Sintered Indium-Tin-Oxide (ITO) Particles: A New Pneumotoxic Entity
Sintered Indium-Tin-Oxide (ITO) Particles: A New Pneumotoxic Entity
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DOI：
10.1093/toxsci/kfp014
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发表时间：
2009-04-01
影响因子：
3.8
通讯作者：
Fubini, Bice
中科院分区：
文献类型：
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作者：
Lison, Dominique;Laloy, Julie;Fubini, Bice
铟锡氧化物(ITO)是铟(In(2)O(3))和氧化锡(SnO(2))按90：10(wt：wt)的比例烧结而成的混合物，用于制造LCD屏幕和相关的高科技应用。最近有报道称，ITO生产工厂的工人患上了间质性肺部疾病。本研究的目的是通过实验确定造成这种毒性的确切化学成分，并探讨可能的作用机制。将可吸入ITO颗粒与其单一组分或未烧结的90：10混合物(混合物)在体内和体外的反应性进行比较。对于所考虑的所有终点，ITO颗粒表现为特定的有毒实体。在体内，在单次咽部给药(每只大鼠2-20毫克)后，ITO颗粒诱导了强烈的炎症反应。在第3天，ITO颗粒的炎症反应(细胞积聚、LDH和支气管肺泡灌洗液中的蛋白质)似乎比单独使用或混合使用的氧化物更明显。这种炎症反应持续存在，甚至在15天后恶化。60天后，这种炎症仍然存在，但没有观察到明显的纤维化反应。体外测定ITO对肺上皮细胞(RLE)和巨噬细胞(NR8383细胞)的细胞毒作用。虽然ITO颗粒(高达200微克/毫升)不影响上皮细胞完整性(LDH释放)，但暴露于ITO的巨噬细胞有强烈的细胞毒反应，但不能单独或混合作用于其成分。ITO颗粒在体内诱导II型肺泡细胞微核率增加，而在体外诱导RLE细胞微核率增加，提示存在二次遗传毒性机制。为了探讨ITO毒性的可能机制，在无细胞体系中用电子顺磁共振波谱分析了活性氧物种的产生。碳心自由基(COO-.)在ITO颗粒存在的情况下，检测到类Fenton活性，而不是单独使用In(2)O(3)、SnO(2)或其混合物。由于未烧结的SnO(2)和In(2)O(3)粒子的混合物不能再现ITO粒子的反应性/毒性，因此在In(2)O(3)晶体结构中引入SnO(2)分子的烧结过程似乎对解释ITO独特的毒理学性质至关重要。ITO粉尘的炎症和遗传毒性表明，在工业环境中需要严格控制接触。
Indium-Tin-Oxide (ITO) is a sintered mixture of indium- (In(2)O(3)) and tin-oxide (SnO(2)) in a ratio of 90:10 (wt:wt) that is used for the manufacture of LCD screens and related high technology applications. Interstitial pulmonary diseases have recently been reported in workers from ITO producing plants. The present study was conducted to identify experimentally the exact chemical component responsible for this toxicity and to address possible mechanisms of action. The reactivity of respirable ITO particles was compared with that of its single components alone or their unsintered 90:10 mixture (MIX) both in vivo and in vitro. For all endpoints considered, ITO particles behaved as a specific toxic entity. In vivo, after a single pharyngeal administration (2-20 mg per rat), ITO particles induced a strong inflammatory reaction. At day 3, the inflammatory reaction (cell accumulation, LDH and protein in bronchoalveolar lavage fluid) appeared more marked with ITO particles than with each oxide separately or the MIX. This inflammatory reaction persisted and even worsened after 15 days. After 60 days, this inflammation was still present but no significant fibrotic response was observed. The cytotoxicity of ITO was assessed in vitro in lung epithelial cells (RLE) and macrophages (NR8383 cell line). While ITO particles (up to 200 mu g/ml) did not affect epithelial cell integrity (LDH release), a strong cytotoxic response was found in macrophages exposed to ITO, but not to its components alone or mixed. ITO particles also induced an increased frequency of micronuclei in type II pneumocytes in vivo but not in RLE in vitro, suggesting the preponderance of a secondary genotoxic mechanism. To address the possible mechanism of ITO toxicity, reactive oxygen species production was assessed by electron paramagnetic resonance spectrometry in an acellular system. Carbon centered radicals (COO-.) and Fenton-like activity were detected in the presence of ITO particles, not with In(2)O(3), SnO(2) alone, or the MIX. Because the unsintered mixture of SnO(2) and In(2)O(3) particles was unable to reproduce the reactivity/toxicity of ITO particles, the sintering process through which SnO(2) molecules are introduced within the crystal structure of In(2)O(3) appears critical to explain the unique toxicological properties of ITO. The inflammatory and genotoxic activities of ITO dust indicate that a strict control of exposure is needed in industrial settings.