Pulmonary responses of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles
Pulmonary responses of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles
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DOI：
10.1093/toxsci/kfh019
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发表时间：
2004-02-01
影响因子：
3.8
通讯作者：
Everitt, JI
中科院分区：
文献类型：
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作者：
Bermudez, E;Mangum, JB;Everitt, JI
进行了一项多物种、亚慢性吸入研究，比较了超细二氧化钛（uf-TiO 2）的肺反应。雌性大鼠、小鼠和仓鼠暴露于浓度为0.5、2.0或10 mg/m（3）uf-TiO 2颗粒的气溶胶中，每天6小时，每周5天，持续13周。暴露期后，将动物饲养4、13、26或52周（暴露于uf-TiO 2的仓鼠为49周）的恢复期，并在每个时间点检查肺和淋巴结中的uf-TiO 2负荷和选定的肺反应。选择研究的反应来评估各种肺参数，包括炎症、细胞毒性、肺细胞增殖和组织病理学改变。在所有三个物种中，残留的肺负荷以剂量依赖性方式增加，并在接触结束时达到最大值。当以mg uf-TiO 2/mg干肺表示时，小鼠和大鼠在暴露结束时具有相似的保留肺负荷，而仓鼠的保留肺负荷显著较低。在暴露后，所有三种物种的肺负荷均随时间推移而下降，在恢复期结束时，10 mg/m3组大鼠、小鼠和仓鼠的肺颗粒负荷百分比分别为57%、45%和3%。10 mg/m3剂量组小鼠和大鼠肺部颗粒清除延迟，表明这些动物已达到肺颗粒过载。暴露于10 mg/m3的大鼠和小鼠的肺部炎症表现为巨噬细胞和中性粒细胞数量增加以及支气管肺泡灌洗液（BALF）中可溶性标记物浓度增加。大鼠的初始中性粒细胞反应大于小鼠，而巨噬细胞的相对增加小于小鼠。大鼠（而非小鼠）的嗜中性粒细胞反应以与肺负荷下降相关的时间依赖性方式下降;然而，两种动物在暴露后52周时恢复的中性粒细胞分数相当。BALF中可溶性毒性指标（LDH和蛋白质）的持续增加主要发生在暴露于10 mg/m3的大鼠和小鼠中，并随着暴露后时间的推移而减少。在仓鼠中，细胞反应或指示毒性的标志物无显著变化，反映了这些动物快速清除肺部颗粒的能力。在10 mg/m3组大鼠中观察到进行性上皮和纤维增生性变化。这些病变包括化生上皮细胞的肺泡上皮增殖灶（所谓的肺泡细支气管化），包围着大量颗粒负载的巨噬细胞的聚集灶。在大鼠中观察到的上皮增殖变化也表现为细胞增殖研究中肺泡上皮细胞标记的增加。与这些上皮增生灶相关的是间质颗粒积聚和肺泡间隔纤维化。这些病变随着暴露后时间的增加而变得更加明显。在小鼠或仓鼠中均未观察到上皮、化生和纤维增生性变化。总之，吸入uf-TiO 2颗粒的肺反应存在显著的种属差异。在肺uf-TiO 2负荷相等的条件下，大鼠比小鼠产生更严重的炎症反应，随后出现进行性上皮和纤维增生性变化。暴露于10 mg/m3 uf-TiO 2的小鼠和大鼠的肺颗粒清除率明显受损，而仓鼠的清除率似乎在任何给药剂量下都没有受到影响。这些数据与使用吸入性Piglitazone（精细模式）TiO 2的伴随研究的结果一致（Piglitazone等人，2002），并证明暴露于可能诱导肺超负荷的超细颗粒浓度的大鼠的肺反应与类似暴露的小鼠和仓鼠不同。这些差异可以解释为肺反应和这些啮齿类动物之间的粒子剂量学差异。
A multispecies, subchronic, inhalation study comparing pulmonary responses to ultrafine titanium dioxide (uf-TiO2) was performed. Female rats, mice, and hamsters were exposed to aerosol concentrations of 0.5, 2.0, or 10 mg/m(3) uf-TiO2 particles for 6 h/day, 5 days/week, for 13 weeks. Following the exposure period, animals were held for recovery periods of 4, 13, 26, or 52 weeks (49 weeks for the uf-TiO2-exposed hamsters) and, at each time point, uf-TiO2 burdens in the lung and lymph nodes and selected lung responses were examined. The responses studied were chosen to assess a variety of pulmonary parameters, including inflammation, cytotoxicity, lung cell proliferation, and histopathological alterations. Retained lung burdens increased in a dose-dependent manner in all three species and were at a maximum at the end of exposures. Mice and rats had similar retained lung burdens at the end of the exposures when expressed as mg uf-TiO2/mg dry lung, whereas hamsters had retained lung burdens that were significantly lower. Lung burdens in all three species decreased with time after exposure, and, at the end of the recovery period, the percentage of the lung particle burden remaining in the 10 mg/m(3) group was 57, 45, and 3% for rat, mouse, and hamster, respectively. The retardation of particle clearance from the lungs in mice and rats of the 10 mg/m(3) group indicated that pulmonary particle overload had been achieved in these animals. Pulmonary inflammation in rats and mice exposed to 10 mg/m(3) was evidenced by increased numbers of macrophages and neutrophils and increased concentrations of soluble markers in bronchoalveolar lavage fluid (BALF). The initial neutrophil response in rats was greater than in mice, whereas the relative increase of macrophages was less than in mice. The neutrophilic response of rats, but not mice, declined in a time-dependent manner correlating with declining lung burdens; however, the fraction of recovered neutrophils at 52 weeks postexposure was equivalent in the two species. Consistent increases in soluble indicators of toxicity in the BALF (LDH and protein) occurred principally in rats and mice exposed to 10 mg/m(3) and diminished with time postexposure. There were no significant changes in cellular response or with markers indicating toxicity in hamsters, reflecting the capacity of these animals to rapidly clear particles from the lung. Progressive epithelial and fibroproliferative changes were observed in rats of the 10 mg/m(3) group. These lesions consisted of foci of alveolar epithelial proliferation of metaplastic epithelial cells (so-called alveolar bronchiolization) circumscribing aggregated foci of heavily particle-laden macrophages. The observed epithelial proliferative changes were also manifested in rats as an increase in alveolar epithelial cell labeling in cell proliferation studies. Associated with these foci of epithelial proliferation were interstitial particle accumulation and alveolar septal fibrosis. These lesions became more pronounced with increasing time postexposure. Epithelial, metaplastic, and fibroproliferative changes were not noted in either mice or hamsters. In summary, there were significant species differences in the pulmonary responses to inhaled uf-TiO2 particles. Under conditions where the lung uf-TiO2 burdens were equivalent, rats developed a more severe inflammatory response than mice and, subsequently, developed progressive epithelial and fibroproliferative changes.Clearance of particles from the lung was markedly impaired in mice and rats exposed to 10 mg/m(3) uf-TiO2, whereas clearance in hamsters did not appear to be affected at any of the administered doses. These data are consistent with the results of a companion study using inhaled pigmentary (fine mode) TiO2 (Bermudez et al., 2002) and demonstrate that the pulmonary responses of rats exposed to ultrafine particulate concentrations likely to induce pulmonary overload are different from similarly exposed mice and hamsters. These differences can be explained both by pulmonary response and by particle dosimetry differences among these rodent species.