Anders Baun

B Nowack

C Marambio-Jones

DI Annear

FM Christensen

GL McHugh

H Cao

HJ Johnston

I Chopra

J Fabrega

K Chaloupka

M Ahamed

M Rai

MC Stensberg

ME Quadros

N Duran

N Musee

NR Panyala

S Gangwal

S Silver

Steffen Foss Hansen

SWP Wijnhoven

VK Sharma

X Chen

Hansen, Steffen Foss

Baun, Anders

Online Research Database In Technology

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Downloaded from orbit.dtu.dk on: Dec 20, 2017When enough is enoughHansen, Steffen Foss; Baun, AndersPublished in:Nature NanotechnologyLink to article, DOI:10.1038/nnano.2012.115Publication date:2012Document VersionPublisher's PDF, also known as Version of recordLink back to DTU OrbitCitation (APA):Hansen, S. F., & Baun, A. (2012). When enough is enough. Nature Nanotechnology, 7(7), 409-411. DOI:10.1038/nnano.2012.115NATURE NANOTECHNOLOGY | VOL 7 | JULY 2012 | www.nature.com/naturenanotechnology 409commentaryWhen enough is enoughSteffen Foss Hansen and Anders BaunThe European Commission should be regulating nanosilver, not asking for yet another report on its impact on health and the environment.In December 2011 the European Commission asked its Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) to provide a scientific opinion on nanosilver1. Specifically, this committee, which consists of independent scientists appointed by the Commission, is being asked to answer four questions under the general heading of ‘Nanosilver: safety, health and environmental effects, and role in antimicrobial resistance’. However, most of these questions (and possibly all of them) have already been addressed by no less than 18 review articles in scientific journals, the oldest dating back to 20082–4, plus at least seven more reviews and reports commissioned and/or funded by governments and other organizations (Table 1). This raises an important question: when will governments and regulatory agencies stop asking for more reports and reviews, and start taking regulatory action?In 2008, Sam Luoma (University of California, Davis) opened what now seems to be Pandora’s silver box with his excellent overview of nanosilver and the environment3. In 2009, six reviews were published on this topic5–10, including reports commissioned by the Department of Environment, Food and Rural Affairs (DEFRA) in the UK6, the Federal Ministry of Food, Agriculture and Consumer Protection (BfR) in Germany7 and the National Institute for Public Health and the Environment (RIVM) in the Netherlands8. One of the two vice-chairs of SCENIHR, Wim De Jong (RIVM), also co-authored a review article in the journal Nanotoxicology that is now one of the most cited papers in the field10.A further eight review articles in scientific journals followed in 201011–18, plus substantial reports commissioned by the Environmental Protection Agency (EPA) in the US (which ran to 221 pages)19 and the Joint Research Centre (JRC) of the European Commission (426 pages)20. Two of the review articles in journals were also funded by the European Commission14,16. And 2011 saw the publication of five more review articles on nanosilver in scientific journals21–25, plus a 136-page report from the Danish Environmental Protection Agency (Danish EPA) about nanosilver and six other nanomaterials26.Many of these reviews and reports go through the same literature, cover the same ground and identify many of the same data gaps and research needs. Hence, we predict that the SCENIHR’s upcoming review will consist of five main sections summarizing: the properties and uses of nanosilver; human and environmental toxicity; microbial resistance; risk assessment; and research needs3,8,10,14,16,18–20,24–26. We also predict that the SCENIHR’s report will say something along the following lines: “Nanosilver is reportedly one of the most widely used nanomaterials in consumer products today but the scale of production and use is unknown. The antibacterial properties of nanosilver are exploited in a very diverse set of products and applications including dietary supplements, personal care products, powdered colours, textile, paper, kitchenware and food storage.” And like many previous reviews and reports3,10,14,18–21,25,26, the new report is likely to cite the Consumer Product Inventory maintained by the Project on Emerging Nanotechnologies27.After reviewing the literature on human toxicity, there is a good chance that the SCENIHR will say that the toxicity of silver metal is generally considered to be relatively low, while noting that a non-life-threatening bluish–grey discolouring of the skin has been found only after high and repeated ingestion or inhalation of colloidal silver2,3,10,20,21,24,26. And the conclusions will probably echo those of the highly cited review published in Nanotoxicology in 2009 and several other recent reviews6,14,20,23 by saying something along the following lines: the number of well-controlled studies on the potential toxicities of nanosilver as well as the current knowledge of the kinetics of nanosilver is too limited to provide a proper foundation of human risk assessment. The SCENIHR is also likely to note that nanosilver has been found to be absorbed and distributed to target organs (such as the liver, lungs and olfactory bulb), and to have caused inflammation and liver damage in rodents after oral exposure. And increases in the production of reactive oxygen species in vitro10,14,16,19,20,26 will probably be mentioned as well.On the environmental toxicity front, the SCENIHR is likely to state something very general about it being well known that both bulk silver and nanosilver are potentially toxic to the environment with the concentration that causes an adverse effect in 50% of a population being in the lower parts-per-billion range for aquatic organisms3,20,23,26. Moreover, because inhibition of nitrifying bacteria by nanosilver has been observed in the very few original studies that have been published, the SCENIHR will have to consider this topic under the heading of ‘Other environmental, health and safety (EHS) issues’ because this phenomenon might affect the proper functioning of wastewater treatment plants20,23,26. It remains uncertain whether nanosilver is more toxic than ionic silver, the report is likely to say, because the effects seen in many cases can be ascribed to ionic silver: however, some studies have documented a more pronounced effect associated with nanosilver, but the data is inconclusive2,9,19,22,24,25.Because there have been very few original studies of the relationship between nanosilver and the development of antimicrobial resistance (less than five to the best of our knowledge), it is likely that the SCENIHR will rely heavily on the seven review articles that have addressed this topic3,7,10,15,17,19,25. Evidence that the increasing use of nanosilver may be leading to bacterial and fungal resistance towards silver include reports of resistance to silver-based burn dressings (originally published in the mid-1970s and reviewed Many of these reviews and reports go through the same literature, cover the same ground and identify many of the same data gaps and research needs.© 2012 Macmillan Publishers Limited. All rights reserved410 NATURE NANOTECHNOLOGY | VOL 7 | JULY 2012 | www.nature.com/naturenanotechnologycommentaryin refs 3,7)28,29 and the finding that 10% of the intestinal bacteria tested randomly in a Chicago hospital had genes that are resistant to silver ions (originally published in 2003 and reviewed in ref. 17)30. However, citing a leading article31 that was published in the Journal of Antimicrobial Chemotherapy in 2007, the reviews collectively conclude that further studies on antimicrobial resistance are needed because there are currently no standardized methods for testing the antimicrobial activity of silver. (This is partly because the solubility of nanosilver is not fully understood, and the solubility influences the bioavailability which, in turn, influences the sensitivity of silver-resistant and silver-sensitive bacteria17.) Finally, we predict that the SCENIHR will underline the importance of silver speciation as this has been a general theme in many previous reviews3,11,14,16,18–20,24–26.The SCENIHR review is due to come out in early 2013. Although the committee can call on additional expertise from outside experts within the specific subject, one permanent committee member often acts as a rapporteur and prepares a draft opinion that is voted on. Given the many high-profile reviews already available, we find it unlikely that the scientific committee will reach any significant new insights. One wonders, therefore, why the European Commission has asked for yet another review on this topic.No regulatory action has so far been taken to limit human and environmental exposure of nanosilver. Although it may be common practice for regulators to ask for ‘their own review’ from a scientific advisory group, rather than acting on reviews published as scientific papers, it seems that many of these reviews have been commissioned by regulators with a purpose of delaying decisions on regulatory measures that should be implemented. It would not be the first time that regulators are ‘buying time’ before making difficult decisions that will be against the interests of certain stakeholders32. Although it is clear that the SCENIHR cannot decline requests from the European Commission for scientific opinions, it seems that the committee is being used by the Commission to stall the regulatory decision-making process until 2013. By initiating one review after the other, regulators have created an unfortunate situation of ‘paralysis by analysis’ because reviews tend to identify additional research needs rather than the options for optimal regulatory policies.We acknowledge that answering the question of how to regulate the use of nanosilver is not easy given the different views of the different stakeholders in this debate and the complex regulatory landscape associated with the many applications of nanosilver. However, some of the reviews already published offer plenty of recommendations on actions that could be taken. Back in 2008, for example, Luoma3 Table 1 | Many of the reviews on nanosilver that have been published since 2008 (first column) have already addressed the four questions on the environmental, health and safety (EHS) aspects of nanosilver that the SCENIHR was recently asked to review. Page numbers for the part(s) of each review that are relevant to these questions are listed in columns 2–5.Reference Human health and the environmental  implications?Increase in selection of silver-resistant microorganisms?Reduction in  the efficacy  of nanosilver?Other EHS issues?Chen and Schluesener2 1–12 27Luoma3 25–35Panyala et  al.4 119–124Sharma et  al.5 93–94 89–93DEFRA (UK)6 71, 73, 80, 97–100, 139, 142, 145 97BfR (Germany)7 3–6RIVM (Netherlands)8 29–41Rai et  al.9 82 77–81Wijnhoven et  al.10 111–114, 121–131 116 115–116Ahamed et  al.11 1842–1846Cao and Liu12 673–674Chaloupka et  al.13 585 581–585Christensen et  al. 14 286–294Duran et  al.15 954–956 951–952 952–954Johnston et  al.16 330–342Marambio-Jones and Hoek17 1539, 1543–154 1531–1538 1542–1543Quadros and Marr18 776–779EPA (US)19 98–133 19–20, 74 134–146JRC (EC)20 121–137, 212–217, 305–325Fabrega et  al.21 518–529 527–528Gangwal et  al.22 1539–1546Musee et  al.23 1169–1174 1179Nowack et  al.24 1180–1182Stensberg et  al.25 880–882 881Danish EPA26 74–88By initiating one review after the other, regulators have created an unfortunate situation of ‘paralysis by  analysis’.© 2012 Macmillan Publishers Limited. All rights reservedNATURE NANOTECHNOLOGY | VOL 7 | JULY 2012 | www.nature.com/naturenanotechnology 411commentarysketched out a multi-faceted strategy that included: (1) the development of clear rules defining the ingredients of a product using the unique physical and chemical attributes of the ingredients to track production, use and environmental release/dispersal data; (2) the assessment of what information is needed to oversee safe use of nanosilver; (3) the evaluation of the relevance and shortcomings of current silver-relevant regulations. In 2009, DEFRA in the UK recommended the application of the precautionary principle6, whereas the BfR in Germany urged producers not to use nanosilver in foods and everyday products7. However, little progress has been made in implementing any of these recommendations.Arguably, we all want that the pros and cons of regulatory policy options be based on the best available science while taking broader socio-economical and ethical aspects into consideration before deciding on the appropriate regulatory measures concerning human and environmental exposure to nanosilver. Although it is common for independent scientific experts to be commissioned to gather, analyse and review the available scientific information, and to provide recommendations on how to address a given risk, we do not see the need for further reviews. It is time for the European Commission to decide on the regulatory measures that are appropriate for nanosilver. These measures should then be implemented wholeheartedly and their effectiveness monitored. ❐Steffen Foss Hansen* and Anders Baun are in the Department of Environmental Engineering, Technical University of Denmark, 2800 Lyngby, Denmark.  *e-mail: sfh@env.dtu.dkReferences1. http://ec.europa.eu/health/scientific_committees/emerging/docs/scenihr_q_027.pdf2. Chen, X. & Schluesener, H. J. Toxicol. Lett. 176, 1–12 (2008).3. Luoma, S. http://www.nanotechproject.org/process/assets/files/7036/nano_pen_15_final.pdf (2008).4. Panyala, N. R. et al. J. Appl. Biomed. 6, 117–129 (2008).5. Sharma, V. K. et al. Adv. Colloid Interface Sci. 145, 83–96 (2009).6. DEFRA; http://go.nature.com/seP6xK (2009).7. BfR; http://go.nature.com/5e2Qnc (2009).8. RIVM; http://go.nature.com/bta72t (2009).9. Rai, M. et al. Biotechnol. Adv. 27, 76–83 (2009).10. Wijnhoven, S. W. P. et al. Nanotoxicol. 3, 109–138 (2009).11. Ahamed, M. et al. Clin. Chim. Acta 411, 1841–1848 (2010).12. Cao, H. & Liu, X. Wiley Interdisciplinary Rev. Nanomed Nanobiotechnol. 2, 670–684 (2010).13. Chaloupka, K. et al. Trends Biotechnol. 28, 580–588 (2010).14. Christensen, F. M. et al. Nanotoxicol. 4, 284–295 (2010).15. Duran, N. et al. J. Brazilian Chem. Soc. 21, 949–959 (2010).16. Johnston, H. J. et al. Critical Rev. Toxicol. 40, 328–346 (2010).17. Marambio-Jones, C. & Hoek, E. M. V. J. Nanoparticle Res.  12, 1531–1551 (2010).18. Quadros, M. E. & Marr, L. C. J. Air Waste Manage. Assoc.  60, 770–781 (2010).19. EPA; http://www.epa.gov/nanoscience/files/ NanoPaper1.pdf (2010).20. JRC; http://ihcp.jrc.ec.europa.eu/whats-new/ enhres-final-report (2010).21. Fabrega, J. et al. Environ. Intl 37, 517–531 (2011).22. Gangwal, S. et al. Environ. Health Perspect. 119, 1539–1546 (2011).23. Musee, N. et al. J. Environ. Monitoring 13, 1164–1183 (2011).24. Nowack, B. et al. Environ. Sci. Technol. 45, 1177–1183 (2011).25. Stensberg, M. C. et al. Nanomedicine 6, 879–898 (2011).26. Danish EPA; http://go.nature.com/qQsSDP (2011).27. http://www.nanotechproject.org/inventories/consumer/ browse/products28. McHugh, G. L. et al. The Lancet 305, 235–240 (1975).29. Annear, D. I. et al. J. Clin. Pathol. 29, 441–443 (1976).30. Silver, S. FEMS Microbiol. Rev. 27, 341–353 (2003).31. Chopra, I. J. Antimicrob. Chemother. 59, 587–590 (2007).32. European Environment Agency; http://www.eea.europa.eu/publications/environmental_issue_report_2001_22 (2002).Published online: 1 July 2012© 2012 Macmillan Publishers Limited. All rights reserved

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