Mode of silver clearance following 28-day inhalation exposure to silver nanoparticles determined from lung burden assessment including post-exposure observation periods
Mode of silver clearance following 28-day inhalation exposure to silver nanoparticles determined from lung burden assessment including post-exposure observation periods
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DOI：
10.1007/s00204-020-02660-2
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发表时间：
2020-03-01
影响因子：
6.1
通讯作者：
Yu, Il Je
中科院分区：
文献类型：
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作者：
Jo, Mi Seong;Kim, Jin Kwon;Yu, Il Je
经修订的经济合作与发展组织（OECD）吸入毒性测试指南要求在纳米材料暴露后立即以及之后的一段时间内对肺部负荷进行测量。肺部负荷是纳米颗粒在肺部沉积和滞留的函数。按照OECD指南进行肺部负荷研究，或许能够评估纳米颗粒的清除机制。在本研究中，雄性大鼠暴露于由火花发生器产生的银纳米颗粒（AgNP）气溶胶（18.1 - 19.6纳米）中。暴露组包括（1）对照组（新鲜空气），（2）低浓度组（31.2 ± 8.5微克/立方米），（3）中浓度组（81.8 ± 11.4微克/立方米），以及（4）高浓度组（115.6 ± 30.5微克/立方米）。根据修订后的OECD测试指南412，大鼠每天暴露6小时，每周5天，持续4周（28天）。在暴露后观察（PEO）第1天和第7天收集支气管肺泡灌洗液（BAL），并对炎症细胞和炎症生物标志物进行分析。在PEO - 1、PEO - 7和PEO - 28天测量来自AgNPs的银在肺部的负荷，以获得每个肺的定量质量浓度。对BAL液中血细胞的分类计数以及炎症生物标志物和肺组织的组织病理学评估表明，暴露于高浓度的AgNP气溶胶在PEO - 1天引发炎症，在PEO - 7天缓慢消退，并在PEO - 28天完全消退。肺部负荷测量表明，来自AgNPs的银通过两种不同的模式清除；快速清除和缓慢清除。快速清除成分与浓度相关，半衰期从2到4天不等，从低浓度到高浓度的清除率为0.35 - 0.17/天⁻¹。缓慢清除的半衰期分别为100天、57天和76天，对于高、中、低浓度暴露的清除率分别为0.009、0.012和0.007/天⁻¹。目前清除的确切机制尚不清楚。与浓度相关的快速清除成分可能取决于AgNPs的溶解，而缓慢清除则是由于由银离子与生物阴离子反应产生的低溶解性AgNPs二次颗粒的缓慢清除。这些二次AgNPs可能通过溶解以外的机制清除，例如黏液纤毛清除、转移到淋巴系统或其他器官。
Recently revised OECD inhalation toxicity testing guidelines require measurements of lung burden immediately after and for periods following exposure for nanomaterials. Lung burden is a function of pulmonary deposition and retention of nanoparticles. Using lung burden studies as per OECD guidelines, it may be possible to assess clearance mechanisms of nanoparticles. In this study, male rats were exposed to silver nanoparticle (AgNP) aerosols (18.1-19.6 nm) generated from a spark generator. Exposure groups consisted of (1) control (fresh air), (2) low (31.2 +/- 8.5 mu g/m(3)), (3) moderate (81.8 +/- 11.4 mu g/m(3)), and (4) high concentrations (115.6 +/- 30.5 mu g/m(3)). Rats were exposed for 6-h/day, 5-days/week for 4 weeks (28-days) based on the revised OECD test guideline 412. Bronchoalveolar lavage (BAL) fluids were collected on post-exposure observation (PEO)-1 and PEO-7 days and analyzed for inflammatory cells and inflammatory biomarkers. The lung burdens of Ag from AgNPs were measured on PEO-1, PEO-7, and PEO-28 days to obtain quantitative mass concentrations per lung. Differential counting of blood cells and inflammatory biomarkers in BAL fluid and histopathological evaluation of lung tissue indicated that exposure to the high concentrations of AgNP aerosol induced inflammation at PEO-1, slowly resolved at PEO-7 and completely resolved at PEO-28 days. Lung burden measurement suggested that Ag from AgNPs was cleared through two different modes; fast and slow clearance. The fast clearance component was concentration-dependent with half-times ranging from two to four days and clearance rates of 0.35-0.17/day(-1) from low to high concentrations. The slow clearance had half-times of 100, 57, and 76 days and clearance rates of 0.009, 0.012, and 0.007/day(-1) for the high, moderate and low concentration exposure. The exact mechanism of clearance is not known currently. The fast clearance component which was concentration-dependent could be dependent on the dissolution of AgNPs and the slow clearance would be due to slow clearance of the low dissolution AgNPs secondary particles originating from silver ions reacting with biogenic anions. These secondary AgNPs might be cleared by mechanisms other than dissolution such as mucociliary escalation, translocation to the lymphatic system or other organs.