Genotoxicity of inhaled nanosized TiO2 in mice

Nanosafety Research Center, Finnish Institute of Occupational Health, FI-00250 Helsinki, Finland.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis (Impact Factor: 3.68). 11/2011; 745(1-2):58-64. DOI: 10.1016/j.mrgentox.2011.10.011
Source: PubMed


In vitro studies have suggested that nanosized titanium dioxide (TiO(2)) is genotoxic. The significance of these findings with respect to in vivo effects is unclear, as few in vivo studies on TiO(2) genotoxicity exist. Recently, nanosized TiO(2) administered in drinking water was reported to increase, e.g., micronuclei (MN) in peripheral blood polychromatic erythrocytes (PCEs) and DNA damage in leukocytes. Induction of micronuclei in mouse PCEs was earlier also described for pigment-grade TiO(2) administered intraperitoneally. The apparent systemic genotoxic effects have been suggested to reflect secondary genotoxicity of TiO(2) due to inflammation. However, a recent study suggested that induction of DNA damage in mouse bronchoalveolar lavage (BAL) cells after intratracheal instillation of nanosized or fine TiO(2) is independent of inflammation. We examined here, if inhalation of freshly generated nanosized TiO(2) (74% anatase, 26% brookite; 5 days, 4 h/day) at 0.8, 7.2, and (the highest concentration allowing stable aerosol production) 28.5 mg/m(3) could induce genotoxic effects in C57BL/6J mice locally in the lungs or systematically in peripheral PCEs. DNA damage was assessed by the comet assay in lung epithelial alveolar type II and Clara cells sampled immediately following the exposure. MN were analyzed by acridine orange staining in blood PCEs collected 48 h after the last exposure. A dose-dependent deposition of Ti in lung tissue was seen. Although the highest exposure level produced a clear increase in neutrophils in BAL fluid, indicating an inflammatory effect, no significant effect on the level of DNA damage in lung epithelial cells or micronuclei in PCEs was observed, suggesting no genotoxic effects by the 5-day inhalation exposure to nanosized TiO(2) anatase. Our inhalation exposure resulted in much lower systemic TiO(2) doses than the previous oral and intraperitoneal treatments, and lung epithelial cells probably received considerably less TiO(2) than BAL cells in the earlier intratracheal study.

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Available from: Antti Joonas Koivisto, Jan 12, 2014
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    • "Alltogether 46 studies investigating the in vivo genotoxicity of nanomaterials were identified by literature search. 19 of these studies were negative (Lindberg et al., 2012; Landsiedel et al., 2010; Saber et al., 2011; Naya et al., 2012; Rehn et al., 2003; Boisen et al., 2012; Ema et al., 2012; Wessels et al., 2011; Wu et al., 2010; Estevanato et al., 2011; Kim et al., 2011; Kim et al., 2008; Schulz et al., 2012; Sayes et al., 2010; Dandekar et al., 2010; Shinohara et al., 2009; Sadiq et al., 2012; Tavares et al., 2012; Li et al., 2012b). Note that most of these studies do not indicate a lack of evidence for genotoxicity as the doses tested were low and/or it was not shown that the material reached the tissue investigated for genotoxicity in sufficient amounts. "
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    ABSTRACT: Nanotechnology offers enormous potential for technological progress. Fortunately, early and intensive efforts have been invested in investigating toxicology and safety aspects of this new technology. However, despite there being more than 6,000 publications on nanotoxicology, some key questions still have to be answered and paradigms need to be challenged. Here, we present a view on the field of nanotoxicology to stimulate the discussion on major knowledge gaps and the critical appraisal of concepts or dogma. First, in the ongoing debate as to whether nanoparticles may harbour a specific toxicity due to their size, we support the view that there is at present no evidence of 'nanospecific' mechanisms of action; no step-change in hazard was observed so far for particles below 100 nm in one dimension. Therefore, it seems unjustified to consider all consumer products containing nanoparticles a priori as hazardous. Second, there is no evidence so far that fundamentally different biokinetics of nanoparticles would trigger toxicity. However, data are sparse whether nanoparticles may accumulate to an extent high enough to cause chronic adverse effects. To facilitate hazard assessment, we propose to group nanomaterials into three categories according to the route of exposure and mode of action, respectively: Category 1 comprises nanomaterials for which toxicity is mediated by the specific chemical properties of its components, such as released ions or functional groups on the surface. Nanomaterials belonging to this category have to be evaluated on a case-by-case basis, depending on their chemical identity. Category 2 focuses on rigid biopersistent respirable fibrous nanomaterials with a specific geometry and high aspect ratio (so-called WHO fibres). For these fibres, hazard assessment can be based on the experiences with asbestos. Category 3 focuses on respirable granular biodurable particles (GBP) which, after inhalation, may cause inflammation and secondary mutagenicity that may finally lead to lung cancer. After intravenous, oral or dermal exposure, nanoscaled GBPs investigated apparently did not show 'nanospecific' effects so far. Hazard assessment of GBPs may be based on the knowledge available for granular particles. In conclusion, we believe the proposed categorization system will facilitate future hazard assessments.
    Archives of Toxicology 10/2014; DOI:10.1007/s00204-014-1383-7 · 5.98 Impact Factor
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    • "As concerns in vivo investigations , a significant increase in DNA strand breaks and MN formation was detected in the peripheral blood cells of TiO 2 - NP treated animals , as compared with controls ( Trouiller et al . 2009 ; Song et al . 2012 ) . However , the genotoxic effects of TiO 2 - NPs were not confirmed in two other studies ( Lindberg et al . 2012 , Sadiq et al . 2012 ) . These conflicting results may be explained , again , by the differences in terms of TiO 2 crystalline structure , route of exposure and administered dose . Other types of metallic or metal oxide NPs , such as CuO - , Fe 2 O 3 - , Fe 3 O 4 , MnO 2 - , Al 2 O 3 - , Ag - and silica NPs , were reported to induce a d"
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    ABSTRACT: Recent advances in nanotechnology have induced a widespread production and application of nanomaterials. As a consequence, an increasing num- ber of workers are expected to undergo exposure to these xenobiotics, while the possible hazards to their health remain not being completely understood. In this context, biological monitoring may play a key role not only to identify potential hazards from and to evaluate occupational exposure to nanomaterials, but also to detect their early biological effects to better assess and manage risks of exposure in respect of the health of workers. Therefore, the aim of this review is to provide a critical evaluation of potential biomarkers of nano- material exposure and effect investigated in human and animal studies. Concerning exposure biomarkers, internal dose of metallic or metal oxide nanoparticle exposure may be assessed measuring the elemental metallic content in blood or urine or other biological materials, whereas specific molecules may be carefully evaluated in target tissues as possible biomarkers of biologically effective dose. Oxidative stress biomark- ers, such as 8-hydroxy-deoxy-guanosine, genotoxicity biomarkers, and inflammatory response indicators may also be useful, although not specific, as biomarkers of nanomaterial early adverse health effects. Finally, potential biomarkers from ‘‘omic’’ technologies appear to be quite innovative and greatly relevant, although mechanistic, ethical, and practical issues should all be resolved before their routine application in occupational settings could be implemented. Although all these findings are interesting, they point out the need for further research to identify and possibly validate sensitive and specific biomarkers of exposure and effect, suitable for future use in occupa- tional biomonitoring programs. A valuable contribu- tion may derive from the studies investigating the biological behavior of nanomaterials and the factors influencing their toxicokinetics and reactivity. In this context, the application of the most recent advances in analytical chemistry and biochemistry to the biological monitoring of nanomaterial exposure may be also useful to detect and define patterns and mechanisms of early nanospecific biochemical alterations.
    Journal of Nanoparticle Research 03/2014; 16:2302. · 2.18 Impact Factor
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    • "No increase in DNA damage was observed in lung epithelial cells, and no induction of micronuclei was detected in blood polychromatic erythrocytes. A clear pulmonary neutrophilia was, however, present at a dosage of 28.5 mg/m3 [46]. "
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