Abstract Boron nitride nanotubes (BNNT) are multi-walled nanotubes composed of hexagonal B N bonds and possess many unique physical and chemical properties, creating a rapidly expanding market for this newly emerging nanomaterial which is still primarily in the research and development stage. The shape and high aspect ratio give rise to concern for the potential toxicity that may be associated with pulmonary exposure, especially in an occupational setting. The goal of this study was to assess lung toxicity using an in vivo time course model. The sample was manufactured to be 5 nm wide and up to 200 μm long, with ~50% purity covalently bound with hexagonal boron nitride (hBN) in the sample. Following preparation for in vivo studies, sonication of the material disrupted the longer tubes in the complex and the size distribution in dispersion medium (DM) of the structures was 13–23 nm in diameter and 0.6–1.6 μm in length. Male C57BL/6 J mice were exposed to 4 or 40 μg of BNNT or DM (vehicle control) by a single oropharyngeal aspiration. Pulmonary and systemic toxicity were investigated at 4 h, 1 d, 7 d, 1 mo and 2 mo post-exposure. Bronchoalveolar lavage (BAL) studies determined pulmonary inflammation (neutrophil influx) and cytotoxicity (lactate dehydrogenase activity) occurred at early time points and peaked at 7 d post-exposure in the high dose group. Histopathological analysis showed a minimal level of inflammatory cell infiltration in the high dose group with resolution over time and no fibrosis, and lung clearance analysis showed ~50% of the material cleared over the time course. The expression of inflammatory- and acute phase response-associated genes in the lung and liver were significantly increased by the high dose at 4 h and 1 d post-exposure. The increases in lung gene expression of Cxcl2, Ccl2, Il6, Ccl22, Ccl11, and Spp1 were significant up to 2 mo but decreased with time. The low dose exposure did not result in significant changes in any toxicological parameters measured. In summary, the BNNT-hBN sample used in this study caused acute pulmonary inflammation and injury at the higher dose, which peaked by 7 d post-exposure and showed resolution over time. Further studies are needed to determine if physicochemical properties and purity will impact the toxicity profile of BNNT and to investigate the underlying mechanisms of BNNT toxicity.

中文翻译：

---

肺部暴露于体内制造的分散氮化硼纳米管 (BNNT) 材料后的毒性评估

摘要 氮化硼纳米管（BNNT）是由六方氮化硼键组成的多壁纳米管，具有许多独特的物理和化学性质，为这种仍处于研发阶段的新兴纳米材料创造了快速扩张的市场。形状和高纵横比引起了人们对可能与肺部暴露相关的潜在毒性的担忧，尤其是在职业环境中。本研究的目的是使用体内时间过程模型评估肺毒性。该样品制造为 5 nm 宽和 200 μm 长，纯度约为 50%，与样品中的六方氮化硼 (hBN) 共价结合。在为体内研究做准备之后，材料的超声处理破坏了复合物中较长的管，并且结构的分散介质 (DM) 中的尺寸分布直径为 13-23 nm，长度为 0.6-1.6 μm。通过单次口咽抽吸将雄性 C57BL/6 J 小鼠暴露于 4 或 40 μg BNNT 或 DM（载体对照）。在暴露后 4 小时、1 天、7 天、1 个月和 2 个月时调查了肺和全身毒性。支气管肺泡灌洗 (BAL) 研究确定了肺部炎症（中性粒细胞流入）和细胞毒性（乳酸脱氢酶活性）发生在早期时间点，并在高剂量组暴露后 7 天达到峰值。组织病理学分析显示，高剂量组炎症细胞浸润水平极低，随着时间的推移逐渐消退且无纤维化，肺清除率分析显示约 50% 的材料在时间过程中被清除。在暴露后 4 小时和 1 天，高剂量显着增加了肺和肝脏中炎症和急性期反应相关基因的表达。Cxcl2、Ccl2、Il6、Ccl22、Ccl11 和 Spp1 的肺基因表达的增加在 2 个月内显着增加，但随着时间的推移而减少。低剂量暴露不会导致任何毒理学参数的显着变化。总之，本研究中使用的 BNNT-hBN 样品在较高剂量下会引起急性肺部炎症和损伤，在暴露后 7 天达到峰值，并随着时间的推移逐渐消退。