Review For reprint orders, please contact:
[email protected]
Nanosilver and global public health: international regulatory issues 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 n nanoregulation n nanosilver n nanotoxicology n silver
Thomas Faunce†1,2,3 & Aparna Watal2 Australian Research Council, Future Fellow 2 College of Law, Australian National University, Canberra, Australia 3 Medical School, College of Medicine, Australian National University, Canberra, Australia † Author for correspondence: Tel.: +61 261 253 563 Fax: +61 261 253 971
[email protected] 1
Nanosilver’s potential benefits to global public health 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. 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 applications in this context, including its role in spectrally selective coatings for solar energy absorption [1] . Nanosilver’s most significant potential contribution to such goals, however, relates to its capacity to kill bacteria that cause disease (particularly 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 nanotechnology 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 pollutants [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 electrical 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 structure 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
10.2217/NNM.10.33 © 2010 Future Medicine Ltd
Nanomedicine (2010) 5(4), 617–632
ISSN 1743-5889
617
Review
Faunce & Watal
[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 particular 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 controversial 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 silver exposed in solution and a potentially higher proportion of bioactive metallic silver (ionic silver 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 bioavailable) [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 treatment of burns, various ulcers (e.g., rheumatoid arthritis-associated leg ulcers and diabetic 618
Nanomedicine (2010) 5(4)
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, orthopedic 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 promote bacterial infection and sepsis [4] . Nanosilver is also incorporated for its antibacterial, antiviral and antifungal properties in a growing range of modern domestic or household items. It has the highest degree of commercialization of nanoparticles in consumer products, with more than 260 nanosilver products, including household appliances and cleaners, clothing (including socks and underwear), cutlery, children’s toys and personal care products (such as menstrual pads) currently on the market in the USA [102,103] . Similar findings are likely to apply to the EU, UK and Australia [104] . A typical example is Samsung’s ‘Nano Silver Health System’, which uses nanosilver 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, nanosilver can be highly toxic to cells. In vitro studies demonstrate that nanosilver is toxic to mammalian 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 phenomenon, given that colloidal silver preparations (which have always contained a certain proportion of silver in nanoparticle form) have been around for so long. It is unclear, for example, whether nanosilver has an unusual capacity for future science group
Nanosilver & global public health: international regulatory issues
attachment to cell membranes, thereby altering 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 spermatogonia of 6‑day-old mouse testes) was exposed to 15 nm nanosilver particles in a solution of phosphate buffered saline, an assay revealed significant inhibition of mitochondrial function starting 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 membranes. 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 mitochondrial 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 concentration 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 nanosilver toxicity through interference with cellular metabolism, inflammation and damage to proteins, membranes and DNA [22,23] . Decreased mitochondrial function particularly characterizes nanosilver cytotoxicity and appears to involve oxidative stress induced by thiol group interactions with the mitochondrial inner membrane, 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 protein (a key marker of DNA repair and apoptosis) after 4 h, as well as corresponding elevations in Rad51 (involved in DNA double strain breakage 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 future science group
Review
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 generation was inhibited by absence of sunlight. Most interestingly, as Ag+ concentrations increased, ROS production also increased, whereas the opposite occurred with nanosilver, with photocatalytic ROS production decreasing as nanoparticle 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 particle 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 abolishment of photosynthesis at an equimolar concentration 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 provide a unique slow-release mechanism for toxic silver ions.
Nanosilver & bacterial resistance Numerous 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 www.futuremedicine.com
619
Review
Faunce & Watal
to antibiotics, such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, enterobacteria with production of extended spectrum b‑lactamases and multiresistant Pseudomonas aeruginosa [32] . There are currently 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 formulations [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 risk In 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 conservation of biological diversity [35] . The two Millennium Development Goals most relevant in this context are Target 7a (“integrate the principles of sustainable development into country policies 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 production of bacterial resistance in hospital settings, as to its high in vitro toxicity for aquatic organisms 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 medicinal applications [32,37,38] . Nanosilver released in domestic wastewater may have a variety of fates, including being converted into ionic silver, complexing with other ions, molecules or molecular groups, agglomerating or remaining in nanoparticle form. Its potential for significant environmental toxicity revolves around its biocidal and catalytic effects on a wide range of organisms in the soil, including bacteria, fungi and earthworms, along with reaction with other toxic substances, a toxic effect on groundwater and accumulation along the food chain [39] . Wastewater treatment relies on heterotrophic micro-organisms for organic and nutrient removal, while autotrophic micro-organisms play an important role in nitrification. Nitrifying bacteria in sewerage systems are especially susceptible to inhibition by silver nanoparticles [40] . 620
Nanomedicine (2010) 5(4)
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 microbial health of the environment” [41] . However, their study on the impact of nanosilver contamination on natural bacterial assemblages in estuarine sediments was conducted over a short exposure time of 1 month and involved samples 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 currently unavailable for the purposes of nanosilver risk assessments, instead a major deficiency here being the inadequacy of government reporting requirements or manufacturer product information 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 layered 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 governed by different regulations [107] . Regulation of nanosilver in the USA is strongly influenced by the considerable existing regulatory restrictions 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/m 3 for all forms of silver [42] . The three main US federal agencies tasked with regulating the environmental and public health impacts of nanosilver are: the EPA, the US FDA and the NIOSH agency [106] . NIOSH is primarily responsible for conducting research and making recommendations to prevent work-related injuries, illnesses and deaths. It is not directly involved in the development or enforcement of regulation concerning nanosilver [109] . future science group
Nanosilver & global public health: international regulatory issues
Nanosilver & the EPA
The EPA’s regulatory framework for nanosilver 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 regulates 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 methods 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 regulate nanomaterials and the FIFRA to regulate pesticides 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 previously) indicating significant controversy regarding 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 obligations include submitting a Premanufacture Notice (PMN) to the EPA at least 90 days prior to manufacturing, or importing for a commercial 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 obligations 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 section 5(a)(2) of the TSCA. In designating new uses, EPA must consider projected production future science group
Review
volumes of the nanoformulation, possible changes in the pattern of exposure, and the prospective manner and methods of manufacturing, 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 confirm whether this is the case [54,114] . Federal agencies, 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 barrier 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 definition that does not directly take into account the novel physical and chemical properties of nanomaterials [107] . Finally, while Section 6 of the TSCA authorizes the EPA to regulate nanomaterials throughout their lifecycle from manufacture to disposal, whenever unreasonable risks become known, the EPA has barely exercized this authority postmarketing 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 containers or products; and require notification of the risk of injury to distributors and, where possible, consumers [114] .���������������������������������� Since its inception in 1976, however, 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. www.futuremedicine.com
621
Review
Faunce & Watal
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 mandates that pesticide manufacturers must register 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 bacteria 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 regulatory 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 settlement with ATEN Technology, Inc., for alleged FIFRA violations by a subsidiary, IOGEAR, Inc., which had allegedly sold unregistered pesticide products (a computer keyboard and mouse coated with nanosilver) with unverified claims that they would kill bacteria. In addition to paying the $208,000 fine, ATEN agreed to have IOGEAR cease marketing claims that its computer products were embedded with ‘nanoshield coating’ and ‘nanocoating technology’ that protected users against germs [117] . Nanosilver & the FDA
The FDA is the US federal regulatory agency responsible for protecting public health in relation to food and therapeutic goods, using legislative instruments such as the Federal Food, Drug and Cosmetic Act (FDCA) [118] .�������� ������� Of particular 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] . 622
Nanomedicine (2010) 5(4)
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 oversight
The 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, effectiveness, 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 information, 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 oversight
Of equal importance, the FDA is empowered to conduct inspections of nanosilver food and drug manufacturing establishments to ensure they are complying with mandatory good manufacturing 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 authority to require manufacturers to run a postmarket surveillance program for medical devices coated with nanosilver in order to continually monitor and test those devices [64] . Similar legislative 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 products
The 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 future science group
Nanosilver & global public health: international regulatory issues
is unsafe or ineffective [66,67] .����������������� This is a critical 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 commercialization of nanosilver in therapeutic goods. The first is the FDA’s predominant internal ideology 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 regulations are “not ‘nano ready’” and urge the FDA to “take some immediate steps to address the first wave of nanotechnology products 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 nonchemically related products in the same therapeutic 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 eroding 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 te chnological innovation [69] . future science group
Review
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 protocols for evaluating hazards to ecological receptors needed to be reassessed [70] . However, by October 2008 little had changed in the protocols and only carbon nanotubes were formally recognized as chemically different from conventional carbon compounds and subject to regulation 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 coordinate Federal nanotechnology research and development, 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 stating that EPA “intends to develop a proposed TSCA Section 8(a) rule to obtain information on the production, uses and exposures of existing nanoscale materials” [71] . These materials specifically include nanosilver [72] . Nanosilver regulation in the the EU The EU has integrated the so-called ‘precautionary 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 www.futuremedicine.com
623
Review
Faunce & Watal
nanosilver and its marketed products is governed by the REACH program [131] and a variety of directives. These include general product safety directives [74] , a medical devices directive [75] , several pharmaceuticals directives [76] ,������������������� an integrated pollution prevention and control directive (IPPC) [77], a control of major accident hazards involving dangerous substances directive (Seveso II), a water framework directive, several waste directives and biocidal products directive [78] . All these are applicable simultaneously [79,132] . Of these regulations, REACH outwardly provides the strongest demonstration of the precautionary principle [73,133] . REACH, introduced in 2007, aims to protect the environment and human health through effective identification of properties and hazards of chemical substances 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 nanoformulations 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 nanomaterials 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 hazardous [132] . The REACH system places the burden on nanosilver manufacturers, importers and downstream users to ensure and gather information 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 manufactured volumes of nanomaterials, in gram to kilogram quantities, well below the regulatory 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, 624
Nanomedicine (2010) 5(4)
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 nanomaterials 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, manufacturers 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 trigger threshold limits “be reassessed once relevant data becomes available” [137] .�������������������� A 2008 report likewise recommends a review of REACH and its product- or sector-specific regulations to facilitate their effective application to nanomaterials and the provision of adequate testing arrangements [118] . Regulation of nanosilver based on tonnage as a threshold, as proposed for chemicals under REACH, is being reconsidered by the Nanomaterials and REACH Sub-Groups [139] . Aside from REACH, the EU regulates nanoenabled therapeutic goods within the existing regulatory framework provided by its generic, nonspecific medical devices directive and pharmaceuticals 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 negative 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 future science group
Nanosilver & global public health: international regulatory issues
subject [85] . Thus, despite adopting the precautionary 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.
provide forums for constructive discussions on the issues of good practices for manufacturing, and regarding the using and disposing of nanotechnology products, with the aim of factoring these discussions into better policy outcomes [86] .
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 controls on nanotechnology that would have explicitly 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 operationalized an action plan that involved a range of regulatory measures focused on self-regulation and stakeholder engagement, as opposed to adopting 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 following sections.
Reviewing existing legislation
Voluntary notification
The 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, generating only 13 submissions over 3 years, the scheme has been far from effective [87] . Promoting nanotechnology research
The UK Research Councils are funding several projects aimed at studying a variety of safety aspects of nanotechnology, including nanosilver [87] . Related funding schemes facilitating development of nanotechnology aimed at global public health challenges are yet to fully emerge. Engaging stakeholders
By launching programs, such as Nanodialogues, the Nanotechnology Engagement Group and Small Talk, the UK government intends to future science group
Review
The 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 interpretations 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 nanochemicals because it is “unlikely that all suppliers will possess the necessary data to make an informed decision relating to whether the presence of nanoparticles suggests a new substance or an existing one” [137] . It also found that the toxicity of chemicals in the form of nanomaterials “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 projects 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 onerous 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 www.futuremedicine.com
625
Review
Faunce & Watal
research needs raised by this report, with emphasis 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 functionalities of nanomaterials. It argues that strict chemical equivalence should not preclude the need for a separate risk assessment for nanoparticle formulations [136] . This approach requires a variety of early warning systems, environmental monitoring systems, risk-handling guidelines and extensive 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 Australia Australia 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 chemicals [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 market to be separately listed (if a low level medical 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, applicants 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 assessment determine there is a case to do so [143] . The 626
Nanomedicine (2010) 5(4)
FSCode also provides a mandatory upper limit for contaminants (possibly including nanosilver) 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 regulated at the state and territory level by a range of agencies. In addition, the Australian Competition and Consumer Commission (ACCC) is responsible for product labeling in accordance with the Trade Practices Act 1974 (Cth). Despite the extensive information requirements 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 voluntary 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 initiated by NICNAS in October 2008, targeted at all manufacturers or importers of nanomaterials or products (mixtures) containing nanomaterials 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 regulators (like their counterparts in the USA and UK) have been reluctant to recognize that nanoparticles 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] . future science group
Nanosilver & global public health: international regulatory issues
The NICNAS is currently involved in a review of regulation of nanomaterials in industrial chemicals regulation in Australia. This is proposing a staged development process involving 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 criterion for “no unreasonable risk” is met on a case-by-case basis. NICNAS can also stipulate enforceable use conditions, amend these conditions or revoke the permit when new information is generated [144] .
Conclusion Significant 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 regulation 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 engineered nanomaterials over their entire life; and develop strategic programs that enable relevant 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 possible 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 definitions and toxicity testing of bulk substances may not accurately represent the physical and chemical characteristics of their nanoequivalents [108] . Compounding this problem is a lack of toxicological data, lifecycle studies or knowledge of optimal environmental exposure limits regarding nanosilver and its products. future science group
Review
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 agencies to treat nanosilver as a new chemical (and require detailed safety data sets from manufacturers), 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 properties 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 nanotechnology products. For example, introducing a category of nanopesticides may assist in avoiding the circuitous route currently adopted to regulate nontraditional pesticidal products (such as washing machines) that utilize nanosilver. In order to minimize the risk of bacterial resistance to nanosilver, systematic guidelines should be prepared that adopt similar restrictions 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 levels of silver ions and that demonstrate rapid bactericidal activity. Premarketing approvals are a good regulatory strategy because they not only allow government agencies to screen for potentially harmful materials, but also facilitate products targeted at public goods [99] . They should be extended to nanosilver and its products, regardless of whether they currently belong to a category exempt from such scrutiny. REACH, for all its faults (i.e., regulatory triggers based on tonnage of manufacture), probably represents a better model of oversight than the TSCA, chiefly because it puts the burden 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 toxicological properties; instead, it should (as standardized measures for determining these parameters become progressively available) include the shape and bioavailability of the nanoformulation in a plasma model and at different concentrations, www.futuremedicine.com
627
Review
Faunce & Watal
particle size range and mean, aggregation characteristics, expected lifetime in various states, biopersistence, synthesis method, crystal structure, surface area and charge, antimicrobial claims, and associated novel physicochemical characteristics and properties. It is just as important to maintain postmarketing surveillance because new information on the lifecycle and toxicity of nanosilver is still being gathered. Given the uncertainty surrounding the release of increasing amounts of nanosilver into the waterways and food chain, postmarketing surveillance should be extended to all nanosilver products. Furthermore, regulations should guide disposal of nanosilver and its products encompassing 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 unconscionable financial or administrative burden seem unreasonable given the importance of facilitating the ready availability of safety information across the various sectors.
Future perspective In the next 10–20 years research is likely to accumulate regarding the unique toxicological profile of nanosilver. This may well prove that its capacity to bring more atoms and ions in contact with biological systems, to interfere with cellular surface 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 nanosilver being classified as a new chemical entity with
mandatory notification and safety data generation requirements imposed on manufacturers. In some jurisdictions, class action litigation will be commenced against manufacturers of nanosilver 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 population shifts create new problems with infectious disease pandemics, nanosilver will continue to play an important role as a biocidal in healthcare systems, particularly in developing nations. National and local (community) governments will increasingly utilize the capacity of nanotechnology 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 manufactured products by allowing nanofactories to generate consumer products in individual homes or suburbs. Hand in hand with this will come a strengthening of local safety, cost–effectiveness assessment 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 taxpayerfunded national testing laboratories as a means of capacity-building good public focus and regulatory expertise in young science graduates, 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.
628
Nanomedicine (2010) 5(4)
future science group
Nanosilver & global public health: international regulatory issues
likely to involve a mixture of private and public funding. Both of these systems will actively promote the creation, development and dissemination of safe nanotechnologies that offer global public benefit. Acknowledgements Thomas Faunce wishes to acknowledge assistance from Nicola Rogers, Mark Weisner and John White for comments on an early draft.
Bibliography Papers of special note have been highlighted as: n of interest nn of considerable interest 1
2
nn
3
4
n
5
n
6
Rand RB, Peumans P, Forrest SR: Long-range absorption enhancement in organic tandem thin-film solar cells containing silver nanoclusters. J. Appl. Phys. 96, 7519–7526 (2004).
Review
Financial & competing interests disclosure Thomas 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 financial 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.
7
Lea MC: Allotropic forms of silver. Am. J. Sci. 37, 476 (1889).
8
Russell AD, Hugo WB: Antimicrobial activity and action of silver. Prog. Med. Chem. 31, 351–370 (1994).
caused raised liver enzymes and argyria-like symptoms in burn patient. J. Trauma 60(3), 648–652 (2006). 20 Choi O, Hu Z: Size dependent and reactive
oxygen species related nanosilver toxicity to nitrifying bacteria. Environ. Sci. Technol. 42, 4583–4588 (2008).
9
Klasen HJ: Historical review of the use of silver in the treatment of burns 1. Early uses. Burns 26, 117–130 (2000).
21
10
Salamanca-Buentello F, Persad DL, Court EB, Martin DK, Daar AS, Singer PA: Nanotechnology and the developing world. PLoS Med. 2(5), 383–386 (2005).
Silver S: Bacterial silver resistance: molecular biology and uses and misuses of silver compounds. FEMS Microbiol. Rev. 27, 341–353 (2003).
nn
11
Valuable summary of how nanotechnology may assist in remedying public health problems in the developing world.
Lansdown AB: Silver in health care: antimicrobial effects and safety in use. Curr. Probl. Dermatol. 33, 17–34 (2006).
22 Brunner TJ, Wick P, Manser P et al.:
12 Fox CL Jr: Silver sulfadiazine – a new topical
Akhavan O, Ghaderi E: Enhancement of antibacterial properties of Ag nanorods by electric field. Sci. Technol. Adv. Mater. 10, 015003 (2009).
13 Wijnhoven SWP, Peijnenburg WJGM,
Chen X, Schluesener HJ: Nanosilver: A nanoproduct in medical application. Toxicol. Lett. 176(1), 1–12 (2008). Valuable study on the ctyotoxicity of nanosilver and other nanomaterials. It discusses routes of nanosilver exposure for human beings, its impact on the human tissue and mechanism of cytoxicity. The paper evidences how increased and unchecked use of nanosilver can directly jeopardize public health.
n
Another valuable study on how increasing numbers of nanosilver products may become a matter of significant public health and environmental concern. The authors theorize that the toxic effects of nanosilver are chiefly due to silver ions.
14
International Standards Organisation: Standard ISO/TS 27687:2008 ISO (2008).
Soto KF, Carrasco A, Powell TG, Garza KM, Murr LE: Comparative in vitro cytotoxicity assessment of some manufactured nanoparticulate materials characterized by transmission electron microscopy. J. Nanopart. Res. 7, 145–169 (2005).
15
Stafford N: New nano rule for EU cosmetics. Chem. World 7(1), 6 (2010).
16
Elechiguerra JL, Burt JL, Morones JR et al.: Interaction of silver nanoparticles with HIV-1. J. Nanobiotechnol. 3, 6–16 (2005).
Interesting comparison of toxicity of different nanoparticles, including nanosilver. Nanosilver appeared to show a higher relative cytotoxicity at lower concentrations than chrysolite asbestos.
17
Atiyeh BS, Costagliola M, Hayek SN, Dibo SA: Effect of silver on burn wound infection control and healing: review of the literature. Burns 33(2), 139–148 (2007).
future science group
Hussain SM, Hess KL, Gearhart JM, Geiss KT, Schlager JJ: In vitro toxicity of nanoparticles in BRL 3A rat liver cells. Toxicol. In vitro 19, 975–983 (2005).
18
Landsdown ABG: Critical observations on the neurotoxictiy of silver. Crit. Rev. Toxicol. 37(3), 237–250 (2007).
19
Trop M, Rodl NS, Hellbom B, Kroell W, Goessler W: Silver coated dressing Acticoat
www.futuremedicine.com
Interesting study appearing to show that nanosilver interferes with cellular metabolism rather than the cell membrane. In vitro cytotoxicity of oxide nanoparticles: comparison to asbestos, silica, and the effect of particle solubility. Env. Sci. Technol. 40(14), 4374–4381 (2006).
therapy for Pseudomonas in burns. Arch. Surg. 96, 184–188 (1968). Herberts CA et al.: Nano-silver – a review of available data and knowledge gaps in human and environmental risk assessment. Nanotoxicology 3(2), 109–138 (2009).
Braydich-Stolle L, Hussain S, Schlager JJ et al.: In vitro cytotoxicity of nanoparticles in mammalian germline stem cells. Toxicol. Sci. 88(2), 412–419 (2005).
23 Nel A, Xia T, Li N: Toxic potential of
materials at the nanolevel. Science 311, 622–627 (2006). 24 Ahamed M, Karns M, Goodson M et al.:
DNA damage response to different surface chemistry of silver nanoparticles in mammalian cells. Toxicol. Appl. Pharmacol. 233, 404–410 (2008). 25 Ji JH, Jung JH, Kim SS et al.:
Twenty-eight-day inhalation toxicity study of silver nanoparticles in SpragueDawley rats. Inhal. Toxicol. 19, 857–871 (2007). 26 Hidalgo E, Dominguez C: Study of
cytotoxicity mechanisms of silver nitrate in human dermal fibroblasts. Toxicol. Lett. 98, 169–179 (1998). 27 Choi O, Hu Z: Size dependent and reactive
oxygen species related nanosilver toxicity to nitrifying bacteria. Environ. Sci. Technol. 42, 4583–4588 (2008). nn
Valuable study appearing to show that nanosilver particles less than 5 nm in size inhibited nitrification in bacteria more than a comparative amount of silver ions. As concentrations increased, the generation of reactive oxygen species increased for silver ions, but not for nanosilver.
629
Review
Faunce & Watal
28 Roh JY, Sim SJ, Yi J et al.: Ecotoxicity of
silver nanoparticles on the soil nematode Caenorhabditis elegans using functional ecotoxicogenomics. Env. Sci. Technol. 43, 10–18 (2009). nn
of sulfide and ligand strength in controlling nanosilver toxicity. Water Res. 43(7), 1879–1886 (2009). 41 Bradford A, Handy RD, Readman JW,
Atfield A, Muhling M: Impact of silver nanoparticle contamination on the genetic diversity of natural bacterial assemblages in estuarine sediments. Env. Sci. Technol. 43, 4535 (2009).
Study showing that nanosilver particles exerted a more deleterious impact on gene expression in a soil nematode than silver ions.
29 Navarro E, Piccapietra F, Wagner B et al.:
Toxicity of silver nanoparticles to Chlamydomonas reinhardtii. Environ. Sci. Technol. 42(23), 8959–8964 (2008). n
40 Choi O, Cleuenger TE, Deng BL et al.: Role
Interesting study suggesting that nanosilver remained more toxic to fresh water algae at lower concentrations and for longer than silver ions.
31
Silver S, Phung LT, Silver G: Silver as biocides in burn and wound dressings and bacterial resistance to silver compounds. J. Ind. Microbiol. Biotechnol. 33, 627–634 (2006).
32 Morones JR, Elechiguerra JL, Camacho A
et al.: The bactericidal effect of silver nanoparticles. Nanotechnology 16, 2346–2353 (2005). 33 Feng QL, Wu J, Chen GQ, Cui FZ,
Kim TM, Kim JOA: Mechanistic study of the antibacterial effect of silver ions on Escherichia coli and Staphylococcus aureus. J. Biomed. Mater. Res. 52, 662–668 (2000).
health effects of silver and silver compounds: a review. Ann. Occup. Hyg. 49(7), 575–585 (2005). 43 Toxic Substances Control Act (TSCA) 15
U.S.C. §2601 (1976).
37 Benn TM, Westerhoff P: Nanoparticle silver
released into the environment from commercially available stock fabrics. Environ. Sci. Technol. 42(11), 4133–4139 (2008). 38 Richardson SD: Water analysis: emerging
contaminants and current issues. Anal. Chem. 81, 4653 (2009). 39 Blaser SA, Scheringer AM, MacLeod M,
Hungerbühler K: Estimation of cumulative aquatic exposure and risk due to silver: contribution of nano-functionalized plastics and textiles. Sci. Total Environ. 390, 396–409 (2008).
630
(the Act) 21 U.S.C § 355(c) (1938). 68 US FDA: Report of the Subcommittee on
Science and Technology: FDA Science and Mission at Risk. US FDA, Science Board, 1–7 (2007). 69 Fairbrother A, Fairbrother JR: Are
environmental regulations keeping up with innovation? A case study of the nanotechnology industry. Ecotoxicol. Environ. Safety 72, 1327–1320 (2009).
46 The Clean Water Act (CWA) 33 U.S.C. §1251
70 US Federal Register: Notices. 73(No. 212),
47 The Resource Conservation and Recovery Act
(RCRA) 42 U.S.C. §6901 (1976).
64946 (2008). 71 US Federal Register: Rules and Regulations.
48 Toxic Substances Control Act (TSCA)
15 U.S.C. §3(2) (1976).
74(No. 120), 64946–64948 (2009). 72 US Federal Register: Rules and Regulations.
49 Toxic Substances Control Act (TSCA)
15 U.S.C. §3(9) (1976).
74(No. 120), 64948 (2009). 73 European Commission: Communication
50 Toxic Substances Control Act (TSCA)
from the Commission on the Precautionary Principle. Communication of the European Commission, COM 1 (2000).
15 U.S.C. §8(b) (1976). 51
Toxic Substances Control Act (TSCA) 15 U.S.C. §5(a) (1976).
52
US Federal Register: Rules and Regulations. 74(No. 120), 29982 (2009).
74
and the potential for regulatory action by the USEPA. Environ. Claims J. 21(3), 200–210 (2009).
regulations. Nat. Nanotechnol. 2, 333–334 (2007). 76 Medicinal Products Directive 2001/83/EC. 77 Council Directive 2008/1/EC concerning
54 Toxic Substances Control Act (TSCA) 55
integrated pollution prevention and control.
15 U.S.C. §2601 sec. 4 (1976).
78 Biocidal Products Directive 98/8/EC.
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) 7 U.S.C. §3 (1996).
79 Regulation 726/2004 on authorization and
supervision of medicinal products for human and veterinary use, Directive 2001/83/EC on medicinal products for human use, Directive 93/42/EEC concerning medical devices, Directive 90/385/EEC relating to active implantable medical devices, and Directive 98/79/EC on in vitro diagnostic medical devices (2004).
56 Federal Insecticide, Fungicide, and Rodenticide
Act (FIFRA) 7 U.S.C. §136 (t)(2) (1996). 57 Federal Insecticide, Fungicide, and Rodenticide
Act (FIFRA) 7 U.S.C. §136 (u)(1) (1996). 58 Owen R, Handy R: Formulating the problems
for environmental risk assessment of nanomaterials. Environ. Sci. Technol. 41(16), 5582–5588 (2007). 59 Helmus MN: The need for rules and
regulations. Nat. Nanotechnol. 2, 333–334 (2007). 60 Federal Food, Drug, and Cosmetic Act
(the Act) 21 U.S.C. § 201(p) (1938). 61
Consumer Products Directive 2001/95/EC2.
75 Helmus MN: The need for rules and
53 Mason EF: Nanotechnology, nanomaterials
36 Brown CL, Parchaso E, Thomson JK,
Luoma SN: Assessing toxicant effects in a complex estury: a case study of effects of silver on reproduction in the bivalve Potamocorbula amurensis in San Francisco bay. J. Hum. Ecol. Risk Assess. 9, 96–119 (2003)
(the Act) 21 U.S.C § 360(f) (1938). 67 Federal Food, Drug, and Cosmetic Act
Clean Air Act (CAA) 42 U.S.C. §7401 (1970). (1972).
Federal Food, Drug, and Cosmetic Act (the Act) 21 U.S.C § 355, 351–355 (1938).
66 Federal Food, Drug, and Cosmetic Act
Act (FIFRA) 7 U.S.C. §136 (1996). 45
resistance to silver in wound care and medical devices. J. Wound Care 16(1), 15–19 (2007). Sutherland WJ, Clout M, Côté IM et al.: A horizon scan of global conservation issues for 2010. Trends Ecol. Evol. 25(1), 1–7 (2010).
(the Act) 21 U.S.C § 360(l) (1938). 65
44 Federal Insecticide, Fungicide, and Rodenticide
34 Landsdown AB, Williams A: Bacterial
35
(the Act) 21 U.S.C. § 360(i) (1938). 64 Federal Food, Drug, and Cosmetic Act
42 Drake PL, Hazelwood KJ: Exposure-related
30 Hwang ET, Lee JH, Chae YJ et al.: Analysis
of the toxic mode of action of silver nanoparticles using stress-specific bioluminescent bacteria. Small 4, 746–750 (2008).
63 Federal Food, Drug, and Cosmetic Act
Federal Food, Drug, and Cosmetic Act (the Act) 21 U.S.C. § 360(e) (1938).
62 Federal Food, Drug, and Cosmetic Act
80 REACH Directive 2006/121/EC. Article 34
(2006). 81
REACH Directive 2006/121/EC. Article 7.1 (2006).
82 Chaudhry Q, Blackburn J, Floyd P et al.: A
Scoping Study to Identify Gaps in Environmental Regulation for the Products and Applications of Nanotechnologies. Department for Environment, Food and Rural Affairs (2006).
(the Act) 21 U.S.C. § 704 (1938). Nanomedicine (2010) 5(4)
future science group
Nanosilver & global public health: international regulatory issues
83 Franco A, Hansen SF, Olsen SI: Limits and
prospects of the “incremental approach” and the European legislation on the management of risks related to nanomaterials. Regul. Toxicol. Pharm. 48, 171–183 (2007). 84 Linkov I, Satterstrom FK, Corey LM:
Nanotoxicology and nanomedicine: making hard decisions. Nanomed. Nanotechnol. Biol. Med. 4, 167–171 (2008). 85 Hansen SF, Larsen BH, Olsen SI, Baun A:
Categorization framework to aid hazard identification of nanomaterials. Nanotoxicology 1, 243–250 (2007). 86 Dorbeck-Jung BR: What can prudent
public regulators learn from the United Kingdom government’s nanotechnological regulatory activities?’ NanoEthics 1, 263–268 (2007). 87 REACH Enforcement Regulations, UK
(2008). 88 Bowman DM, Calster GV: Does REACH go
too far? Nat. Nanotechnol. 2, 525 (2007). 89 Hansen SF, Maynard A, Baun A, Tickner JA:
Late lessons from early warnings for nanotechnology. Nat. Nanotechnol. 3, 444–447 (2007). 90 Food Standards Australia New Zealand Act
1991 (Cth) (1991). 91
Industrial Chemicals (Notification and Assessment) Act 1989 (Cth) (1989).
92 Agricultural and Veterinary Chemicals (Code)
Act 1994 (Cth); Agricultural and Veterinary Chemicals Administration Act 1992 (Cth). 93 Therapeutic Goods Act 1989 (Cth) § 16, 23
(1989). 94 Therapeutic Goods (Medical Devices)
Regulations 2002 (Cth) reg 5.3 (2002). 95 National Nanotechnology Strategy Taskforce:
Options for a national nanotechnology strategy – report to Minister Industry, Tourism and Resources. 32 (2006). 96 Dreher KL: Health and environmental impact
of nanotechnology: toxicological assessment of manufactured nanoparticles. Toxicol. Sci. 77, 3–5 (2004). 97 Maynard AD, Aitken RJ, Butz T et al.: Safe
handling of nanotechnology. Nature 444, 267–269 (2006). 98 Drew R, Frangos J, Hagen T: Engineered
nanomaterials: a review of the toxicology and health hazards. Safe Work Australia (2009). 99 Faunce TA, White J, Matthaei K:
Integrated research into the nanoparticleprotein corona: a new focus for safe, sustainable and equitable development of nanomedicines. Nanomedicine 3(6), 859–865 (2008).
future science group
Websites 101 United Nations: Millennium development
goals. www.un.org/millenniumgoals/ (Accessed 8 February 2010) 102 Kimbrell GA: Citizen petition for rulemaking
to the United States Environmental Protection Agency. International Center for Technology Assessment. www.icta.org/nanoaction/doc/CTA_nanosilver%20petition__final_5_1_08.pdf (Accessed 9 May 2009) 103 Woodrow Wilson Institute: Inventory on
consumer nanoproducts. (2009). www.nanotechproject.org/inventories (Accessed 9 September 2009) 104 The UK Government: Response to The
Royal Commission on Environmental Pollution (RCEP) Report “Novel materials in the environment: the case of nanotechnology”. 10–11 (2009). [Updated 21 May 2009]. www.rcep.org.uk/reports/27-novel%20 materials/27-novelmaterials.htm (Accessed 9 September 2009) 105 Silver Institute: Silver facts: silver in the home
(2009). www.silverinstitute.org/in_home.php (Accessed 15 Sept 2009) 106 Luoma S: Silver nanotechnologies and the
environment: old problems or new challenges? Project on Emerging Nanotechnologies, 1–10 (2008). www.nanotechproject.org/publications/ archive/silver/ (Accessed 6 March 2010) 107 Davies JC: EPA and nanotechnology:
oversight for the 21st century. Woodrow Wilson International Center for Scholars Project on Emerging Nanotechnologies, 20 (2007). www.nanotechproject.org/publications/ archive/epa_nanotechnology_oversight_ for_21st/ (Accessed 14 September 2009) 108 United States Environmental Protection
Agency: Priority pollutants. www.epa.gov/waterscience/methods/ pollutants.htm (Accessed 6 March 2010) 109 NIOSH: Strategic plan for NIOSH
nanotechnology. www.cdc.gov/niosh/topics/nanotech/strat_ plan.html (Accessed 10 September 2009) 110 US EPA: Summary of the Toxic Substances
Control Act. www.epa.gov/regulations/laws/tsca.html (Accessed 14 September 2009)
www.futuremedicine.com
Review
111 US EPA: Summary of the Federal Insecticide,
Fungicide, and Rodenticide Act. www.epa.gov/regulations/laws/fifra.html (Accesssed 14 September 2009) 112 Sadowsky D: Regulation of nanotechnology:
a TSCA perspective (2006). www.eli.org/Program_Areas/Events/ nanotech_05.19.06.cfm (Accessed 14 September 2009) 113 US EPA: TSCA inventory status of nanoscale
substances – general approach. 1–2 (2007). www.epa.gov/oppt/nano/nmspinventorypaper.pdf (Accessed 14 September 2009). 114 Schierow L: The Toxic Substances Control
Act (TSCA): implementation and new challenges. Congressional Research Service. 3 (2007). http://assets.opencrs.com/rpts/ RL34118_20080718.pdf (Accessed 14 September 2009) 115 Brooks E: Evolution of risk management of
existing chemicals under TSCA. In: TSCA at Twenty, Chemicals in the Environment: Public Access Information. 4 (1996). www.epa.gov/oppt/cie/archive/issue04j.htm (Accessed May 2010) 116 Kinney J: EPA to regulate nanoscale silver
used in washing machines to kill bacteria. Daily Environment (2006). www.nrdc.org/media/docs/061127.pdf (Accessed 14 September 2009) 117 USEPA: US EPA fines Southern California
technology company $208,000 for ‘nano coating’ pesticide claims on computer peripherals. USEPA Region 9 press release, 5 March 2008. http://yosemite.epa.gov/opa/admpress.nsf/2dd 7f669225439b78525735900400c31/16a19049 2f2f25d585257403005c2851!OpenDocument 118 FDA: Federal Food, Drug, and Cosmetic Act
(FD&C Act). (2009). www.fda.gov/RegulatoryInformation/ Legislation/ FederalFoodDrugandCosmeticActFDCAct/ default.htm (Accessed 24 September 2009). 119 FDA: Centers & Offices. (2009).
www.fda.gov/AboutFDA/CentersOffices/ default.htm (Accessed 24 September 2009) 120 Taylor M: Regulating the products of
nanotechnology: does FDA have the tools it needs? Woodrow Wilson International Center for Scholars Project on Emerging Nanotechnologies. 7 (2006). www.wilsoncenter.org/index.cfm?topic_ id=166192&fuseaction=topics.event_ summary&event_id=202902 (Accessed 14 September 2009)
631
Review
Faunce & Watal
121 FDA: New Drug Application (NDA). (2009).
www.fda.gov/Drugs/ DevelopmentApprovalProcess/ HowDrugsareDevelopedandApproved/ ApprovalApplications/ NewDrugApplicationNDA/default.htm (Accessed 24 September 2009). 122 Inside Washington Publishers: Senate
Environment Panel Expands focus on nanotechnology. Inside EPA’s risk policy report. (2006). http://environmentalnewsstand.com/ (Accessed 14 September 2009). 123 IFT International Nanoscience Conference.
Nanotech Safety. www.foodproductiondaily.com/QualitySafety/FDA-we-can-handle-nanotech-safety (Accessed 23 September 2009) 124 US FDA: Nanotechnology Task Force. A
Report of the US FDA Nanotechnology Task Force. (2007). www.fda.gov/downloads/ScienceResearch/ SpecialTopics/Nanotechnology/ucm110856. pdf (Accessed 14 September 2009) 125 Marchant G, Sylvester D, Abbott K:
Nanotechnology regulation: The United States approach. 196–197 (2007). http://ssrn.com/abstract=1305256 (Accessed 24 September 2009) 126 US EPA: Draft Nanomaterial Research
Strategy (NRS). 41–42 (2008). http://nepis.epa.gov/Exe/ZyPURL. cgi?Dockey=P1000I4A.txt (Accessed 14 September 2009) 127 US EPA: Petition for rulemaking requesting
EPA regulate nanoscale silver products as pesticides; extension of comment period. (2009). www.epa.gov/EPA-PEST/2009/January/ Day-14/p622.htm (Accessed 24 September 2009) 128 National Nanotechnology Initiative. About
the NNI – home. www.nano.gov/html/about/home_about. html (Accessed 13 September 2009) 129 US EPA: Nanoscale Materials Stewardship
Program interim report. 3, 6–8 (2009). www.epa.gov/oppt/nano/nmsp-interimreport-final.pdf (Accessed 13 September 2009)
632
130 Schlyter C: European Commission’s
Committee on the Environment, Public Health and Food Safety Report on Regulatory Aspects of Nanomaterials. (2008). www.europarl.europa.eu/sides/getDoc. do?pubRef=-//EP// NONSGML+REPORT+A6-20090255+0+DOC+PDF+V0//EN (Accessed 13 September 2009) 131 Directive 2006/121/EC of the European
Parliament and of the Council. http://reach-compliance.eu/english/ legislation/reach-legislation.html (Accessed 2 September 2009) 132 European Commission: Communication
from the Commission to the European Parliament, the Council and the European Economic and Social Committee on Regulatory Aspects Of Nanomaterials. 7 (2008). http://eur-lex.europa.eu/LexUriServ/ LexUriServ. do?uri=COM:2008:0366:FIN:en:PDF (Accessed 2 September 2009) 133 Directive 2006/121/Ec of the European
Parliament and of the Council. Article 1(1). http://reach-compliance.eu/english/ legislation/reach-legislation.html (Accessed 2 September 2009) 134 Directive 2006/121/EC of the European
Parliament and of the Council. Article 1(3). http://reach-compliance.eu/english/ legislation/reach-legislation.html (Accessed 2 September 2009) 135 European Commissions’ Scientific
Committee on Emerging and Newly Identified Health Risks: The synthesis report. (2006). http://ec.europa.eu/health/ph_risk/ committees/ 04_scenihr/scenihr_cons_01_ en.htm (Accessed 2 September 2009) 136 Royal Commission on Environmental
Pollution: Novel materials in the environment: the case of nanotechnology. 60–65 (2008). www.official-documents.gov.uk/document/ cm74/7468/7468.pdf (Accessed 12 September 2009) 137 Frater L, Stokes E Lee R, Oriola T: Novel
materials in the environment: the case of nanotechnology. (2006).
Nanomedicine (2010) 5(4)
www.berr.gov.uk/files/file36167.pdf (Accessed 12 September 2009) 138 DSilva J, Calster GV: Regulating
nanomedicine: a European perspective. 1–5 (2008). http://precedings.nature.com/ documents/2388/version/1/files/ npre20082388-1.pdf (Accessed 23 September 2009) 139 The UK Government: Response to The Royal
Commission on Environmental Pollution (RCEP) Report “Novel Materials in the Environment: The Case Of Nanotechnology”. 11 (2009). www.rcep.org.uk/reports/27-novel%20 materials/27-novelmaterials.htm (Accessed 9 September 2009) 140 Royal Society and the Royal Academy of
Engineering. Report on nanoscience and nanotechnologies. 43, 46, 50, 80, 85 (2004). http://royalsociety.org/WorkArea/ DownloadAsset.aspx?id=4294970333 (Accessed 15 September 2009) 141 Therapeutic Goods Act 1989 (Cth).
www.comlaw.gov.au/ComLaw/Legislation/ ActCompilation1.nsf/0/1F0596D49BF6AE2 7CA2576F200209FC6/$file/ TherapeuticGoods1989_WD02.pdf (Accessed 1 September 2009) 142 Therapeutic Goods Administration: Medicine
regulation and the TGA. www.tga.gov.au/DOCS/HTML/medregs. htm (Accessed 2 October 2009) 143 Food Standards Australia and New Zealand:
small particles, nanotechnology and food. www.foodstandards.gov.au/ scienceandeducation/factsheets/ factsheets2008/smallparticlesnanote3923.cfm (Accesssed 2 October 2009) 144 National industrial chemical notification and
assessment scheme: nanotechnologystakeholder consultation. Department of Health and Ageing. www.nicnas.gov.au/Current_Issues/ Nanotechnology/Stakeholder_Consultation. asp (Accessed 10 March 2010) 145 Swiss Report Reinsurance Company:
Nanotechnology: small matter, many unknowns. (2004). www.swissre.com (Accessed 15 August 2009)
future science group