Intelligent testing strategy and analytical techniques for the safety assessment of nanomaterials

Nanomaterials (NMs) are widely used in various areas because of their unique and useful physicochemical properties. However, they may pose toxicity risks to human health after exposure. Applicable and reliable approaches are needed for risk assessment of NMs. Herein, an intelligent analytical strategy for safety assessment of NMs is proposed that focuses on toxicity assessment using an in vitro cell model. The toxicity assessment by testing on the adverse outcome pathway in a cell culture system was defined by application of a tiered testing approach. To provide an overview of the applicable approach for risk assessment of NMs, we discuss the most commonly used techniques and analytical methods, including computational toxicology methods in dosimetry assessment, high-throughput screening for toxicity testing with high efficiency, and omics-based toxicology assessment methods. The final section focuses on the route map for an integrated approach to a testing and assessment strategy on how to extrapolate the in vitro NM toxicity testing data to in vivo risk assessment of NMs. The intelligent analytical strategy, having evolved step-by-step, could contribute to better applications for safety evaluation and risk assessment of NMs in reality.

[1]  M. Stroscio,et al.  Modulation of voltage-gated conductances of retinal horizontal cells by UV-excited TiO2 nanoparticles. , 2017, Nanomedicine : nanotechnology, biology, and medicine.

[2]  K. Kang,et al.  Molecular mechanism of nrf2 activation by oxidative stress. , 2005, Antioxidants & redox signaling.

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

[4]  S. Hackenberg,et al.  Cytotoxic, genotoxic and pro-inflammatory effects of zinc oxide nanoparticles in human nasal mucosa cells in vitro. , 2011, Toxicology in vitro : an international journal published in association with BIBRA.

[5]  Liying Wang,et al.  Caveolin-1 regulates lung cancer stem-like cell induction and p53 inactivation in carbon nanotube-driven tumorigenesis , 2014, Oncotarget.

[6]  L. Costa,et al.  Neurotoxicity of traffic‐related air pollution , 2017, Neurotoxicology.

[7]  J. Everitt,et al.  Draft OECD Guidance Document on Histopathology for inhalation toxicity studies, Supporting TG 412 (Subacute Inhalation Toxicity: 28-Day) and TG 413 (Subchronic Inhalation Toxicity: 90-Day) , 2009 .

[8]  Stephen W. Edwards,et al.  An integrative data mining approach to identifying adverse outcome pathway signatures. , 2016, Toxicology.

[9]  Minghong Wu,et al.  The cytotoxicity of oxidized multi-walled carbon nanotubes on macrophages , 2016, Science China Chemistry.

[10]  Lin Zhao,et al.  Parallel Comparative Studies on Mouse Toxicity of Oxide Nanoparticle- and Gadolinium-Based T1 MRI Contrast Agents. , 2015, ACS nano.

[11]  C. Blackman,et al.  Investigating oxidative stress and inflammatory responses elicited by silver nanoparticles using high-throughput reporter genes in HepG2 cells: effect of size, surface coating, and intracellular uptake. , 2013, Toxicology in vitro : an international journal published in association with BIBRA.

[12]  Endoplasmic reticulum stress in disease pathogenesis. , 2008, Annual review of pathology.

[13]  G. Jiang,et al.  Silver nanoparticle exposure attenuates the viability of rat cerebellum granule cells through apoptosis coupled to oxidative stress. , 2013, Small.

[14]  C. Jeffrey Brinker,et al.  Surface Interactions with Compartmentalized Cellular Phosphates Explain Rare Earth Oxide Nanoparticle Hazard and Provide Opportunities for Safer Design , 2014, ACS nano.

[15]  W. Yantasee,et al.  Oxidative stress in cancer and fibrosis: Opportunity for therapeutic intervention with antioxidant compounds, enzymes, and nanoparticles , 2016, Redox biology.

[16]  Mohd Talib Latif,et al.  Health impact assessment from building life cycles and trace metals in coarse particulate matter in urban office environments. , 2018, Ecotoxicology and environmental safety.

[17]  B. Sanderson,et al.  Cyto- and genotoxicity of ultrafine TiO2 particles in cultured human lymphoblastoid cells. , 2007, Mutation research.

[18]  D. Chaudhary,et al.  Oxidative Stress and Nano-Toxicity Induced by TiO2 and ZnO on WAG Cell Line , 2015, PloS one.

[19]  M. Ahamed,et al.  Nanocubes of indium oxide induce cytotoxicity and apoptosis through oxidative stress in human lung epithelial cells. , 2017, Colloids and surfaces. B, Biointerfaces.

[20]  S. Hackenberg,et al.  Nanosized titanium dioxide particles do not induce DNA damage in human peripheral blood lymphocytes , 2011, Environmental and molecular mutagenesis.

[21]  Christoph Studer,et al.  Green Toxicology: a strategy for sustainable chemical and material development , 2017, Environmental Sciences Europe.

[22]  Meiying Wang,et al.  Use of a pro-fibrogenic mechanism-based predictive toxicological approach for tiered testing and decision analysis of carbonaceous nanomaterials. , 2015, ACS nano.

[23]  R. Bai,et al.  Subchronic toxicity and cardiovascular responses in spontaneously hypertensive rats after exposure to multiwalled carbon nanotubes by intratracheal instillation. , 2015, Chemical research in toxicology.

[24]  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.

[25]  Christine Pohl,et al.  Gold nanoparticles induce cytotoxicity in the alveolar type-II cell lines A549 and NCIH441 , 2009, Particle and Fibre Toxicology.

[26]  H. Autrup,et al.  Cytotoxicity and genotoxicity of silver nanoparticles in the human lung cancer cell line, A549 , 2011, Archives of Toxicology.

[27]  T. Skopek,et al.  Dose‐dependent cytotoxic and mutagenic effects of antineoplastic alkylating agents on human lymphoblastoid cells , 1991, Environmental and molecular mutagenesis.

[28]  M. Kruszewski,et al.  Proteomic approach to nanotoxicity. , 2016, Journal of proteomics.

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

[30]  R. Bai,et al.  Endoplasmic reticulum stress induced by zinc oxide nanoparticles is an earlier biomarker for nanotoxicological evaluation. , 2014, ACS nano.

[31]  Ying Liu,et al.  The triggering of apoptosis in macrophages by pristine graphene through the MAPK and TGF-beta signaling pathways. , 2012, Biomaterials.

[32]  Multi-walled carbon nanotubes induce human microvascular endothelial cellular effects in an alveolar-capillary co-culture with small airway epithelial cells , 2013, Particle and Fibre Toxicology.

[33]  F. Martinon,et al.  The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. , 2002, Molecular cell.

[34]  Y. Liu,et al.  Understanding the toxicity of carbon nanotubes. , 2013, Accounts of chemical research.

[35]  Chunying Chen,et al.  Environment, Health and Safety Issues in Nanotechnology , 2017 .

[36]  Wolfgang Link,et al.  High content screening: seeing is believing. , 2010, Trends in biotechnology.

[37]  W. Kreyling,et al.  Translocation of Inhaled Ultrafine Particles to the Brain , 2004, Inhalation toxicology.

[38]  Jae Hong Park,et al.  Toxicity of copper oxide nanoparticles in lung epithelial cells exposed at the air-liquid interface compared with in vivo assessment. , 2015, Toxicology in vitro : an international journal published in association with BIBRA.

[39]  Huitu Liu,et al.  MAPK signal pathways in the regulation of cell proliferation in mammalian cells , 2002, Cell Research.

[40]  D. Pui,et al.  Airborne Nanoparticle Pollution in a Wire Electrical Discharge Machining Workshop and Potential Health Risks , 2015 .

[41]  Limin Wang,et al.  Multi-platform genotoxicity analysis of silver nanoparticles in the model cell line CHO-K1. , 2013, Toxicology letters.

[42]  Peng Wang,et al.  Multiwall carbon nanotubes mediate macrophage activation and promote pulmonary fibrosis through TGF-β/Smad signaling pathway. , 2013, Small.

[43]  H. Bi,et al.  Zinc oxide nanoparticles inhibit Ca2+-ATPase expression in human lens epithelial cells under UVB irradiation. , 2013, Toxicology in vitro : an international journal published in association with BIBRA.

[44]  M. Schladweiler,et al.  Cardiovascular and thermoregulatory responses of unrestrained rats exposed to filtered or unfiltered diesel exhaust , 2012, Inhalation toxicology.

[45]  Barbara Rothen-Rutishauser,et al.  A dose-controlled system for air-liquid interface cell exposure and application to zinc oxide nanoparticles , 2009, Particle and Fibre Toxicology.

[46]  Junya Chen,et al.  Inflammatory MAPK and NF-κB signaling pathways differentiated hepatitis potential of two agglomerated titanium dioxide particles. , 2016, Journal of hazardous materials.

[47]  K. Avgoustakis,et al.  Physiologically based pharmacokinetic modeling of PLGA nanoparticles with varied mPEG content , 2012, International journal of nanomedicine.

[48]  X. Liang,et al.  Reactive oxygen species trigger NF-κB-mediated NLRP3 inflammasome activation induced by zinc oxide nanoparticles in A549 cells , 2017, Toxicology and industrial health.

[49]  W. Willmore,et al.  Cadmium telluride quantum dots cause oxidative stress leading to extrinsic and intrinsic apoptosis in hepatocellular carcinoma HepG2 cells. , 2013, Toxicology.

[50]  R. Chen,et al.  From the Cover: Comparative Numerical Modeling of Inhaled Nanoparticle Deposition in Human and Rat Nasal Cavities. , 2016, Toxicological sciences : an official journal of the Society of Toxicology.

[51]  A. Luch,et al.  Comparative modeling of exposure to airborne nanoparticles released by consumer spray products , 2016, Nanotoxicology.

[52]  W. Meier,et al.  Effects of Silver Nanoparticles on Primary Mixed Neural Cell Cultures: Uptake, Oxidative Stress and Acute Calcium Responses , 2012, Toxicological sciences : an official journal of the Society of Toxicology.

[53]  W. Chin,et al.  A mixture of anatase and rutile TiO2 nanoparticles induces histamine secretion in mast cells , 2012, Particle and Fibre Toxicology.

[54]  Jae-Seung Lee,et al.  Ultrasensitive colorimetric detection of NF-κB protein at picomolar levels using target-induced passivation of nanoparticles , 2018, Analytical and Bioanalytical Chemistry.

[55]  Tao Zhang,et al.  Influences of nanoparticle zinc oxide on acutely isolated rat hippocampal CA3 pyramidal neurons. , 2009, Neurotoxicology.

[56]  Xiang Wang,et al.  Nanomaterial toxicity testing in the 21st century: use of a predictive toxicological approach and high-throughput screening. , 2013, Accounts of chemical research.

[57]  Maria Dusinska,et al.  Mechanisms of genotoxicity. A review of in vitro and in vivo studies with engineered nanoparticles , 2014, Nanotoxicology.

[58]  Á. González-Fernández,et al.  Metal oxide nanoparticles interact with immune cells and activate different cellular responses , 2016, International journal of nanomedicine.

[59]  J. Lawrence,et al.  ZnO Nanoparticles Impose a Panmetabolic Toxic Effect Along with Strong Necrosis, Inducing Activation of the Envelope Stress Response in Salmonella enterica Serovar Enteritidis , 2015, Antimicrobial Agents and Chemotherapy.

[60]  Vincent Castranova,et al.  Carbon nanotubes induce malignant transformation and tumorigenesis of human lung epithelial cells. , 2011, Nano letters.

[61]  S. Cormier,et al.  Copper oxide nanoparticles induce oxidative stress and cytotoxicity in airway epithelial cells. , 2009, Toxicology in vitro : an international journal published in association with BIBRA.

[62]  P. Carmichael,et al.  A PGC-1α-Mediated Transcriptional Network Maintains Mitochondrial Redox and Bioenergetic Homeostasis against Doxorubicin-Induced Toxicity in Human Cardiomyocytes: Implementation of TT21C. , 2016, Toxicological sciences : an official journal of the Society of Toxicology.

[63]  Mary Gulumian,et al.  Label-free in vitro toxicity and uptake assessment of citrate stabilised gold nanoparticles in three cell lines , 2013, Particle and Fibre Toxicology.

[64]  Shanshan Cheng,et al.  The endoplasmic reticulum stress inducer thapsigargin enhances the toxicity of ZnO nanoparticles to macrophages and macrophage-endothelial co-culture. , 2017, Environmental toxicology and pharmacology.

[65]  Xianqing Zhou,et al.  Amorphous silica nanoparticles induce malignant transformation and tumorigenesis of human lung epithelial cells via P53 signaling , 2017, Nanotoxicology.

[66]  J. Tu,et al.  Numerical modelling of nanoparticle deposition in the nasal cavity and the tracheobronchial airway , 2011, Computer methods in biomechanics and biomedical engineering.

[67]  M. Berridge Unlocking the secrets of cell signaling. , 2005, Annual review of physiology.

[68]  K. Hungerbuhler,et al.  Using physiologically based pharmacokinetic (PBPK) modeling for dietary risk assessment of titanium dioxide (TiO2) nanoparticles , 2015, Nanotoxicology.

[69]  Jeffry D Schroeter,et al.  Olfactory deposition of inhaled nanoparticles in humans , 2015, Inhalation toxicology.

[70]  Lin Zhao,et al.  Silver nanoparticles activate endoplasmic reticulum stress signaling pathway in cell and mouse models: The role in toxicity evaluation. , 2015, Biomaterials.

[71]  Joel G Pounds,et al.  ISDD: A computational model of particle sedimentation, diffusion and target cell dosimetry for in vitro toxicity studies , 2010, Particle and Fibre Toxicology.

[72]  L. Strużyńska,et al.  The role of the glutamatergic NMDA receptor in nanosilver-evoked neurotoxicity in primary cultures of cerebellar granule cells. , 2014, Toxicology.

[73]  Wei Li,et al.  Time-dependent translocation and potential impairment on central nervous system by intranasally instilled TiO(2) nanoparticles. , 2008, Toxicology.

[74]  J. Tu,et al.  A combined experimental and numerical study on upper airway dosimetry of inhaled nanoparticles from an electrical discharge machine shop , 2017, Particle and Fibre Toxicology.

[75]  Yuliang Zhao,et al.  Fullerenol inhibits the cross-talk between bone marrow-derived mesenchymal stem cells and tumor cells by regulating MAPK signaling. , 2017, Nanomedicine : nanotechnology, biology, and medicine.

[76]  Chunying Chen,et al.  Fast intracellular dissolution and persistent cellular uptake of silver nanoparticles in CHO-K1 cells: implication for cytotoxicity , 2015, Nanotoxicology.

[77]  Qingyang Liu,et al.  Oxidative potential and inflammatory impacts of source apportioned ambient air pollution in Beijing. , 2014, Environmental science & technology.

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

[79]  S. Hackenberg,et al.  Intracellular distribution, geno- and cytotoxic effects of nanosized titanium dioxide particles in the anatase crystal phase on human nasal mucosa cells. , 2010, Toxicology letters.

[80]  L. Morawska,et al.  Particle doses in the pulmonary lobes of electronic and conventional cigarette users. , 2015, Environmental pollution.

[81]  Xiang Li,et al.  Atmospheric size-resolved trace elements in a city affected by non-ferrous metal smelting: Indications of respiratory deposition and health risk. , 2017, Environmental pollution.

[82]  Da-Ren Chen,et al.  Oxidative stress, calcium homeostasis, and altered gene expression in human lung epithelial cells exposed to ZnO nanoparticles. , 2010, Toxicology in vitro : an international journal published in association with BIBRA.

[83]  Ligeng Xu,et al.  Acute pulmonary and moderate cardiovascular responses of spontaneously hypertensive rats after exposure to single-wall carbon nanotubes , 2012, Nanotoxicology.

[84]  S. Cole,et al.  Rapid chemosensitivity testing of human lung tumor cells using the MTT assay , 2004, Cancer Chemotherapy and Pharmacology.

[85]  Ru Bai,et al.  Surface chemistry of gold nanorods: origin of cell membrane damage and cytotoxicity. , 2013, Nanoscale.

[86]  Robert Kavlock,et al.  The U.S. Environmental Protection Agency Strategic Plan for Evaluating the Toxicity of Chemicals , 2010, Journal of toxicology and environmental health. Part B, Critical reviews.

[87]  W G Kreyling,et al.  Long-Term Clearance Kinetics of Inhaled Ultrafine Insoluble Iridium Particles from the Rat Lung, Including Transient Translocation into Secondary Organs , 2004, Inhalation toxicology.

[88]  Z. Chai,et al.  Advanced nuclear analytical and related techniques for the growing challenges in nanotoxicology. , 2013, Chemical Society reviews.

[89]  H. Bi,et al.  Zinc oxide nanoparticles decrease the expression and activity of plasma membrane calcium ATPase, disrupt the intracellular calcium homeostasis in rat retinal ganglion cells. , 2013, The international journal of biochemistry & cell biology.

[90]  Junchao Duan,et al.  Mitochondrial dysfunction, perturbations of mitochondrial dynamics and biogenesis involved in endothelial injury induced by silica nanoparticles. , 2017, Environmental pollution.

[91]  J. Rach,et al.  Direct exposure at the air–liquid interface: evaluation of an in vitro approach for simulating inhalation of airborne substances , 2014, Journal of applied toxicology : JAT.

[92]  E. Gálová,et al.  Gentiana asclepiadea exerts antioxidant activity and enhances DNA repair of hydrogen peroxide- and silver nanoparticles-induced DNA damage. , 2012, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[93]  R. Aitken Nitroblue tetrazolium (NBT) assay. , 2018, Reproductive biomedicine online.

[94]  Fan Qu,et al.  Review of current and "omics" methods for assessing the toxicity (genotoxicity, teratogenicity and nephrotoxicity) of herbal medicines and mushrooms. , 2012, Journal of ethnopharmacology.

[95]  W. Kreyling,et al.  TRANSLOCATION OF ULTRAFINE INSOLUBLE IRIDIUM PARTICLES FROM LUNG EPITHELIUM TO EXTRAPULMONARY ORGANS IS SIZE DEPENDENT BUT VERY LOW , 2002, Journal of toxicology and environmental health. Part A.

[96]  Chunying Chen,et al.  Multiwall carbon nanotubes directly promote fibroblast-myofibroblast and epithelial-mesenchymal transitions through the activation of the TGF-β/Smad signaling pathway. , 2015, Small.

[97]  Lin Zhao,et al.  An Experimental and Computational Approach to the Development of ZnO Nanoparticles that are Safe by Design. , 2016, Small.

[98]  C. Miracco,et al.  Skin Damage Mechanisms Related to Airborne Particulate Matter Exposure. , 2016, Toxicological sciences : an official journal of the Society of Toxicology.

[99]  B. Sanderson,et al.  Ultrafine Quartz-Induced Damage in Human Lymphoblastoid Cells in vitro Using Three Genetic Damage End-Points , 2007, Toxicology mechanisms and methods.

[100]  S. Her,et al.  Zinc oxide nanoparticles induce lipoxygenase-mediated apoptosis and necrosis in human neuroblastoma SH-SY5Y cells , 2015, Neurochemistry International.

[101]  Lang Tran,et al.  Comprehensive In Vitro Toxicity Testing of a Panel of Representative Oxide Nanomaterials: First Steps towards an Intelligent Testing Strategy , 2015, PloS one.

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

[103]  Rui Chen,et al.  Functional tumor imaging based on inorganic nanomaterials , 2017, Science China Chemistry.

[104]  Qixing Zhou,et al.  Review on attenuation of nanotoxicity and the mechanisms , 2016 .

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

[106]  Yubing Xie,et al.  The nanobiotechnology handbook , 2012 .

[107]  Hong Yin,et al.  Effects of iron or manganese doping of ZnO nanoparticles on their dissolution, ROS generation and cytotoxicity , 2014 .

[108]  M. Vetten,et al.  From the Cover: An Investigation of the Genotoxicity and Interference of Gold Nanoparticles in Commonly Used In Vitro Mutagenicity and Genotoxicity Assays , 2017, Toxicological sciences : an official journal of the Society of Toxicology.

[109]  M. Lag,et al.  Activation of Proinflammatory Responses in Cells of the Airway Mucosa by Particulate Matter: Oxidant- and Non-Oxidant-Mediated Triggering Mechanisms , 2015, Biomolecules.

[110]  Flemming R. Cassee,et al.  Particle size-dependent total mass deposition in lungs determines inhalation toxicity of cadmium chloride aerosols in rats. Application of a multiple path dosimetry model , 2002, Archives of Toxicology.

[111]  Tullio Pozzan,et al.  Microdomains of intracellular Ca2+: molecular determinants and functional consequences. , 2006, Physiological reviews.

[112]  Feng Chen,et al.  Silver nanoparticles induced oxidative and endoplasmic reticulum stresses in mouse tissues: implications for the development of acute toxicity after intravenous administration. , 2016, Toxicology research.

[113]  Chunying Chen,et al.  Reducing the cytotoxicity of ZnO nanoparticles by a pre-formed protein corona in a supplemented cell culture medium , 2015 .

[114]  J. Bailar,et al.  Toxicity testing in the 21st century—a vision and a strategy , 2012 .

[115]  C. Roca,et al.  Effect assessment of engineered nanoparticles in solid media - Current insight and the way forward. , 2016, Environmental pollution.

[116]  D. Pereira,et al.  Origin and evolution of high throughput screening , 2007, British journal of pharmacology.

[117]  A. Châtel,et al.  Omics tools: New challenges in aquatic nanotoxicology? , 2017, Aquatic toxicology.

[118]  T. Beach,et al.  Role of Environmental Contaminants in the Etiology of Alzheimer's Disease: A Review , 2015, Current Alzheimer research.

[119]  Yuliang Zhao,et al.  Synchrotron radiation techniques for nanotoxicology. , 2015, Nanomedicine : nanotechnology, biology, and medicine.

[120]  Philip Demokritou,et al.  Estimating the effective density of engineered nanomaterials for in vitro dosimetry , 2014, Nature Communications.

[121]  Liming Wang,et al.  Interference of Steroidogenesis by Gold Nanorod Core/Silver Shell Nanostructures: Implications for Reproductive Toxicity of Silver Nanomaterials. , 2017, Small.

[122]  P. Schwarze,et al.  Silver nanoparticles induce premutagenic DNA oxidation that can be prevented by phytochemicals from Gentiana asclepiadea. , 2012, Mutagenesis.

[123]  H. Autrup,et al.  PVP-coated silver nanoparticles and silver ions induce reactive oxygen species, apoptosis and necrosis in THP-1 monocytes. , 2009, Toxicology letters.

[124]  Konrad Hungerbühler,et al.  A physiologically based pharmacokinetic model for ionic silver and silver nanoparticles , 2013, International journal of nanomedicine.

[125]  M. Dusinska,et al.  Impact of nanosilver on various DNA lesions and HPRT gene mutations – effects of charge and surface coating , 2015, Particle and Fibre Toxicology.

[126]  Y. Li,et al.  Genotoxic evaluation of titanium dioxide nanoparticles in vivo and in vitro. , 2014, Toxicology letters.

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

[128]  Craig A. Poland,et al.  Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study. , 2008, Nature nanotechnology.

[129]  Exposure Scenarios in the Workplace and Risk Assessment of Carbon Nanomaterials , 2016 .

[130]  D. Pui,et al.  Evaluation of Nanoparticles Emitted from Printers in a Clean Chamber, a Copy Center and Office Rooms: Health Risks of Indoor Air Quality. , 2015, Journal of nanoscience and nanotechnology.

[131]  T. Kevin Hitchens,et al.  Tracking T-cells in vivo with a new nano-sized MRI contrast agent. , 2012, Nanomedicine : nanotechnology, biology, and medicine.

[132]  R. Service Can High-Speed Tests Sort Out Which Nanomaterials Are Safe? , 2008, Science.

[133]  Rudolf Hagen,et al.  Silver nanoparticles: evaluation of DNA damage, toxicity and functional impairment in human mesenchymal stem cells. , 2011, Toxicology letters.

[134]  S. H. Bennekou,et al.  Adverse outcome pathways: opportunities, limitations and open questions , 2017, Archives of Toxicology.

[135]  Lauren A Austin,et al.  Cytotoxic effects of cytoplasmic-targeted and nuclear-targeted gold and silver nanoparticles in HSC-3 cells--a mechanistic study. , 2015, Toxicology in vitro : an international journal published in association with BIBRA.

[136]  Vincent Castranova,et al.  Dispersal state of multiwalled carbon nanotubes elicits profibrogenic cellular responses that correlate with fibrogenesis biomarkers and fibrosis in the murine lung. , 2011, ACS nano.

[137]  M. Wang,et al.  New methods for nanotoxicology: synchrotron radiation-based techniques , 2010, Analytical and bioanalytical chemistry.

[138]  Thomas Hartung,et al.  Making big sense from big data in toxicology by read-across. , 2016, ALTEX.

[139]  Tian Xia,et al.  NLRP3 inflammasome activation induced by engineered nanomaterials. , 2013, Small.

[140]  B. Asgharian,et al.  A multiple-path model of particle deposition in the rat lung. , 1995, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[141]  Harald F. Krug Nanosafety Research — Are We on the Right Track? , 2015 .

[142]  Jing Wang,et al.  Analytical methods for nano-bio interface interactions , 2016, Science China Chemistry.

[143]  M. T. Donato,et al.  High-Content Imaging Technology for the Evaluation of Drug-Induced Steatosis Using a Multiparametric Cell-Based Assay , 2012, Journal of biomolecular screening.

[144]  C. Gabriel,et al.  Determination of nitric oxide generation in mammalian neurons using dichlorofluorescin diacetate and flow cytometry. , 1997, Journal of pharmacological and toxicological methods.

[145]  S. Dhara,et al.  Carbon nanodots from date molasses: new nanolights for the in vitro scavenging of reactive oxygen species. , 2014, Journal of materials chemistry. B.

[146]  Marc Burghartz,et al.  Repetitive exposure to zinc oxide nanoparticles induces dna damage in human nasal mucosa mini organ cultures , 2011, Environmental and molecular mutagenesis.

[147]  Ying Liu,et al.  The dose-dependent toxicological effects and potential perturbation on the neurotransmitter secretion in brain following intranasal instillation of copper nanoparticles , 2012, Nanotoxicology.

[148]  J. Finkelstein,et al.  Translocation of Inhaled Ultrafine Manganese Oxide Particles to the Central Nervous System , 2006, Environmental health perspectives.