Nanotoxicology Lab Project, Nagoya City University, 3-1 Tanabe-Dohri, Mizuho-ku, Nagoya, 467-8603, Japan.
Department of Experimental Pathology and Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.
Part Fibre Toxicol. 2022 Apr 22;19(1):30. doi: 10.1186/s12989-022-00469-8.
Considering the expanding industrial applications of carbon nanotubes (CNTs), safety assessment of these materials is far less than needed. Very few long-term in vivo studies have been carried out. This is the first 2-year in vivo study to assess the effects of double walled carbon nanotubes (DWCNTs) in the lung and pleura of rats after pulmonary exposure.
Rats were divided into six groups: untreated, Vehicle, 3 DWCNT groups (0.12 mg/rat, 0.25 mg/rat and 0.5 mg/rat), and MWCNT-7 (0.5 mg/rat). The test materials were administrated by intratracheal-intrapulmonary spraying (TIPS) every other day for 15 days. Rats were observed without further treatment until sacrifice.
DWCNT were biopersistent in the rat lung and induced marked pulmonary inflammation with a significant increase in macrophage count and levels of the chemotactic cytokines CCL2 and CCL3. In addition, the 0.5 mg DWCNT treated rats had significantly higher pulmonary collagen deposition compared to the vehicle controls. The development of carcinomas in the lungs of rats treated with 0.5 mg DWCNT (4/24) was not quite statistically higher (p = 0.0502) than the vehicle control group (0/25), however, the overall incidence of lung tumor development, bronchiolo-alveolar adenoma and bronchiolo-alveolar carcinoma combined, in the lungs of rats treated with 0.5 mg DWCNT (7/24) was statistically higher (p < 0.05) than the vehicle control group (1/25). Notably, two of the rats treated with DWCNT, one in the 0.25 mg group and one in the 0.5 mg group, developed pleural mesotheliomas. However, both of these lesions developed in the visceral pleura, and unlike the rats administered MWCNT-7, rats administered DWCNT did not have elevated levels of HMGB1 in their pleural lavage fluids. This indicates that the mechanism by which the mesotheliomas that developed in the DWCNT treated rats is not relevant to humans.
Our results demonstrate that the DWCNT fibers we tested are biopersistent in the rat lung and induce chronic inflammation. Rats treated with 0.5 mg DWCNT developed pleural fibrosis and lung tumors. These findings demonstrate that the possibility that at least some types of DWCNTs are fibrogenic and tumorigenic cannot be ignored.
考虑到碳纳米管（CNTs）在工业应用中的不断扩大，对这些材料的安全评估远远不够。很少有长期的体内研究。这是首次对肺部暴露后大鼠双层碳纳米管（DWCNTs）在肺和胸膜中的影响进行为期 2 年的体内研究。
将大鼠分为六组：未处理组、对照组、3 个 DWCNT 组（0.12mg/rat、0.25mg/rat 和 0.5mg/rat）和 MWCNT-7 组（0.5mg/rat）。通过气管内肺喷雾（TIPS）每隔一天给药 15 天。大鼠在没有进一步治疗的情况下观察到处死。
DWCNT 在大鼠肺部具有生物持久性，并引起明显的肺部炎症，巨噬细胞计数和趋化因子 CCL2 和 CCL3 的水平显著增加。此外，与对照组相比，0.5mg DWCNT 处理的大鼠肺胶原沉积明显升高。与对照组（0/25）相比，0.5mg DWCNT 处理的大鼠肺部（4/24）癌的发展并不统计学上更高（p=0.0502），但 0.5mg DWCNT 处理的大鼠肺部肿瘤发展、细支气管肺泡腺瘤和细支气管肺泡癌的总发生率（7/24）统计学上高于对照组（1/25）。值得注意的是，0.25mg 组和 0.5mg 组的 2 只 DWCNT 处理的大鼠发生了胸膜间皮瘤。然而，这两种病变均发生在脏层胸膜上，与给予 MWCNT-7 的大鼠不同，给予 DWCNT 的大鼠胸膜灌洗液中 HMGB1 水平没有升高。这表明在 DWCNT 处理的大鼠中发展的间皮瘤的机制与人类无关。
我们的结果表明，我们测试的 DWCNT 纤维在大鼠肺部具有生物持久性，并引起慢性炎症。用 0.5mg DWCNT 处理的大鼠发生胸膜纤维化和肺肿瘤。这些发现表明，至少某些类型的 DWCNTs 具有纤维发生和肿瘤发生的可能性不容忽视。
