Assessment of Early Acute Lung Injury in Rats Exposed to Aerosols of Consumer Products: Attempt to Disentangle the "Magic Nano" Conundrum
Assessment of Early Acute Lung Injury in Rats Exposed to Aerosols of Consumer Products: Attempt to Disentangle the "Magic Nano" Conundrum
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DOI：
10.1080/08958370802220634
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发表时间：
2008-01-01
影响因子：
2.1
通讯作者：
Spielmann, Horst
中科院分区：
文献类型：
--
作者：
Pauluhn, Juergen;Hahn, Axel;Spielmann, Horst
2006年，在德国，在正常使用“神奇纳米玻璃和陶瓷”喷雾剂和“神奇纳米浴”喷雾剂后，观察到一系列迅速发展、有时甚至严重的肺部健康损害病例。相比之下，此前上市的“Magic Nano”泵式喷雾产品（手持式触发装置，不含推进剂）则显得并不引人注目。对这些产品排出的颗粒的分析没有发现稳定的（固体）纳米尺寸颗粒。 “神奇纳米喷雾剂”对人类肺部健康损害的急剧增加引发了对“神奇纳米玻璃陶瓷”喷雾剂、“神奇纳米浴”喷雾剂和“神奇纳米”泵式喷雾剂对大鼠急性吸入毒性的比较评估。使用间歇产生原理将前两个测试样本作为喷雾罐气溶胶进行检查，而泵喷雾的未稀释液体内容物则连续气雾化。 Wistar 大鼠组仅鼻子暴露 4 小时。然而，由于在暴露于玻璃和陶瓷喷雾后的暴露过程中已经发生死亡，因此在某些组中暴露持续时间减少至大约 2 小时。除了当代测试指南要求的终点外，还通过暴露期间的呼吸功能测量来探讨呼吸道损伤，并辅以暴露后第一天的支气管肺泡灌洗（BAL）液分析，包括暴露于玻璃和陶瓷喷雾的大鼠的肺组织病理学。玻璃和陶瓷喷雾在 2269 mg/m(3) 及以上会导致死亡，泵喷雾在 81222 mg/m(3) 时处于开始致死范围，而浴喷雾在最高测试标称浓度 28100 mg/m(3) 下可以耐受，不会造成死亡。玻璃和陶瓷喷雾的时间调整 4 小时 LC(50) 为 5098 mg/m(3)。呼吸模式分析揭示了上呼吸道和下呼吸道感觉刺激的变化。除了提示明显肺部刺激的临床症状外，尤其是暴露于玻璃陶瓷喷雾的大鼠，组织病理学显示肺部炎症、出血、水肿和局灶性间隔增厚。肺重量和 BAL 终点（乳酸脱氢酶 [LDH]、蛋白质、γ=谷氨酰转氨酶和中性粒细胞）显着增加。总之，这项比较研究表明，传统的 OECD 403 协议适合比较评估这些类型的消费品在其最终用途配置中的潜力和效力。 BAL 测量最适合识别急性肺损伤。相比之下，暴露期间的肺功能测量并未表明与肺损伤有任何决定性的关联。颗粒大小本身似乎并不是“神奇纳米玻璃和陶瓷”喷雾毒性的关键决定因素（MMAD 接近 7 μm 时死亡率接近 100%；GSD 接近 3）。这可能表明测试物品中含有更多的挥发性物质或与溶剂或水共蒸发的物质可能是观察到的结果的原因。因此，本研究的结果支持这样的观点，即复杂最终用途产品的急性吸入毒性的评估在方法上具有挑战性，并且不能根据成分或物理（粒径）数据轻易预测。因此，在缺乏预测性和验证性的体外测定的情况下，潜在有毒的商业化喷雾产品的体内吸入测试对于消费者安全似乎是必不可少的。为了防止在生物测定中对此类产品进行不加区别的测试，应高度优先考虑开发标准化的体外替代品。
In Germany in 2006 a series of rapidly developing and sometimes severe cases of pulmonary health impairment were observed after normal use of the "Magic Nano Glass & Ceramic" spray and "Magic Nano Bath" spray. In contrast, the previously marketed "Magic Nano" pump spray product (handheld trigger device without propellants) was unobtrusive. Analysis of particles discharged from these products did not reveal stable (solid) nano-sized particles. The precipitous increase of pulmonary health impairment in humans caused by "Magic Nano Sprays" triggered a comparative assessment of the acute inhalation toxicity of "Magic Nano Glass & Ceramic" spray, "Magic Nano Bath" spray, and "Magic Nano" pump spray in rats. The first two test specimens were examined as spray-can aerosols using an intermittent generation principle, whereas the undiluted liquid content of the pump spray was continuously aerosolized. Groups of Wistar rats were nose-only exposed for 4 h. However, due to mortality occurring already during exposure following exposure to Glass & Ceramic spray, the exposure duration was reduced to similar to 2 h in some groups. In addition to endpoints called for by contemporary testing guidelines, respiratory tract injury was also probed by respiratory function measurements during exposure supplemented by analyses in bronchoalveolar lavage (BAL) fluid on the first postexposure day, including lung histopathology in rats exposed to Glass & Ceramic spray. The Glass & Ceramic spray caused mortality at 2269 mg/m(3) and above, the pump spray was in the beginning lethal range at 81222 mg/m(3), while the bath spray was tolerated without mortality up to the maximum tested nominal concentrations of 28100 mg/m(3). The time-adjusted 4-h LC(50) of Glass & Ceramic spray was 5098 mg/m(3). The analysis of respiratory patterns revealed changes indicative of both upper and lower respiratory tract sensory irritation. In addition to clinical signs suggestive of marked lung irritation, especially in the rats exposed to the Glass & Ceramic spray, histopathology revealed lung inflammation, hemorrhages, edema, and focal septal thickening. Lung weights and BAL endpoints (lactate dehydrogenase [LDH], protein, gamma=glutamyltransaminase, and neutrophilic granulocytes) were markedly increased. In summary, this comparative study demonstrates that the conventional OECD 403 protocol is suitable to comparatively assess the potential and potency of these types of consumer products in their end-use configuration. Measurements in BAL were most suitable for the identification of acute lung injury. By contrast, lung function measurements during exposure did not demonstrate any conclusive association with lung injury. It does not appear that the particle size per se is a key determinant in the toxicity of "Magic Nano Glass & Ceramic" spray (approximately 100% mortality occurred at a MMAD of similar to 7 mu m; GSD approximate to 3). This might suggest that more volatile substances or substances contained in the test articles that co-evaporate with solvents or water may be causative for the findings observed. Hence, the findings of this study support the notion that the assessment of the acute inhalation toxicity of complex end-use products is methodologically challenging and cannot be readily anticipated based on compositional or physical (particle size) data. Accordingly, in the absence of predictive and validated in vitro assays, in vivo inhalation testing of potentially toxic commercialized spray products appears to be indispensable for consumer safety.In rder to prevent indiscriminant testing of such products in bioassays, the development of standardized in vitro alternatives should be considered with high priority.