ToxSci Advance Access originally published online on January 28, 2009
Toxicological Sciences 2009 108(2):472-481; doi:10.1093/toxsci/kfp014
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Sintered Indium-Tin-Oxide (ITO) Particles: A New Pneumotoxic Entity
* Industrial Toxicology and Occupational Medicine unit, Catholic University of Louvain, Brussels, Belgium
Dipartimento di Chimica IFM, Interdepartmental Center "G. Scansetti" for Studies on Asbestos and other Toxic Particulates and Interdepartmental Center for Nanostructured Interfaces and Surfaces, Università degli Studi di Torino, 7 10125 Torino, Italy
1 To whom correspondence should be addressed at Industrial Toxicology and Occupational Medicine unit, Avenue E. Mounier, 53.02, 1200 Brussels, Belgium. Fax: +32-2-764-53-38. E-mail: dominique.lison{at}uclouvain.be.
Received October 22, 2008; accepted January 14, 2009
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Abstract |
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Indium-Tin-Oxide (ITO) is a sintered mixture of indium- (In2O3) and tin-oxide (SnO2) 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 µg/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 In2O3, SnO2 alone, or the MIX. Because the unsintered mixture of SnO2 and In2O3 particles was unable to reproduce the reactivity/toxicity of ITO particles, the sintering process through which SnO2 molecules are introduced within the crystal structure of In2O3 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.
Key Words: indium oxide; ITO; occupational lung disease; sintering.