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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 microg/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.

No abstract

The concentration of titanium in EBC may serve as a direct exposure marker in workers producing TiO2 pigment; the markers of oxidative stress reflect the local biological effect of (nano)TiO2 in the respiratory tract of the exposed workers.

No abstract

New outbursts of silicosis were recently reported among workers manufacturing an engineered material known as "artificial stone," composed by high percentages of quartz (up to 98%) agglomerated with pigments and polymeric resins. Dusts released by abrasion during artificial stone polishing were characterized for particle size, morphology, and elemental composition and studied for (1) ability to catalyze free radical generation in acellular tests, (2) membranolytic potential on human erythrocytes, (3) cytotoxic activity (lactate dehydrogenase release) on murine alveolar macrophages (MH-S) and human bronchial epithelial (BEAS-2B) cell lines, (4) induction of epithelial-mesenchymal transition (EMT) in BEAS-2B cells. Min-U-Sil 5 was used as reference quartz. Artificial stone dusts exhibited morphological features close to quartz, but contained larger amount of metal transition ions (mainly, Fe, Cu, and Ti), potentially responsible for the high reactivity in free radical generation observed. Opposite to Min-U-Sil 5, they were neither hemolytic nor cytotoxic on MH-S cells, a low cytotoxicity only being observed with BEAS-2B cells. The presence on the particle surface of residues of the resin accounts for this attenuated behavior, as hemolysis appeared and cytotoxicity increased after thermal degradation of the resin, when the free quartz surface was exposed. All dusts induced EMT with loss of E-cadherin expression and increased the expression of mesenchymal proteins (α-smooth muscle actin and vimentin). This may contribute to explain the development of fibrosis on workers exposed to artificial stone dusts.

Nanometric TiO2 has been reported to be cytotoxic and genotoxic in different in vitro models when activated by UV light. However, a clear picture of the species mediating the observed toxic effects is still missing. Here, a nanometric TiO2 powder has been modified at the surface to completely inhibit its photo-catalytic activity and to inhibit the generation of all reactive species except for singlet oxygen. The prepared powders have been tested for their ability to induce strand breaks in plasmid DNA and for their cytotoxicity and genotoxicity toward human keratinocyte (HaCaT) cells (100-500 μg mL(-1), 15 min UVA/B exposure at 216-36 mJ m(-2) respectively). The data reported herein indicate that the photo-toxicity of TiO2 is mainly triggered by particle-derived singlet oxygen. The data presented herein contribute to the knowledge of structure-activity relationships which are needed for the design of safe nanomaterials.

Nanoscale titanium dioxide (nanoTiO 2 ) is a commercially important nanomaterial. Animal studies have documented lung injury and inflammation, oxidative stress, cytotoxicity and genotoxicity. Yet, human health data are scarce and quantitative risk assessments and biomonitoring of exposure are lacking. NanoTiO 2 is classified by IARC as a group 2B, possible human carcinogen. In our earlier studies we documented an increase in markers of inflammation, as well as DNA and protein oxidative damage, in exhaled breath condensate (EBC) of workers exposed nanoTiO 2 . This study focuses on biomarkers of lipid oxidation. Several established lipid oxidative markers (malondialdehyde, 4-hydroxy-trans-hexenal, 4-hydroxytrans-nonenal, 8-isoProstaglandin F2a and aldehydes C 6 -C 12 ) were studied in EBC and urine of 34 workers and 45 comparable controls. The median particle number concentration in the production line ranged from 1.98 Â 10 4 to 2.32 Â 10 4 particles/cm 3 with $80% of the particles <100 nm in diameter. Mass concentration varied between 0.40 and 0.65 mg/m 3 . All 11 markers of lipid oxidation were elevated in production workers relative to the controls (p < 0.001). A significant dose-dependent association was found between exposure to TiO 2 and markers of lipid oxidation in the EBC. These markers were not elevated in the urine samples. Lipid oxidation in the EBC of workers exposed to (nano)TiO 2 complements our earlier findings on DNA and protein damage. These results are consistent with the oxidative stress hypothesis and suggest lung injury at the molecular level. Further studies should focus on clinical markers of potential disease progression. EBC has reemerged as a sensitive technique for noninvasive monitoring of workers exposed to engineered nanoparticles. ARTICLE HISTORY