Abstract
Nanoparticles are increasingly used in a wide range of applications in science, technology and medicine. Since they are produced for specific purposes which cannot be met by larger particles and bulk material they are likely to be highly reactive, in particular, with biological systems. On the other hand a large body of know-how in environmental sciences is available from toxicological effects of ultrafine particles (smaller than 100 nm in size) after inhalation. Since nanoparticles feature similar reactivity as ultrafine particles a sustainable development of new emerging nanoparticles is required. This paper gives a brief review on the dosimetry of nanoparticles, including deposition in the various regions of the respiratory tract and systemic translocation and uptake in secondary target organs, epidemiologic associations with health effects and toxicology of inhaled nanoparticles. General principles and current paradigms to explain for the specific behaviour of nanoparticles in toxicology are discussed. With that respect we consider nanoparticles to be in the range from 1 to 2 nm (clusters of atoms/molecules) to particles that are smaller than 100 nm at least in one dimension. Since the evidence for health risks of ultrafine and nanoparticles after inhalation has been increasing over the last decade, the paper attempts to extrapolate these findings and principles observed in particle inhalation toxicology into recommendations for an integrated concept of risk assessment of nanoparticles for a broad range of use in science, technology and medicine.
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Asgharian B., Hofmann W., Bergmann R., (2001). Particle deposition in a multiple-path model of the human lung. Aerosol Sci. Technol. 34:332–339
Barnes P.J. (2001). Neurogenic inflammation in the airways. Respir. Physiol. 125(1–2):145–154
Bathori G., Cervenak L., and Karadi I. (2004). Caveolae–an alternative endocytotic pathway for targeted drug delivery. Crit Rev. Ther. Drug Carrier Syst. 21(2):67–95
Bodian D., and Howe H.A., (1941). The rate of progression of poliomyelitis virus in nerves. Bull. Johns Hopkins Hosp. 69:79–85
Boland S., Baeza-Squiban A., Fournier T., Houcine O., Gendron M.C., Chévrier M., Jouvenot G., Coste A., Aubier M., and Marano F., (1999). Diesel exhaust particles are taken up by human airway epithelial cells in vitro and alter cytokine production. Am. J. Physiol. 276(4):L604–L613
Boland S., Bonvallot V., Fournier T., Baeza-Squiban A., Aubier M., and Marano F., (2000). Mechanisms of GM-CSF increase by diesel exhaust particles in human airway epithelial cells. Am. J. Physiol. 278(1):L25–L32
Borm P.J., and Kreyling W., (2004). Toxicological hazards of inhaled nanoparticles – potential implications for drug delivery. J. Nanosci. Nanotech. 4(5):521–531
Brook R.D., Franklin B., Cascio W., Hong Y., Howard G., Lipsett M., Luepker R., Mittleman M., Samet J., Smith S.C. Jr., and Tager I., (2004). Air pollution and cardiovascular disease: a statement for healthcare professionals from the Expert Panel on Population and Prevention Science of the American Heart Association. Circulation 109(21):2655–2671
Brooking J., Davis S.S., and Illum L., (2001). Transport of nanoparticles across the rat nasal mucosa. J. Drug Target 9(4):267–279
Brown J.S., Zeman K.L., and Bennett W.D., (2002). Ultrafine particle deposition and clearance in the healthy and obstructed lung. Am. J. Respir. Crit. Care Med. 166(9):1240–1247
BSI-PAS71, 2005. Vocabulary – Nanoparticles. British Standard Institution (BSI). http://www.bsi-global.com/nano
Chin B.Y., Choi M.E., Burdick M.D., Strieter R.M., Risby T.H., Choi A.M., (1998). Induction of apoptosis by particulate matter: role of TNF-alpha and MAPK. Am. J. Physiol. 275(5 Pt 1):L942–L949
de Lorenzo A.J.D., and Darin J. (1970). The olfactory neuron and the blood–brain barrier. In: Wolstenholme G.E.W. and Knight J., (eds). Taste and Smell in Vertebrates. Churchill, London, pp. 151–176
Donaldson K., (2003). The biological effects of coarse and fine particulate matter. Occup. Environ. Med. 60(5):313–4
Donaldson K., Li X.Y., and MacNee W., (1998). Ultrafine (nanometre) particle mediated lung injury. J. Aerosol Sci. 29(5–6):553–560
Donaldson K., Stone V., Borm P.J., Jimenez L.A., Gilmour P.S., Schins R.P., Knaapen A.M., Rahman I., Faux S.P., Brown D.M., and MacNee W., (2003). Oxidative stress and calcium signaling in the adverse effects of environmental particles (PM10). Free Radic. Biol. Med. 34(11):1369–1382
Donaldson K., Stone V., Seaton A., and MacNee W., (2001). Ambient particle inhalation and the cardiovascular system: potential mechanisms. Environ. Health Persp. 109(Suppl 4):523–527
Donaldson K., and Tran C.L., (2004). An introduction to the short-term toxicology of respirable industrial fibres. Mutat. Res. 553(1–2):5–9
Dye J.A., Lehmann J.R., McGee J.K., Winsett D.W., Ledbetter A.D., Everitt J.I., Ghio A.J., and Costa D.L., (2001). Acute pulmonary toxicity of particulate matter filter extracts in rats: coherence with epidemiologic studies in Utah Valley residents. Environ. Health Persp. 109(3):395–403
ESF, 2005. ESF forward look on Nanomedicine. European Science Foundation Policy Briefings. http://www.esf.org/newsrelease/83/SPB23Nanomedicine.pdf
Fahy O., Tsicopoulos A., Hammad H., Pestel J., Tonnel A.B., and Wallaert B., (1999). Effects of diesel organic extracts on chemokine production by peripheral blood mononuclear cells. J. Allergy Clin. Immunol. 103(6):1115–1124
Faux S.P., Tran C.L., Miller B.G., Jones A.D., Monteiller C., and Donaldson K. (2003). In Vitro Determinants of Particulate Toxicity: the Dose-Metric for Poorly Soluble Dusts. Health and Safety Executive, Crown, Norwich UK
Gavett S.H., Bishop L.R., Haykal-Coates N., Heinrich J., and Gilmour M.I., (2001). Effects of particles from two german cities on allergic responses in mice. Am. J. Respir. Crit. Care Med. 163:A50
Geiser M., Rothen-Rutishauser B., Kapp N., Schurch S., Kreyling W., Schulz H., Semmler M., Hof V.I., Heyder J., and Gehr P., (2005). Ultrafine particles cross cellular membranes by nonphagocytic mechanisms in lungs and in cultured cells. Environ. Health Persp. 113(11):1555–1560
Ghio A.J., and Devlin R.B., (2001). Inflammatory lung injury after bronchial instillation of air pollution particles. Am. J. Respir. Crit. Care Med. 164(4):704–708
Gilmour P.S., Rahman I., Hayashi S., Hogg J.C., Donaldson K., and MacNee W., (2001). Adenoviral E1A primes alveolar epithelial cells to PM(10)-induced transcription of interleukin-8. Am. J. Physiol. Lung Cell Mol. Physiol. 281(3):L598–L606
Gumbleton M., (2001). Caveolae as potential macromolecule trafficking compartments within alveolar epithelium. Adv. Drug Deliv. Rev. 49(3):281–300
Heckel K., Kiefmann R., Dorger M., Stoeckelhuber M., and Goetz A.E., (2004). Colloidal gold particles as a new in vivo marker of early acute lung injury. Am. J. Physiol. Lung Cell Mol. Physiol. 287(4):L867–L878
Heinrich J., Hoelscher B., Frye C., Meyer I., Pitz M., Cyrys J., Wjst M., Neas L., and Wichmann H.E., (2002a). Improved air quality in reunified Germany and decreases in respiratory symptoms. Epidemiology 13(4):394–401
Heinrich J., Hoelscher B., Frye C., Meyer I., Wjst M., and Wichmann H.E., (2002b). Trends in prevalence of atopic diseases and allergic sensitization in children in Eastern Germany. Eur. Respir. J. 19(6):1040–6
Heinrich J., Hoelscher B., and Wichmann H.E., (2000). Decline of ambient air pollution and respiratory symptoms in children. Am. J. Respir. Crit. Care Med. 161(6):1930–1936
Hopwood D., Spiers E.M., Ross P.E., Anderson J.T., McCullough J.B., and Murray F.E., (1995). Endocytosis of fluorescent microspheres by human oesophageal epithelial cells: comparison between normal and inflamed tissue. Gut 37(5):598–602
Howe H.A., and Bodian D., (1940). Poliomyelitis in the chimpanzee: a clinical–pathological study. Proc. Soc. Exp. Biol. Med. 43:718–721
Hunter D.D., and Undem B.J., (1999). Identification and substance P content of vagal afferent neurons innervating the epithelium of the guinea pig trachea. Am. J. Respir. Crit. Care Med. 159(6):1943–1948
ICRP Publication 66, 1994. Human respiratory tract model for radiological protection. A report of a Task Group of the International Commission on Radiological Protection. Ann. ICRP 24(1–3), 1–482
Innes N.P., and Ogden G.R., (1999). A technique for the study of endocytosis in human oral epithelial cells. Arch. Oral Biol. 44(6):519–523
Kapp N., Kreyling W., Schulz H., Im Hof V., Gehr P., Semmler M., and Geiser M., (2004). Electron energy loss spectroscopy for analysis of inhaled ultrafine particles in rat lungs. Microsc. Res. Tech. 63(5):298–305
Kawasaki S., Takizawa H., Takami K., Desaki M., Okazaki H., Kasama T., Kobayashi K., Yamamoto K., Nakahara K., Tanaka M., Sagai M., and Ohtoshi T., (2001). Benzene-extracted components are important for the major activity of diesel exhaust particles: effect on interleukin-8 gene expression in human bronchial epithelial cells. Am. J. Respir. Cell Mol. Biol. 24(4):419–426
Kreuter J., Shamenkov D., Petrov V., Ramge P., Cychutek K., Koch-Brandt C., and Alyautdin R., (2002). Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood–brain barrier. J. Drug Target 10(4):317–325
Kreyling W.G., and Scheuch G. (2000). Clearance of particles deposited in the lungs. In: Gehr P. and Heyder J., (eds). Particle-Lung Interactions. Marcel Dekker Inc., New York, Basel pp. 323–376
Kreyling W.G., Semmler M., Erbe F., Mayer P., Takenaka S., Schulz H., Oberdörster G., and Ziesenis A., (2002). Translocation of ultrafine insoluble iridium particles from lung epithelium to extrapulmonary organs is size dependent but very low. J. Toxicol. Env. Health A 65(20):1513–1530
Kreyling W.G., Semmler M., and Möller W., (2004). Dosimetry and toxicology of ultrafine particles. J. Aerosol Med. 17(2):140–152
Kreyling W.G., Tuch T., Peters A., Pitz M., Heinrich J., Stölzel M., Cyrys J., Heyder J., and Wichmann H.E., (2003). Diverging long-term trends in ambient urban particle mass and number concentrations associated with emission changes caused by the German unification. Atmos. Environ. 37(27):3841–3848
Kreyling W.G.., Semmler-Behnkel M., and Moeller W., (2006). Dosimetry, epidomology and toxicology of nanoparticles – Chapter 4. In: Kumar C.S.S.R. ed. Nanomaterials–Toxicity, Health and Environmental Issues. Nanotechnologies for the Life Sciences. WILEY-VCH Publishers, Weinheim, Vol. 50
Li N., Kim S., Wang M., Froines J., Sioutas C., and Nel A., (2002a). Use of a stratified oxidative stress model to study the biological effects of ambient concentrated and diesel exhaust particulate matter. Inhal. Toxicol. 14(5):459–486
Li N., Wang M., Oberley T.D., Sempf J.M., and Nel A.E., (2002b). Comparison of the pro-oxidative and proinflammatory effects of organic diesel exhaust particle chemicals in bronchial epithelial cells and macrophages. J. Immunol. 169(8):4531–4541
Li X.Y., Gilmour P.S., Donaldson K., and MacNee W., (1996). Free radical activity and pro-inflammatory effects of particulate air pollution (PM10) in vivo and in vitro. Thorax 51(12):1216–1222
Meiring J.J., Borm P.J., Bagate K., Semmler M., Seitz J., Takenaka S., and Kreyling W.G., (2005). The influence of hydrogen peroxide and histamine on lung permeability and translocation of iridium nanoparticles in the isolated perfused rat lung. Part. Fibre Toxicol. 2(1):3
Nel A.E., Diaz-Sanchez D., and Li N., (2001). The role of particulate pollutants in pulmonary inflammation and asthma: evidence for the involvement of organic chemicals and oxidative stress. Curr. Opin. Pulm. Med. 7(1):20–26
Nemmar A., Hoet P.H., Dinsdale D., Vermylen J., Hoylaerts M.F., and Nemery B., (2003). Diesel exhaust particles in lung acutely enhance experimental peripheral thrombosis. Circulation 107(8):1202–1208
Nemmar A., Hoet P.H., Vanquickenborne B., Dinsdale D., Thomeer M., Hoylaerts M.F., Vanbilloen H., Mortelmans L., and Nemery B., (2002). Passage of inhaled particles into the blood circulation in humans. Circulation 105(4):411–414
Nemmar A., Hoylaerts M.F., Hoet P.H., Dinsdale D., Smith T., Xu H., Vermylen J., and Nemery B., (2002). Ultrafine particles affect experimental thrombosis in an in vivo hamster model. Am. J. Respir. Crit. Care Med. 166(7):998–1004
Nemmar A., Vanbilloen H., Hoylaerts M.F., Hoet P.H., Verbruggen A., and Nemery B., (2001). Passage of intratracheally instilled ultrafine particles from the lung into the systemic circulation in hamster. Am. J. Respir. Crit. Care Med. 164(9):1665–1668
Nichols B., (2003). Caveosomes and endocytosis of lipid rafts. J. Cell Sci. 116(Pt 23):4707–4714
Oberdoerster G., Ferin J., and Lehnert B.E., (1994). Correlation between particle size, in vivo particle persistence, and lung injury. Environ. Health Persp. 102(Suppl 5):173–179
Oberdörster G., (1988). Lung clearance of inhaled insoluble and soluble particles. J. Aerosol Med. 1(4):289–330
Oberdörster G., (1993). Lung dosimetry: pulmonary clearance of inhaled particles. Aerosol Sci. Technol. 18:279–289
Oberdörster G., (1996). Significance of particle parameters in the evaluation of exposure-dose-response relationships of inhaled particles. Inhal. Toxicol. 8(Suppl):73–89
Oberdörster G., (2000). Toxicology of ultrafine particles: in vivo studies. Philos. T. Roy. Soc. A 358(1775):2719–2739
Oberdörster G., Oberdörster E., and Oberdörster J., (2005). Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ. Health Persp. 113:823–839
Oberdörster G., Sharp Z., Atudorei V., Elder A., Gelein R., Kreyling W., and Cox C., (2004). Translocation of inhaled ultrafine particles to the brain. Inhal. Toxicol. 16(6–7):437–445
Oberdörster G., Sharp Z., Atudorei V., Elder A., Gelein R., Lunts A., Kreyling W.G., and Cox C., (2002). Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats. J. Toxicol. Env. Health A 65(20):1531–1543
Oberdörster G., and Utell M.J., (2002). Ultrafine particles in the urban air: to the respiratory tract and beyond?. Environ. Health Persp. 110(8):A440–A441
Parton R.G., and Richards A.A., (2003). Lipid rafts and caveolae as portals for endocytosis: new insights and common mechanisms. Traffic 4(11):724–738
Pitz M., Kreyling W.G., Holscher B., Cyrys J., Wichmann H.E., and Heinrich J., (2001). Change of the ambient particle size distribution in East Germany between 1993 and 1999. Atmos. Environ. 35(25):4357–4366
Pope C.A. III, 1989. Respiratory disease associated with community air pollution and a steel mill, Utah Valley. Am. J. Public Health 79(5), 623–628
Pope C.A. III, 2000. Epidemiology of fine particulate air pollution and human health: biologic mechanisms and who’s at risk?. Environ. Health Persp. 108(Suppl 4), 713–723
Pope C.A. III, Schwartz J. & Ransom M.R., 1992. Daily mortality and PM10 pollution in Utah Valley. Arch. Environ. Health 47(3), 211–217
Ransom M.R., and Pope C.A. III, (1992). Elementary school absences and PM10 pollution in Utah Valley. Environ. Res. 58(2):204–219
Rejman J., Oberle V., Zuhorn I.S., and Hoekstra D., (2004). Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis. Biochem. J. 377(Pt 1):159–169
Roth C., Ferron G.A., Karg E., Lentner B., Schumann G., Takenaka S., Heyder J., (2004). Generation of ultrafine particles by spark discharging. Aerosol Sci. Technol. 38(3):228–235
Schaumann F., Borm P.J., Herbrich A., Knoch J., Pitz M., Schins R.P., Luettig B., Hohlfeld J.M., Heinrich J., and Krug N., (2004). Metal-rich ambient particles (particulate matter 2.5) cause airway inflammation in healthy subjects. Am. J. Respir. Crit. Care Med. 170(8):898–903
Schulz H., Brand P., Heyder J. (2000). Particle deposition in the respiratory tract. In: Gehr P., Heyder J., (eds). Particle-Lung Interactions. Marcel Dekker Inc., New York, Basel, pp. 229–290
Schulz H., Harder V., Ibald-Mulli A., Khandoga A., Koenig W., Krombach F., Radykewicz R., Stampfl A., Thorand B., Peters A., (2005). Cardiovascular effects of fine and ultrafine particles. J. Aerosol Med. 18(1):1–22
Seaton A., and Donaldson K., (2005). Nanoscience, nanotoxicology, and the need to think small. Lancet 365(9463):923–924
Semmler M., Seitz J., Erbe F., Mayer P., Heyder J., Oberdörster G., Kreyling W.G., (2004). Long-term clearance kinetics of inhaled ultrafine insoluble iridium particles from the rat lung, including transient translocation into secondary organs. Inhal. Toxicol. 16(6–7):453–459
Shi T., Schins R.P., Knaapen A.M., Kuhlbusch T.A.J., Pitz M., Heinrich J., Borm P.J.A., (2003). Hydroxyl radical generation by electron paramagnetic resonance as a new method to monitor abient particulate matter composition. J. Environ. Monitor. 5(4):550–556
Silva V.M., Corson N., Elder A., and Oberdörster G., (2005). The rat ear vein model for investigating in vivo thrombogenicity of ultrafine articles (UFP). Toxicol. Sci. 85:983–989
Szymczak W., Kreyling W.G., Seitz J., and Wittmaack K., (2004). Mass spectrometric characterisation of pure and mixed ultrafine particles of iridium and carbon. J. Aerosol Sci. 35(Suppl. 1):37–38
Takenaka S., Karg E., Roth C., Schulz H., Ziesenis A., Heinzmann U., Schramel P., and Heyder J., (2001). Pulmonary and systemic distribution of inhaled ultrafine silver particles in rats. Environ. Health Persp. 109(Suppl. 4):547–551
The Royal Society (2004). Nanoscience and Nanotechnologies: Opportunities and Uncertainties. The Royal Society and The Royal Academy of Engineering, London, UK
US Environmental Protection Agency (EPA). Air quality criteria for particulate matter. EPA/600/P-99/0022aD and bD. 2004. Research Triangle Park, NC, USEPA, National Center for Environmental Assessment
Warheit D.B., Laurence B.R., Reed K.L., Roach D.H., Reynolds G.A., and Webb T.R., (2004). Comparative pulmonary toxicity assessment of single-wall carbon nanotubes in rats. Toxicol. Sci. 77(1):117–125
Wichmann H.E., and Peters A., (2000). Epidemiological evidence of the effects of ultrafine particle exposure. Philos. T. Roy. Soc. A 358(1775):2751–2769
Wiebert P., A. Sanchez-Crespo, J. Seitz, R. Falk, K. Philipson, W.G. Kreyling, W. Möller, K. Sommerer, S. Larsson & M. Svartengren, 2005. Negligible clearance of ultrafine carbonaceous particles retained in healthy and affected human lungs. Eur. Respir. J. submitted
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Based on this article a book chapter will appear soon (Kreyling et al., 2006).
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Kreyling, W.G., Semmler-Behnke, M. & Möller, W. Health implications of nanoparticles. J Nanopart Res 8, 543–562 (2006). https://doi.org/10.1007/s11051-005-9068-z
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DOI: https://doi.org/10.1007/s11051-005-9068-z