Bernstein David M, Rogers Rick, Smith Paul, Chevalier Jörg
Rogers Imaging Corporation, Needham, Massachusetts, USA.
Inhal Toxicol. 2006 May;18(5):313-32. doi: 10.1080/08958370500515871.
Inhalation toxicology studies with chrysotile asbestos have in the past been performed at exceedingly high doses without consideration of fiber number or dimensions. As such, the exposures have exceeded lung overload levels, making quantitative assessment of these studies difficult if not impossible. To assess the cellular and pathological response in the rat lung to a well-characterized aerosol of chrysotile asbestos, a 90-day subchronic inhalation toxicology study was performed using a commercial Brazilian chrysotile (CA 300). The protocol was based on that established by the European Commission for the evaluation of synthetic vitreous fibers. The study was also designed to assess the potential for reversibility of any such changes and to permit association of responses with fiber dose in the lung and the influence of fiber length. Wistar male rats were randomly assigned to an air control group and to 2 CA 300 exposure groups at mean fiber aerosol concentrations of 76 fibers L > 20 microm/cm3 (3413 total fibers/cm3; 536 WHO fibers/cm3) or 207 fibers L > 20 microm/cm3 (8941 total fibers/cm3; 1429 WHO fibers/cm3). The animals were exposed using a flow-past, nose-only exposure system for 5 days/wk, 6 h/day, during 13 consecutive weeks (65 exposures), followed by a subsequent nonexposure period lasting for 92 days. Animals were sacrificed after cessation of exposure and after 50 and 92 days of nonexposure recovery. At each sacrifice, subgroups of rats were assessed for the determination of the lung burden; histopathological examination; cell proliferation response; bronchoalveolar lavage with the determination of inflammatory cells; clinical biochemistry; and for analysis by confocal microscopy. Through 90 days of exposure and 92 days of recovery, chrysotile at a mean exposure of 76 fibers L > 20 microm/cm3 (3413 total fibers/cm3) resulted in no fibrosis (Wagner score 1.8 to 2.6) at any time point. The long chrysotile fibers were observed to break apart into small particles and smaller fibers. In vitro modeling has indicated that these particles are essentially amorphous silica. At an exposure concentration of 207 fibers L > 20 microm/cm3 (8941 total fibers/cm3) slight fibrosis was observed. In comparison with other studies, chrysotile produced less inflammatory response than the biosoluble synthetic vitreous fiber CMS. As predicted by the recent biopersistence studies on chrysotile, this study clearly shows that at that at an exposure concentration 5000 times greater than the U.S. threshold limit value of 0.1 f(WHO)/cm3, chrysotile produces no significant pathological response.
过去，温石棉吸入毒理学研究是在极高剂量下进行的，未考虑纤维数量或尺寸。因此，暴露剂量超过了肺部过载水平，使得对这些研究进行定量评估即便不是不可能，也是困难重重。为评估大鼠肺部对特性明确的温石棉气雾剂的细胞和病理反应，采用巴西商用温石棉（CA 300）进行了一项为期90天的亚慢性吸入毒理学研究。该方案基于欧盟委员会制定的用于评估合成玻璃纤维的方案。该研究还旨在评估任何此类变化的可逆性潜力，并使反应与肺部纤维剂量以及纤维长度的影响相关联。将雄性Wistar大鼠随机分为空气对照组和2个CA 300暴露组，平均纤维气雾剂浓度分别为76根纤维/L＞20微米/立方厘米（3413根总纤维/立方厘米；536根世界卫生组织纤维/立方厘米）或207根纤维/L＞20微米/立方厘米（8941根总纤维/立方厘米；1429根世界卫生组织纤维/立方厘米）。动物使用流经式、仅经鼻暴露系统，每周暴露5天，每天6小时，连续暴露13周（65次暴露），随后是持续92天的非暴露期。在暴露停止后以及非暴露恢复期的50天和92天后处死动物。每次处死时，对大鼠亚组进行评估以确定肺部负荷；组织病理学检查；细胞增殖反应；进行支气管肺泡灌洗并测定炎症细胞；临床生物化学；以及通过共聚焦显微镜进行分析。在90天的暴露期和92天的恢复期内，平均暴露浓度为76根纤维/L＞20微米/立方厘米（3413根总纤维/立方厘米）的温石棉在任何时间点均未导致纤维化（瓦格纳评分1.8至2.6）。观察到长的温石棉纤维会断裂成小颗粒和更细的纤维。体外建模表明这些颗粒本质上是无定形二氧化硅。在暴露浓度为207根纤维/L＞20微米/立方厘米（8941根总纤维/立方厘米）时，观察到轻微纤维化。与其他研究相比，温石棉产生的炎症反应比生物可溶合成玻璃纤维CMS少。正如近期对温石棉的生物持久性研究所预测的，该研究清楚地表明，在暴露浓度比美国阈限值0.1根（世界卫生组织）/立方厘米高5000倍的情况下，温石棉不会产生显著的病理反应。
