A subchronic inhalation toxicity study of inhaled vapor grown carbon nanofibers (CNF) (VGCF-H) was conducted in male and female Sprague Dawley rats. The CNF test sample was composed of > 99.5% carbon with virtually no catalyst metals; Brunauer, Emmett, and Teller (BET) surface area measurements of 13.8 m2/g; and mean lengths and diameters of 5.8 µm and 158 nm, respectively.Four groups of rats per sex were exposed nose-only, 6 h/day, for 5 days/week to target concentrations of 0, 0.50, 2.5, or 25 mg/m3 VGCF-H over a 90-day period and evaluated 1 day later. Assessments included conventional clinical and histopathological methods, bronchoalveolar lavage fluid (BALF) analysis, and cell proliferation (CP) studies of the terminal bronchiole (TB), alveolar duct (AD), and subpleural regions of the respiratory tract. In addition, groups of 0 and 25 mg/m3 exposed rats were evaluated at 3 months postexposure (PE). Aerosol exposures of rats to 0.54 (4.9 f/cc), 2.5 (56 f/cc), and 25 (252 f/cc) mg/m(3) of VGCF-H CNFs produced concentration-related small, detectable accumulation of extrapulmonary fibers with no adverse tissue effects. At the two highest concentrations, inflammation of the TB and AD regions of the respiratory tract was noted wherein fiber-laden alveolar macrophages had accumulated. This finding was characterized by minimal infiltrates of inflammatory cells in rats exposed to 2.5mg/m(3) CNF, inflammation along with some thickening of interstitial walls, and hypertrophy/hyperplasia of type II epithelial cells, graded as slight for the 25mg/m(3) concentration. At 3 months PE, the inflammation in the high dose was reduced. No adverse effects were observed at 0.54mg/m(3). BALF and CP endpoint increases versus controls were noted at 25mg/m(3) VGCF-H but not different from control values at 0.54 or 2.5mg/m(3). After 90 days PE, BALF biomarkers were still increased at 25mg/m(3), indicating that the inflammatory response was not fully resolved. Greater than 90% of CNF-exposed, BALF-recovered alveolar macrophages from the 25 and 2.5mg/m(3) exposure groups contained nanofibers (> 60% for 0.5mg/m(3)). A nonspecific inflammatory response was also noted in the nasal passages. The no-observed-adverse-effect level for VGCF-H nanofibers was considered to be 0.54mg/m(3) (4.9 fibers/cc) for male and female rats, based on the minimal inflammation in the terminal bronchiole and alveolar duct areas of the lungs at 2.5mg/m(3) exposures. It is noteworthy that the histopathology observations at the 2.5mg/m(3) exposure level did not correlate with the CP or BALF data at that exposure concentration. In addition, the results with CNF are compared with published findings of 90-day inhalation studies in rats with carbon nanotubes, and hypotheses are presented for potency differences based on CNT physicochemical characteristics. Finally, the (lack of) relevance of CNF for the high aspect ratio nanomaterials/fiber paradigm is discussed.

译文

在雄性和雌性Sprague Dawley大鼠中进行了吸入蒸气生长的碳纳米纤维 (CNF) (vgcf-h) 的亚慢性吸入毒性研究。CNF测试样品由> 99.5% 碳组成,几乎没有催化剂金属; Brunauer,Emmett和Teller (BET) 的表面积测量值为13.8平方米/g; 平均长度和直径分别为5.8微米和158纳米。6 h/天,持续5天/周,在90天期间达到0、0.50、2.5或25 mg/m3 VGCF-H的目标浓度,并在1天后评估。评估包括常规的临床和组织病理学方法,支气管肺泡灌洗液 (BALF) 分析以及末端细支气管 (TB),肺泡管 (AD) 和呼吸道胸膜下区域的细胞增殖 (CP) 研究。此外,在暴露后3个月 (PE) 评估0和25 mg/m3暴露大鼠组。大鼠气溶胶暴露于0.54 (4.9 f/cc) 、2.5 (56 f/cc) 和25 (252 f/cc) mg/m(3) 的VGCF-H CNFs产生与浓度相关的小的可检测的肺外纤维蓄积,没有不良组织影响。在两个最高浓度下,注意到TB和AD呼吸道区域的炎症,其中富含纤维的肺泡巨噬细胞已经积累。该发现的特征是暴露于2.5 mg/m(3) CNF的大鼠中炎症细胞的最小浸润,炎症以及间质壁的一些增厚以及II型上皮细胞的肥大/增生,对于25 mg/m(3) 浓度而言是轻微的。在3个月的PE时,高剂量的炎症减少。在0.54 mg/m(3) 下未观察到不良反应。在25 mg/m(3) VGCF-H时,BALF和CP端点相对于对照增加,但与0.54或2.5 mg/m(3) 时的对照值没有差异。PE 90天后,BALF生物标志物仍在25 mg/m(3) 处增加,表明炎症反应尚未完全解决。来自25和2.5 mg/m(3) 暴露组的大于90% 的CNF暴露、BALF回收的肺泡巨噬细胞含有纳米纤维 (> 60% 0.5 mg/m(3))。在鼻腔中也发现了非特异性炎症反应。基于终末细支气管和肺泡管区域的最小炎症,对于雄性和雌性大鼠,VGCF-H纳米纤维的未观察到的不良反应水平被认为是0.54 mg/m(3) (4.9纤维/cc)。在2.5 mg/m(3) 暴露下的肺的区域。值得注意的是,在2.5mg/m(3) 暴露水平下的组织病理学观察与该暴露浓度下的CP或BALF数据不相关。此外,将CNF的结果与碳纳米管大鼠90天吸入研究的公开结果进行了比较,并提出了基于CNT理化特性的效力差异假设。最后,讨论了CNF与高纵横比纳米材料/纤维范例的 (缺乏) 相关性。

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