Challenges on the toxicological predictions of engineered nanoparticles

Abstract The perceived enormous potential of nanotechnology in contributing to sustainable innovation has led to the growth of investments into new industrial applications and consumer products. However, the lack of tools that are needed to generate early knowledge about the potential adverse effects, combined with the uncertainties regarding the health and safety risks of engineered nanoparticles (ENPs), are a potential threat to the acceptability by society of the nanotechnology innovations, due to the rising societal concerns that are based on generic worries. In order to tackle these issues, it has been necessary to adopt a more proactive approach into nanotechnology safety assessments. Multiple projects have been initiated around the world in order to understand how ENPs interact with living organisms, but the validation of most of the emerging knowledge may take years. This is while robust risk assessment results are urgently needed, in order to support timely regulatory decisions and risk management actions. The goal of this paper has been to review the present knowledge on the physicochemical characteristics of ENPs, focusing on titanium dioxide (TiO2), gold (Au), copper oxide (CuO), and zinc oxide (ZnO), as well as on their biological interactions. In addition, the paper has been aimed at the identification of the main challenges on the current toxicological characterisation of these ENPs. Focus will also be given in this article to those ENPs that have been described by the Consumer Product Inventory as having prevalent nanomaterials present in consumer products, but also, with those having therapeutic and diagnostic applications, due to their physical (ex: confined plasmon resonances) and biological (biocompatibility and antimicrobial) properties.

[1]  G. Jena,et al.  Clastogenic effects of copper sulphate in chick in vivo test system. , 1996, Mutation research.

[2]  G. Ayoko,et al.  Engineered nanomaterials: knowledge gaps in fate, exposure, toxicity, and future directions , 2014 .

[3]  Daniel J. Hellebusch,et al.  High-Resolution EM of Colloidal Nanocrystal Growth Using Graphene Liquid Cells , 2012, Science.

[4]  Chor Yong Tay,et al.  Biomimicry 3D gastrointestinal spheroid platform for the assessment of toxicity and inflammatory effects of zinc oxide nanoparticles. , 2015, Small.

[5]  Alaaldin M. Alkilany,et al.  Gold nanoparticles in biology: beyond toxicity to cellular imaging. , 2008, Accounts of chemical research.

[6]  Jing Guo,et al.  Role of the dissolved zinc ion and reactive oxygen species in cytotoxicity of ZnO nanoparticles. , 2010, Toxicology letters.

[7]  Reinhard Kreiling,et al.  A decision-making framework for the grouping and testing of nanomaterials (DF4nanoGrouping). , 2015, Regulatory toxicology and pharmacology : RTP.

[8]  Massimo Bovenzi,et al.  Titanium Dioxide Nanoparticle Penetration into the Skin and Effects on HaCaT Cells , 2015, International journal of environmental research and public health.

[9]  Ana Luísa Almaça da Cruz Fernando,et al.  Nanoparticles in food packaging: Biodegradability and potential migration to food—A review , 2016 .

[10]  Annegret Potthoff,et al.  Dispersion of nanomaterials used in toxicological studies: a comparison of sonication approaches demonstrated on TiO2 P25 , 2014, Journal of Nanoparticle Research.

[11]  Wojciech Zareba,et al.  Ambient fine particulate air pollution triggers ST-elevation myocardial infarction, but not non-ST elevation myocardial infarction: a case-crossover study , 2014, Particle and Fibre Toxicology.

[12]  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.

[13]  Vincent M Rotello,et al.  Toxicity of gold nanoparticles functionalized with cationic and anionic side chains. , 2004, Bioconjugate chemistry.

[14]  A Paul Alivisatos,et al.  3D motion of DNA-Au nanoconjugates in graphene liquid cell electron microscopy. , 2013, Nano letters.

[15]  Craig A. Poland,et al.  Zeta potential and solubility to toxic ions as mechanisms of lung inflammation caused by metal/metal oxide nanoparticles. , 2012, Toxicological sciences : an official journal of the Society of Toxicology.

[16]  David W Grainger,et al.  Nanoparticles in medicine: Current challenges facing inorganic nanoparticle toxicity assessments and standardizations. , 2015, Nanomedicine : nanotechnology, biology, and medicine.

[17]  Xinxin Zhao,et al.  Evaluation of the cytotoxic and inflammatory potential of differentially shaped zinc oxide nanoparticles , 2011, Archives of Toxicology.

[18]  M. Mortimer,et al.  Toxicity of Ag, CuO and ZnO nanoparticles to selected environmentally relevant test organisms and mammalian cells in vitro: a critical review , 2013, Archives of Toxicology.

[19]  M. Vinardell,et al.  Antitumor Activities of Metal Oxide Nanoparticles , 2015, Nanomaterials.

[20]  Michael T. Postek,et al.  Nanoscale reference materials for environmental, health and safety measurements: needs, gaps and opportunities , 2012, Nanotoxicology.

[21]  P. Schulte,et al.  Occupational exposure limits for nanomaterials: state of the art , 2010 .

[22]  Antonio Marcomini,et al.  Risk assessment of engineered nanomaterials: a review of available data and approaches from a regulatory perspective , 2012, Nanotoxicology.

[23]  E. Salvati,et al.  Titanium wear debris in failed cemented total hip arthroplasty. An analysis of 71 cases. , 1992, The Journal of arthroplasty.

[24]  G. Oberdörster,et al.  Safety assessment for nanotechnology and nanomedicine: concepts of nanotoxicology , 2010, Journal of internal medicine.

[25]  N. Gjerdet,et al.  Agglomeration and sedimentation of TiO2 nanoparticles in cell culture medium. , 2009, Colloids and surfaces. B, Biointerfaces.

[26]  L. Capitán-Vallvey,et al.  A General Perspective of the Characterization and Quantification of Nanoparticles: Imaging, Spectroscopic, and Separation Techniques , 2014 .

[27]  Jinatta Jittiwat,et al.  Biodistribution of gold nanoparticles and gene expression changes in the liver and spleen after intravenous administration in rats. , 2010, Biomaterials.

[28]  Pablo Del Pino,et al.  Interfacing engineered nanoparticles with biological systems: anticipating adverse nano-bio interactions. , 2013, Small.

[29]  Nanna B. Hartmann,et al.  Adapting OECD Aquatic Toxicity Tests for Use with Manufactured Nanomaterials: Key Issues and Consensus Recommendations. , 2015, Environmental science & technology.

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

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

[32]  Ineke Malsch,et al.  Hazards and Risks of Engineered Nanoparticles for the Environment and Human Health , 2009 .

[33]  Myrtill Simkó,et al.  Metrics, Dose, and Dose Concept: The Need for a Proper Dose Concept in the Risk Assessment of Nanoparticles , 2014, International journal of environmental research and public health.

[34]  Sophie Lanone,et al.  Comparative toxicity of 24 manufactured nanoparticles in human alveolar epithelial and macrophage cell lines , 2009, Particle and Fibre Toxicology.

[35]  Margaret Rolfe,et al.  Perceptions of risk from nanotechnologies and trust in stakeholders: a cross sectional study of public, academic, government and business attitudes , 2015, BMC Public Health.

[36]  Gadi Borkow,et al.  Use of Biocidal Surfaces for Reduction of Healthcare Acquired Infections , 2014, Springer International Publishing.

[37]  Maria Dusinska,et al.  Impact of agglomeration and different dispersions of titanium dioxide nanoparticles on the human related in vitro cytotoxicity and genotoxicity. , 2012, Journal of environmental monitoring : JEM.

[38]  Adriele Prina-Mello,et al.  Towards a nanospecific approach for risk assessment. , 2016, Regulatory toxicology and pharmacology : RTP.

[39]  Igor Linkov,et al.  A weight of evidence approach for hazard screening of engineered nanomaterials , 2014, Nanotoxicology.

[40]  Shakeel Ahmed Ansari,et al.  New vision to CuO, ZnO, and TiO2 nanoparticles: their outcome and effects , 2013, Journal of Nanoparticle Research.

[41]  Olivier Toussaint,et al.  How does the deposited dose of oxide nanomaterials evolve in an in vitro assay? , 2013 .

[42]  David Rejeski,et al.  Nanotechnology in the real world: Redeveloping the nanomaterial consumer products inventory , 2015, Beilstein journal of nanotechnology.

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

[44]  Michala E Pettitt,et al.  Minimum physicochemical characterisation requirements for nanomaterial regulation. , 2013, Environment international.

[45]  G. Roebben,et al.  Interlaboratory comparison of size and surface charge measurements on nanoparticles prior to biological impact assessment , 2011 .

[46]  Sean M Geary,et al.  Size-dependent cytotoxicity of copper oxide nanoparticles in lung epithelial cells. , 2016, Environmental science. Nano.

[47]  Lutz Mädler,et al.  Use of metal oxide nanoparticle band gap to develop a predictive paradigm for oxidative stress and acute pulmonary inflammation. , 2012, ACS nano.

[48]  Mark D. Hoover,et al.  Occupational safety and health criteria for responsible development of nanotechnology , 2013, Journal of Nanoparticle Research.

[49]  이재상,et al.  Potential risks of TiO2 and ZnO nanoparticles released from sunscreens into outdoor swimming pools , 2016 .

[50]  C. Murphy,et al.  Gold nanoparticles are taken up by human cells but do not cause acute cytotoxicity. , 2005, Small.

[51]  Guangzhao Mao,et al.  Size-Dependent Toxicity of Gold Nanoparticles on Human Embryonic Stem Cells and Their Neural Derivatives. , 2016, Small.

[52]  P. Zambonin,et al.  Analytical characterization of bioactive fluoropolymer ultra-thin coatings modified by copper nanoparticles , 2005, Analytical and bioanalytical chemistry.

[53]  Erik C. Dreaden,et al.  The Golden Age: Gold Nanoparticles for Biomedicine , 2012 .

[54]  James F. Ranville,et al.  Nanoparticle analysis and characterization methodologies in environmental risk assessment of engineered nanoparticles , 2008, Ecotoxicology.

[55]  Claude Emond,et al.  Development of an Integrative Program of Nanosafety: Promote the Coordination Between Industries and Risk Assessor , 2013 .

[56]  L S Spångberg,et al.  In vitro antimicrobial and cytotoxic effects of Kri 1 paste and zinc oxide-eugenol used in primary tooth pulpectomies. , 1994, Pediatric dentistry.

[57]  Yinfa Ma,et al.  Toxicity of nano- and micro-sized ZnO particles in human lung epithelial cells , 2009 .

[58]  K. Schwirn,et al.  Why are nanomaterials different and how can they be appropriately regulated under REACH? , 2014, Environmental Sciences Europe.

[59]  Tolou Shokuhfar,et al.  High‐Resolution Electron Microscopy and Spectroscopy of Ferritin in Biocompatible Graphene Liquid Cells and Graphene Sandwiches , 2014, Advanced materials.

[60]  Md. Mujibur Rahman,et al.  Usage of nanoparticles with their potential toxicity assessment and regulatory guidelines , 2013, Toxicology and Environmental Health Sciences.

[61]  Annegret Potthoff,et al.  Pan-European inter-laboratory studies on a panel of in vitro cytotoxicity and pro-inflammation assays for nanoparticles , 2017, Archives of Toxicology.

[62]  Philip Demokritou,et al.  Preparation, characterization, and in vitro dosimetry of dispersed, engineered nanomaterials , 2017, Nature Protocols.

[63]  H. Karlsson,et al.  Size-dependent toxicity of metal oxide particles--a comparison between nano- and micrometer size. , 2009, Toxicology letters.

[64]  M. Peana,et al.  Toxicity of nanoparticles. , 2014, Current medicinal chemistry.

[65]  T. Smijs,et al.  Titanium dioxide and zinc oxide nanoparticles in sunscreens: focus on their safety and effectiveness. , 2011, Nanotechnology, science and applications.

[66]  Christian Micheletti,et al.  Analysis of currently available data for characterising the risk of engineered nanomaterials to the environment and human health--lessons learned from four case studies. , 2011, Environment international.

[67]  C. Marquardt,et al.  Environmental benefits and concerns on safety: communicating latest results on nanotechnology safety research—the project DaNa2.0 , 2016, Environmental Science and Pollution Research.

[68]  Jae Hoon Shin,et al.  Size-dependent clearance of gold nanoparticles from lungs of Sprague–Dawley rats after short-term inhalation exposure , 2014, Archives of Toxicology.

[69]  S. Saptarshi,et al.  Investigating the immunomodulatory nature of zinc oxide nanoparticles at sub-cytotoxic levels in vitro and after intranasal instillation in vivo , 2015, Journal of Nanobiotechnology.

[70]  I. Yu,et al.  Subchronic inhalation toxicity of gold nanoparticles , 2011, Particle and Fibre Toxicology.

[71]  Thomas Scheper,et al.  Evaluation of CdTe/CdS/ZnS core/shell/shell quantum dot toxicity on three-dimensional spheroid cultures. , 2016, Toxicology research.

[72]  Rui Chen,et al.  Beyond PM2.5: The role of ultrafine particles on adverse health effects of air pollution. , 2016, Biochimica et biophysica acta.

[73]  Suprakas Sinha Ray,et al.  Optical properties of nanoparticles and nanocomposites , 2014 .

[74]  Maria Dusinska,et al.  Toxicity screenings of nanomaterials: challenges due to interference with assay processes and components of classic in vitro tests , 2015, Nanotoxicology.

[75]  Petra Krystek,et al.  Particle size-dependent organ distribution of gold nanoparticles after intravenous administration. , 2008, Biomaterials.

[76]  Xiaojia He,et al.  Toxicity of engineered metal oxide nanomaterials mediated by nano–bio–eco–interactions: a review and perspective , 2015 .

[77]  Jin-Ho Choy,et al.  Biokinetics of zinc oxide nanoparticles: toxicokinetics, biological fates, and protein interaction , 2014, International journal of nanomedicine.

[78]  Sara Linse,et al.  Modeling the Time Evolution of the Nanoparticle-Protein Corona in a Body Fluid , 2010, PloS one.

[79]  Erik C. Dreaden,et al.  Size matters: gold nanoparticles in targeted cancer drug delivery. , 2012, Therapeutic delivery.

[80]  J. Pedraza-Chaverri,et al.  Cell cycle synchronization reveals greater G2/M-phase accumulation of lung epithelial cells exposed to titanium dioxide nanoparticles , 2014, Environmental Science and Pollution Research.

[81]  Thomas J Webster,et al.  Effect of the protein corona on nanoparticles for modulating cytotoxicity and immunotoxicity , 2014, International journal of nanomedicine.

[82]  Mohamed Alaraby,et al.  A comprehensive study of the harmful effects of ZnO nanoparticles using Drosophila melanogaster as an in vivo model. , 2015, Journal of hazardous materials.

[83]  Holger Moch,et al.  Nanoparticle cytotoxicity depends on intracellular solubility: comparison of stabilized copper metal and degradable copper oxide nanoparticles. , 2010, Toxicology letters.

[84]  Hiroshi Sakagami,et al.  Antioxidant and prooxidant action of eugenol-related compounds and their cytotoxicity. , 2002, Toxicology.

[85]  Sara Novak,et al.  An interlaboratory comparison of nanosilver characterisation and hazard identification: Harmonising techniques for high quality data. , 2016, Environment international.

[86]  Jinshun Zhao,et al.  Genotoxicity and carcinogenicity of cobalt-, nickel- and copper-based nanoparticles , 2012, Experimental and therapeutic medicine.

[87]  ON EMERGING AND NEWLY IDENTIFIED HEALTH RISKS ( SCENIHR ) modified Opinion ( after public consultation ) on The appropriateness of existing methodologies to assess the potential risks associated with engineered and adventitious products of nanotechnologies , 2006 .

[88]  Valérie Forest,et al.  Detection and analysis of nanoparticles in patients: A critical review of the status quo of clinical nanotoxicology. , 2016, Biomaterials.

[89]  Kevin Robbie,et al.  Nanomaterials and nanoparticles: Sources and toxicity , 2007, Biointerphases.

[90]  Carl Walkey.  The Biological Identity of Nanoparticles , 2014 .

[91]  Hugh J. Byrne,et al.  Concern-driven integrated approaches to nanomaterial testing and assessment – report of the NanoSafety Cluster Working Group 10 , 2013, Nanotoxicology.

[92]  Albert Duschl,et al.  Interaction of nanoparticles with proteins: relation to bio-reactivity of the nanoparticle , 2013, Journal of Nanobiotechnology.

[93]  Johnny Ferraz Dias,et al.  Occupational genotoxicity among copper smelters , 2012, Toxicology and industrial health.

[94]  Deborah M Proctor,et al.  Development of linear and threshold no significant risk levels for inhalation exposure to titanium dioxide using systematic review and mode of action considerations. , 2016, Regulatory toxicology and pharmacology : RTP.

[95]  Sabine Neuss,et al.  Size-dependent cytotoxicity of gold nanoparticles. , 2007, Small.

[96]  J. Banfield,et al.  Water-driven structure transformation in nanoparticles at room temperature , 2003, Nature.

[97]  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.

[98]  Blanca Suarez-Merino,et al.  High throughput toxicity screening and intracellular detection of nanomaterials , 2016, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[99]  Jiaping Zhou,et al.  Cytotoxicity, DNA damage, and apoptosis induced by titanium dioxide nanoparticles in human non-small cell lung cancer A549 cells , 2015, Environmental Science and Pollution Research.

[100]  V Wendel,et al.  Distribution of sunscreens on skin. , 2002, Advanced drug delivery reviews.

[101]  Na Li,et al.  CuO nanoparticle interaction with human epithelial cells: cellular uptake, location, export, and genotoxicity. , 2012, Chemical research in toxicology.

[102]  Baruch Fischhoff,et al.  Decision-Making Framework , 2019, Encyclopedia of Food and Agricultural Ethics.

[103]  Deborah Berhanu,et al.  Comparative study using spheres, rods and spindle-shaped nanoplatelets on dispersion stability, dissolution and toxicity of CuO nanomaterials , 2014, Nanotoxicology.

[104]  Maity Gouranga,et al.  COMPREHENSIVE STUDY OF , 2018 .

[105]  Gerhard Mueller,et al.  Penetration of Titanium Dioxide Microparticles in a Sunscreen Formulation into the Horny Layer and the Follicular Orifice , 1999, Skin Pharmacology and Physiology.

[106]  Warren C W Chan,et al.  Understanding and controlling the interaction of nanomaterials with proteins in a physiological environment. , 2012, Chemical Society reviews.

[107]  S. Schulte,et al.  Safety evaluation of sunscreen formulations containing titanium dioxide and zinc oxide nanoparticles in UVB sunburned skin: an in vitro and in vivo study. , 2011, Toxicological sciences : an official journal of the Society of Toxicology.

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

[109]  Toshiro Hirai,et al.  Amorphous nanosilica induce endocytosis-dependent ROS generation and DNA damage in human keratinocytes , 2011, Particle and Fibre Toxicology.

[110]  Aharon Gedanken,et al.  Sonochemical coatings of ZnO and CuO nanoparticles inhibit Streptococcus mutans biofilm formation on teeth model. , 2012, Langmuir : the ACS journal of surfaces and colloids.

[111]  Jie Li,et al.  Formation of Nano-Bio-Complex as Nanomaterials Dispersed in a Biological Solution for Understanding Nanobiological Interactions , 2012, Scientific Reports.

[112]  James E. Evans,et al.  Controlled growth of nanoparticles from solution with in situ liquid transmission electron microscopy. , 2011, Nano letters.

[113]  Marco P Monopoli,et al.  Biomolecular coronas provide the biological identity of nanosized materials. , 2012, Nature nanotechnology.

[114]  Yi-Hui Lee,et al.  Differential cytotoxic effects of gold nanoparticles in different mammalian cell lines. , 2014, Journal of hazardous materials.

[115]  Chen Xu,et al.  Direct Observation of Wet Biological Samples by Graphene Liquid Cell Transmission Electron Microscopy. , 2015, Nano letters.

[116]  Robert Landsiedel,et al.  Toxico-/biokinetics of nanomaterials , 2012, Archives of Toxicology.

[117]  C. Murphy,et al.  Anisotropic metal nanoparticles: Synthesis, assembly, and optical applications. , 2005, The journal of physical chemistry. B.

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

[119]  Sumio Iijima,et al.  High resolution electron microscopy , 2008 .

[120]  J. Werckmann,et al.  Trojan-Like Internalization of Anatase Titanium Dioxide Nanoparticles by Human Osteoblast Cells , 2016, Scientific Reports.

[121]  Feng Zhao,et al.  Acute toxicological effects of copper nanoparticles in vivo. , 2006, Toxicology letters.

[122]  Julie W. Fitzpatrick,et al.  Principles for characterizing the potential human health effects from exposure to nanomaterials: elements of a screening strategy , 2005, Particle and Fibre Toxicology.

[123]  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.

[124]  C. Murphy,et al.  Global transcriptomic analysis of model human cell lines exposed to surface-modified gold nanoparticles: the effect of surface chemistry. , 2015, Nanoscale.

[125]  Anne Kahru,et al.  Sub-toxic effects of CuO nanoparticles on bacteria: kinetics, role of Cu ions and possible mechanisms of action. , 2012, Environmental pollution.

[126]  Werner Österle,et al.  Multi-parametric reference nanomaterials for toxicology: state of the art, future challenges and potential candidates , 2013 .

[127]  Tolou Shokuhfar,et al.  High resolution in-situ study of reactions in graphene liquid cells , 2014 .

[128]  Lang Tran,et al.  Nanoparticles, human health hazard and regulation , 2010, Journal of The Royal Society Interface.

[129]  Dana Kühnel,et al.  Exploring LA-ICP-MS as a quantitative imaging technique to study nanoparticle uptake in Daphnia magna and zebrafish (Danio rerio) embryos , 2015, Analytical and Bioanalytical Chemistry.

[130]  Morteza Mahmoudi,et al.  Biological Identity of Nanoparticles In Vivo: Clinical Implications of the Protein Corona. , 2017, Trends in biotechnology.

[131]  Kaja Kasemets,et al.  Toxicity of nanoparticles of ZnO, CuO and TiO2 to yeast Saccharomyces cerevisiae. , 2009, Toxicology in vitro : an international journal published in association with BIBRA.

[132]  A Sharma,et al.  Clastogenic effects of copper sulphate on the bone marrow chromosomes of mice in vivo. , 1990, Mutation research.

[133]  Haimei Zheng,et al.  Observation of growth of metal nanoparticles. , 2013, Chemical communications.

[134]  Mohammed S Khan,et al.  Gold nanoparticles: a paradigm shift in biomedical applications. , 2013, Advances in colloid and interface science.

[135]  G. Janer,et al.  Cell uptake and oral absorption of titanium dioxide nanoparticles. , 2014, Toxicology letters.

[136]  Pratim Biswas,et al.  Role of Surface Area, Primary Particle Size, and Crystal Phase on Titanium Dioxide Nanoparticle Dispersion Properties , 2010, Nanoscale research letters.

[137]  V. Grassian,et al.  Inhalation Exposure Study of Titanium Dioxide Nanoparticles with a Primary Particle Size of 2 to 5 nm , 2006, Environmental health perspectives.

[138]  Marike Kolossa-Gehring,et al.  The carcinogenic potential of nanomaterials, their release from products and options for regulating them. , 2011, International journal of hygiene and environmental health.

[139]  Isamu Tanaka,et al.  Hazard assessments of manufactured nanomaterials. , 2010, Journal of occupational health.

[140]  P. Westerhoff,et al.  Titanium dioxide nanoparticles in food and personal care products. , 2012, Environmental science & technology.

[141]  M. Dorée,et al.  Table of Contents , 1992 .

[142]  Kenneth A. Dawson,et al.  Role of cell cycle on the cellular uptake and dilution of nanoparticles in a cell population. , 2011, Nature nanotechnology.

[143]  E. Kuempel,et al.  Occupational exposure to titanium dioxide , 2011 .

[144]  Lennart Möller,et al.  Intracellular uptake and toxicity of Ag and CuO nanoparticles: a comparison between nanoparticles and their corresponding metal ions. , 2013, Small.

[145]  R. Ortega,et al.  Low-solubility particles and a Trojan-horse type mechanism of toxicity: the case of cobalt oxide on human lung cells , 2014, Particle and Fibre Toxicology.

[146]  Ying Liu,et al.  Effects of Internalized Gold Nanoparticles with Respect to Cytotoxicity and Invasion Activity in Lung Cancer Cells , 2014, PloS one.

[147]  Muhammad Shakeel,et al.  Toxicity of Nano-Titanium Dioxide (TiO2-NP) Through Various Routes of Exposure: a Review , 2015, Biological Trace Element Research.

[148]  Masami T Takeuchi,et al.  State of the art on the initiatives and activities relevant to risk assessment and risk management of nanotechnologies in the food and agriculture sectors. , 2014, Food research international.

[149]  H Rothe,et al.  Principle considerations for the risk assessment of sprayed consumer products. , 2014, Toxicology letters.

[150]  Monic Shah,et al.  Biological applications of gold nanoparticles. , 2014, Journal of nanoscience and nanotechnology.

[151]  R. Shukla,et al.  Biocompatibility of gold nanoparticles and their endocytotic fate inside the cellular compartment: a microscopic overview. , 2005, Langmuir : the ACS journal of surfaces and colloids.

[152]  Brian F. G. Johnson,et al.  Selective oxidation with dioxygen by gold nanoparticle catalysts derived from 55-atom clusters , 2008, Nature.

[153]  Keishiro Tomoda,et al.  Biodistribution of colloidal gold nanoparticles after intravenous administration: effect of particle size. , 2008, Colloids and surfaces. B, Biointerfaces.

[154]  Azlan Abdul Aziz,et al.  Merging Worlds of Nanomaterials and Biological Environment: Factors Governing Protein Corona Formation on Nanoparticles and Its Biological Consequences , 2015, Nanoscale Research Letters.

[155]  Laura Hodson,et al.  Approaches to safe nanotechnology; managing the health and safety concerns associated with engineered nanomaterials , 2009 .

[156]  Alexandra Kroll,et al.  Testing Metal‐Oxide Nanomaterials for Human Safety , 2010, Advanced materials.

[157]  Mary K Schubauer-Berigan,et al.  Workshop Summary: Epidemiologic Design Strategies for Studies of Nanomaterial Workers , 2011, Journal of occupational and environmental medicine.

[158]  Lang Tran,et al.  ITS-NANO - Prioritising nanosafety research to develop a stakeholder driven intelligent testing strategy , 2014, Particle and Fibre Toxicology.

[159]  Y. Schneider,et al.  Engineered Nanomaterials in Food: Implications for Food Safety and Consumer Health , 2014, International journal of environmental research and public health.

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

[161]  Hicham Fenniri,et al.  Widespread Nanoparticle-Assay Interference: Implications for Nanotoxicity Testing , 2014, PloS one.

[162]  Aoneng Cao,et al.  Cytotoxicity of zinc oxide nanoparticles: importance of microenvironment. , 2010, Journal of nanoscience and nanotechnology.

[163]  Dan Peer,et al.  Nanoparticles for Imaging, Sensing, and Therapeutic Intervention , 2014, ACS nano.

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

[165]  Teófilo Rojo,et al.  The challenge to relate the physicochemical properties of colloidal nanoparticles to their cytotoxicity. , 2013, Accounts of chemical research.