CORRESPONDENCE/REBUTTAL pubs.acs.org/est
Reply to Comments on ”120 Years of Nanosilver History: Implications for Policy Makers”
W
e respond to the letters submitted by Costanza et al. and Schaefer et al. concerning our article “120 Years of Nanosilver History: Implications for Policy Makers”.1 Over the past decade numerous disciplines and sectors of society have increasingly found utility for the “nano”-prefix. In many cases “nano” can undoubtedly signify radically new materials with interesting and hitherto unknown properties. However, the fact remains that not all nanomaterials are “new”. Before painting all nanomaterials with the “new, unknown, and potentially hazardous” brush it is essential to thoroughly understand the historical development and chemical basis of the material at hand. This is the central theme of the Nowack et al. paper.1 The paper seeks to make clear that “nanosilver” is a category of materials with over 120 years of scientific and commercial exploitation. A thorough review of the historical grounding of nanosilver materials reveals that many names have been used to describe small particles of silver including “silver allotropes” (18892), “collargol” (1900s3), “protargol” (1900s4), “millimicrometer silver” (1900s5), and “colloidal silver”6 through to the 1990s when “nanosilver” began to be a more popular term to describe these materials. In the present day, many policy-makers have come to see nanosilver as a focal point in their efforts to highlight their capacity to address the broader emerging “nano” topic, supported by a focus on this material in the scientific literature. The comments by Costanza et al. (from the U.S. Environmental Protection Agency (EPA) and The University of Cincinnati) and Schaefer et al. (from the German Institute for Risk Assessment (BfR)) reveal different attitudes as to how the historical record can inform regulatory decisions.
’ HISTORICAL CONTEXT OF NANOSILVER MATERIALS Costanza et al. “find that only 7 of the 92 registered silver products...are confirmed to contain nanosilver and only two of these have been used for more than 20 years”. The core of our analysis was that although just 7 out of 92 registered products are confirmed to contain nanosilver, a significant proportion of the registered products have a rational basis for equally being considered as nanosilver containing materials, even when considered only with publicly available product information. Given the relevance to policy determinations this historical record should not be so readily discounted. Costanza et al. contend that the 0.8% silver content of the Algaedyn product is sufficient basis to conclude the annual mass of silver is low. The missing information required to establish that conclusion is the volume of product available on the market, with the combination of silver content and product volume giving the overall mass of nanosilver. Colloidal silver algaecides are used primarily as swimming pool treatments7 and with a few conservative assumptions and a simple “back-of-the-envelope” calculation we can estimate the total mass of silver used in this application sector: Considering there are approximately 8.6 million swimming pools in the U.S.;8 an assumed average pool volume of 75 m3; a dosing rate of 1.9 L/75 m3;7 a single pool treatment each r 2011 American Chemical Society
year and an algaecide silver content of 0.8%. If we assume a conservative market share of 5% for colloidal silver algaecide products, this results in 6.5 tons of nanosilver used per year in the U.S., a number that can be compared to a recent estimate for the total U.S. nanosilver production of 2.8 20 tons/year.9 Clearly colloidal silver swimming pool treatments may make up a significant share of the total U.S. nanosilver use. It should also be noted that in textile uses nanosilver loadings are typically on the order of 0.001% to 0.01% silver per weight.10
’ NOMENCLATURE While Schaefer et al. correctly acknowledge that colloidal silver and nanosilver are synonyms, they go on to conveniently differentiate colloidal silver as “10 to 1000 nm” (definition without citation) while nanosilver is “1 to 100 nm”. By arbitrarily discounting the applicability of colloidal silver materials Schaefer et al. build a fundamental bias into their evaluation of the historical data. This distinction of nomenclature appears to be the primary basis for the perception of data gaps for nanosilver. Schaefer et al. emphasize that nanosilver must differ from bulk silver based on size characteristics. In reality most applications of silver in antimicrobial applications are based on ionic exchange materials (e.g., silver glass, silver zeolites), silver salts or colloidal nanosilvers. Furthermore, the historical data informing what is assumed to be “bulk silver” derives from colloidal and ionic silver. Costanza et al. refer to the growing number of different nanosilver synthesis methods yet the analysis leading to this statement was based on a literature search limited to the “nano” term and so reflects a limited historical perspective.11 Consequently only 2 references prior to 2000 are considered. The study also does not consider commercially applicable materials. Schaefer et al. claim that BfR have made an “exhaustively detailed look” into the literature, yet in the BfR assessment12 it would appear that colloidal silver and other historical synonyms have not been thoroughly considered within the analysis. An example of insufficiently exhaustive analysis is for a silver chloride material deemed to be safe by BfR where “no evidence showing any risk”,12 (page 9) is concluded, yet the type of material cited, silver chloride supported on titania, is in fact based on nanosilver chloride 13 (Figure 1 in ref 13). The BfR approach therefore appears to be OK with concluding nanosilver products are safe as long as the “nano” prefix is not employed. This treatment is at odds with the statement by Schaefer et al. that a “(nano) label does not itself imply new hazard or specific risks”. ’ CHARACTERIZATION OF NANOSILVER Schaefer et al. state that characterization of size was not possible until the advent of electron microscopes, thereby implying that historical colloidal silver could not have been intended or shown Published: August 05, 2011 7593
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Environmental Science & Technology to be nanosilver. However, more than 100 years ago scientists were able to determine the size of nanosilver particles. Collargol has a mean particle size of 10 nm 14 and already in 1907 its diameter was determined to be in that range.5 The authors also fail to acknowledge the 1969 work of Frens and Overbeek15 cited in the Nowack et al. paper. By revisiting the historical synthesis of the Carey Lea silver,2 reproducing this substance experimentally, and thoroughly characterizing the material using both transmission electron microscopy (TEM) and X-ray diffraction (XRD) techniques, Frens and Overbeek showed that this classic colloidal silver material consisted of elemental nanosilver particles with a typical size of ca. 7 9 nm.
’ CONSIDERING TOXICOLOGY AND EXPOSURE Costanza and coauthors correctly acknowledge that data for colloidal silver has informed “the toxicological end points for silver”, yet proceed to discount the relevance of the historical data with the unusual statement that “colloidal silver health supplements” are not relevant for evaluating nanosilver. A review of the historical data shows that colloidal silver materials were not tested as “health supplements” rather the tests included a variety of exposure patterns to colloidal nanosilver materials to determine limits for the onset of argyria.16,17 As Costanza et al. underline, these same studies directly inform the toxicological limits for all conventional silver forms yet they dismiss the relevance to assessing nanosilver despite the material properties having more in common with nanosilver materials. Costanza et al. acknowledge that nanosilver studies show toxicological effects only “under extreme use conditions” reflective of unrealistically high exposure levels. This approach acknowledges the need to balance both toxicological information and the context of exposure in real-life. In contrast, Schaefer et al. cite in vitro studies where nanosilver has shown toxicological effects. What is apparently not considered in this analysis is that these studies are generally performed at very high loadings that do not reflect realistic expectations of exposure in real-life scenarios. Risk assessment is a balance between toxicology and exposure and by emphasizing toxicology results without exposure context, idealized toxicology can provide a misleading view.18 ’ REFERENCE MATERIALS Schaefer et al. claim that well characterized standard reference materials and GLP-level toxicology studies are required in order to sufficiently inform risk assessment processes. The purpose of standard reference materials is “primarily to evaluate and qualify methodology and/or instrument performance related to the physical/dimensional characterization of nanoscale particles”.19 Standard reference materials may be informative for studying fundamental mechanisms of toxicity, however this approach bears little relevance with directly assessing risk of real-world materials. Furthermore, OECD Working Party on Manufactured Nanomaterials (WPMN) efforts to evaluate a standardized nanosilver chose a commercial nanosilver material synthesized using classical colloidal silver methods.20 The BfR rationale advocates that risk cannot be estimated until a perfect reference material is synthesized, characterized exhaustively and toxicology assessed under GLP level conditions. Extrapolating this rationale would be to require that risk assessment for historical materials must be redone in every case to these high levels before judgment can be made on real-life risk. While perhaps this approach has merit in increasing the level of certainty and generating fundamental
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knowledge, reserving judgment until this approach is implemented is difficult to justify and not pragmatic for materials that have been used for a long time in real-life, apparently without evidence indicating any extreme hazard.
’ BACTERIA RESISTANCE Schaefer et al. express concern for the development of bacterial silver resistance if nanosilver is widely used. Logically, this concern can equally well apply to every form of silver available on the market (in significantly higher volumes than nanosilver21). A broader consideration of the literature gives pause that the reallife risk of silver resistance is low, for example Percival et al.22 state that “it is important to note that bacteria have been exposed to subinhibitory levels of Ag+ for over four billion years and no widespread resistance has been evident to date, whereas widespread antibiotic resistance has developed within the last 60 years”. As a natural element, silver is by definition a widespread naturally occurring substance. Recent studies have also discovered that nanosilver is even found to form under environmental conditions via ubiquitous natural processes.23 Given the already widespread presence of silver, and even naturally formed nanosilver, the fear of widespread resistance through use of silver would appear to be overstated by the authors and is insufficient grounds for singling out nanosilver for special treatment. ’ DIFFERING REGULATORY APPROACHES Referring to the 2009 EPA scientific advisory panel (SAP) meeting, Costanza et al. advocate a “case-by-case” basis for evaluating nanosilver materials. However, consistent with the theme of the Nowack et al. paper, the SAP findings also variously encouraged EPA to review historical colloidal silver products in an effort to directly inform the risk assessment of nanosilver materials.24 In their comment, Schaefer et al. cite the oversight provided by the EU cosmetics and food regulations, yet fail to acknowledge the direct relevance of the European Biocidal Product directive25 in regulating antimicrobial applications of silver materials. Schaefer and coauthors contend that more information is required to determine safe use of nanosilver. The perceived “lack of data” appears to derive from limitations of nomenclature used in literature searches and a severely restrictive sense of considering the worth of historical data. Applying these starting criteria to other historical materials would require a comprehensive re-evaluation of most legacy materials. By applying a separate standard for considering nanosilver, Schaefer and coauthors actively discount real-life experience for a material that has undeniably been in wide-scale commercial use for decades. The long historical record of widespread commercial use of nanoscale silver materials over a period of more than 120 years gives a vivid illustration that not all nanomaterials are “new”. The historical basis behind material developments must be taken into account in order to avoid falsely casting all nanomaterials as “new” with an automatic assumption of new and unknown hazards. Emerging policy on broader nano issues would be well served to allow capacity to reconcile the historical profile of materials, such as nanosilver, that undeniably have a long legacy of real-life experience and cannot reasonably be considered as new. 7594
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Environmental Science & Technology Bernd Nowack,†,* Harald F. Krug,† and Murray Height‡ †
Empa, Swiss Federal Laboratories for Materials Science and Technology, Lerchenfeldstrasse 5, CH-9014 St. Gallen, Switzerland
‡
HeiQ Materials AG, CH-5330 Bad Zurzach, Switzerland
’ AUTHOR INFORMATION Corresponding Author
* phone +41 (0)58 765 76 92; e-mail:
[email protected].
’ ACKNOWLEDGMENT We thank Dr. James Delattre and Dr. Rosalind Volpe of the Silver Nanotechnology Working Group (SNWG) for valuable contributions to the background of this article. Dr. Murray Height is an employee of the company HeiQ Materials AG which has a pending silver-based product registration before EPA. ’ REFERENCES (1) Nowack, B.; Krug, H. F.; Height, M. 120 years of nanosilver history: implications for policy makers. Environ. Sci. Technol. 2011, 45, 1177–1183. (2) Lea, M. C. On allotropic forms of silver. Am. J. Sci. 1889, 37, 476–491. (3) Shouse, S. S.; Whipple, G. H. Effects of intravenous injection of colloidal silver upon the hematopoietic system in dogs. J. Exp. Med. 1931, 53 (3), 413–420. (4) Kolthoff, I. M. The state of silver in Protargol (Argenti proteinatum) and Collargol (colloid silver; argentum crede). J. Am. Pharm. Assoc. 1925, 14, 183–189. (5) Bechhold, H. Die Gallertfiltration. Z. Chem. Ind. Kolloide 1907, 2, 3–9. and33–41. € ber colloidales Silber. Ber. Dtsch. Chem. Ges. 1902, 35 (6) Paal, C. U (2), 2224–2236. (7) Adamson, R. P.; Sommerfeld, M. R. Laboratory comparison of the effectiveness of several algicides in isolated swimming pool algae. Appl. Environ. Microbiol. 1980, 39 (2), 348–353. (8) U.S. Market for Swimming Pool Equipment and Maintenance Products; Marketresearch.com, 2007. (9) Hendren, C. O.; Mesnard, X.; Dr€oge, J.; Wiesner, M. R. Estimating production data for five engineered nanomaterials as a basis for exposure assessment. Environ. Sci. Technol. 2011, 45 (7), 2562–2569. (10) Geranio, L.; Heuberger, M.; Nowack, B. Behavior of silver nano-textiles during washing. Environ. Sci. Technol. 2009, 43, 8113–8118. (11) Tolaymat, T. M.; El Badawy, A. M.; Genaidy, A.; Scheckel, K. G.; Luxton, T. P.; Suidan, M. An evidence-based environmental perspective of manufactured silver nanoparticle in syntheses and applications: A systematic review and critical appraisal of peer-reviewed scientific papers. Sci. Total Environ. 2010, 408 (5), 999–1006. (12) BfR BfR r€at von Nanosilber in Lebensmitteln und Produkten des t€aglichen Bedarfs ab, Bundesinstitut f€ur Risikobewertung, Germany, Stellungnahme Nr. 024/2010; 2009. http://www.bfr.bund.de/cm/343/ bfr_raet_von_nanosilber_in_lebensmitteln_und_produkten_des_ taeglichen_bedarfs_ab.pdf (accessed July 11, 2011). (13) Kulthong, K.; Srisung, S.; Boonpavanitchakul, K.; Kangwansupamonkon, W.; Maniratanachote, R., Determination of silver nanoparticle release from antibacterial fabrics into artificial sweat. Part. Fibre Toxicol. 2010, 7. (14) Bogdanchikova, N. E.; Kurbatov, A. V.; Tret’yakov, V. V.; Rodionov, P. P. Activity of colloidal silver preparations towards smallpox virus. Pharm. Chem. J. 1992, 26 (9 10), 778–779. (15) Frens, G.; Overbeek, J. T. Carey Leas colloidal silver. Kolloid-Z. Z. Polym. 1969, 233 (1 2), 922–&. (16) Hill, W. R.; Pillsbury, D. M., Argyria, the Pharmacology of Silver; The Williams & Wilkins Co.: Baltimore, 1939.
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(17) Gaul, L. E.; Staud, A. H. Seventy cases of generalized argyria following organic and colloidal silver medication, including biospectrometric analysis of ten cases. J. Am. Med. Assoc. 1935, 104 (16), 1387–1390. (18) Krug, H. F.; Wick, P. Nanotoxicology: An interdisciplinary challenge. Angew. Chem., Int. Ed. 2011, 50 (6), 1260–1278. (19) NIST. Report of Investigation, Reference Material 8011: Gold Nanoparticles, Nominal 10 nm Diameter”, National Institute of Standards & Technology, 2007. https://www-s.nist.gov/srmors/view_ detail.cfm?srm=8011 (accessed July 11. 2011). (20) Klein, C. L.; Comero, S.; Stahlmecke, B.; Romazanov, J.; Kuhlbusch, T. A. J.; Doren, E. V.; Temmerman, P.-J. D.; Mast, J.; Wick, P.; Krug, H.; Locoro, G.; Hund-Rinke, K.; K€ordel, W.; Friedrichs, S.; Maier, G.; Werner, J.; Linsinger, T.; Gawlik, B. M., NM-Series of Representative Manufactured Nanomaterials, NM-300 Silver: Characterisation, Stability, Homogeneity”, European Commission, Joint Research Centre, Institute for Health and Consumer Protection, 2011. http://publications.jrc.ec.europa.eu/repository/bitstream/111111111/ 16076/1/60709final_report_nm-300_08-09-2010 final 2011 01 isbn.pdf. (21) Blaser, S. A.; Scheringer, M.; MacLeod, M.; Hungerbuhler, K. Estimation of cumulative aquatic exposure and risk due to silver: Contribution of nano-functionalized plastics and textiles. Sci. Total Environ. 2008, 390 (2 3), 396–409. (22) Percival, S. L.; Bowler, P. G.; Russell, D. Bacterial resistance to silver in wound care. J. Hosp. Infect. 2005, 60, 1–7. (23) Akaighe, N.; MacCuspie, R. I.; Navarro, D. A.; Aga, D. S.; Banerjee, S.; Sohn, M.; Sharma, V. K. Humic Acid-Induced Silver Nanoparticle Formation Under Environmentally Relevant Conditions. Environ. Sci. Technol. 2011, 45 (9), 3895–3901. (24) FIFRA Scientific Advisory Panel Meeting held November 3 - 5, 2009 on “the Evaluation of Hazard and Exposure Associated with Nanosilver and Other Nanometal Pesticide Products”, 2009 http://www.epa. gov/scipoly/sap/meetings/2009/november/110309ameetingminutes.pdf (accessed July 11, 2011). (25) Directive 98/8/EC of the European Parliament and of the Council of 16 February 1998 concerning the placing of biocidal products on the market, L123/1. Off. J. Eur. Communities: Legis., 1988, http://ec. europa.eu/environment/biocides/pdf/dir_98_8_biocides.pdf (accessed July 11, 2011).
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