Toxicokinetics and effects of fibrous and nonfibrous particles
Toxicokinetics and effects of fibrous and nonfibrous particles
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DOI：
10.1080/089583701753338622
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发表时间：
2002-01-01
影响因子：
2.1
通讯作者：
Oberdörster, G
中科院分区：
文献类型：
--
作者：
Oberdörster, G
如果大鼠长期吸入高浓度的纤维和非纤维颗粒，如果这些颗粒在肺中溶解不良，就会导致肺癌形成。即使是像二氧化钛这样相当良性的非纤维颗粒也会产生这种结果。在慢性吸入低细胞毒性难溶颗粒物(PSP)期间，一个显著的变化是大鼠肺泡区的正常清除机制受损，导致高肺负荷持续堆积，并伴有慢性肺泡炎、纤维化和突变事件。由于这些明显是高剂量效应，因此关于它们对暴露在低得多浓度下的人类的推断提出了问题。已报道的大鼠长期吸入PSP的关键研究结果表明，高剂量PSP诱导的肺癌机制在低剂量水平下不起作用。此外，可以假设存在两个阈值：一个是终点肺泡巨噬细胞介导的清除的剂量学阈值，它与肺颗粒超载有关。另一个是终点突变的机制阈值，这是由抗氧化剂防御水平决定的，以平衡激活的炎症细胞释放的活性氧化剂物种。因此，未观察到的不良反应水平(NOAEL)可以基于避免改变颗粒的毒代动力学，从而使肺负荷保持在剂量学阈值以下。在慢性吸入研究中观察到的与PSP相关的有机化合物(例如，柴油颗粒物)有助于大鼠肺部肿瘤反应的说法，并未得到体内研究的实验数据的支持。结论：PSP所致大鼠肺癌不能用于低剂量外推，肺负荷以下的PSP水平不能预测对人类肺癌风险的显著贡献。关于吸入纤维颗粒的肺毒代动力学，长纤维(>；20um)的生物持久性是与长期致癌效应相关的关键参数，它不能被肺泡巨噬细胞吞噬。生物持久性很低的长纤维不应被视为致癌物质。由于纤维的清除动力学通常可以用两相或多相模式来描述--快速的初始阶段和缓慢的最终阶段--因此在生物持久性分析中考虑纤维长于20微米的保留动力学的慢相是至关重要的。根据这种分析的结果，纤维可以分为两类：一种是在可接受的时间段内不能在肺中溶解的生物持久性纤维；另一种是生物可溶纤维，即使是长的不可吞噬的纤维也会从肺中迅速消失。然而，除了生物持久性之外，还应该对长期影响众所周知的纤维进行适当的检测，以评估纤维的毒性。此外，对于有机纤维，可能必须建立不同的规则来表征其毒性和致癌潜力。
Chronic inhalation of fibrous and nonfibrous particles by rats at high concentrations results in lung tumor formation if the particles are poorly soluble in the lung. Even rather benign nonfibrous particles such as TiO2 produce this result. One significant change during a chronic inhalation exposure of poorly soluble particles of low cytotoxicity ( PSP) is an impairment of normal clearance mechanisms in the alveolar region of the lung in rats, resulting in a continued buildup to high lung burdens accompanied by chronic alveolar inflammation, fibrosis, and mutational events. Since these are obviously high-dose effects, questions about their extrapolation to humans exposed to much lower concentrations have been raised. Results of key studies reported for chronic inhalation of PSP in rats indicate that mechanisms of PSP-induced lung tumors at high doses do not operate at low dose levels. Furthermore, the existence of two thresholds can be postulated: One is a dosimetric threshold for the endpoint alveolar macrophage-mediated clearance, which is related to lung particle overload. The other is a mechanistic threshold for the endpoint mutation, which is determined by the level of antioxidant defenses to counterbalance reactive oxidant species released by activated inflammatory cells. A no-observed-adverse-effect level ( NOAEL) could therefore be based on avoiding alteration of the toxicokinetic of the particles such that the lung burdens stay below the dosimetric threshold. The suggestion that PSP-associated organic compounds (e.g., diesel particulate matter) contribute to the lung tumor responses in rats observed in chronic inhalation studies is not supported by experimental data from in vivo studies. It can be concluded that high-dose rat lung tumors due to PSP should not be used for low-dose extrapolations, and no significant contribution to human lung cancer risk can be predicted from levels of PSP below lung overload. With respect to the pulmonary toxicokinetics of inhaled fibrous particles, the biopersistence of long fibers ( >20 mum) which cannot be phagocytized by alveolar macrophages is a key parameter related to long-term carcinogenic effects. Long fibers with a very low biopersistence should not be considered as carcinogenic. Since the clearance kinetics of fibers can generally be described by a biphasic or multiphasic pattern-fast initial and slow final phase-it is essential that the slow phase of the retention kinetics of fibers longer than 20 mum is considered in a biopersistence assay. Based on the results of such assay, fibers can be classified into one of two categories: a biopersistent fiber that cannot be dissolved in the lung within an acceptable time period; or a biosoluble fiber when even long nonphagocytizable fibers will be disappearing rapidly from the lung. However, in addition to biopersistence, it should be mandatory to evaluate fiber toxicity in an appropriate assay relative to a fiber whose long-term effects are well known. Moreover, for organic fibers it is likely that different rules may have to be established for characterization of their toxic and carcinogenic potential.