A Pilot Study Towards Ranking Occupational Health Risk Factors Emanating from Engineered Nanoparticles: Review of a Decade of Literature

A Pilot Study Towards Ranking Occupational Health Risk Factors Emanating from Engineered Nanoparticles: Review of a Decade of Literature

J. Fatisson S. Nadeau S. Hallé C. Viau M. Camus Y. Cloutier 

Mechanical Engineering, École de Technologie Supérieure, Montreal, Quebec, Canada

Institut de Recherche en Santé Publique, Université of Montreal, Montreal, Quebec, Canada

Occupational and Environmental Health Department, Université of Montreal, Montreal, Quebec, Canada

Institut de Recherche Robert Sauvé en Santé et Sécurité du Travail, Montreal, Québec, Canada

Page: 
241-264
|
DOI: 
https://doi.org/10.2495/SAFE-V3-N4-241-264
Received: 
N/A
| |
Accepted: 
N/A
| | Citation

OPEN ACCESS

Abstract: 

As beneficial applications of nanotechnologies in industry and medicine continue to emerge, so do new problems associated with engineered nanoparticle (ENP) production, which so far is going ahead without prior evaluation of its impact on human health and environment. Worker exposure continues to increase while no global consensus on ENP regulation has been reached. Protection of workers requires an approach to risk management properly adapted to the ENP context. Although ENP properties have been studied in depth over the past 10 years, much uncertainty continues to loom over the definition of the key parameters. The aim of this review of the literature was to construct a detailed list of known risks associated with ENPs from an occupational health and safety perspective. A hierarchised network of risks was thus revealed, illustrating the complexity of the system in terms of interdependence of elements of risk.

Keywords: 

Engineered nanoparticle, hierarchised network, risk assessment, risk categorisation, risk management

  References

[1] Nanotechproject. Project on Emerging Nanotechnologies. Inventories, available at http://www.nanotechproject.org/inventories/2011 (accessed 15 November 2011).

[2] The recession’s ripple effect on nanotech: State of the market report. New-York: Lux Research Inc, 2009, June 9.

[3] Nanowerk. Databases/Company and Labs Directory, available at http://www. nanowerk.com/nanotechnology/research/nanotechnology_links.php2012 (accessed 6 January 2012).

[4] Johnson, D., Nanotech Employment Numbers Remain Inscrutable, available at http://spectrum.ieee.org/nanoclast/semiconductors/nanotechnology/nanotech-employment-numbers-remain-inscrutable-, 2010 (accessed 18 January 2012).

[5] Schulte, P., Geraci, C., Zumwalde, R., Hoover, M. & Kuempel, E. Occupational risk management of engineered nanoparticles. Journal of Occupational and Environmental Hygiene, 5(4), pp. 239–249, 2008. doi: http://dx.doi.org/10.1080/15459620801907840

[6] OECD. Nanotechnology: an overview based on indicators and statistics. Organisation for Economic Co-operation and Development, 2009, Contract No.: 2009/7.

[7] Maynard, A. Don’t define nanomaterials. Nature, 475, p. 31, 2011.

[8] Commission Recommendation of 18 october 2011 on the definition of nanomaterial. Report. Official Journal of the European Union: European Commission, 2011 October 18th. Report No.: Contract No.: 2011/696/EU.

[9] EPA. Control of Nanoscale Materials under the Toxic Substances Control Act, Washington, DC, available at http://www.epa.gov/oppt/nano/, 2011 (accessed 25 July 2012).

[10] WHO. Resolution II/4 on Emerging Policy Issues, available at http://www.who.int/ iomc/saicm/iccm2_resolution_II_4.pdf, 2009–2010 (accessed 25 July 2012).

[11] Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH). Brussels, Belgium: European Commission, 2006 December 30th Report No.: Contract No.: 1907/2006.

[12] Morawska, L., Airborne engineered nanoparticles: are they a health problem? Air Quality and Climate Change, 44(3), p. 18, 2010.

[13] Morawska, L., Airborne particles and health. Air Quality and Climate Change, 44(2), pp. 13–15, 2010.

[14] Ostiguy, C., Roberge, B., Ménard, L. & Endo, C-A., Best Practices Guide to Synthetic Nanoparticle Risk Management, Montreal, QC: Institut Robert Sauvé de Recherche en Santé et Sécurité au Travail, 2009 Contract No.: R-599.

[15] Ostiguy, C., Roberge, B., Woods, C. & Soucy, B., Engineered Nanoparticles: Current Knowledge about Occupational Health and Safety Risks and Prevention Measures, 2nd edn., Montreal, QC: Institut Robert Sauvé de Recherche en Santé et Sécurité au Travail, 2010 Contract No.: R-656.

[16] Oberdörster, G., Oberdörster, E. & Oberdörster, J., Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environmental Health Perspectives, 113(7), pp. 823–839, 2005. doi: http://dx.doi.org/10.1289/ehp.7339

[17] Oberdorster, G., Maynard, A., Donaldson, K., Castranova, V., Fitzpatrick, J. & Ausman, K. et al., Principles for characterizing the potential human health effects from exposure to nanomaterials: Elements of a screening strategy. Particle and Fibre Toxicology, 2, No pp given, 2005.

[18] Balbus, J.M., Maynard. A.D., Colvin, Vicki L., Castranova, V., Daston, G.P. & Denison, R.A. et al., Meeting report: hazard assessment for nanoparticles--report from an interdisciplinary workshop. Environmental Health Perspectives, 115(11), pp. 1654–1659, 2007. doi: http://dx.doi.org/10.1289/ehp.10327

[19] Grieger, K.D., Hansen, S.F. & Baun, A., The known unknowns of nanomaterials: describing and characterizing uncertainty within environmental, health and safety risks. Nanotoxicology, 3(3), pp. 222–233, 2009.

[20] Thomas, T., Bahadori, T., Savage, N. & Thomas, K., Moving toward exposure and risk evaluation of nanomaterials: challenges and future directions. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, 1(4), pp. 426–433, 2009.

[21] Aitken, R., Creely, K. & Tran, C., Nanoparticles: An occupational hygiene review. Institute of Occupational Medicine, 2004 Contract No.: Research Report 274.

[22] Balbus, J.M., Florini. K. & Denisond, R.A., Walsh SA. Getting it right the first time: developing nanotechnology while protecting workers, public health, and the environment. Annals of the New York Academy of Sciences, 1076, pp. 331–342, 2006. doi: http://dx.doi.org/10.1196/annals.1371.027

[23] ISO. Nanotechnologies - Health and safety practices in occupational settings relevant to nanotechnologies - ISO/TR 12885:2008. 2008.

[24] ISO. Nanotechnologies - Nanomaterial risk evaluation - ISO/TR 13121:2011. 2011.

[25] OECD. Report of the workshop on risk assessement of manufactured nanomaterials in a regulatory context. Organisation for Economic Co-operation and Development, 2010 Contract No.: ENV/JM/MONO(2010)10.

[26] OECD. Current developments/activities on the safety of manufactured nanomaterials. Organisation for Economic Co-operation and Development, 2011 Contract No.: ENV/JM/MONO(2011)12.

[27] Regulatory aspects of nanomaterials. Brussels, Belgium: European Commission, 2008 Contract No.: COM/2008/0366.

[28] Ostiguy, C., Roberge, B., Menard, L. & Endo, C.A., A good practice guide for safe work with nanoparticles: the Quebec approach. Journal of Physics: Conference Series, 151, No pp given, 2009.

[29] Marchant, G.E., Sylvester, D.J. & Abbott, K.W., Risk Management principles for nanotechnology. Nanoethics, 2, pp. 43–60, 2008.

[30] Morgan, K., Development of a preliminary framework for informing the risk analysis and risk management of nanoparticles. Risk Analysis 25(6), pp. 1621–1635, 2005. doi: http://dx.doi.org/10.1111/j.1539-6924.2005.00681.x

[31] Nadeau, S., Hallé, S. Viau, C,. & Cloutier, Y., Call for the development of an adaptative tool to appreciate or evaluate risks to human health posed by synthetic nanoparticles. International Journal of Safety and Security Engineering, 2(1), pp. 40–53, 2012. doi: http://dx.doi.org/10.2495/SAFE-V2-N1-40-53

[32] Kuzma, J., Paradise, J., Ramachandran, G., Kim, J-A., Kokotovich, A. & Wolf, S.M., An integrated approach to oversight assessment for emerging technologies. Risk Analysis, 28(5), pp. 1197–1219, 2008. doi: http://dx.doi.org/10.1111/j.1539-6924.2008.01086.x

[33] Hansen, S.F., Maynard, A., Baun, A. & Tickner, J.A., Late lessons from early warnings for nanotechnology. Nature Nanotechnology, 3(8), pp. 444–447, 2008. doi: http://dx. doi.org/10.1038/nnano.2008.198

[34] NAS. Risk Assessment in the Federal Government: Managing the Process, Washington, DC, 1983.

[35] Boote, D.N. & Beile, P., Scholars before researchers: on the centrality of the dissertation literature review in research preparation. Educational Researcher, 34(6), pp. 3–15, 2005.

[36] Villemeur, A., Surete de fonctionnement des systemes industriels : fiabilite, facteurs humains, informatisation, Librairies Eyrolles and Électricité de France (EDF): Paris, France, 1988.

[37] Wardak, A., Gorman, M.E., Swami, N. & Deshpande, S., Identification of risks in the life cycle of nanotechnology-based products. Journal of Industrial Ecology, 12(3), 435–448, 2008. doi: http://dx.doi.org/10.1111/j.1530-9290.2008.00029.x

[38] Warheit, D.B., Sayes, C.M., Reed, K.L. & Swain, K.A., Health effects related to nanoparticle exposures: environmental, health and safety considerations for assessing hazards and risks. Pharmacology and Therapeutics, 120(1), pp. 35–42, 2008. doi: http://dx.doi.org/10.1016/j.pharmthera.2008.07.001

[39] Mortureux, Y., Arbres de défaillance, des causes et d’événement. Techniques de l’ingénieur. p. 24, 2002.

[40] Nadeau, S., Outil d’analyse multi-factorielle pour la prévention des lésions au dos, Universié de Montréal: Montréal, Canada, 2001.

[41] Grass, R.N., Limbach, L.K., Athanassiou, E.K. & Stark, W.J., Exposure of aerosols and nanoparticle dispersions to in vitro cell cultures: a review on the dose relevance of size, mass, surface and concentration. Journal of Aerosol Science, 41(12), pp. 1123–1142, 2010. doi: http://dx.doi.org/10.1016/j.jaerosci.2010.10.001

[42] Oberdorster, G., Stone, V. & Donaldson, K., Toxicology of nanoparticles: a historical perspective. Nanotoxicology, 1(1), pp. 2–25, 2007. doi: http://dx.doi.org/ 10.1080/17435390701314761

[43] SCENIHR. Risk Assessment of Products of Nanotechnologies. European Commission: Scientific Committee on Emerging and Newly Identified Health Risks, 2009 January 19.

[44] CEN. Workplace atmospheres: size fraction definitions for measurements of airborne particles in the workplace, Brussels, Belgium, 1993.

[45] Nanoscience and nanotechnologies: opportunities and uncertainties. London: Royal Society, 2004.

[46] Paik, S.Y., Zalk, D.M. & Swuste, P., Application of a pilot control banding tool for risk level assessment and control of nanoparticle. The Annals of Occupational Hygiene, 52(6), pp. 419–428, 2008. doi: http://dx.doi.org/10.1093/annhyg/men041

[47] Berube, D., Cummings, C., Cacciatore, M., Scheufele, D. & Kalin, J., Characteristics and classification of nanoparticles: expert Delphi survey. Nanotoxicology, 5(2), pp. 236–243, 2011. doi: http://dx.doi.org/10.3109/17435390.2010.521633

[48] EPA. Asbestos Mechanisms of Toxicity Workshop. Available at http://www.epa.gov/ oswer/asbestos_ws/summary.htm, 2003 (updated 26 December 2008; accessed 22 January 2012).

[49] HCSP. Haut Conseil de la santé publique - Avis relatif à la sécurité des travailleurs lors de l’exposition aux nanotubes de carbone. France, available at http://www.hcsp.fr/docspdf/ avisrapports/hcspa20090107_ExpNanoCarbone.pdf, 2009 (accessed 1 September 2012).

[50] AFSSET. Évaluation des risques liés aux nanomatériaux pour la population générale et pour l’environnement. Agence Française de Sécurité Sanitaire de l’Environnement et du Travail: France, 2008 Contract No.: 2008/005.2008.

[51] von Gleich, A., Steinfeldt, M. & Petschow, U., A suggested three-tiered approach to assessing the implications of nanotechnology and influencing its development. Journal of Cleaner Production, 16, pp. 899–909, 2008. doi: http://dx.doi.org/10.1016/j. jclepro.2007.04.017

[52] Linkov, I., Bates, M.E., Canis, L.J., Seager, T.P. & Keisler, J.M., A decision-directed approach for prioritizing research into the impact of nanomaterials on the environment and human health. Nature Nanotechnology, 6(12), pp. 784–787. 2011. doi: http:// dx.doi.org/10.1038/nnano.2011.163

[53] Tsuji, J.S., Maynard, A.D., Howard, P.C., James, J.T., Lam, C-W. & Warheit, D.B. et al., Research strategies for safety evaluation of nanomaterials, Part IV: risk assessment of nanoparticles. Toxicological Sciences, 89(1), pp. 42–50, 2006. doi: http://dx.doi.org/10.1093/toxsci/kfi339

[54] Borm, P.J.A., Robbins, D., Haubold, S., Kuhlbusch, T., Fissan, H. & Donaldson. K. et al., The potential risks of nanomaterials: a review carried out for ECETOC. Particle and Fibre Toxicology, 3, No pp given, 2006.

[55] Lundqvist,  M.,  Sethson,  I.  &  Jonsson,  B-H.,  Protein  adsorption  onto  silica nanoparticles: conformational changes depend on the particles’ curvature and the protein stability. Langmuir, 20(24), pp. 10639–10647, 2004. doi: http://dx.doi. org/10.1021/la0484725

[56] Cedervall, T., Lynch, I., Foy, M., Berggard, T., Donnelly, S.C. & Cagney, G. et al., Detailed identification of plasma proteins adsorbed on copolymer nanoparticles. Angewandte Chemie (International ed. in English), 46(30), pp. 5754–5756, 2007. doi: http://dx.doi.org/10.1002/anie.200700465

[57] Cedervall, T., Lynch, I., Lindman, S., Berggard, T., Thulin, E. & Nilsson, H. et al., Understanding the nanoparticle-protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticles. Proceedings of the National Academy of Sciences of the United States of America, 104(7), pp. 2050–2055, 2007. doi: http:// dx.doi.org/10.1073/pnas.0608582104

[58] Fubini, B., Ghiazza, M. & Fenoglio, I., Physico-chemical features of engineered nanoparticles relevant to their toxicity. Nanotoxicology, 4(4), pp. 347–363, 2010. doi: http://dx.doi.org/10.3109/17435390.2010.509519

[59] Barillet, S., Simon-Deckers, A., Herlin-Boime, N., Mayne-L’Hermite, M., Reynaud, C. & Cassio, D. et al., Toxicological consequences of TiO2, SiC nanoparticles and multi-walled carbon nanotubes exposure in several mammalian cell types: an in vitro study. Journal of Nanoparticle Research, 12(1), pp. 61–73, 2010. doi: http://dx.doi. org/10.1007/s11051-009-9694-y

[60] Auffan, M., Rose, J., Wiesner, M.R. & Bottero, J-Y., Chemical stability of metallic nanoparticles: a parameter controlling their potential cellular toxicity in vitro. Environmental Pollution (Oxford, United Kingdom), 157(4), pp. 1127–1133, 2009.

[61] Derfus, A.M., Chan, W.C.W. & Bhatia, S.N., Probing the cytotoxicity of semiconductor quantum dots. Nano Letters, 4(1), pp. 11–18, 2004. doi: http://dx.doi.org/10.1021/ nl0347334

[62] Kittler, S., Greulich, C., Diendorf, J., Koeller, M. & Epple, M., Toxicity of silver nanoparticles increases during storage because of slow dissolution under release of silver ions. Chemistry of Materials, 22(16), pp. 4548–4554, 2010. doi: http://dx.doi. org/10.1021/cm100023p

[63] Lubick, N., Nanosilver toxicity: ions, nanoparticles-or both? Environmental Science and Technology, 42(23), p. 8617, 2008. doi: http://dx.doi.org/10.1021/es8026314

[64] Domingos, R.F., Baalo usha, M.A., Ju-Nam, Y., Reid, M.M., Tufenkji, N. & Lead, J.R. et al., Characterizing manufactured nanoparticles in the environment: multimethod determination of particle sizes. Environmental Science and Technology, 43(19), pp. 7277–7284, 2009. doi: http://dx.doi.org/10.1021/es900249m

[65] Verma, A. & Stellacci, F., Effect of surface properties on nanoparticle-cell interactions. Small, 6(1), pp. 12–21, 2010. doi: http://dx.doi.org/10.1002/smll.200901158

[66] Guo, L., Liu, X., Sanchez, V., Vaslet, C., Kane, A.B. & Hurt, R.H., A window of opportunity: designing carbon nanomaterials for environmental safety and health. Materials Science Forum, 544–545, pp. 16–23, 2007.

[67] Ostiguy, C., Lapointe, G., Ménard, L., Cloutier, Y., Trottier, M. & Boutin, M. et al., Actual Knowledge about Occupational Health and Safety Risks and Prevention Measures, Institut Robert Sauvé de Recherche en Santé et Sécurité au Travail, 2006 Contract No.: R-470.

[68] Shatkin, J.A. & Barry, B.E., Approaching risk assessment of nanoscale materials. NSTI Nanotech 2006, NSTI Nanotechnology Conference and Trade Show, Boston, MA, United States, May 7–11, 2006, 1, pp. 553–556, 2006.

[69] Schulte, P., Geraci, C., Zumwalde, R., Hoover, M. & Kuempel, E., Occupational risk management of engineered nanoparticles. Journal of Occupational and Environmental Hygiene, 5, pp. 239–249, 2008. doi: http://dx.doi.org/10.1080/15459620801907840

[70] Schulte, P., Geraci, C., Zumwalde, R., Hoover, M., Castranova, V. & Kuempel, E. et al., Sharpening the focus on occupational safety and health in nanotechnology. Scandinavian Journal of Work, Environment & Health, 34(6), pp. 471–478, 2008. doi: http://dx.doi.org/10.5271/sjweh.1292

[71] O’Shaughnessy, P.T., Occupational health hazards of nanoparticles. In Nanoscience and Nanotechnology: Environmental and Health Impacts, ed. V.H. Grassian, John Wiley & Sons, Inc.: Hoboken, NJ, USA, pp. 427–460, 2008. doi: http://dx.doi. org/10.1002/9780470396612.ch17

[72] Murashov, V., Engel, S., Savolainen, K., Fullam, B., Lee, M. & Kearns, P., Occupational safety and health in nanotechnology and Organisation for Economic Cooperation and Development. Journal of Nanoparticle Research, 11, pp. 1587–1591, 2009. doi: http://dx.doi.org/10.1007/s11051-009-9637-7

[73] Rozhkova, E.A., Ulasov, I., Lai, B., Dimitrijevic, N.M., Lesniak, M. & Rajh, T., A high-performance nanobio photocatalyst for targeted brain cancer therapy. Nano Letters, 9(9), pp. 3337–3342, 2009. doi: http://dx.doi.org/10.1021/nl901610f

[74] Johnston, H.J., Hutchison, G.R., Christensen, F.M., Peters, S., Hankin, S. & Stone, V., Identification of the mechanisms that drive the toxicity of TiO2 particulates: the contribution of physicochemical characteristics. Particle and Fibre Toxicology, 6, 2009.

[75] Kouam, J., Songmene, V., Djebara, A. & Khettabi, R., Effect of friction testing of metals on particle emission. Journal of Materials Engineering and Performance, 21(6), pp. 965–972, 2012.

[76] Kuhlbusch, T.A., Asbach, C., Fissan, H., Gohler, D. & Stintz, M., Nanoparticle exposure at nanotechnology workplaces: a review. Particle and Fibre Toxicology, 8, p. 22, 2011. doi: http://dx.doi.org/10.1186/1743-8977-8-22

[77] Kandlikar, M., Ramachandran, G., Maynard Andrew, D. & Murdock, B., Health risk assessment for nanoparticles: a case for using expert judgment. Journal of Nanoparticle Research, 9, pp. 137–156, 2007. doi: http://dx.doi.org/10.1007/s11051-006-9154-x

[78] Oberdorster, G., Sharp, Z., Elder, A.P., Gelein, R., Kreyling, W.G. & Cox, C., Translocation of inhaled ultrafine particles to the brain. Inhalation Toxicology, 16, pp. 437–445, 2004. doi: http://dx.doi.org/10.1080/08958370490439597

[79] Aschberger, K., Micheletti, C., Sokull-Kluettgen, B. & Christensen, F.M., Analysis of currently available data for characterising the risk of engineered nanomaterials to the environment and human health - lessons learned from four case studies. Environment International, 37(6), pp. 1143–1156, 2011. doi: http://dx.doi.org/10.1016/j.envint. 2011.02.005

[80] SCENIHR. The appropriateness of the risk assessment methodology in accordance with the technical guidance documents for new and existing substances for assessing the risks of nanomaterials. European Commission: Scientific Committee on Emerging and Newly-Identified Health Risks, 2007 June 21–22.

[81] Becker, H., Herzberg, F., Schulte, A. & Kolossa-Gehring, M., The carcinogenic potential of nanomaterials, their release from products and options for regulating them. International Journal of Hygiene and Environmental Health, 214(3), pp. 231–238, 2011. doi: http://dx.doi.org/10.1016/j.ijheh.2010.11.004

[82] Binet, S., Drais, E., Chazelet, S., Fontaine, J-R., Radauceanu, A. & Reynier, M. et al., Risques liés aux nanoparticules et nanomatériaux: Compte-rendu de la conférence Nano2011 et perspectives.: INRS: France, 2011 Contract No.: HST 224–16.

[83] Nemmar, A., Vanbilloen, H., Hoylaerts, M.F., Hoet, P.H., Verbruggen, A. & Nemery, B., Passage of intratrachelly instilled ultrafine particles from the lung into the systemic circulation in hamster. American Journal of Respiratory and Critical Care Medicine, 164, pp. 1665–1668, 2001. doi: http://dx.doi.org/10.1164/ajrccm.164.9.2101036

[84] Auffan, M., Rose, J., Bottero, J-Y., Lowry, G.V., Jolivet, J-P. & Wiesner, M.R., Towards a definition of inorganic nanoparticles from an environmental, health and safety perspective. Nature Nanotechnology, 4(10), pp. 634–641, 2009. doi: http:// dx.doi.org/10.1038/nnano.2009.242

[85] Borm, P., Klaessig, F.C., Landry, T.D., Moudgil, B., Pauluhn, J. & Thomas, K. et al., Research strategies for safety evaluation of nanomaterials, Part V: role of dissolution in biological fate and effects of nanoscale particles. Toxicological Sciences, 90(1), pp. 23–32, 2006. doi: http://dx.doi.org/10.1093/toxsci/kfj084

[86] Vertegel, A.A., Siegel, R.W. & Dordick, J.S., Silica nanoparticle size influences the structure and enzymatic activity of adsorbed lysozyme. Langmuir, 20(16), pp. 6800–6807, 2004. doi: http://dx.doi.org/10.1021/la0497200

[87] Lord, M.S., Cousins, B.G., Doherty, P.J., Whitelock, J.M., Simmons, A. & Williams, R.L. et al., The effect of silica nanoparticulate coatings on serum protein adsorption and cellular response. Biomaterials, 27, pp. 4856–4862, 2006. doi: http://dx.doi.org/10.1016/j. biomaterials.2006.05.037

[88] Chithrani, B.D. & Chan, W.C.W., Elucidating the mechanism of cellular uptake and removal of protein-coated gold nanoparticles of different sizes and shapes. Nano Letters, 7(6), pp. 1542–1550, 2007. doi: http://dx.doi.org/10.1021/nl070363y

[89] Clift, M.J.D., Rothen-Rutishauser, B., Brown, D.M., Duffin, R., Donaldson, K. & Proudfoot, L. et al., The impact of different nanoparticle surface chemistry and size on uptake and toxicity in a murine macrophage cell line. Toxicology and Applied Pharmacology, 232(3), pp. 418–427, 2008. doi: http://dx.doi.org/10.1016/j. taap.2008.06.009

[90] Braydich-Stolle, L.K., Schaeublin, N.M., Murdock, R.C., Jiang, J., Biswas, P. & Schlager, J.J. et al., Crystal structure mediates mode of cell death in TiO2 nanotoxicity. Journal of Nanoparticle Research, 11(6), pp. 1361–1374, 2009. doi: http://dx.doi. org/10.1007/s11051-008-9523-8

[91] Gratton, S.E.A., Ropp, P.A., Pohlhaus, P.D., Luft, J.C., Madden, V.J. & Napier, M.E. et al., The effect of particle design on cellular internalization pathways. Proceedings of the National Academy of Sciences of the United States of America, 105(33), pp. 11613–11618, 2008. doi: http://dx.doi.org/10.1073/pnas.0801763105

[92] Hoshino, A., Fujioka, K., Oku, T., Suga, M., Sasaki, Y.F. & Ohta, T. et al., Physicochemical properties and cellular toxicity of nanocrystal quantum dots depend on their surface modification. Nano Letters, 4(11), pp. 2163–2169, 2004. doi: http:// dx.doi.org/10.1021/nl048715d

[93] Papageorgiou, I., Brown, C., Schins, R., Singh, S., Newson, R. & Davis, S. et al., The effect of nano- and micron-sized particles of cobalt-chromium alloy on human fibroblasts in vitro. Biomaterials, 28(19), pp. 2946–2958, 2007. doi: http://dx.doi. org/10.1016/j.biomaterials.2007.02.034

[94] Simko, M. & Mattsson, M-O., Risks from accidental exposures to engineered nanoparticles and neurological health effects: a critical review. Particle and Fibre Toxicology, 7, p. 42, 2010. doi: http://dx.doi.org/10.1186/1743-8977-7-42

[95] Gonzalez, L., Lison, D. & Kirsch-Volders, M., Genotoxicity of engineered nanomaterials: a critical review. Nanotoxicology, 2(4), pp. 252–273, 2008. doi: http:// dx.doi.org/10.1080/17435390802464986

[96] Kreyling, W.G., Semmler, M., Erbe, F., Mayer, P., Takenaka, S. & Schulz, H. et al., Translocation of ultrafine insoluble iridium particles from lung epithelium to extrapulmonary organs is size dependent but very low. Journal of Toxicology and Environmental Health, Part A, 65(20), pp. 1513–1530, 2002. doi: http://dx.doi. org/10.1080/00984100290071649

[97] Strong, M., Oakley, J.E. & Chilcott, J., Managing structural uncertainty in health economic decision models: a discrepancy approach. Applied Statistics, 61, pp. 25–45, 2012. doi: http://dx.doi.org/10.1111/j.1467-9876.2011.01014.x

[98] Leedy, P.D. & Ormrod, J.L., Practical Research: Planning and Design, 9th edn., Merril: Upper Saddle River, New Jersey, 2010.

[99] Gagnon, Y-C., L’étude de cas comme méthode de recherche, Presses de l’Université du Québec: Québec, 2005.

[100] Nanotechnology risk governance. International Risk Governance Council, 2007.

[101] Zuin, S., Micheletti, C., Critto, A., Pojana, G., Johnston, H. & Stone, V. et al., Weight of Evidence approach for the relative hazard ranking of nanomaterials. Nanotoxicology, 5(3), pp. 445–458, 2011. doi: http://dx.doi.org/10.3109/17435390.2010.512986

[102] Murashov ,V. & Howard, J., Essential features for proactive risk management. Nature Nanotechnology, 4(8), pp. 467–470, 2009. doi: http://dx.doi.org/10.1038/ nnano.2009.205

[103] Hansen, S.F., Larsen, B.H., Olsen, S.I. & Baun, A., Categorization framework to aid hazard identification of nanomaterials. Nanotoxicology, 1(3), pp. 243–50, 2007. doi: http://dx.doi.org/10.1080/17435390701727509

[104] Singh, N., Manshian, B., Jenkins, G.J.S., Griffiths, S.M., Williams, P.M. & Maffeis, T.G.G. et al., NanoGenotoxicology: the DNA damaging potential of engineered nanomaterials. Biomaterials, 30(23–24), pp. 3891–3914, 2009. doi: http://dx.doi. org/10.1016/j.biomaterials.2009.04.009

[105] Woskie, S., Workplace practices for engineered nanomaterial manufacturers. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, 2(6), pp. 685–692, 2010.

[106] Linkov, I., Satterstrom, F.K., Steevens, J., Ferguson, E. & Pleus, R.C., Multi-criteria decision analysis and environmental risk assessment for nanomaterials. Journal of Nanoparticle Research, 9, pp. 543–554, 2007. doi: http://dx.doi.org/10.1007/s11051-007-9211-0