LUNG PARTICLE OVERLOAD - IMPLICATIONS FOR OCCUPATIONAL EXPOSURES TO PARTICLES
LUNG PARTICLE OVERLOAD - IMPLICATIONS FOR OCCUPATIONAL EXPOSURES TO PARTICLES
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DOI：
10.1006/rtph.1995.1017
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发表时间：
1995-02-01
影响因子：
3.4
通讯作者：
OBERDORSTER, G
中科院分区：
文献类型：
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作者：
OBERDORSTER, G
在大鼠的大量慢性吸入研究中，发现了慢性肺部炎症、肺纤维化甚至肺部肿瘤，这些研究使用了高度不溶性的低细胞毒性非纤维颗粒。人们担心这些反应是由于肺颗粒负荷过多所致，并创造了术语“颗粒过载”来描述这些情况。颗粒过载肺的标志是肺泡巨噬细胞（AM）介导的肺清除功能受损，这在迄今为止测试的所有种属中均得到证实，最终导致过度肺负荷的累积。实验证据表明，被AM吞噬的颗粒的体积对于导致它们的清除功能受损是最关键的，并且一旦保留的肺颗粒负荷达到相当于约1 μ l/g肺的体积的水平，就达到肺超负荷的条件。细胞毒性颗粒也会导致AM清除功能受损，但肺负荷低得多，不符合颗粒过载的条件。在响应肺超负荷诱导不良慢性效应方面存在显著的种属差异;即，小鼠和仓鼠不易发生慢性炎症和肺纤维化，仅在大鼠研究中观察到肺肿瘤。仅在导致颗粒清除受损的肺负荷下观察到大鼠的肺肿瘤或纤维化，并且可以假定不良慢性效应的阈值剂量，其定义为肺颗粒负荷不会导致清除受损。因此，在大鼠慢性研究中，在极高的颗粒接触浓度下观察到的肺肿瘤可能与人类外推至低接触浓度无关。人类的证据表明，颗粒超载的肺，例如，在煤工中，对纤维化有反应，但在该组中未发现肺肿瘤的发病率增加。然而，不能排除其他类型的长期吸入颗粒如果累积到非常高的肺负荷，可能在人肺中具有致癌潜力。需要更多的研究来详细了解导致不同物种肺中非纤维性颗粒诱导肿瘤发生的基本机制。改变的颗粒积聚和保留动力学以及超负荷肺中的慢性炎症表明已超过最大耐受剂量（MTD）。尚未制定定义MTD的吸入研究的具体指南;一般指南不一定适用于慢性吸入研究。一种建议是将慢性颗粒吸入研究中的MTD定义为基于肺颗粒清除功能参数的最大功能耐受剂量（MFTD）。然而，基于肺泡炎症和肺组织学评价的其他终点也应包括在内。为了估计MTD或MFTD，需要进行足够长时间的范围探索研究，最好是3个月。然而，重要的是要认识到，随着暴露的慢性化和动物年龄的增加，剂量-反应关系可能发生变化，从我们对肺颗粒过载的理解中得出的一个重要结论是，应设定职业暴露限值，以防止AM介导的肺清除受损，从而避免高肺粉尘负荷的积累;可以想象的是，这也将防止随后诱发包括炎症、纤维化和肿瘤在内的不利的慢性效应，因为这些颗粒诱发的肿瘤可能继发于持续的炎症，组织损伤，从大鼠研究的这种接触限值推断，目前的低细胞毒性的高度不溶性颗粒的职业标准可能不防止人类肺超负荷，应该重新评估。(C)出版社：Academic Press
Chronic pulmonary inflammation, pulmonary fibrosis, and even lung tumors developed in a number of chronic inhalation studies in rats with highly insoluble nonfibrous particles of low cytotoxicity. Concerns were expressed that these responses are due to excessive particulate lung burdens, and the term ''particle overload'' was coined to characterize these conditions. The hallmark of the particle-overloaded lung is an impairment of alveolar macrophage (AM)-mediated lung clearance which has been demonstrated in all species tested so far and which eventually leads to accumulation of excessive lung burdens. Experimental evidence suggests that the volume of the particles phagocytized by AM: is most critical for causing their impaired clearance function, and that the condition of lung overload is reached once the retained lung particle burden reaches a level equivalent to a volume of approximately 1 mu l/g of lung. Cytotoxic particles also cause impaired AM clearance function, yet at a much lower lung burden which does not qualify as particle overload. Significant species differences exist with respect to the induction of adverse chronic effects in response to lung overload; i.e., mice and hamsters are less prone to developing chronic inflammation and pulmonary fibrosis, and lung tumors have been observed only in rat studies. Lung tumors or fibrosis in the rats were seen only at lung burdens having caused impaired particle clearance, and a threshold dose for the adverse chronic effects can be postulated which is defined by a lung particle burden not causing impairment of clearance. Thus, the lung tumors observed in chronic rat studies at very high particulate exposure concentrations may not be relevant for human extrapolation to low-exposure concentrations. Evidence in humans suggests that particle-overloaded lungs, e.g., in coal workers, respond with fibrosis, but no increased incidence of lung tumors has been found in this group. However, it cannot be excluded that other types of chronically inhaled particles may have a carcinogenic potential in the human lung if accumulating to very high lung burdens. More research is needed for a detailed understanding of the basic mechanism leading to nonfibrous particle-induced tumorigenesis in the lungs of different species. Altered particle accumulation and retention kinetics and chronic inflammation in the overloaded lung indicate that the maximum tolerated dose (MTD) has been exceeded. No specific guidelines for inhalation studies defining the MTD have been established; general guidelines are not necessarily applicable for chronic inhalation studies. One suggestion is to define the MTD in chronic particle inhalation studies as a maximum functionally tolerated dose (MFTD) based on a functional parameter of lung particle clearance. However, other endpoints based on an evaluation of alveolar inflammation and lung histology should be included as well. For the estimation of the MTD or MFTD a range-finding study of sufficient length, preferably 3 months, would be required. It is important to realize, however, that with increasing chronicity of exposure and increasing age of the animals, a shift in the dose-response relationship may occur.One important conclusion from our understanding of lung particle overload is that occupational exposure limits should be set to prevent impaired AM-mediated lung clearance which will-avert the accumulation of high pulmonary dust burdens; conceivably, this will also prevent the subsequent induction of adverse chronic effects including inflammation, fibrosis, and tumors since these particle-induced tumors are likely secondary to continued inflammation, tissue damage, and cell proliferation.Extrapolation from rat studies of such exposure limits predicts that present occupational standards for highly insoluble particles of low cytotoxicity may not prevent lung overload in humans and should be reevaluated. (C) 1995 Academic Press, Inc.