotheliomas near the heart, thoracic cavity, and diaphragm are negative for TTF‐1 (D, F, and H)

Figure 4

A‐D, Scanning electron microscopic images of MWCNT‐7 fibers (arrows) phagocytosed by macrophages in the lung and mediastinal lymph node. E‐F, representative images of MWCNT‐7 fibers from the lung and mediastinal lymph node after tissue digestion

Figure 5

Histogram of the length distribution of MWCNT‐7 fibers in the lung (black bars) and mediastinal lymph node (white bars)