Lung Injury Induced by TiO2 Nanoparticles Depends on Their Structural Features: Size, Shape, Crystal Phases, and Surface Coating

With the rapid development of nanotechnology, a variety of engineered nanoparticles (NPs) are being produced. Nanotoxicology has become a hot topic in many fields, as researchers attempt to elucidate the potential adverse health effects of NPs. The biological activity of NPs strongly depends on physicochemical parameters but these are not routinely considered in toxicity screening, such as dose metrics. In this work, nanoscale titanium dioxide (TiO2), one of the most commonly produced and widely used NPs, is put forth as a representative. The correlation between the lung toxicity and pulmonary cell impairment related to TiO2 NPs and its unusual structural features, including size, shape, crystal phases, and surface coating, is reviewed in detail. The reactive oxygen species (ROS) production in pulmonary inflammation in response to the properties of TiO2 NPs is also briefly described. To fully understand the potential biological effects of NPs in toxicity screening, we highly recommend that the size, crystal phase, dispersion and agglomeration status, surface coating, and chemical composition should be most appropriately characterized.

[1]  Annette M Schmidt,et al.  Contrasting macrophage activation by fine and ultrafine titanium dioxide particles is associated with different uptake mechanisms , 2011, Particle and Fibre Toxicology.

[2]  U. Vogel,et al.  Pulmonary instillation of low doses of titanium dioxide nanoparticles in mice leads to particle retention and gene expression changes in the absence of inflammation. , 2013, Toxicology and applied pharmacology.

[3]  Nianqiang Wu,et al.  Interlaboratory Evaluation of in Vitro Cytotoxicity and Inflammatory Responses to Engineered Nanomaterials: The NIEHS Nano GO Consortium , 2013, Environmental health perspectives.

[4]  J. Ferin,et al.  Biological effects and toxicity assessment of titanium dioxides: anatase and rutile. , 1985, American Industrial Hygiene Association journal.

[5]  Kurt Straif,et al.  Carcinogenicity of carbon black, titanium dioxide, and talc. , 2006, The Lancet Oncology.

[6]  A. Nel,et al.  Interlaboratory Evaluation of Rodent Pulmonary Responses to Engineered Nanomaterials: The NIEHS Nano GO Consortium , 2013, Environmental health perspectives.

[7]  T. Tetley,et al.  Nano-titanium dioxide bioreactivity with human alveolar type-I-like epithelial cells: Investigating crystalline phase as a critical determinant , 2015, Nanotoxicology.

[8]  J. Everitt,et al.  Pulmonary responses of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[9]  Gianmario Martra,et al.  The surface area rather than the surface coating determines the acute inflammatory response after instillation of fine and ultrafine TiO2 in the rat. , 2002, International journal of hygiene and environmental health.

[10]  K. Jan,et al.  Ultrafine titanium dioxide particles in the absence of photoactivation can induce oxidative damage to human bronchial epithelial cells. , 2005, Toxicology.

[11]  F. Seiler,et al.  Investigations on the inflammatory and genotoxic lung effects of two types of titanium dioxide: untreated and surface treated. , 2003, Toxicology and applied pharmacology.

[12]  Francesco Stellacci,et al.  Effect of surface properties on nanoparticle-cell interactions. , 2010, Small.

[13]  Mark R Wiesner,et al.  Comparison of the abilities of ambient and manufactured nanoparticles to induce cellular toxicity according to an oxidative stress paradigm. , 2006, Nano letters.

[14]  V. Colvin.  The potential environmental impact of engineered nanomaterials , 2003, Nature Biotechnology.

[15]  David B Warheit,et al.  Long-term pulmonary responses of three laboratory rodent species to subchronic inhalation of pigmentary titanium dioxide particles. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[16]  Yue-Wern Huang,et al.  Cytotoxicity in the age of nano: the role of fourth period transition metal oxide nanoparticle physicochemical properties. , 2013, Chemico-biological interactions.

[17]  D. Taylor,et al.  Human Respiratory Tract Model for Radiological Protection , 1996 .

[18]  John A Tomenson,et al.  Titanium dioxide: inhalation toxicology and epidemiology. , 2005, The Annals of occupational hygiene.

[19]  P. Borm,et al.  Endocytosis, oxidative stress and IL-8 expression in human lung epithelial cells upon treatment with fine and ultrafine TiO2: role of the specific surface area and of surface methylation of the particles. , 2007, Toxicology and applied pharmacology.

[20]  R. Baggs,et al.  Intratracheal instillation versus intratracheal inhalation: influence of cytokines on inflammatory response. , 1997, Environmental health perspectives.

[21]  N. Herlin‐Boime,et al.  In vitro investigation of oxide nanoparticle and carbon nanotube toxicity and intracellular accumulation in A549 human pneumocytes. , 2008, Toxicology.

[22]  C. rd,et al.  Epidemiology of fine particulate air pollution and human health: biologic mechanisms and who's at risk? , 2000 .

[23]  B. Lehnert,et al.  Correlation between particle size, in vivo particle persistence, and lung injury. , 1994, Environmental health perspectives.

[24]  Z. Chai,et al.  Acute toxicity and biodistribution of different sized titanium dioxide particles in mice after oral administration. , 2007, Toxicology letters.

[25]  David B Warheit,et al.  Pulmonary instillation studies with nanoscale TiO2 rods and dots in rats: toxicity is not dependent upon particle size and surface area. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[26]  F. Hong,et al.  Molecular Mechanisms of Nanosized Titanium Dioxide–Induced Pulmonary Injury in Mice , 2013, PloS one.

[27]  S. Wong,et al.  Evaluating cytotoxicity and cellular uptake from the presence of variously processed TiO2 nanostructured morphologies. , 2010, Chemical research in toxicology.

[28]  H. Lindberg,et al.  Genotoxic effects of nanosized and fine TiO2 , 2009, Human & experimental toxicology.

[29]  Robert A Hoke,et al.  Development of a base set of toxicity tests using ultrafine TiO2 particles as a component of nanoparticle risk management. , 2007, Toxicology letters.

[30]  Yves Cloutier,et al.  Rat pulmonary responses to inhaled nano-TiO2: effect of primary particle size and agglomeration state , 2013, Particle and Fibre Toxicology.

[31]  Jiang Wang,et al.  TiO2 nanoparticles translocation and potential toxicological effect in rats after intraarticular injection. , 2009, Biomaterials.

[32]  F. Hong,et al.  Oxidative damage of lung and its protective mechanism in mice caused by long-term exposure to titanium dioxide nanoparticles. , 2012, Journal of biomedical materials research. Part A.

[33]  R Tardif,et al.  Effects of inhaled nano-TiO2 aerosols showing two distinct agglomeration states on rat lungs. , 2012, Toxicology letters.

[34]  G. Sunahara,et al.  In vitro cytotoxicity and genotoxicity studies of titanium dioxide (TiO2) nanoparticles in Chinese hamster lung fibroblast cells. , 2013, Toxicology in vitro : an international journal published in association with BIBRA.

[35]  Ulrike Diebold,et al.  The surface science of titanium dioxide , 2003 .

[36]  Jeremy J. W. Chen,et al.  Titanium dioxide nanoparticles induce emphysema‐like lung injury in mice , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[37]  J. West,et al.  Correlating nanoscale titania structure with toxicity: a cytotoxicity and inflammatory response study with human dermal fibroblasts and human lung epithelial cells. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[38]  Feng Yang,et al.  Differential mouse pulmonary dose and time course responses to titanium dioxide nanospheres and nanobelts. , 2013, Toxicological sciences : an official journal of the Society of Toxicology.

[39]  Robert M Zucker,et al.  Darkfield-Confocal Microscopy detection of nanoscale particle internalization by human lung cells , 2011, Particle and Fibre Toxicology.

[40]  L. Forró,et al.  Cellular toxicity of TiO2-based nanofilaments. , 2009, ACS nano.

[41]  G. Oberdörster,et al.  Pulmonary effects of inhaled ultrafine particles , 2000, International archives of occupational and environmental health.

[42]  Alex Weir,et al.  Biological Response to Nano-Scale Titanium Dioxide (TiO2): Role of Particle Dose, Shape, and Retention , 2013, Journal of toxicology and environmental health. Part A.

[43]  E. Dopp,et al.  Titanium dioxide nanoparticles induce oxidative stress and DNA-adduct formation but not DNA-breakage in human lung cells , 2009, Particle and Fibre Toxicology.

[44]  Robert Landsiedel,et al.  Development of a short-term inhalation test in the rat using nano-titanium dioxide as a model substance. , 2009, Inhalation toxicology.

[45]  G. Oberdörster,et al.  Intratracheal inhalation vs intratracheal instillation: differences in particle effects. , 1997, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[46]  Dario Mirabelli,et al.  Mortality Among Workers Employed in the Titanium Dioxide Production Industry in Europe , 2004, Cancer Causes & Control.

[47]  Liping Tang,et al.  Surface chemistry influences cancer killing effect of TiO2 nanoparticles. , 2008, Nanomedicine : nanotechnology, biology, and medicine.

[48]  A. Nemmar,et al.  The Acute Proinflammatory and Prothrombotic Effects of Pulmonary Exposure to Rutile TiO2 Nanorods in Rats , 2008, Experimental biology and medicine.

[49]  Pratim Biswas,et al.  Crystal structure mediates mode of cell death in TiO2 nanotoxicity , 2009 .

[50]  B. Mossman,et al.  Activation of NF-kappaB-dependent gene expression by silica in lungs of luciferase reporter mice. , 2002, American journal of physiology. Lung cellular and molecular physiology.

[51]  G. Oberdörster,et al.  Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles , 2005, Environmental health perspectives.

[52]  Z. Chai,et al.  Distribution of TiO2 particles in the olfactory bulb of mice after nasal inhalation using microbeam SRXRF mapping techniques , 2007 .

[53]  Pratim Biswas,et al.  Does nanoparticle activity depend upon size and crystal phase? , 2008, Nanotoxicology.

[54]  Sylvie Sauvaigo,et al.  Titanium dioxide nanoparticles exhibit genotoxicity and impair DNA repair activity in A549 cells , 2012, Nanotoxicology.

[55]  Ying Tang,et al.  Mitochondrial injury induced by nanosized titanium dioxide in A549 cells and rats. , 2013, Environmental toxicology and pharmacology.

[56]  T. Xia,et al.  Toxic Potential of Materials at the Nanolevel , 2006, Science.

[57]  T. Douki,et al.  Cytotoxic and genotoxic impact of TiO2 nanoparticles on A549 cells. , 2011, Journal of Biomedical Nanotechnology.

[58]  C. Dion,et al.  Generating Nano-Aerosols from TiO2 (5 nm) Nanoparticles Showing Different Agglomeration States. Application to Toxicological Studies , 2013, Journal of occupational and environmental hygiene.

[59]  J B Lucas,et al.  The National Institute for Occupational Safety and Health , 1977, Contact dermatitis.

[60]  N. Wu,et al.  Particle length-dependent titanium dioxide nanomaterials toxicity and bioactivity , 2009, Particle and Fibre Toxicology.

[61]  S C Soderholm,et al.  Role of the alveolar macrophage in lung injury: studies with ultrafine particles. , 1992, Environmental health perspectives.

[62]  S. Yamada.  [The ten leading work-related diseases and injuries proposed by the National Institute for Occupational Safety and Health (NIOSH)]. , 1986, Journal of UOEH.

[63]  J. Finkelstein,et al.  Acute pulmonary effects of ultrafine particles in rats and mice. , 2000, Research report.

[64]  K. Donaldson,et al.  Impairment of alveolar macrophage phagocytosis by ultrafine particles. , 2001, Toxicology and applied pharmacology.

[65]  J. Tschopp,et al.  Nanoparticles activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome and cause pulmonary inflammation through release of IL-1α and IL-1β , 2010, Proceedings of the National Academy of Sciences.

[66]  Jinshun Zhao,et al.  Titanium dioxide nanoparticles: a review of current toxicological data , 2013, Particle and Fibre Toxicology.

[67]  W. J. Brock,et al.  Comparative pulmonary toxicity inhalation and instillation studies with different TiO2 particle formulations: impact of surface treatments on particle toxicity. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[68]  W. MacNee,et al.  Ultrafine (nanometre) particle mediated lung injury , 1998 .

[69]  K. Jensen,et al.  Airway exposure to silica-coated TiO2 nanoparticles induces pulmonary neutrophilia in mice. , 2010, Toxicological Sciences.

[70]  D. Warheit,et al.  Inhalation of high concentrations of low toxicity dusts in rats results in impaired pulmonary clearance mechanisms and persistent inflammation. , 1997, Toxicology and applied pharmacology.

[71]  T. Webb,et al.  Pulmonary toxicity study in rats with three forms of ultrafine-TiO2 particles: differential responses related to surface properties. , 2007, Toxicology.

[72]  Christine Kirschhock,et al.  Toxicity of nanoparticles embedded in paints compared with pristine nanoparticles in mice. , 2014, Toxicological sciences : an official journal of the Society of Toxicology.

[73]  G. Oberdörster,et al.  Pulmonary retention of ultrafine and fine particles in rats. , 1992, American journal of respiratory cell and molecular biology.

[74]  Franz Oesch,et al.  Genotoxicity investigations on nanomaterials , 2012, Archives of Toxicology.

[75]  C. P. Yu,et al.  Modeling of deposition and clearance of inhaled Ni compounds in the human lung. , 1999, Regulatory toxicology and pharmacology : RTP.

[76]  L. Forró,et al.  Cellular Toxicity of TiO 2 -Based Nanofilaments , 2009 .

[77]  R. Henderson,et al.  A comparison of the inflammatory response of the lung to inhaled versus instilled particles in F344 rats. , 1995, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[78]  I. Iavicoli,et al.  Toxicological effects of titanium dioxide nanoparticles: a review of in vitro mammalian studies. , 2011, European review for medical and pharmacological sciences.