Warheit D B, Laurence B R, Reed K L, Roach D H, Reynolds G A M, Webb T R
DuPont Haskell Laboratory for Health and Environmental Sciences, Newark, Delaware 19714, USA.
Toxicol Sci. 2004 Jan;77(1):117-25. doi: 10.1093/toxsci/kfg228. Epub 2003 Sep 26.
The aim of this study was to evaluate the acute lung toxicity of intratracheally instilled single-wall carbon nanotubes (SWCNT) in rats. The lungs of rats were instilled either with 1 or 5 mg/kg of the following control or particle types: (1) SWCNT, (2) quartz particles (positive control), (3) carbonyl iron particles (negative control), (4) phosphate-buffered saline (PBS) + 1% Tween 80, or (5) graphite particles (lung tissue studies only). Following exposures, the lungs of PBS and particle-exposed rats were assessed using bronchoalveolar lavage (BAL) fluid biomarkers and cell proliferation methods, and by histopathological evaluation of lung tissue at 24 h, 1 week, 1 month, and 3 months postinstillation. Exposures to high-dose (5 mg/kg) SWCNT produced mortality in ~15% of the SWCNT-instilled rats within 24 h postinstillation. This mortality resulted from mechanical blockage of the upper airways by the instillate and was not due to inherent pulmonary toxicity of the instilled SWCNT particulate. Exposures to quartz particles produced significant increases versus controls in pulmonary inflammation, cytotoxicity, and lung cell parenchymal cell proliferation indices. Exposures to SWCNT produced transient inflammatory and cell injury effects. Results from the lung histopathology component of the study indicated that pulmonary exposures to quartz particles (5 mg/kg) produced dose-dependent inflammatory responses, concomitant with foamy alveolar macrophage accumulation and lung tissue thickening at the sites of normal particle deposition. Pulmonary exposures to carbonyl iron or graphite particles produced no significant adverse effects. Pulmonary exposures to SWCNT in rats produced a non-dose-dependent series of multifocal granulomas, which were evidence of a foreign tissue body reaction and were nonuniform in distribution and not progressive beyond 1 month postexposure (pe). The observation of SWCNT-induced multifocal granulomas is inconsistent with the following: (1) lack of lung toxicity by assessing lavage parameters, (2) lack of lung toxicity by measuring cell proliferation parameters, (3) an apparent lack of a dose response relationship, (4) nonuniform distribution of lesions, (5) the paradigm of dust-related lung toxicity effects, (6) possible regression of effects over time. In addition, the results of two recent exposure assessment studies indicate very low aerosol SWCNT exposures at the workplace. Thus, the physiological relevance of these findings should ultimately be determined by conducting an inhalation toxicity study.
本研究的目的是评估经气管内注入单壁碳纳米管（SWCNT）对大鼠的急性肺毒性。给大鼠肺部注入以下对照物或颗粒类型，剂量为1或5mg/kg：（1）SWCNT，（2）石英颗粒（阳性对照），（3）羰基铁颗粒（阴性对照），（4）磷酸盐缓冲盐水（PBS）+1%吐温80，或（5）石墨颗粒（仅用于肺组织研究）。暴露后，通过支气管肺泡灌洗（BAL）液生物标志物和细胞增殖方法，以及在注入后24小时、1周、1个月和3个月对肺组织进行组织病理学评估，来评估PBS和颗粒暴露大鼠的肺部情况。高剂量（5mg/kg）SWCNT暴露在注入后24小时内导致约15%的SWCNT注入大鼠死亡。这种死亡是由于注入物对上呼吸道的机械性阻塞，而非注入的SWCNT颗粒本身的肺毒性所致。与对照组相比，石英颗粒暴露导致肺部炎症、细胞毒性和肺实质细胞增殖指数显著增加。SWCNT暴露产生短暂的炎症和细胞损伤效应。该研究的肺组织病理学部分结果表明，肺部暴露于石英颗粒（5mg/kg）会产生剂量依赖性炎症反应，同时在正常颗粒沉积部位伴有泡沫状肺泡巨噬细胞积聚和肺组织增厚。肺部暴露于羰基铁或石墨颗粒未产生明显的不良反应。大鼠肺部暴露于SWCNT产生了一系列非剂量依赖性的多灶性肉芽肿，这是异物组织反应的证据，其分布不均匀，且在暴露后1个月（pe）后无进展。观察到的SWCNT诱导的多灶性肉芽肿与以下情况不一致：（1）通过评估灌洗参数显示缺乏肺毒性，（2）通过测量细胞增殖参数显示缺乏肺毒性，（3）明显缺乏剂量反应关系，（4）病变分布不均匀，（5）与粉尘相关的肺毒性效应模式，（6）效应可能随时间消退。此外，最近两项暴露评估研究的结果表明，工作场所空气中SWCNT的暴露水平非常低。因此，这些发现的生理相关性最终应通过进行吸入毒性研究来确定。
