Development of a Short-Term Inhalation Test in the Rat Using Nano-Titanium Dioxide as a Model Substance
Development of a Short-Term Inhalation Test in the Rat Using Nano-Titanium Dioxide as a Model Substance
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DOI：
10.1080/08958370802361057
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发表时间：
2009-01-01
影响因子：
2.1
通讯作者：
Landsiedel, Robert
中科院分区：
文献类型：
--
作者：
Ma-Hock, Lan;Burkhardt, Silke;Landsiedel, Robert
有证据表明，短期吸入研究可提供与90天研究相当的呼吸道毒性预测，从而有机会节省筛选供试物质吸入毒性的时间和资源。本研究的目的是开发一种短期吸入试验，可用于提供长期暴露于纳米材料气溶胶可能发生的呼吸道影响的早期证据。将雄性Wistar大鼠吸入0（对照）、2、10和50 mg/m3纳米二氧化钛（TiO 2）气溶胶，每天6 h，持续5 d。在末次暴露后立即或暴露后3天和16天（分别为研究第5、8和21天）进行尸检。纳米TiO 2治疗导致肺形态学变化，50 mg/m3纳米TiO 2导致肺重量增加。肺部炎症与支气管肺泡灌洗液（BALF）总细胞和中性粒细胞计数、总蛋白含量、酶活性和许多细胞介质水平的剂量依赖性增加相关。通过测量适当的临床病理学参数，未发现全身效应的迹象。在大/中支气管和终末细支气管中，所有纳米TiO 2剂量水平下的细胞复制（通过掺入5-溴-2 '-脱氧尿苷测定）均增加。对测量参数的影响在研究第5天或第8天最为显著，一些终点在第21天恢复至对照水平。总体而言，在这项短期研究中观察到的纳米TiO 2的肺部效应与之前在亚慢性吸入研究中报告的效应相当。
Evidence suggests that short-term inhalation studies may provide comparable prediction of respiratory tract toxicity to 90-day studies, presenting the opportunity to save time and resources in screening inhalation toxicity of test substances. The aim of this study was to develop a short-term inhalation test that could be employed to provide early evidence on respiratory tract effects which might occur from long-term exposure to aerosols of nano-materials. Male Wistar rats were exposed to aerosols of 0 (control), 2, 10 and 50 mg/m3 nano-titanium dioxide (TiO2) by inhalation for 6 h/day for 5 days. Necropsies were performed either immediately after the last exposure or after 3 and 16 days post exposure (study days 5, 8 and 21, respectively). Treatment with nano-TiO2 resulted in morphological changes in the lung, with 50 mg/m3 nano-TiO2 producing an increase in lung weight. Lung inflammation was associated with dose-dependent increases in bronchoalveolar lavage fluid (BALF) total cell and neutrophil counts, total protein content, enzyme activities and levels of a number of cell mediators. No indications of systemic effects could be found by measurement of appropriate clinical pathology parameters. Cell replication (determined by incorporation of 5-bromo-2'-deoxyuridine) was increased at all nano-TiO2 dose levels in large/medium bronchi and terminal bronchioles. The effects on the parameters measured were most prominent either on study day 5 or 8, with some endpoints returning to control levels by day 21. Overall, the pulmonary effects of nano-TiO2 observed in this short-term study were comparable to those previously reported in subchronic inhalation studies.