Warheit David B, Reed Kenneth L, DeLorme Michael P
DuPont Haskell Global Centers for Health and Environmental Sciences, Newark, Delaware 19714, USA.
Toxicol Pathol. 2013 Feb;41(2):387-94. doi: 10.1177/0192623312467401. Epub 2012 Dec 12.
The goal of this article is to evaluate a recently published subchronic inhalation study with carbon nanofibers in rats and discuss the importance of a weight-of-evidence (WOE) framework for determining no adverse effect levels (NOAELs). In this Organization for Economic Cooperation and Development (OECD) 413 guideline inhalation study with VGCF-H carbon nanofibers (CNFs), rats were exposed to 0, 0.54, 2.5 or 25 mg/m(3) CNF for 13 weeks. The standard toxicology experimental design was supplemented with bronchoalveolar lavage (BAL) and respiratory cell proliferation (CP) endpoints. BAL fluid (BALF) recovery of inflammatory cells and mediators (i.e., BALF- lactate dehydrogenase [LDH], microprotein [MTP], and alkaline phosphatase [ALKP] levels) were increased only at 25 mg/m(3), 1 day after exposure. No differences versus control values in were measured at 0.54 or 2.5 mg/m(3) exposure concentrations for any BAL fluid endpoints. Approximately 90% (2.5 and 25 mg/m(3)) of the BAL-recovered macrophages contained CNF. CP indices at 25 mg/m(3) were increased in the airways, lung parenchyma, and subpleural regions, but no increases in CP versus controls were measured at 0.54 or 2.5 mg/m(3). Based upon histopathology criteria, the NOAEL was set at 0.54 mg/m(3), because at 2.5 mg/m(3), "minimal cellular inflammation" of the airways/lung parenchyma was noted by the study pathologist; while the 25 mg/m(3) exposure concentration produced slight inflammation and occasional interstitial thickening. In contrast, none of the more sensitive pulmonary biomarkers such as BAL fluid inflammation/cytotoxicity biomarkers or CP turnover results at 2.5 mg/m(3) were different from air-exposed controls. Given the absence of convergence of the histopathological observations versus more quantitative measures at 2.5 mg/m(3), it is recommended that more comprehensive guidance measures be implemented for setting adverse effect levels in (nano)particulate, subchronic inhalation studies including a WOE approach for establishing no adverse effect levels; and a suggestion that some findings should be viewed as normal physiological adaptations (e.g., normal macrophage phagocytic responses-minimal inflammation) to long-term particulate inhalation exposures.
本文的目的是评估最近发表的一项关于大鼠碳纳米纤维亚慢性吸入研究，并讨论证据权重（WOE）框架对于确定无不良反应水平（NOAELs）的重要性。在这项按照经济合作与发展组织（OECD）413指南进行的VGCF-H碳纳米纤维（CNF）吸入研究中，大鼠暴露于0、0.54、2.5或25mg/m³的CNF环境中，为期13周。标准毒理学实验设计补充了支气管肺泡灌洗（BAL）和呼吸细胞增殖（CP）终点指标。仅在暴露1天后，25mg/m³组的BAL液（BALF）中炎症细胞和介质（即BALF-乳酸脱氢酶[LDH]、微蛋白[MTP]和碱性磷酸酶[ALKP]水平）的回收率增加。在0.54或2.5mg/m³暴露浓度下，任何BAL液终点指标与对照值均无差异。回收的BAL巨噬细胞中约90%（2.5和25mg/m³组）含有CNF。25mg/m³组气道、肺实质和胸膜下区域的CP指数增加，但在0.54或2.5mg/m³时，与对照组相比CP指数未增加。基于组织病理学标准，NOAEL设定为0.54mg/m³，因为在2.5mg/m³时，研究病理学家观察到气道/肺实质有“轻微细胞炎症”；而25mg/m³的暴露浓度产生了轻微炎症和偶尔的间质增厚。相比之下，2.5mg/m³时更敏感的肺部生物标志物，如BAL液炎症/细胞毒性生物标志物或CP周转率结果，与空气暴露对照组没有差异。鉴于在2.5mg/m³时组织病理学观察结果与更定量的测量结果缺乏一致性，建议在（纳米）颗粒亚慢性吸入研究中实施更全面的指导措施来设定不良反应水平，包括采用WOE方法来确定无不良反应水平；并建议一些发现应被视为对长期颗粒吸入暴露的正常生理适应（例如正常巨噬细胞吞噬反应 - 轻微炎症）。
