Biomarkers of nanomaterial exposure and effect: current status

Abstract Recent advances in nanotechnology have induced a widespread production and application of nanomaterials. As a consequence, an increasing number 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 nanomaterial 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 biomarkers, 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 occupational biomonitoring programs. A valuable contribution 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.

[1]  Jürgen Seitz,et al.  Efficient Elimination of Inhaled Nanoparticles from the Alveolar Region: Evidence for Interstitial Uptake and Subsequent Reentrainment onto Airways Epithelium , 2007, Environmental health perspectives.

[2]  Kyunghee Choi,et al.  Inflammatory responses may be induced by a single intratracheal instillation of iron nanoparticles in mice. , 2010, Toxicology.

[3]  W. MacNee,et al.  Combustion-derived nanoparticles: A review of their toxicology following inhalation exposure , 2005, Particle and Fibre Toxicology.

[4]  Mingming Huang,et al.  Metabonomic studies of biochemical changes in the serum of rats by intratracheally instilled TiO2 nanoparticles. , 2011, Journal of nanoscience and nanotechnology.

[5]  G. Biskos,et al.  Mini-Symposium: Nanoparticles and Children's Lungs Airborne Engineered Nanoparticles: Potential Risks and Monitoring Challenges for Assessing their Impacts on Children , 2012 .

[6]  M. Ghosh,et al.  Cytotoxic, genotoxic and the hemolytic effect of titanium dioxide (TiO2) nanoparticles on human erythrocyte and lymphocyte cells in vitro , 2013, Journal of applied toxicology : JAT.

[7]  Paul A. White,et al.  Gene expression profiling to identify potentially relevant disease outcomes and support human health risk assessment for carbon black nanoparticle exposure , 2012, Toxicology.

[8]  T. Fennell,et al.  Distribution of carbon‐14 labeled C60 ([14C]C60) in the pregnant and in the lactating dam and the effect of C60 exposure on the biochemical profile of urine , 2010, Journal of applied toxicology : JAT.

[9]  E Sabbioni,et al.  Comparative genotoxicity of cobalt nanoparticles and ions on human peripheral leukocytes in vitro. , 2008, Mutagenesis.

[10]  J. Grothaus,et al.  Tissue distribution of 20 nm, 100 nm and 1000 nm fluorescent polystyrene latex nanospheres following acute systemic or acute and repeat airway exposure in the rat. , 2009, Toxicology.

[11]  Hak Soo Choi,et al.  Rapid translocation of nanoparticles from the lung airspaces to the body , 2010, Nature Biotechnology.

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

[13]  Su Jin Kang,et al.  Titanium dioxide nanoparticles trigger p53‐mediated damage response in peripheral blood lymphocytes , 2008, Environmental and molecular mutagenesis.

[14]  W G Kreyling,et al.  Distribution Pattern of Inhaled Ultrafine Gold Particles in the Rat Lung , 2006, Inhalation toxicology.

[15]  M. Jakubowski,et al.  Biological Monitoring of Exposure: Trends and Key Developments , 2005, Journal of occupational health.

[16]  Y. Yoshioka,et al.  Hemopexin as biomarkers for analyzing the biological responses associated with exposure to silica nanoparticles , 2012, Nanoscale Research Letters.

[17]  Dhermendra K. Tiwari,et al.  Dose-dependent in-vivo toxicity assessment of silver nanoparticle in Wistar rats , 2011, Toxicology mechanisms and methods.

[18]  U. Heinzmann,et al.  Pulmonary and systemic distribution of inhaled ultrafine silver particles in rats. , 2001, Environmental health perspectives.

[19]  H. Chiang,et al.  Epidemiological study of health hazards among workers handling engineered nanomaterials , 2012, Journal of Nanoparticle Research.

[20]  F. André,et al.  Molecular circuits of solid tumors: prognostic and predictive tools for bedside use , 2010, Nature Reviews Clinical Oncology.

[21]  Vincent Castranova,et al.  Impairment of Coronary Arteriolar Endothelium-Dependent Dilation after Multi-Walled Carbon Nanotube Inhalation: A Time-Course Study , 2012, International journal of molecular sciences.

[22]  W. Ong,et al.  Short- and long-term changes in blood miRNA levels after nanogold injection in rats—potential biomarkers of nanoparticle exposure , 2012, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[23]  Ting Zhang,et al.  Dose dependent in vivo metabolic characteristics of titanium dioxide nanoparticles. , 2010, Journal of nanoscience and nanotechnology.

[24]  U. Vogel,et al.  Distribution of silver in rats following 28 days of repeated oral exposure to silver nanoparticles or silver acetate , 2011, Particle and Fibre Toxicology.

[25]  B. Kim,et al.  Cytotoxicity and genotoxicity of titanium dioxide nanoparticles in UVA-irradiated normal peripheral blood lymphocytes , 2011, Drug and chemical toxicology.

[26]  Seung‐Min Paek,et al.  Pharmacokinetics, tissue distribution, and excretion of zinc oxide nanoparticles , 2012, International journal of nanomedicine.

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

[28]  Tao Chen,et al.  Genotoxicity of TiO(2) anatase nanoparticles in B6C3F1 male mice evaluated using Pig-a and flow cytometric micronucleus assays. , 2012, Mutation research.

[29]  Anoop K. Pal,et al.  Nanoparticles from photocopiers induce oxidative stress and upper respiratory tract inflammation in healthy volunteers , 2013, Nanotoxicology.

[30]  P. Apostoli.  Elements in environmental and occupational medicine. , 2002, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[31]  J. Lindon,et al.  Metabonomics: a platform for studying drug toxicity and gene function , 2002, Nature Reviews Drug Discovery.

[32]  I. Yu,et al.  Twenty-Eight-Day Oral Toxicity, Genotoxicity, and Gender-Related Tissue Distribution of Silver Nanoparticles in Sprague-Dawley Rats , 2008 .

[33]  Y. Yoshioka,et al.  Acute phase proteins as biomarkers for predicting the exposure and toxicity of nanomaterials. , 2011, Biomaterials.

[34]  Li Wang,et al.  Distribution And Persistence Of Pleural Penetrations By Multi-Walled Carbon Nanotubes , 2010, ATS 2010.

[35]  S. Doak,et al.  NanoGenotoxicology: the DNA damaging potential of engineered nanomaterials. , 2009, Biomaterials.

[36]  R Singh,et al.  NMR-based metabonomics study of sub-acute hepatotoxicity induced by silica nanoparticles in rats after intranasal exposure. , 2012, Cellular and molecular biology.

[37]  Kwangsik Park,et al.  Bioavailability and Toxicokinetics of citrate-coated silver nanoparticles in rats , 2011, Archives of pharmacal research.

[38]  C. Ong,et al.  Translocation and effects of gold nanoparticles after inhalation exposure in rats , 2007 .

[39]  Wei Zhang,et al.  Studies of single-walled carbon nanotubes-induced hepatotoxicity by NMR-based metabonomics of rat blood plasma and liver extracts , 2013, Nanoscale Research Letters.

[40]  V. Ambros,et al.  The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 , 1993, Cell.

[41]  Wei Bai,et al.  Lung deposition and extrapulmonary translocation of nano-ceria after intratracheal instillation , 2010, Nanotechnology.

[42]  Paul A. Schulte,et al.  The use of biomarkers in occupational health research, practice, and policy. , 2012, Toxicology letters.

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

[44]  Jürgen Seitz,et al.  Size dependence of the translocation of inhaled iridium and carbon nanoparticle aggregates from the lung of rats to the blood and secondary target organs , 2009, Inhalation toxicology.

[45]  I. Kennedy,et al.  Novel lanthanide-labeled metal oxide nanoparticles improve the measurement of in vivo clearance and translocation , 2013, Particle and Fibre Toxicology.

[46]  Manuela Semmler-Behnke,et al.  Biodistribution of 1.4- and 18-nm gold particles in rats. , 2008, Small.

[47]  Benjamin Gilbert,et al.  Comparison of the mechanism of toxicity of zinc oxide and cerium oxide nanoparticles based on dissolution and oxidative stress properties. , 2008, ACS nano.

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

[49]  Andrew Williams,et al.  Hepatic and Pulmonary Toxicogenomic Profiles in Mice Intratracheally Instilled With Carbon Black Nanoparticles Reveal Pulmonary Inflammation, Acute Phase Response, and Alterations in Lipid Homeostasis , 2012, Toxicological sciences : an official journal of the Society of Toxicology.

[50]  Baoan Chen,et al.  The changes of T lymphocytes and cytokines in ICR mice fed with Fe3O4 magnetic nanoparticles , 2011, International journal of nanomedicine.

[51]  D. Giustarini,et al.  Biomarkers of oxidative damage in human disease. , 2006, Clinical chemistry.

[52]  Y. Oytam,et al.  Small amounts of zinc from zinc oxide particles in sunscreens applied outdoors are absorbed through human skin. , 2010, Toxicological sciences : an official journal of the Society of Toxicology.

[53]  I. Yu,et al.  A health surveillance case study on workers who manufacture silver nanomaterials , 2012, Nanotoxicology.

[54]  Jinshun Zhao,et al.  Recent progress in studies of metallic nickel and nickel-based nanoparticles' genotoxicity and carcinogenicity. , 2012, Environmental toxicology and pharmacology.

[55]  Na Li,et al.  The chronic spleen injury of mice following long-term exposure to titanium dioxide nanoparticles. , 2012, Journal of biomedical materials research. Part A.

[56]  U. Murty,et al.  Comparative study of genotoxicity and tissue distribution of nano and micron sized iron oxide in rats after acute oral treatment. , 2013, Toxicology and applied pharmacology.

[57]  L. Andersson,et al.  Experimental exposure to wood smoke: effects on airway inflammation and oxidative stress , 2007, Occupational and Environmental Medicine.

[58]  M. Malim,et al.  Gold nanoparticle-mediated gene delivery induces widespread changes in the expression of innate immunity genes , 2011, Gene Therapy.

[59]  E. Nakamura,et al.  In vivo biological behavior of a water-miscible fullerene: 14C labeling, absorption, distribution, excretion and acute toxicity. , 1995, Chemistry & biology.

[60]  Lars Barregard,et al.  Experimental Exposure to Wood-Smoke Particles in Healthy Humans: Effects on Markers of Inflammation, Coagulation, and Lipid Peroxidation , 2006, Inhalation toxicology.

[61]  Qingxiu Wang,et al.  Integrated metabolomic analysis of the nano-sized copper particle-induced hepatotoxicity and nephrotoxicity in rats: a rapid in vivo screening method for nanotoxicity. , 2008, Toxicology and applied pharmacology.

[62]  B. Bolon,et al.  Distribution and Systemic Effects of Intranasally Administered 25 nm Silver Nanoparticles in Adult Mice , 2012, Toxicologic pathology.

[63]  W. Prozialeck,et al.  Early biomarkers of cadmium exposure and nephrotoxicity , 2010, BioMetals.

[64]  Claude Viau,et al.  Biomonitoring for occupational health risk assessment (BOHRA). , 2010, Toxicology letters.

[65]  Paul A Schulte,et al.  Occupational nanosafety considerations for carbon nanotubes and carbon nanofibers. , 2013, Accounts of chemical research.

[66]  M. Jakubowski.  Biological monitoring versus air monitoring strategies in assessing environmental-occupational exposure. , 2012, Journal of environmental monitoring : JEM.

[67]  Sue-N. Park,et al.  Pulmonary toxicity and kinetic study of Cy5.5-conjugated superparamagnetic iron oxide nanoparticles by optical imaging. , 2009, Toxicology and applied pharmacology.

[68]  L. Migliore,et al.  Multiple cytotoxic and genotoxic effects induced in vitro by differently shaped copper oxide nanomaterials. , 2013, Mutagenesis.

[69]  Stefan Pfuhler,et al.  Silica nanoparticles administered at the maximum tolerated dose induce genotoxic effects through an inflammatory reaction while gold nanoparticles do not. , 2012, Mutation research.

[70]  Linlin Li,et al.  The absorption, distribution, excretion and toxicity of mesoporous silica nanoparticles in mice following different exposure routes. , 2013, Biomaterials.

[71]  Valtencir Zucolotto,et al.  Cyto and genotoxicity of gold nanoparticles in human hepatocellular carcinoma and peripheral blood mononuclear cells. , 2012, Toxicology letters.

[72]  R M Albrecht,et al.  Gastrointestinal persorption and tissue distribution of differently sized colloidal gold nanoparticles. , 2001, Journal of pharmaceutical sciences.

[73]  Robert N Grass,et al.  In vitro cytotoxicity of oxide nanoparticles: comparison to asbestos, silica, and the effect of particle solubility. , 2006, Environmental science & technology.

[74]  P. Barnes,et al.  Exhaled biomarkers. , 2006, Chest.

[75]  V. Himabindu,et al.  Evaluation of oxidative stress and anti-oxidant status in rat serum following exposure of carbon nanotubes. , 2011, Regulatory toxicology and pharmacology : RTP.

[76]  Sudipta Seal,et al.  Bio‐distribution and in vivo antioxidant effects of cerium oxide nanoparticles in mice , 2013, Environmental toxicology.

[77]  Ying Liu,et al.  Cardiovascular Toxicity of Different Sizes Amorphous Silica Nanoparticles in Rats After Intratracheal Instillation , 2013, Cardiovascular Toxicology.

[78]  Yu Tian,et al.  Integrated metabonomics analysis of the size-response relationship of silica nanoparticles-induced toxicity in mice , 2011, Nanotechnology.

[79]  I. Yu,et al.  Subchronic inhalation toxicity of silver nanoparticles. , 2009, Toxicological sciences : an official journal of the Society of Toxicology.

[80]  Andre E Nel,et al.  Feasibility of Biomarker Studies for Engineered Nanoparticles: What Can Be Learned From Air Pollution Research , 2011, Journal of occupational and environmental medicine.

[81]  Lehui Lu,et al.  An insight into the metabolic responses of ultra-small superparamagnetic particles of iron oxide using metabonomic analysis of biofluids , 2010, Nanotechnology.

[82]  M. Kumari,et al.  Toxicity assessment of manganese oxide micro and nanoparticles in Wistar rats after 28 days of repeated oral exposure , 2013, Journal of applied toxicology : JAT.

[83]  H. Lindberg,et al.  Genotoxicity of inhaled nanosized TiO(2) in mice. , 2012, Mutation research.

[84]  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.

[85]  Wolfgang G Kreyling,et al.  The effect of primary particle size on biodistribution of inhaled gold nano-agglomerates. , 2013, Biomaterials.

[86]  E. Bergamaschi.  Human biomonitoring of engineered nanoparticles: an appraisal of critical issues and potential biomarkers , 2012 .

[87]  J. Yi,et al.  Induction of chronic inflammation in mice treated with titanium dioxide nanoparticles by intratracheal instillation. , 2009, Toxicology.

[88]  B. Masereel,et al.  Effects of SiC nanoparticles orally administered in a rat model: biodistribution, toxicity and elemental composition changes in feces and organs. , 2012, Toxicology and applied pharmacology.

[89]  Dong Wook Kim,et al.  Optical imaging to trace near infrared fluorescent zinc oxide nanoparticles following oral exposure , 2012, International journal of nanomedicine.

[90]  Niels Hadrup,et al.  Nanoparticulate silver increases uric acid and allantoin excretion in rats, as identified by metabolomics , 2012, Journal of applied toxicology : JAT.

[91]  Paul A Schulte,et al.  Nanomaterials and Worker Health: Medical Surveillance, Exposure Registries, and Epidemiologic Research , 2011, Journal of occupational and environmental medicine.

[92]  Kyunghee Choi,et al.  Repeated-dose toxicity and inflammatory responses in mice by oral administration of silver nanoparticles. , 2010, Environmental toxicology and pharmacology.

[93]  G. Joksiċ,et al.  Using carbon nanotubes to induce micronuclei and double strand breaks of the DNA in human cells , 2010, Nanotechnology.

[94]  Robert H Schiestl,et al.  Titanium dioxide nanoparticles induce DNA damage and genetic instability in vivo in mice. , 2009, Cancer research.

[95]  V. Castranova,et al.  Mechanisms of pulmonary toxicity and medical applications of carbon nanotubes: Two faces of Janus? , 2009, Pharmacology & therapeutics.

[96]  T. Kumaravel,et al.  Characterization of synthesized silver nanoparticles and assessment of its genotoxicity potentials using the alkaline comet assay. , 2012, Mutation research.

[97]  H. Bouwmeester,et al.  Distribution, elimination, and toxicity of silver nanoparticles and silver ions in rats after 28-day oral exposure. , 2012, ACS nano.

[98]  Yu Zhang,et al.  The effect of magnetic nanoparticles of Fe3O4 on immune function in normal ICR mice , 2010, International journal of nanomedicine.

[99]  Maumita Bandyopadhyay,et al.  In vitro and in vivo genotoxicity of silver nanoparticles. , 2012, Mutation research.

[100]  S. Caruthers,et al.  A fibrin-specific thrombolytic nanomedicine approach to acute ischemic stroke. , 2011, Nanomedicine.

[101]  Meng Wang,et al.  Particokinetics and extrapulmonary translocation of intratracheally instilled ferric oxide nanoparticles in rats and the potential health risk assessment. , 2009, Toxicological sciences : an official journal of the Society of Toxicology.

[102]  S. Dwivedi,et al.  Characterization of coal fly ash nanoparticles and induced oxidative DNA damage in human peripheral blood mononuclear cells. , 2012, The Science of the total environment.

[103]  Paul A Schulte,et al.  Medical surveillance, exposure registries, and epidemiologic research for workers exposed to nanomaterials. , 2010, Toxicology.

[104]  Byeong-Cheol Kang,et al.  Comparative absorption, distribution, and excretion of titanium dioxide and zinc oxide nanoparticles after repeated oral administration , 2013, Particle and Fibre Toxicology.

[105]  G. Selvam,et al.  Oxidative stress and inflammatory responses of rat following acute inhalation exposure to iron oxide nanoparticles , 2012, Human & experimental toxicology.

[106]  Paramjit Grover,et al.  In vivo genotoxicity assessment of aluminium oxide nanomaterials in rat peripheral blood cells using the comet assay and micronucleus test. , 2009, Mutagenesis.

[107]  Maria João Silva,et al.  Genotoxicity evaluation of nanosized titanium dioxide, synthetic amorphous silica and multi-walled carbon nanotubes in human lymphocytes. , 2014, Toxicology in vitro : an international journal published in association with BIBRA.

[108]  G. Selvam,et al.  Acute inhalation toxicity of cerium oxide nanoparticles in rats. , 2011, Toxicology letters.

[109]  V. Castranova,et al.  Cross-talk between lung and systemic circulation during carbon nanotube respiratory exposure. Potential biomarkers. , 2009, Nano letters.

[110]  H. Drexler,et al.  Determination of cadmium in biological samples. , 2013, Metal ions in life sciences.

[111]  D. Sheehan.  The Potential of Proteomics for Providing New Insights into Environmental Impacts on Human Health , 2007, Reviews on environmental health.

[112]  B. Gulson,et al.  Comparison of dermal absorption of zinc from different sunscreen formulations and differing UV exposure based on stable isotope tracing. , 2012, The Science of the total environment.

[113]  M. Kussmann,et al.  Proteomics-based diagnosis of chronic obstructive pulmonary disease: the hunt for new markers , 2008, Expert review of proteomics.

[114]  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.

[115]  Qian Bu,et al.  NMR-based metabonomic study of the sub-acute toxicity of titanium dioxide nanoparticles in rats after oral administration , 2010, Nanotechnology.

[116]  E. Rojas,et al.  Environmental and occupational biomonitoring using the Comet assay. , 2009, Mutation research.

[117]  A. Valavanidis,et al.  Airborne Particulate Matter and Human Health: Toxicological Assessment and Importance of Size and Composition of Particles for Oxidative Damage and Carcinogenic Mechanisms , 2008, Journal of environmental science and health. Part C, Environmental carcinogenesis & ecotoxicology reviews.

[118]  M Methner,et al.  Nanoparticle Emission Assessment Technique (NEAT) for the Identification and Measurement of Potential Inhalation Exposure to Engineered Nanomaterials—Part B: Results from 12 Field Studies , 2010, Journal of occupational and environmental hygiene.

[119]  D. Appelhans,et al.  Genotoxicity of poly(propylene imine) dendrimers. , 2012, Biopolymers.

[120]  Hiroshi Kasai,et al.  Metal nanoparticle-induced micronuclei and oxidative DNA damage in mice , 2012, Journal of clinical biochemistry and nutrition.

[121]  Tian Xia,et al.  The role of oxidative stress in ambient particulate matter-induced lung diseases and its implications in the toxicity of engineered nanoparticles. , 2008, Free radical biology & medicine.

[122]  Maumita Bandyopadhyay,et al.  Genotoxicity of titanium dioxide (TiO2) nanoparticles at two trophic levels: plant and human lymphocytes. , 2010, Chemosphere.

[123]  Siva K. Nalabotu,et al.  Intratracheal instillation of cerium oxide nanoparticles induces hepatic toxicity in male Sprague-Dawley rats , 2011, International journal of nanomedicine.