Warheit D B, Hartsky M A
Du Pont Haskell Laboratory for Toxicology and Industrial Medicine, Newark, Delaware 19714, USA.
J Expo Anal Environ Epidemiol. 1997 Jul-Sep;7(3):313-25.
This study describes a short term inhalation bioassay in rats to predict the potential for inhaled particles to produce chronic lung disease in humans (e.g., pulmonary fibrosis). To validate the method, rats were exposed for 6 h or 3 days to various concentrations of two reference materials: (1) a known fibrogenic material (i.e., aerosolized alpha-quartz silica particles in the form of Berkeley Min-U-Sil (Pennsylvania Glass and Sand Company, Pittsburgh, PA), or (2) carbonyl iron (CI) particles, as a negative control. Cells and fluids from groups of sham and dust exposed animals were recovered by bronchoalveolar lavage (BAL). Alkaline phosphatase, lactate dehydrogenase and protein values were measured in BAL fluids at several times postexposure. Cells were identified, counted, and evaluated for viability. The lungs of additional exposed animals were processed for histopathology. Although particle deposition patterns for the two dusts were similar, brief exposures to silica particles produced a persistent pulmonary inflammatory response characterized by neutrophil recruitment at sites of particle deposition and consistently elevated biomarkers of cytotoxicity in BAL fluids. In addition, alveolar macrophage clearance functions were impaired. Progressive histopathologic lesions were observed within 1 mo after a 3-day exposure. Light and electron microscopy of silica exposed lung tissue revealed a chronically active pulmonary inflammatory response characterized by hyperplasia of Type II alveolar epithelial cells and the infiltration of macrophages and neutrophils into alveoli and interstitial compartments. The lesions were progressive, leading to the development of a multifocal, granulomatous-type pneumonitis within 2 mo postexposure. In contrast to the observed effects of silica, 3-day exposures to CI particles produced no significant adverse biochemical or histopathological effects on pulmonary tissues. These results demonstrate that short term, high dose inhalation exposures of silica produce effects similar to those previously observed using intratracheal instillation or chronic inhalation models and lend support to this method as a reliable short term bioassay for evaluating the pulmonary toxicity and mechanisms associated with exposure to new and untested respirable materials.
本研究描述了一种在大鼠中进行的短期吸入生物测定，以预测吸入颗粒在人类中产生慢性肺病（如肺纤维化）的可能性。为验证该方法，将大鼠暴露于两种参考物质的不同浓度下6小时或3天：（1）一种已知的致纤维化物质（即宾夕法尼亚玻璃与砂公司（匹兹堡，宾夕法尼亚州）生产的雾化α-石英二氧化硅颗粒，商品名为伯克利微硅粉（Berkeley Min-U-Sil）），或（2）羰基铁（CI）颗粒，作为阴性对照。通过支气管肺泡灌洗（BAL）回收假手术组和粉尘暴露组动物的细胞和液体。在暴露后的几个时间点测量BAL液中的碱性磷酸酶、乳酸脱氢酶和蛋白质值。对细胞进行鉴定、计数并评估其活力。对另外一些暴露动物的肺进行组织病理学处理。尽管两种粉尘的颗粒沉积模式相似，但短时间暴露于二氧化硅颗粒会产生持续的肺部炎症反应，其特征是在颗粒沉积部位有中性粒细胞募集，并且BAL液中细胞毒性生物标志物持续升高。此外，肺泡巨噬细胞的清除功能受损。在3天暴露后的1个月内观察到进行性组织病理学病变。对暴露于二氧化硅的肺组织进行光镜和电镜检查，发现有慢性活跃的肺部炎症反应，其特征为II型肺泡上皮细胞增生以及巨噬细胞和中性粒细胞浸润到肺泡和间质区。这些病变是进行性的，在暴露后2个月内导致多灶性、肉芽肿型肺炎的发展。与二氧化硅观察到的效应相反，3天暴露于CI颗粒对肺组织未产生显著的不良生化或组织病理学效应。这些结果表明，短期、高剂量吸入二氧化硅产生的效应与先前使用气管内注入或慢性吸入模型观察到的效应相似，并支持该方法作为一种可靠的短期生物测定方法，用于评估与接触新的和未经测试的可吸入物质相关的肺毒性及机制。
