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ISSN 1743-5889Nanomedicine (2010) 5(4), 617–63210.2217/NNM.10.33 © 2010 Future Medicine Ltd

Nanosilver and global public health: international regulatory issues

Nanosilver’s potential benefits to global public healthAmongst the Millennium Development Goals enunciated by the United Nations, there are two where silver nanoparticles, otherwise known as nanosilver, could make a direct positive contri-bution. These are Target 7c: reduce by half the proportion of people without sustainable access to safe drinking water and basic sanitation, and Target 7d: achieve significant improvement in the lives of at least 100 million slum dwellers by 2020 [101].

Nanosilver has a wide range of potential appli-cations in this context, including its role in spec-trally selective coatings for solar energy absorp-tion [1]. Nanosilver’s most significant potential contribution to such goals, however, relates to its capacity to kill bacteria that cause disease (par-ticularly in living conditions with low hygiene) through the contamination of food, water and wounds. Interestingly, when 63 experts were asked to specify which aspects of nanotechnol-ogy could most assist the developing world, the role of nanosilver in water purification was not specifically mentioned. The nanotechnologies cited as likely to be important in this context were nanomembranes for water purification

(admittedly this could involve embedded nanosilver), desalination and detoxification, nanosensors for the detection of contaminants and pathogens, nanoporous zeolites, polymers and attapulgite clays for water purification, magnetic nanoparticles for water treatment and remediation and titanium dioxide nanoparticles for the catalytic degradation of water pollut-ants [2]. One reason for the diminished advocacy for nanosilver in this context is likely to relate to its potential environmental toxicity.

Silver has long been known to keep water pure and keep external wounds clean, a capacity now known to be due to its oligodynamic lethality (only minute amounts are required) for bacteria. This is in part due to thiol group reactions that inactivate enzymes, a process enhanced by electric fields [3], pure silver having the highest e lectrical and thermal conductivity of any metal [4].

The silver ion (Ag+) is an atom of radius 0.1 nm with one less electron than its protons, creating a reactive positive charge. Silver nanoparticles are silver particles engineered in a size range less than 100 nm; they have a face-centered crystal struc-ture and a 4.1 Å distance between atoms [5]. The term colloidal silver refers to silver particles (sized approximately 10 nm [10 ! 10-9 m] to 1000 nm

Silver in nanoparticle form is used extensively worldwide in hospital and general practice settings, in dressings as a treatment for external wounds, burns and ulcers. Nanosilver is also an increasingly important coating over embedded medical devices, inhibiting the development of biofilm. Nanosilver disinfectant sprays and polymer coatings are being widely promoted as protective against viral infections. In addition, nanosilver is widely used for its antibacterial properties in food processing and packaging, as well as in consumer products used for domestic cleaning and clothing. This article argues that medical devices, therapeutic products, and domestic food and goods containing nanosilver, although offering therapeutic benefits, must be subject to precautionary regulation owing to associated public health and environmental risks, particularly from large volumes of nanosilver in waste water. The article first examines the use of nanosilver in a variety of contemporary medical and domestic products, the utilization of which may assist in resolving global public health problems, such as restricted access to safe food, water and medical care. It then discusses the mechanisms of toxicity for nanosilver, whether it should be classified as a new chemical entity for regulatory purposes and whether its increased usage poses significant environmental and public health risks. The article next critically analyses representative international regulatory regimes (the USA, EU, UK and Australia) for medical and domestic use of nanosilver. The conclusion includes a set of recommendations for improving international regulation of nanosilver.

KEYWORDS: environmental toxicology ! nanoregulation ! nanosilver ! nanotoxicology ! silver

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[1 micon or 10-6m]) in a suspension, for example of de-ionized water [6]. Colloidal silver was first developed by Carey Lea in 1889 [7]. It was used by CSF Crede as a neonatal opthalmic solution to protect against maternal gonorrhea [8]. It was applied as a wound dressing and disinfectant through the First World War into the 1920s and 1930s, being superseded by penicillin in the 1940s [9]. Its marketing as an alternative medicine used in allergy prophylaxis has been the subject of considerable regulatory controversy [10]. One par-ticular side effect is argyria: irreversible blue–gray discoloration of the skin due to photoreduction to Ag0 in the upper layer of the dermis [11]. In the 1960s the combination of silver nitrate (AgNO3) in a 0.5% solution with a sulfonamide antibiotic produced silver sulfadiazine cream, which is still widely used for the treatment of burns [12]. Silver continues to be utilized in a range of applications from jewellery, coins, cloud seeding and batteries, to flower preservation [13].

Nanoparticle-sized silver can be made by spark discharging, electrochemical reduction, solution irradiation, cryochemical synthesis and chemical reduction (e.g., by borohydride [BH4

+] or ferrous ion [Fe2+] in the presence of a stabilizer such as citrate or EDTA) [14]. The International Standards Organization (ISO) has proposed a definition of a nanoparticle as one with all three external dimensions in the size range of 1 to 100 nm [14]. Other definitions in use by some regulatory agencies also emphasize insolubility and biopersistence [15]. This is con-troversial here, as little is yet known about the oxidation and dissolution processes occurring in suspensions of silver nanoparticles.

A case can be made that nanosilver represents a new chemical entity with important physical and chemical characteristics distinct from silver on the macroscale. Nanosilver preparations, for example, provide a greater surface area of sil-ver exposed in solution and a potentially higher proportion of bioactive metallic silver (ionic sil-ver becomes silver chloride in the stomach or bloodstream, being less bioactive, although some silver-chloro complexes, being uncharged, are therefore lipid soluble and potentially highly bio-available) [8]. Conversely, it has also been argued that nanosilver acts similar to metallic silver in terms of toxicity (i.e., it dissolves to form ionic silver) [13].

Nanosilver is used extensively in medicine for prosthetics, in the treatment of skin disease wound management, particularly for the treat-ment of burns, various ulcers (e.g., rheuma-toid arthritis-associated leg ulcers and diabetic

ulcers) and toxic epidermal necrolysis, for healing of donor sites and in surgical mesh [4].

Nanosilver particles in the 1–10 nm range have been shown to inhibit binding of HIV-1 to host cells [16]. Nanosilver is also used to coat urethral and central line catheters and other implantable medical devices, such as infusion ports, ortho-pedic protruding fixateurs, endovascular stents, urological stents, endotracheal tubes, contact lens coatings, endoscopes, electrodes, peritoneal dialysis devices, subcutaneous cuffs, and surgical and dental instruments, to prevent the growth of slime-containing biofilms that p romote b acterial infection and sepsis [4].

Nanosilver is also incorporated for its anti-bacterial, antiviral and antifungal properties in a growing range of modern domestic or household items. It has the highest degree of commercialization of nanoparticles in con-sumer products, with more than 260 nanosilver products, including household appliances and cleaners, clothing (including socks and under-wear), cutlery, children’s toys and personal care products (such as menstrual pads) currently on the market in the USA [102,103]. Similar find-ings are likely to apply to the EU, UK and Australia [104]. A typical example is Samsung’s ‘Nano Silver Health System’, which uses nanosil-ver in refrigerator trays, filters, air conditioners and tubing to kill bacteria and the odors they produce [105]. Particularly widespread household uses of nanosilver include cosmetics, clothing de-odorizers, paints, disinfectants and cleaning products [103].

Nanosilver’s cellular toxicity: is it the ions?There is little doubt that like silver itself, nanosil-ver can be highly toxic to cells. In vitro studies demonstrate that nanosilver is toxic to mam-malian liver cells, stem cells and even brain cells [17]. Silver ions and nanoparticles released from medical devices (such as catheters) form protein–silver complexes deposited in the liver, kidney, spleen, lung, brain and skin [18]. In 2006, a case report described a 17-year-old boy with burns on 30% of his body, whose nanosilver coated wound dressings caused liver toxicity as well as argyria [19].

A central regulatory issue here is whether nanosilver’s cellular toxicity is a new phenom-enon, given that colloidal silver preparations (which have always contained a certain propor-tion of silver in nanoparticle form) have been around for so long. It is unclear, for example, whether nanosilver has an unusual capacity for

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Nanosilver & global public health: international regulatory issues !"#$"%

attachment to cell membranes, thereby alter-ing membrane permeability and the redox cycle in the cytosol, or for intracellular free radical accumulation or dissipation of the proton motive force for ATP synthesis [20].

When a culture of mammalian germline stem cells (a C-18–4 cell line from type A spermato-gonia of 6-day-old mouse testes) was exposed to 15 nm nanosilver particles in a solution of phos-phate buffered saline, an assay revealed signifi-cant inhibition of mitochondrial function start-ing at concentrations between 5 and 10 µg/ml, with an EC50 of 8.75 µg/ml, but only minimal leakage of lactate dehydrogenase, a cytosolic enzyme released on cell lysis. This suggested that nanosilver may uniquely interfere with the stem cells’ metabolism, rather than their plasma mem-branes. Interestingly, nanoparticle aggregation and precipitation prevented testing of nanosilver concentrations higher than 10 µg/ml [21].

When the viability of a culture of murine macrophages was assessed using the same mito-chondrial function assay, nanosilver particles (mean size: 30 nm) in a solution of dimethyl sulfoxide had a relative cytotoxicity index (using chrysolite asbestos as a control) of 1.5 at a con-centration of 5 µg/ml but, unusually, a lower cytotoxicity of 0.8 at a higher concentration of 10 µg/ml (the cytotoxicity indices being 1.8 and 0.1 respectively for a coated form of the same sized nanosilver at similar concentrations) [5].

Generation of reactive oxygen species (ROS) appears to be a key mechanism for nanosil-ver toxicity through interference with cellular metabolism, inflammation and damage to pro-teins, membranes and DNA [22,23]. Decreased mitochondrial function particularly charac-terizes nanosilver cytotoxicity and appears to involve oxidative stress induced by thiol group interactions with the mitochondrial inner mem-brane, these effects being blocked by sulfhydryl reagents such as reduced glutathione, superoxide dismutases and catalases [5].

DNA damage may be a uniquely significant outcome of cellular exposure to nanosilver. When nanosilver particles (mean diameter: 25 nm) were exposed to mouse embryonic stem cells, a significant rise occurred in the p53 pro-tein (a key marker of DNA repair and apoptosis) after 4 h, as well as corresponding elevations in Rad51 (involved in DNA double strain break-age repair) and annexin V protein (a marker of apoptosis) [24].

Many studies have attempted to compare the toxicity of nanosilver with silver ions [25,26]. In an experiment where 10–20 nm nanosilver particles

in solution were applied to nitrifying bacteria, nanosilver particles less than 5 nm in size showed a greater inhibition of nitrification than Ag+. The degree of inhibition strongly correlated with measured intracellular ROS concentration for both nanosilver and Ag+; although at the same total Ag concentrations, Ag+ generated less ROS than nanosilver and in both cases ROS genera-tion was inhibited by absence of sunlight. Most interestingly, as Ag+ concentrations increased, ROS production also increased, whereas the opposite occurred with nanosilver, with photo-catalytic ROS production decreasing as nano-particle concentrations increased [27]. Even when the phenomenon of aggregation is taken into account, such results support the finding that nanosilver (particularly at the lower edge of the nanorange) may present a unique toxicity at low concentrations in vivo or in the environment.

Similarly, it has been found that nanosilver (which has been determined by transmission electron microscopy to be of 20 nm mean parti-cle size) appeared to have a worse impact on gene expression measured by quantitative real-time PCR than silver ions (in the form of aqueous AgNO3) when exposed in de-ionized water to Caenorhabditis elegans, a soil nematode and the first multicellular organism to have its genome completely sequenced [28].

Similarly, the role of Ag+ in determining the toxicity (in terms of photosynthetic yield) of 5 and 10 µM nanosilver suspensions was assessed in freshwater algae (Chlamydomonas reinhardtii) in the presence of the Ag+ ligand cysteine. Inhibition of photosynthesis by nanosilver over 1 h was similar (60%) at cysteine concentrations between 10 and 100 nM, with a complete abol-ishment of photosynthesis at an equimolar con-centration of cysteine. When capacity to inhibit photosynthesis relative to control was related to the Ag+ concentration after 2 h, nanosilver appeared to be more toxic than the ion source AgNO3 [29].. This research supports the view that nanosilver, like silver itself, primarily owes both its bactericidal effects and toxicity to the rate of release of free silver ions [13,30]. However, the latter finding suggests that nanosilver may pro-vide a unique slow-release mechanism for toxic silver ions.

Nanosilver & bacterial resistanceNumerous published reports confirm silver resistance in bacteria, although the mechanism is unclear [31]. Bacterial resistance to nanosilver is most easily developed in vitro in bacteria with already documented resistance mechanisms



to antibiotics, such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, enterobacteria with production of extended spectrum !-lactamases and multiresis-tant Pseudomonas aeruginosa [32]. There are cur-rently no standardized methods to determine bacterial sensitivity to nanosilver, a task made more difficult by the wide variation in clinical silver product delivery systems and silver formu-lations [33]. Dressings that release low levels of silver ions are likely to be more problematic in terms of selection for resistance, especially if the silver concentration is sublethal [34].

Nanosilver’s environmental riskIn 2010, nanosilver in waste water was listed by a team of public health experts as one of 15 nascent issues that could deleteriously affect the con-servation of biological diversity [35]. The two Millennium Development Goals most relevant in this context are Target 7a (“integrate the princi-ples of sustainable development into country pol-icies and programs; reverse loss of environmental resources”) and Target 7b (“reduce biodiversity loss, achieving, by 2010, a significant reduction in the rate of loss”) [101]. The experts’ concerns about widespread use of nanosilver relate not so much to direct poisoning of humans or the pro-duction of bacterial resistance in hospital settings, as to its high in vitro toxicity for aquatic organ-isms and capacity to environmentally persist [106]. No doubt they were aware that bulk form silver released into waste streams, particularly from photographic development, had previously been a major source of ecological toxicity [36].

The volume of waste containing residue nanosilver is increasing proportionally with its utilization in domestic products and medici-nal applications [32,37,38]. Nanosilver released in domestic wastewater may have a variety of fates, including being converted into ionic silver, com-plexing with other ions, molecules or molecular groups, agglomerating or remaining in nanopar-ticle form. Its potential for significant environ-mental toxicity revolves around its biocidal and catalytic effects on a wide range of organisms in the soil, including bacteria, fungi and earth-worms, along with reaction with other toxic sub-stances, a toxic effect on groundwater and accu-mulation along the food chain [39]. Wastewater treatment relies on heterotrophic micro-organ-isms for organic and nutrient removal, while autotrophic micro-organisms play an impor-tant role in nitrification. Nitrifying bacteria in sewerage systems are especially s usceptible to i nhibition by silver nanoparticles [40].

Most recently, Bradford et al. determined that the “current and future predicted environmental concentrations of silver nanoparticles appear to be well below any impact threshold to the micro-bial health of the environment” [41]. However, their study on the impact of nanosilver con-tamination on natural bacterial assemblages in estuarine sediments was conducted over a short exposure time of 1 month and involved sam-ples collected from a single estuary [41]. Further research needs to be undertaken with longer exposure times, covering different estuarine environments as well as investigating the effects of nanosilver in fresh water systems. Information about mass loading in the environment is cur-rently unavailable for the purposes of nanosilver risk assessments, instead a major deficiency here being the inadequacy of government reporting requirements or manufacturer product infor-mation to construct reliable estimates of mass discharges [106].

International regulatory regimes for nanosilver"! Nanosilver regulation in the USA

The US model for regulating nanosilver is lay-ered and complex. For example, not only is nanosilver regulated by multiple federal agencies and legislative schemes covering different phases in the lifecycle of nanosilver and its products, but distinct applications of nanosilver are gov-erned by different regulations [107]. Regulation of nanosilver in the USA is strongly influenced by the considerable existing regulatory restric-tions on the release of silver to the environment. Since 1977 the US Environmental Protection Agency (EPA), for example, has listed silver in surface waters as a priority pollutant [108]. The US Conference of Governmental Industrial Hygienists has established separate threshold limit values for metallic silver (0.1 mg/m3) and soluble compounds of silver (0.01 mg/m3). The permissible exposure limit recommended by the US National Institute for Occupational Safety and Health (NIOSH) is 0.01 mg/m3 for all forms of silver [42].

The three main US federal agencies tasked with regulating the environmental and pub-lic health impacts of nanosilver are: the EPA, the US FDA and the NIOSH agency [106]. NIOSH is primarily responsible for conduct-ing research and making recommendations to prevent work-related injuries, illnesses and deaths. It is not directly involved in the devel-opment or e nforcement of regulation concerning nanosilver [109].



Nanosilver & the EPAThe EPA’s regulatory framework for nanosil-ver consists of the following statues: the Toxic Substances Control Act (TSCA), which regulates chemicals [43]; the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) [110], which regu-lates pesticides and biocides [44,111]; the Clean Air Act (CAA) [45]; the Clean Water Act (CWA) [46]; and the Resource Conservation and Recovery Act (RCRA) [47]. The absence of effective meth-ods to monitor nanosilver in ambient air or water increases the difficulty of regulating nanosilver under the CAA, CWA or RCRA. The EPA has predominantly employed the TSCA to regu-late nanomaterials and the FIFRA to regulate p esticides containing nanomaterials [112].

Nanosilver falls within the TSCA’s broad definition of ‘chemical substances’ covering any combination of “organic or inorganic substance of a particular molecular identity” [48]. However, current US regulatory opinion is that nanosilver does not qualify as a ‘new’ chemical substance under the TSCA; silver in bulk form being already on the Chemical Substance Inventory and having the same molecular identity (based on structural and compositional features) as nanosilver [49,50]. Such a conclusion subjects nanosilver to the same reporting requirements, threshold levels and toxicity tests as bulk silver, despite the scientific literature (discussed previ-ously) indicating significant controversy regard-ing differences between their physical, chemical and toxicological properties [107].

Should nanosilver be considered a ‘new chemical substance’ under the TSCA, then its manufacture and use would be subject to more onerous ‘new chemical’ reporting requirements under section 5(a)(1) of the TSCA. These obli-gations include submitting a Premanufacture Notice (PMN) to the EPA at least 90 days prior to manufacturing, or importing for a commer-cial purpose, a chemical substance that is not listed on the inventory, unless the substance is exempt from reporting under section 5(h) of the TSCA. It would only be after a PMN review and upon receipt of a Notice of Commencement of Manufacture or Import (NOC) that nanosilver would be added as a new chemical substance to the inventory [113].

Alternatively, the EPA can impose these obli-gations upon manufacture and use of nanosilver, even though nanosilver is not a ‘new chemical substance’, by exercising its power to introduce Significant New Use Rules (SNUR) under sec-tion 5(a)(2) of the TSCA. In designating new uses, EPA must consider projected production

volumes of the nanoformulation, possible changes in the pattern of exposure, and the prospective manner and methods of manufac-turing, processing, distributing and disposing of the substance [51]. In June 2009, the EPA issued its first two SNURs for nanomaterials, namely multiwalled and single-walled carbon nanotubes [52]. This means that manufacturers of these nanomaterials will have to notify the EPA 90 days before commencement [53].

Even though the EPA has some flexibility to regulate nanosilver using SNURs, there are some inherent problems. First, the burden of proof lies on the agency to show that nanosilver actually poses an ‘unreasonable risk’ before the EPA can acquire the data from the manufacturer to con-firm whether this is the case [54,114]. Federal agen-cies, such as the EPA, whose limited resources are already spread thin and whose scientific expertise may not adequately cover nanomaterials, will be under considerable pressure where data from the manufacturer appears inadequate to fully characterize a risk [114]. Second, a significant bar-rier arises from the EPA’s consistent refusal to consider nanomaterials as new substances unless they are structurally unique from the materials on the Chemical Substance Inventory, a defi-nition that does not directly take into account the novel physical and chemical properties of nanomaterials [107].

Finally, while Section 6 of the TSCA autho-rizes the EPA to regulate nanomaterials through-out their lifecycle from manufacture to disposal, whenever unreasonable risks become known, the EPA has barely exercized this authority postmar-keting of a product [107]. This section gives the EPA considerable authority to: prohibit or limit the amount of production or distribution of a toxic substance; prohibit or limit the production or distribution of a substance for a particular use; limit the volume or concentration of the chemical produced; prohibit or regulate the manner or method of commercial use; require warning labels and/or instructions on contain-ers or products; and require notification of the risk of injury to distributors and, where possible, consumers [114]. Since its inception in 1976, how- Since its inception in 1976, how-ever, the EPA has used this authority to regulate a total of six existing chemicals [114]. It has been suggested that the EPA’s sparing use of Section 6 is due to the fact that “the Agency came to view Section 6 rulemaking as an inherently large and complex undertaking that offered little prospect of resulting in success” [115]. The absence of data on the lifecycle of nanosilver in its multitude of applications compounds this problem.



The other important piece of regulation enforced by the EPA is the FIFRA. Unlike the TSCA, the FIFRA focuses on products and not substances [114]. Section 3 of the FIFRA man-dates that pesticide manufacturers must regis-ter their products prior to commercializing the products [55]. FIFRA defines a pesticide as ‘any material’ that is intended to destroy or repel a pest and it explicitly defines ‘pest’ to include bac-teria and viruses [56,57]. Nanosilver’s primary use as an antimicrobial in a majority of the reported 244 nanosilver products being marketed and its ability to generate silver ions could place it squarely under such registration obligations in the FIFRA [58,106,116].

The FIFRA appears to provide a stronger reg-ulatory regime for nanosilver than the TSCA. First, the FIFRA requires the EPA to review the safety of nanosilver prior to its marketing. Second, it places obligations on manufacturers to provide toxicity data and safety data, and can prohibit initial marketing of nanosilver. However, the FIFRA fails to expressly include nanosilver or other nanomaterials within its regulatory scheme. A distinct category of nanopesticides could greatly enhance the EPA’s ability to effectively regulate nanosilver and other similar nanomaterials under FIFRA [107]. As an example, in March 2008 the EPA Region 9 announced a US$208,000 settle-ment with ATEN Technology, Inc., for alleged FIFRA violations by a subsidiary, IOGEAR, Inc., which had allegedly sold unregistered pes-ticide products (a computer keyboard and mouse coated with nanosilver) with unverified claims that they would kill bacteria. In addition to pay-ing the $208,000 fine, ATEN agreed to have IOGEAR cease marketing claims that its com-puter products were embedded with ‘nanoshield coating’ and ‘nanocoating t echnology’ that p rotected users against germs [117].

Nanosilver & the FDAThe FDA is the US federal regulatory agency responsible for protecting public health in rela-tion to food and therapeutic goods, using leg-islative instruments such as the Federal Food, Drug and Cosmetic Act (FDCA) [118]. Of par- Of par-Of par-ticular relevance to nanosilver regulation are the Medical Device Act (Amendments) 1976, which expanded the FDCA’s medical device regulation provisions [118]. The main centers at the FDA that are involved in regulating the use of nanosilver in therapeutic goods are the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research and the Center for Devices and Radiological Health [59,119].

Key components of the FDA’s regulatory regime in monitoring and ensuring the safe use of nanosilver in therapeutic goods include those described in the following sections.

Premarket oversightThe FDA subjects certain products, whether or not they contain nanosilver, to a premarket authorization process, either individually or by category [120]. For example, new nanosilver drugs would be subject to the New Drug Application (NDA), which ensures the composition, effec-tiveness, proposed labeling and manufacturing method meet the requisite standards of quality and safety for commercialization [60,121]. Likewise, class III nanosilver-coated medical devices that are life supporting or life sustaining or present a potential unreasonable risk of illness or injury will be subject to Premarket Approval (PMA) [61]. In general, only the “best understood and lowest-risk devices” are exempted from PMA, and even for those, the manufacturer must register with the FDA and list its products with the agency [120]. Such premarket oversight has great public safety advantages as it assists in acquiring early informa-tion, for example on nanosilver-coated stents and catheters, places the burden to demonstrate safety on the product’s sponsor right from the start and allows the FDA to impose conditions as needed to ensure the final product is safe [120].

Postmarket oversightOf equal importance, the FDA is empowered to conduct inspections of nanosilver food and drug manufacturing establishments to ensure they are complying with mandatory good manu-facturing practices, inspect safety records of the products and require manufacturers to report adverse events [62,63,120]. For example, the FDA may use its explicit and broad legislative author-ity to require manufacturers to run a postmarket surveillance program for medical devices coated with nanosilver in order to continually moni-tor and test those devices [64]. Similar legisla-tive tools are available for regulating new drugs involving nanosilver [65]. These allow the FDA to ascertain whether nanosilver drugs warrant a suspension or ban from the market to protect environmental and public health and maintain public confidence [120].

Removal of unsafe productsThe FDA can choose to withdraw a company’s marketing authorization for medical devices and new drugs if it can show that new information has emerged that indicates the device or drug



is unsafe or ineffective [66,67]. This is a criti- This is a criti-cal statutory power with respect to nanosilver products because new data on their toxicity and effectiveness are still emerging.

The FDA has a strong policy emphasis on protecting and promoting public health [68].However, it currently faces handicaps that may hinder it from effectively preventing unsafe com-mercialization of nanosilver in therapeutic goods. The first is the FDA’s predominant internal ideol-ogy that existent regulatory authority is wholly sufficient to address nanotechnology [122,123]. This arguably contradicts the research conducted by the Wilson International Center and by the FDA itself to gauge whether the FDA’s regulatory regime was adequate to address the issues arising out of commercialization of products containing nanomaterials such as nanosilver [120,124]. The reports explicitly state that existing FDA regula-tions are “not ‘nano ready’” and urge the FDA to “take some immediate steps to address the first wave of n anotechnology p roducts now entering the market” [120].

A second handicap is that the FDA’s regime is product-centric, that is, the FDA will regulate products containing nanosilver according to the regulatory requirements that may include non-chemically related products in the same thera-peutic category [107]. This poses a significant risk of undertesting the toxicity of nanosilver products placed within the regulatory criteria of a generic product category [125]. Product-based regulation may create differential standards for nanosilver in categories such as medical devices and new drugs, rather than cosmetics [125]. Such a disparity may also restrict the capacity of the FDA to detect risk patterns [68].

Another handicap is that claims have been made that the FDA’s “scientific base has eroded and its scientific organizational structure is weak” [68]. The FDA may lack the resources to expand its scientific knowledge base regarding nanosilver [68]. Government policies increasing corporate influence over the FDA and eroding its scientific independence may have eroded its ability to oversee commercialization of safe nanotechnology [120]. Examples involve erod-ing its capacity to conduct effective regulatory reviews and provide toxicity-testing protocols to the manufacturers [120]. Another issue for both the EPA and FDA in this context is the reluctance of US regulatory systems to embrace the precautionary principle, due to probably unwarranted fears that it will inhibit so-called free market conceptions of t echnological i nnovation [69].

Recent US regulatory developments about nanosilver In January 2008, the EPA published a draft Nanomaterial Research Strategy (NRS). This acknowledged that although nanomaterials, or products containing nanomaterials, were being submitted for approval under TSCA and FIFRA, the appropriateness of the existing pro-tocols for evaluating hazards to ecological recep-tors needed to be reassessed [70]. However, by October 2008 little had changed in the proto-cols and only carbon nanotubes were formally recognized as chemically different from conven-tional carbon compounds and subject to regula-tion as ‘new’ chemicals under the TSCA [126]. A month later, the EPA invited public comments on a petition filed by a coalition of consumer and environmental groups demanding that the EPA regulate nanosilver explicitly as a pesticide under the FIFRA, and halt the sale of consumer products containing nanosilver [127].

In 2009 a group of Senators led by Senator John Kerry introduced a bill in the Senate aimed at rejuvenating the National Nanotechnology Initiative (NNI) program, established to coordi-nate Federal nanotechnology research and devel-opment, and create a new panel to increase the focus on the environmental, health and safety aspects of the nanotechnology developments such as nanosilver [122,128].

After the failure of its voluntary industry reporting scheme, the EPA signalled it intended to use the TSCA to gather more risk data on nanomaterials such as nanosilver [129]. In August 2009, TSCA’s Interagency Testing Committee published a report in the Federal Register stat-ing that EPA “intends to develop a proposed TSCA Section 8(a) rule to obtain information on the production, uses and exposures of exist-ing nanoscale materials” [71]. These materials s pecifically include nanosilver [72].

"! Nanosilver regulation in the the EUThe EU has integrated the so-called ‘precaution-ary principle’ into its environmental, health and safety regulation much more thoroughly than the USA [130]. The principle presumes a product to be harmful in the presence of insufficient or uncertain scientific data regarding its human and environmental safety, until the contrary is demonstrated [73]. The EU’s commitment to the precautionary principle is evident in the motto of the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) program – ‘no data, no market’ [130]. The EU’s approach to the safety and environmental regulations for



nanosilver and its marketed products is governed by the REACH program [131] and a variety of direc-tives. These include general product safety direc-tives [74], a medical devices directive [75], several pharmaceuticals directives [76], an integrated pol- an integrated pol-lution prevention and control directive (IPPC) [77], a control of major accident hazards involving dan-gerous substances directive (Seveso II), a water framework directive, several waste directives and biocidal products directive [78]. All these are a pplicable simultaneously [79,132].

Of these regulations, REACH outwardly provides the strongest demonstration of the precautionary principle [73,133]. REACH, intro-duced in 2007, aims to protect the environment and human health through effective identifica-tion of properties and hazards of chemical sub-stances before commercial deployment [133]. The European Commission has clarified in a review that nanomaterials fall within the scope of ‘chemical substances’ regulated by REACH [132].

The REACH program is enforced by the European Chemicals Agency (ECHA) [72]. It mandates that any introduction of nanoformu-lations of an existing chemical substance, already placed on the market as bulk substance, should be accompanied with an updated registration dossier that includes specific properties of the nano-formulation [80,132]. At present, REACH requires toxicological data and environmental exposure assessment results for nanomateri-als produced or imported in amounts greater than 1 tonne per year [81]. In addition, should a nanomaterial be of concern, the ECHA can set additional authorization requirements or place restrictions on its use if shown to be hazard-ous [132]. The REACH system places the bur-den on nanosilver manufacturers, importers and downstream users to ensure and gather informa-tion establishing that such nanoproducts are safe for human health and the environment [134].

Significant gaps exist in the REACH regime’s regulation of nanosilver [82]. At present, several applications of nanomaterials involve low man-ufactured volumes of nanomaterials, in gram to kilogram quantities, well below the regu-latory trigger of 1 tonne in a year [82,83]. This creates an opportunity for manufacturers and importers to escape reporting requirements for nanomaterials [82].

Another limitation in the REACH legislation, similar to that under the TSCA, relates to the criteria by which nanoformulations exhibiting different physical, chemical and toxicological properties from the bulk form may be considered new chemical substances [134]. Prior to REACH,

in 2006 the European Commission’s Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) published its Synthesis Report based on public consultations [135]. The report concluded that risks associated with nano-materials should not be classified along with their bulk counterparts [135]. Nonetheless, companies still use existing testing and toxicity reporting guidelines based on conventional methodologies for assessing chemical risks [135]. Thus, manufac-turers and importers of nanosilver are required to provide a chemical safety assessment, which may or may not rely on the toxicological profile of the equivalent bulk material [82].

The case has been made that REACH should be amended so as to make it adhere more strongly to the precautionary principle with regard to nanoscale materials such as nanosilver [135–138]. A 2006 study, for example, recommended that chemicals in the nanosize scale be treated as new substances under REACH and their trig-ger threshold limits “be reassessed once relevant data becomes available” [137]. A 2008 report like- A 2008 report like-wise recommends a review of REACH and its product- or sector-specific regulations to facili-tate their effective application to nanomaterials and the provision of adequate testing arrange-ments [118]. Regulation of nanosilver based on tonnage as a threshold, as proposed for chemi-cals under REACH, is being reconsidered by the Nanomaterials and REACH Sub-Groups [139].

Aside from REACH, the EU regulates nano-enabled therapeutic goods within the existing regulatory framework provided by its generic, nonspecific medical devices directive and phar-maceuticals legislation [75]. Arguments in favor of using such existing regulations to regulate nanosilver are, first, that extensive premarket testing requirements, similar to that of the FDA, are sufficient to detect any possible nega-tive impacts of such novel therapeutic goods and, second, that benefits of quickly commercializing nanosilver-incorporating medicines and devices overshadow the potential adverse effects [138].

Problems with such an approach relate to the fact that regulations facilitating extensive testing are more likely to benefit the public interest if they accommodate (as they currently do not, in a systematic manner) the special physical and chemical properties of nanosilver in their risk assessment methodology [82]. The second issue is that the available data reveal that traditional assessments of environmental hazard may well be insufficient to deal with widespread industrial and domestic use of nanosilver [84]. So far, no comprehensive study has been published on the



subject [85]. Thus, despite adopting the precau-tionary principle in the REACH program, it may be that the EU’s overall approach to balancing the human health and environmental benefits and risks posed by nanosilver lacks coherence.

"! Nanosilver regulation in the UK The UK’s approach to regulating nanosilver is influenced by EU directives and regulations [86]. In 2003, however, the UK government refused to implement recommendations of the Better Regulation Taskforce to create regulatory con-trols on nanotechnology that would have explic-itly acknowledged the regulatory importance of the precautionary principle in this context [86]. Likewise, in 2004, upon the recommendations of the Royal Society and the Royal Academy of Engineering (RS-RAEng), the UK operational-ized an action plan that involved a range of regu-latory measures focused on self-regulation and stakeholder engagement, as opposed to adopt-ing a precautionary regulatory model [86]. This was despite the fact that the RS-RAEng’s report had concluded that release of nanoparticles to the environment should be “avoided as far as possible” since very little is known about their environmental effects [140].

The key features of the UK’s regulatory model relevant to nanosilver are outlined in the f ollowing sections.

Voluntary notificationThe government and some of its departments, such as the Department for Environment, Food and Rural Affairs (DEFRA), launched a voluntary reporting scheme for industry, as well as research institutions involved in manufacturing or using nanoparticles such as nanosilver [86]. The purpose was to accumulate information on the properties, potential risks and hazards of nanomaterials, and to consolidate that information. However, gener-ating only 13 submissions over 3 years, the scheme has been far from effective [87].

Promoting nanotechnology researchThe UK Research Councils are funding several projects aimed at studying a variety of safety aspects of nanotechnology, including nanosil-ver [87]. Related funding schemes facilitating development of nanotechnology aimed at global public health challenges are yet to fully emerge.

Engaging stakeholdersBy launching programs, such as Nanodialogues, the Nanotechnology Engagement Group and Small Talk, the UK government intends to

provide forums for constructive discussions on the issues of good practices for manufacturing, and regarding the using and disposing of nan-otechnology products, with the aim of factoring these discussions into better policy outcomes [86].

Reviewing existing legislationThe Office of Science and Innovation (OSI) has assessed whether existing regulation adequately dealt with the hazards of nanomaterials such as nanosilver [137]. It found that existing regulations were inadequate to deal with the threat posed by nanomaterials [137]. Specific regulatory gaps related to thresholds, definitions and interpre-tations of safety standards in, for example, the Chemicals (Hazard Information and Packaging for Supply) Regulations 2002 (CHIP) and Notification of New Substances Regulations 1993 (NONS) [137]. The OSI advocated not giving suppliers discretion to classify nano-chemicals because it is “unlikely that all suppli-ers will possess the necessary data to make an informed decision relating to whether the pres-ence of nanoparticles suggests a new substance or an existing one” [137]. It also found that the toxicity of chemicals in the form of nanomateri-als “cannot be predicted from their toxicity in a larger form and consequently in some cases they may/will be more toxic than the same mass of the same chemical in its larger form” [86]. In 2008, the UK government passed regulations that enforce the EU’s REACH program within the UK [87]. This may in time shift the UK’s position toward the precautionary principle.

The UK government has forged intranational and international collaborations with research institutions and governments (e.g., the OECD Working Party on Manufactured Nanomaterials [WPMN]) and is funding several research proj-ects focused on the safety of nanoparticles [86]. Such public funding critically supplements a precautionary model of regulation, insofar (as appears to be the US position) that the model is held to drive investors away by creating oner-ous obligations and reporting requirements for manufacturers and suppliers [88].

In 2008 the Royal Commission on Environmental Pollution (RCEP) published its report ‘Novel materials in the environment: the case of nanotechnology’ [135]. It acknowledges that “ionic silver, unlike bulk silver, may be toxic to living organisms such as bacteria and fish” [136]. Similar to its predecessors, the report urges the government to adopt a “more directed, more co-ordinated and larger response led by the Research Councils to address the critical



research needs raised by this report, with empha-sis on regulatory and policy programs” [136]. The report requests that the relevant authorities should focus specifically on not just the size and chemical structure, but the properties and func-tionalities of nanomaterials. It argues that strict chemical equivalence should not preclude the need for a separate risk assessment for nanopar-ticle formulations [136]. This approach requires a variety of early warning systems, environmental monitoring systems, risk-handling guidelines and e xtensive research [89].

In June 2009, the UK government published its response to RCEP’s report [139]. This stated: “given the potential for use of nanosilver in products such as clothing, cosmetics and wound dressings, the Government has asked the UK’s Advisory Committee on Hazardous Substances (ACHS) to consider the research undertaken to date and advise on how the use of this material may be best managed” [139].

"! Nanosilver regulation in AustraliaAustralia has four national chemicals assessment and registration schemes that may be relevant to nanosilver: Food Standards Australia New Zealand (FSANZ) covering the food industry [90]; National Industrial Chemicals and Assessment Scheme (NICNAS) that covers industrial chemi-cals [91]; Therapeutic Goods Administration (TGA) that deals with pharmaceuticals [141]; and Australian Pesticides and Veterinary Medicines Authority (APVMA) that deals with agricultural and veterinary chemicals [92].

Both the agricultural/veterinary regulator and the TGA regulate products rather than chemical substances [92,142]. The TGA requires each individual product placed on the mar-ket to be separately listed (if a low level medi-cal device or therapeutic product) or registered (most drugs and higher level medical devices) on the Australian Register of Therapeutic Goods (ARTG) [93,142]. As a part of this process, appli-As a part of this process, appli-cants are required to submit comprehensive characterization data sets, which include, where appropriate, particle size and characteristics [94]. All food products (including those potentially containing nanosilver) supplied in Australia must comply with the Australia New Zealand Food Standards Code (FSCode) and be safe for human consumption [143]. Through the standards in the FSCode, the FSANZ has the capacity to regulate nanosilver food products through its authority to prohibit or grant different permissions for marketing, should the relevant safety assess-ment determine there is a case to do so [143]. The

FSCode also provides a mandatory upper limit for contaminants (possibly including nanosil-ver) and residues of agricultural and veterinary residues in food [143]. All new food substances are subject to a premarket approval process that involves a rigorous safety assessment before they can legally be supplied [143].

Safety data for each agency must address the specific material for which approval is being sought. The use of industrial chemicals is also reg-ulated at the state and territory level by a range of agencies. In addition, the Australian Competition and Consumer Commission (ACCC) is respon-sible for product labeling in accordance with the Trade Practices Act 1974 (Cth).

Despite the extensive information require-ments in the existing Australian regime, only 58 silver-containing chemicals are currently registered with the Australian Inventory of Chemical Substances (AICS). Nanosilver is not mentioned specifically. As with the European and US regulatory systems, relevant Australian regulations largely incorporate nanosilver as an ‘existing chemical’ under the AICS.

In February 2006, NICNAS issued a volun-tary call for information to Australian industry to provide information on the uses and quantities of nanomaterials being manufactured or imported for industrial purposes, or for use in cosmetics and personal care products. Only approximately 20 companies responded. Approximately a third of those surveyed indicated that the nanomaterial(s) were only being used for research purposes. A second voluntary call for information was initi-ated by NICNAS in October 2008, targeted at all manufacturers or importers of nanomaterials or products (mixtures) containing nanomateri-als for commercial or research and development purposes in 2008 (the first call excluded the use of nanomaterials for R&D purposes). This had a similarly poor response [144].

The NICNAS, similar to its counterparts REACH and TSCA, faces the challenge of whether to deem nanoformulations of existing chemicals to be ‘new chemicals’ for regulatory and safety purposes. To date, Australian regula-tors (like their counterparts in the USA and UK) have been reluctant to recognize that nanopar-ticles present new and often greater toxicity risks than larger particles of the same chemical composition. This was evident in the National Nanotechnology Strategy Taskforce’s report that recognized the need for a “whole of government approach” to deal with the problems posed by nanotechnology and suggested that “existing regulations may need some adjustments” [95].



The NICNAS is currently involved in a review of regulation of nanomaterials in indus-trial chemicals regulation in Australia. This is proposing a staged development process involv-ing the introduction of mandatory reporting of nanomaterials above a 100-g limit, as well as a permit system involving a declaration by the notifier that a chemical is a nanomaterial. More specific information (e.g., particle size, shape and other specific information on properties) may be required under specified conditions. Nanomaterials will be administratively excluded from the nonhazardous self-assessment category on the basis of the uncertainty concerning their hazard, and NICNAS can determine if the cri-terion for “no unreasonable risk” is met on a case-by-case basis. NICNAS can also stipulate enforceable use conditions, amend these condi-tions or revoke the permit when new i nformation is generated [144].

ConclusionSignificant knowledge and regulatory gaps exist in all the studied jurisdictions with respect to managing the environmental and public health implications associated with nanosilver and its products [96,145]. The grand challenges for nanosilver regulation are similar to those for reg-ulation of nanotechnology in general, including: develop instruments to assess exposure in air and water; develop and validate methods to evaluate the toxicity; develop models for predicting the potential impact on the environment and human health; develop robust systems for evaluating the health and environmental impact of engi-neered nanomaterials over their entire life; and develop strategic programs that enable r elevant risk-focused research [97].

A major regulatory problem is that whilst it is clear from in vitro test systems that nanosilver has deleterious dose- and time-dependent effects on cell function and viability at unusually low applied concentrations, such in vitro data may be of limited assistance in in vivo risk assessment. Nevertheless, it may assist in investigating pos-sible mechanisms of toxicity and add to a weight of evidence evaluation in risk assessment [98].

There is a growing consensus in the EU, the UK and Australia that regulatory defini-tions and toxicity testing of bulk substances may not accurately represent the physical and chemical characteristics of their nanoequiva-lents [108]. Compounding this problem is a lack of toxicological data, lifecycle studies or knowl-edge of optimal environmental exposure limits r egarding nanosilver and its products.

Given the extensive use of nanosilver and the ongoing controversy about whether its toxicity exceeds that of bulk silver, it conforms to the precautionary principle for government agen-cies to treat nanosilver as a new chemical (and require detailed safety data sets from manufac-turers), until it is certain that nanosilver does not possesses unique toxicological properties. Regulators should then, for example, provide clear guidance as to the circumstances in which nanoscale silver may be classified as ‘new’ for legal, regulatory and safety purposes. The existing statutory threshold levels for quantity of manufactured nanomaterials are high and unlikely to be triggered in many cases where risks could eventuate. Hence, regulators should look to lowering these thresholds or modifying them to take into account unique chemical prop-erties and toxicities of nanosilver (e.g., in the less than 5 nm size range).

Where appropriate, safety legislation should be amended to explicitly deal with nanotech-nology products. For example, introducing a category of nanopesticides may assist in avoid-ing the circuitous route currently adopted to regulate nontraditional pesticidal products (such as washing machines) that utilize nanosil-ver. In order to minimize the risk of bacterial resistance to nanosilver, systematic guidelines should be prepared that adopt similar restric-tions on unnecessary clinical use (e.g., similar to those with antibiotics), involving a staged protocol related to severity of infection for application of dressings that release high lev-els of silver ions and that demonstrate rapid b actericidal activity.

Premarketing approvals are a good regulatory strategy because they not only allow government agencies to screen for potentially harmful materi-als, but also facilitate products targeted at public goods [99]. They should be extended to nanosil-ver and its products, regardless of whether they currently belong to a category exempt from such scrutiny. REACH, for all its faults (i.e., regula-tory triggers based on tonnage of manufacture), probably represents a better model of oversight than the TSCA, chiefly because it puts the bur-den on the manufacturer to prove safety, rather than on the government to prove the risk. The safety data required should not be limited to nanosilver’s physical, chemical and toxicologi-cal properties; instead, it should (as standard-ized measures for determining these parameters become progressively available) include the shape and bioavailability of the nanoformulation in a plasma model and at different concentrations,



particle size range and mean, aggregation char-acteristics, expected lifetime in various states, biopersistence, synthesis method, crystal struc-ture, surface area and charge, antimicrobial claims, and associated novel physicochemical characteristics and properties.

It is just as important to maintain postmar-keting surveillance because new information on the lifecycle and toxicity of nanosilver is still being gathered. Given the uncertainty sur-rounding the release of increasing amounts of nanosilver into the waterways and food chain, postmarketing surveillance should be extended to all nanosilver products. Furthermore, regula-tions should guide disposal of nanosilver and its products e ncompassing its entire lifecycle.

Given that the voluntary nanomanufacturing reporting programs were a failure in the USA, the UK and in Australia, it is recommended that mandatory reporting schemes be introduced. Claims that this would compromise confidential business information or constitute an unconscio-nable financial or administrative burden seem unreasonable given the importance of facilitat-ing the ready availability of safety information across the various sectors.

Future perspectiveIn the next 10–20 years research is likely to accu-mulate regarding the unique toxicological profile of nanosilver. This may well prove that its capac-ity to bring more atoms and ions in contact with biological systems, to interfere with cellular sur-face and carrier proteins, and to damage DNA and intracellular machinery particularly in the mitochondria, creates an additional hazard upon discharge into the environment to that posed by silver in bulk form. If so, this will lead to nanosil-ver being classified as a new chemical entity with

mandatory notification and safety data genera-tion requirements imposed on manufacturers. In some jurisdictions, class action litigation will be commenced against manufacturers of nanosil-ver and governments that failed to put in place appropriate environmental protections despite knowledge of the risks.

Over the next 50–100 years, as climate change and resultant famine, social unrest and popula-tion shifts create new problems with infectious disease pandemics, nanosilver will continue to play an important role as a biocidal in health-care systems, particularly in developing nations. National and local (community) governments will increasingly utilize the capacity of nano-technology to make manufacturing a localized, rather than a globalized, process. There will be sound economic and national security interests in reducing the global transportation of manu-factured products by allowing nanofactories to generate c onsumer products in individual homes or suburbs.

Hand in hand with this will come a strength-ening of local safety, cost–effectiveness assess-ment and regulation processes. New technology will allow increasing nonexpert toxicological assessments of nanoproducts, and their impact on biosystems and human physiology. This will expose manufacturers (e.g., of nanosilver) who seek to evade the production of safety data or compliance with safety standards, increasingly vulnerable to litigation.

Nations will develop separate taxpayer-funded national testing laboratories as a means of capacity-building good public focus and regulatory expertise in young science gradu-ates, along with more rigorously critique safety assessments performed in other jurisdictions. The development of nanosilver products is

Executive summary

# Amongst the Millennium Development Goals enunciated by the United Nations there are two where silver nanoparticles, otherwise known as nanosilver, could make a direct positive contribution: providing safe drinking water and improving the lives of slum dwellers.

# Nanosilver is the nanotechnology product with the largest existing use in consumer goods, particularly in its role in removing bacteria from food and water-related products.

# Issues about the safety of nanosilver in the environment may adversely impact on its capacity to assist with the achievement of such global public goods. Of particular concern are nanosilver’s potential adverse impacts on nitrifying bacteria in sewerage systems and capacity to accumulate in the environment and disrupt food chains.

# An unresolved debate exists about whether nanosilver exerts a unique toxicity related to its increased surface area or mechanisms of cellular disruption, either enhancing release of ions at low concentrations or unrelated to ionization.

# Despite accumulating in vitro evidence of nanosilver’s cellular toxicity, in vivo and environmental toxicity data are more incomplete. # Regulators are reluctant to apply the precautionary principle in this setting. Momentum is gathering, however, for mandatory

notification to regulators of nanosilver manufacture and its treatment for regulatory purposes as a new chemical entity requiring a unique safety data set from the manufacturer.

# National and local (community) governments will increasingly utilize the capacity of nanotechnology to make manufacturing a localized, rather than a globalized, process. New technology will allow increasing nonexpert toxicological assessments of nanoproducts, and their impact on biosystems and human physiology.



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AcknowledgementsThomas Faunce wishes to acknowledge assistance from Nicola Rogers, Mark Weisner and John White for comments on an early draft.

Financial & competing interests disclosureThomas Faunce is supported by an Australian Research Council (ARC) Future Fellowship. The ARC was not involved in writing this paper. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or finan-cial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.



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