Nanomedicine new solutions or new problems? ACKNOWLEDGEMENTS

Author: Rye Senjen, PhD Editors: Maria José Amaral, PhD (HCWH Europe), Mary Taylor With special thanks to: Aïda Ponce, PhD (European Trade Union Institute), Anja Leetz (HCWH Europe), Erik Petersen, MD (International Society of Doctors for the Environment - Germany), Grazia Cioci (HCWH Europe), Louise Sales (Friends of the Earth - Australia), Peter Orris, MD, MPH (University of Illinois at Chicago School of Public Health), Ruth Stringer (HCWH) and Ted Schettler, MD, MPH (Science and Environmental Health Network)

Copyright of images: HCWH Europe (Figure 1 and 2) | Flickr /Argonne National Laboratory (p.1, 5 and Laboratory (p.22 and 36) | SXC /q83 (p.25), /Pacco (p.33), /Kurhan (p.35) | Wikimedia Commons /Hasan Zulic (p.30), /Raysonho (p.39)

Design: Mariana Rei, Portugal | http://marianarei.pt.vu Printer: Art & Print, Belgium Printed on 100% recycled paper using vegetable based ink Published December 2013 TABLE OF CONTENTS

FOREWORD 3

EXECUTIVE SUMMARY 5

INTRODUCTION 7

7 1.2 What are nanomaterials? 8 1.3 Nanomedicine has the potential to revolutionise healthcare 9 10 1 11

NANOMEDICINE – AN EMERGING FIELD 12

12 14 16 2 18 3 CASE STUDY: NANOSILVER IN NANOMEDICINE 19

1 POTENTIAL RISKS FOR HUMAN HEALTH AND THE ENVIRONMENT 22

4.1 Human health concerns 22 24 4.3 Environmental concerns 26 4 28

CLARIFYING THE REGULATORY PATHWAY 31

31 5.2 Nanomaterials under REACH 31 5.3 Medicinal product or medical device? 32 34 34 5.6 Nanowaste 5 35 6 CONCLUSIONS AND RECOMMENDATIONS OF HCWH 36 7 REFERENCES 39

2 FOREWORD

“Real knowledge is to know the extent precautionary principle, we should improve of one’s ignorance.” Confucius the European regulation to start covering nanomaterials and nanomedicine, identify “Doubt grows with knowledge.” and label nanomaterials in products, and Johann Wolfgang von Goethe prioritise research to address safety concerns The world of nanotechnology is a fascinating of nanomedicine products. one. The use of nanoscale technology in Instead we observe a slow, haphazard medicine is already being used in medical approach by the European Commission devices and medicine. We have learned how to manipulate tiny molecules and risks related to nanomaterials. This report take advantage of the novel properties hopes to contribute to the debate in Europe that materials exhibit at this scale, without and provide some extra momentum to the questioning aspects, such as on human health processes here. It wants to shine a light on a not very well-known fact: patients and health science and commercial interests are leaping workers are already exposed to nanomaterials even though we are quite ignorant of regulatory framework. As our understanding the long-term impacts on health and the and knowledge of the impact of nanoscale environment. The potential of and the risks of products grows we only gradually turn the nanotechnology and nanomedicine need to focus of research towards impacts. be openly researched, analysed, debated It is already ten years since the UK’s and regulated. Royal Society and the Royal Academy of Health Care Without Harm is a global non- Engineering’s report on nanoscience and nanotechnologies pointed out that some transform the healthcare sector worldwide, without compromising patient safety or care, precautionary basis. Since then many reports so that it is ecologically sustainable and no on nanomaterials from various institutions longer a source of harm to public health and have been published with similar calls. Our the environments. This report is part of Health report on nanomaterials and nanomedicine Care Without Harm’s work in Europe to raise in healthcare is no different: while awareness about safer products, materials acknowledging that nanomedicine may bring and chemicals in healthcare. We want to some improvements in delivering treatment ensure that patients and workers have full and in healthcare outcomes, we need to apply access to information about chemicals used some fairly fundamental rules which should in healthcare and can participate in decisions govern our handling and development about exposure to chemicals. of nanomaterials. Keeping in mind the

3 In a world that is facing an unprecedented with lead, asbestos and DDT. Instead let us global economic, social and environmental learn from mistakes in the past: we need to crisis we need to question short-term be transparency on data to manage risks political action, our response to science and and adapt our legislation speedily to protect regulation and how we conduct science and humans and the environment. We need action run businesses. and not delay!

Let’s not repeat history with environmental disaster and human cost, such as occurred Anja Leetz Executive Director, Health Care Without Harm Europe

4 EXECUTIVE SUMMARY

Nanotechnology, the science and business may be very useful, changing materials at this of manipulating matter at the atomic scale, scale can also result in the introduction of new is positioned to initiate the next industrial toxicological risks. revolution. Already, nanotechnology products While a greater surface reactivity and are starting to be used in many areas of solubility or the ability to cross biological everyday life, including in the healthcare barriers such as the blood-brain barrier may sector. A wide variety of commercial be desirable behaviours for a nanoformulated applications are already on the market, drug, these properties may be less desirable and continuing investment in research and development will undoubtedly lead to further patient or if the drug enters the environment. innovation and a multitude of uses. It is therefore essential to understand and In the healthcare sector, nanomaterials offer monitor the bioavailability, bioaccumulation, the prospect of a wide range of medical toxicity and/or environmental transformations applications, such as improved drug solubility, and interactions of nanomaterials. Currently, drug delivery systems, cellular and tissue it appears that standard risk assessment repair systems, diagnostic and imaging procedures are inappropriate for dealing with tools, and therapeutic medicines that can nanomaterials and tools for environmental monitoring of such tiny materials have not yet patient’s body. Nanoscale healthcare and been developed. pharmaceutical applications and products This report gives an overview of (collectively known as nanomedicine) are nanomedicine in general with particular becoming more prevalent and a number of emphasis on environmental and human products have already reached clinical use. health risks, as well as raising regulatory

Nanomaterials are engineered to take issues that need to be addressed in order advantage of unique properties at the for nanomedicine to deliver on its promises nanoscale (where at least one dimension without unduly introducing new risks. is measured in billionths of a metre). Size Health Care Without Harm believes that is a key property of nanomaterials and nanomedicine may offer advantages nanomedicines because it confers a large and innovative solutions to some of our increase in surface area, which in turn results current health problems. However, we in novel properties of the material when are also concerned that some of the new compared to the same material at a larger properties of nanomaterial products, while scale. Thus a nanomaterial may have greater desirable from a strictly clinical perspective, chemical and/or biological reactivity or can introduce new risks for human health catalytic activity. While these new properties and the environment. It is impossible for

5 nanomedicines to be completely contained of the need for safe waste disposal of within a clinical/healthcare setting and it is nanomaterials. imperative that their whole lifecycle is taken Nanomaterial characteristics need to into consideration. Unintentional exposure of workers and associates and environmental appropriate testing methodologies. contamination may arise during manufacture, Research is necessary to both address use and waste disposal, leading to possible health and environmental impacts which are persistence of nanomaterials in humans and the environment; and to develop given the gaps in knowledge, understanding guidelines and tools for the detection and and regulatory control. monitoring of nanomaterials and their effects The European Union chemical legislation on human health and the environment. The entire lifecycle of nanomedicines, chemicals and does not explicitly recognise including manufacture, disposal and possible that such materials can have very different environmental impacts, must be taken into properties from the parent “bulk” chemicals. Given the extraordinary characteristics of risks. For example: nanomaterials, Health Care Without Harm ¬ Guidelines to assess end-of-life believes that they should be regarded as new management options are needed, taking substances for the purposes of regulation. into account toxicity and environmental fate; ¬ The use of nano-based cleaners and disinfectants should be discouraged proposed. These are further elaborated in wherever feasible as their use will Chapter 6, but are given in summary here: contribute to the exacerbation of The precautionary principle must underline antibacterial resistance resistance, along the regulatory approach to nanomaterials. with other unknown consequences for the The limitations of EU regulatory frameworks environment. must be addressed: Patients, workers and communities need full ¬ access to information and to be included in new substances in EU legislation; decision-making processes. This would include: ¬ should not ¬ An EU register listing the production, restrict the size threshold to 100 nm; import and use of nanomaterials; ¬ REACH should take into consideration a ¬ Compulsory labelling of all need for lower threshold requirements for nanomedicine products; nanomaterials (i.e., less than 100 g); ¬ Public participation in decisions relating ¬ REACH should require to the exposure of patients, workers and data for nanomaterials; communities to nanomaterials. ¬ Nanomedicines that combine both pharmacological and mechanical functions should be regulated strictly, recognising the risks of both intentional and unintentional releases; ¬ Waste management legislation and guidance should be reviewed in light

6 INTRODUCTION 1

1.1 The promise of nanotechnology and regenerative medicine. Proposed European development priorities include Nanotechnology, the science and business of insulin measurement and delivery by nano- manipulating matter at the atomic, molecular enabled devices, 3-D nanomaterials for 1 and macromolecular scale , is positioned to stem cell immobilisation at site of injury and initiate the next industrial revolution. Billions image-guided implantation of advanced of euros are being funnelled into research neurostimulators, to name just a few4. and development around the world, including in the EU2, with the prospect of nanoscale But with new technologies come new technologies and materials being used in responsibilities, such as the need to assess the many diverse applications. Indeed, consumers overall impacts of nanoscale products during are already in contact with nanomaterials – manufacture, use and disposal. Concerns products with nanoscale components include have already been raised about certain self-cleaning windows, sunscreen lotions and nanomaterials and their potential detrimental cosmetics, anti-bacterial deodorising socks, effects on humans. Notable issues include fuel additives for motor vehicles, DIY coatings, asbestos-like pathogenicity induced by the 5 glues and cleaning products. inhalation of carbon nanotubes and reduced sperm counts associated with the inhalation of In the healthcare sector, nanotechnology carbon black and nano titanium dioxide6. The has already been put to use in many ways environment may also be adversely affected, and nanomedicine is now a recognised as many nanomaterials may be toxic to non- target organisms or enter the food chain7. the application of nanotechnology for the diagnosis, monitoring, prevention and This report provides a brief overview of treatment of clinical conditions. Applications nanomedicine with particular regard to include nanoscale drugs and targeted drug patient and worker safety and environmental delivery systems, anti-microbial medical protection. Whilst the use of nanotechnology dressings and textiles, in vivo imaging, bone in the healthcare sector is likely to offer a substitutes and dental materials, coatings for number of advantages over conventional in vivo implants and tissue repair structures3. Nanotechnology is also providing tools to takes a look at the regulatory and legislative of biomarkers involved in the different stages issues that need to be addressed in order of diseases3. Future developments in this area for nanomedicine to deliver on its promises are expected to provide solutions to many without unduly introducing new risks for of modern medicine’s unsolved problems patients, workers and to the environment. by focusing on personalised, targeted

7 1.2 What are nanomaterials? While many of these new properties may be extremely useful, using materials at this scale Nanomaterials are materials that have can also result in the introduction of new been engineered to have one, two or three risks. Nanomaterials have a very large surface dimensions measured in nanometres (see Box area compared to their bulk counterparts 1). These include items such as carbon wires (see Figure 2). This typically results in greater and tubes, and even tiny mechanical devices. chemical reactivity, biological activity This nanoscale world is breathtakingly small and catalytic behaviour when compared – one nanometre is a billionth of a metre or to larger particles of the same chemical a millionth of a millimetre. To put this into composition9,10,11. Such attributes can be context, a strand of DNA is 2.5 nm wide. At the very useful but at the same time they may micrometre scale, a red blood cell measures result in greater toxicity12,13. Nanomaterials 7,000 nm across (i.e., 7 microns) and a human may also more readily penetrate biological hair is 80,000 nm wide – still small but much membranes and gain access to cells, tissues larger than nanomaterials (see Figure 1). and organs of living organisms9,14. This can

A critical point is that this scale confers novel be highly desirable for therapeutic purposes properties on nanomaterials8. The European but detrimental when unintentional exposure Comission has explicitly recognised this in its occurs.

Other properties of nanomaterials that

of materials at atomic, molecular and chemical composition, shape, surface macromolecular scales, where properties structure, surface charge, catalytic behaviour, extent of particle aggregation scale”1. or disaggregation and the presence or

water drop pin head red blood cell nanotube 2.5 millimetres 1 millimetre 7 micrometres 2 nanometres

Figure 1 | The relative size of a nanomaterial

Box 1 | Disentangling nano terms OTHER NANO-OBJECTS NANOMATERIALS NANOMEDICINE NANOPARTICLES 3.

NANOCRYSTAL

8 1.3 Nanomedicine has the potential to revolutionise healthcare

big particle The promise of nanomedicine is far reaching, ranging from improved, less toxic, more targeted and even personalised medicines, to more sensitive and cheaper diagnostic medium particles tools, innovative structural materials 20x more surface area and the prospect of cellular and tissue repair systems (see Table 1). Nanoscale or nanostructured materials have unique medical effects based on their size and tiny particles structure and include nanoformulations of 60x more surface area existing drugs and new nanosized drugs, as well as a variety of medical devices. Much research effort is focused on drugs that are Figure 2 | The increased surface area provided by nanomaterials techniques due to their low water solubility, absence of other chemicals attached to and thereby improve bioavailability. the nanomaterial15,16,17,18. Because these The creation of structurally engineered properties are often different from the parent nanocarriers capable of delivering drugs compound, it is imperative that nanomaterials should be considered as “new” chemicals diseased cells and tissues is another area with rather than a variant of the parent compound. huge potential19.

HEALTHCARE AREA APPLICATION EXAMPLE

In vitro

In vivo

Therapeutics nanostructures such as liposomes. Therapeutics release their content on contact with certain disease structures. Therapeutics

Table 1 | Examples of nanomedicine applications 25.

9 A number of nanomedicine products are Other materials used include quantum dots, already on the market. At present the majority dendrimers and liposomes (see Boxes 2 and 3 of products are nanoformulations of existing or new drugs (58%) or nanobiomaterials as carriers of a variety of drugs such as anti- (25%)20. It has been claimed that the cancer, anti-viral and anti-bacterial drugs, may worldwide nanomedicine market reached have limited use currently because of their €37.4 billion by 2011 and that the market cytotoxicity (see Box 6)23,24. may double by 201621. In 2011, the largest market share was held by central nervous system products worth €10.4 billion, for regulation followed by anti-cancer products at €4.1 A critical question when assessing the billion21. Both these areas continue to be regulation of nanomaterials is their precise the two most rapidly growing sectors22. In geographical terms, currently North America International Organization for Standardization is the major nanomedicine market, followed by the European region; however, the Asia- of “approximately 1 nm to 100 nm”8. Similarly, the European Commission has adopted expected to exhibit the fastest growth rate in the near future21. nanomaterial to mean Commonly used nanomaterials for medical “A natural, incidental or manufactured purposes include carbon nanotubes and nano material containing particles, in an forms of silicon, gold, platinum, silver and unbound state or as an aggregate or as an a number of metal oxides. These materials agglomerate and where, for 50% or more of may occur in a range of sizes and shapes, the particles in the number size distribution, and are often encapsulated or coated with one or more external dimensions is in the other materials to improve their performance. size range 1 nm - 100 nm”26.

Box 2 | Nanomedicine: drugs, diagnostics, imaging and materials

NANOSCALE DRUGS BIOMATERIALS Nanomaterials that improve the mechanical properties NANOSCALE FORMULATIONS OF EXISTING DRUGS ACTIVE IMPLANTS 34 . DRUG DELIVERY SYSTEMS IN VITRO DIAGNOSTICS Nanoscale particles/molecules developed to enhance the

IN VIVO IMAGING 35.

10 a nanoscale of between 1 nm and 100 nm is inappropriate, especially for nanomedicine applications, as size is only a crude index need a new regulatory approach to assess of novel properties. Indeed the biological toxicological risks and more directly involve behaviour of materials between 100 nm and 1000 nm (in one, two or three dimensions) In Europe (and elsewhere), key points of can pose novel risks, as at this scale they may dissension in terms of regulatory issues are share many of the characteristic behaviours of nanomaterials below 100 nm in size. These chemicals and how to properly conduct risk shared properties may include very high assessments. While the European Commission itself believes that REACH (the EU legislation of particle surface effects, strong particle on Registration, Evaluation and Authorisation surface adhesion, strong ability to bind proteins and very high bioavailability9,27,28,29,30. various Member States, the European Many nanomedicine products do not fall Parliament, non-governmental organisations (NGOs) and trade unions have all called nanomaterials of approximately 1-100 nm. For for changes to the main text of REACH and instance, nanomedicines that aim to passively target sites are typically between 100 nm to regulations36,37, 38,39,40. Calls for an up-to-date 200 nm in size, but particles up to 400 nm have public inventory of nano products have also 3 also been used successfully . Nanomaterials been increasing. being developed for a variety of clinical applications include liposomes measuring 100- A key issue in Europe is the regulatory 200 nm, nanoshells measuring 60-400 nm31 distinction between medicinal products and and drug delivery systems measuring 100- medical devices, with different regulatory 200 nm32. A recent survey of nanomedicine approaches for market access. This makes the products noted that most were sized up to 300 nm, but that some were larger still3. Perhaps products as medicines or devices crucial. this is the reason why both the European Some nanomedicine products will fall into Medicines Agency and the US Food and clear regulatory rules to ensure products are assessed using rigorous procedures. “… the use of tiny structures - less than 1,000 Other issues that remain largely unexplored nanometres across - that are designed to are the fate and possible transformation of 3,33 . nanomedicines after use if they enter the environment, for example during waste 1.5 Regulatory uncertainties may expose disposal41, and the exposure of workers. The humans and the environment to risks same qualities that make nanomedicines While nanotechnology in general and highly desirable for the healthcare sector, nanomedicines in particular promise new and such as increased solubility and enhanced innovative solutions to many of our current bioavailability, may increase the risk of health problems, regulation of these new toxic effects on public health and/or the approaches is largely unresolved. Are the environment34,41.

11 NANOMEDICINE – AN EMERGING FIELD 2

Nanomedicine, while often positioned as stages of clinical study and 100 commercially revolutionary, has been under development for available products, including anaesthetics a considerable time. Many of the technologies and treatments for cancer, hepatitis, cardiac anticipated in the literature or currently in the research stage may take 20 or more years disorders, endocrine/ exocrine disorders and before becoming available in a clinical setting. degenerative disorders3. Nanomedicines It is for this reason that this report focuses on for cancer treatment are by far the most applications and products that are already in common nanomedicines approved or under commercial use or which are already being development3. tested in clinical studies (taking 1 to 7 years before commercial availability), as these are 2.1 Nanoscale formulations and targeted and society, including with implications for drug delivery systems

regulation, in the relatively near future. Nanoscale formulations

A recent international review of nanomedicine Drug delivery and the introduction of new products yielded 147 products in various medical properties may be optimised by

Box 3 | Nanomedicines come in many guises DENDRIMERS POLYMER NANOCOMPOSITES 24. NANOSHELLS MAGNETIC NANOPARTICLES in vivo cancer therapies47. LIPOSOMES QUANTUM DOTS Quantum dots are semiconductors whose electronic characteristics cells. MICELLES 42 43in vitro44 45 CARBON NANOMATERIALS pharmaceuticals. NANOFILLER composite material to improve its properties. 46.

12 production of nanoscale versions of existing Particles that have been used extensively drugs26. Nanoformulations of existing drugs are made of nano cerium oxide with a thin can overcome common pharmaceutical coating of fatty oleic acid. These particles problems by increasing solubility, limiting act as anti-oxidants and have potential in the systemic toxicities, increasing bioavailability treatment of traumatic brain injury, cardiac and improving immuno-compatibility and arrest and Alzheimer’s disease, and they cellular uptake34. Bioavailability, i.e., the could alleviate radiation-induced side effects absorption of a drug that reaches systemic suffered by cancer patients49. They are also viewed as having great potential for treating is administered intravenously and may be cancer and other diseases such as macular much reduced in oral and other formulations. degeneration and hepatitis50.

Nanoscale formulations of a drug enable the The features and advantages of a targeted bioavailability of this drug to be greater when system are various. Encapsulation of a compared to the bulk formulation. However, drug (such as in a liposome or micelle) can increased bioavailability, while on one hand avoid local irritation and decrease local and desirable to treat diseases, may be a problem systemic toxicity, partly because less drug for organisms in the environment7. might be needed45. One of the early delivery systems was built from nanoparticles of A number of nanoformulations of existing (non-toxic) polyethylene-glycol designed drugs are already on the market. Commercial to carry antibiotics in their cores, reducing products include an anti-organ rejection immunogenicity and prolonging plasma drug in tablet form, which is easier to half-life35. administer and has higher bioavailability in comparison to the oral solution48, a drug used While targeted drug delivery often reduces to prevent nausea and vomiting caused by the side effects of drugs, the drug delivery chemotherapy48 and a nanocrystal drug used mechanisms may also introduce toxicities of to improve cholesterol levels48. their own and have unintended side effects. After the drug is released into the target cells Targeted drug delivery systems it is often unclear what happens to the Nanotechnology has also been heralded as carriers. They may move through the body the cornerstone of targeted drug delivery mechanisms which will allow controlled drug release at just the right place and dose, Box 4 | Finding out more about nano pharmaceuticals improving patient safety and compliance and reducing side effects. Targeted drug delivery 20. Once involves a transport device and an active www.ema. ingredient. Drug delivery vehicles under europa.eu investigation vary widely and include objects known as polymeric particles, dendrimers, nanoshells, liposomes, micelles and magnetic nanoparticles (see Box 3)45. Most targeted eu drug delivery mechanisms have focused on cancer treatment where these advantages are of great importance.

13 and accumulate in other organs, or carriers replacement of tissue and organ function may be excreted and end up in the and it is expected that nanotechnology will environment or may accumulate in the body substantially contribute to this. Nanomaterials and perhaps cause damage51. for tissue regeneration are in the very early stages of development. Currently only two

BENEFITS applications related to tissue regeneration, ¬ both implantable soft tissue scaffolds with ¬ nanostructured surfaces, are in clinical trial or ¬ 3 ¬ on the market . into the environment. ¬ Further developments in this area can be

RISKS expected for the near future. For instance, ¬ the use of nanoparticles in implant cement 7. ¬ is expected to overcome many of its current ¬ limitations such as breakdown of material, ¬ currently in the preclinical research stage52. Other more futuristic applications include the disposal. nanoporous silicon membranes to selectively 2.2 Regenerative nanomedicine, implants and nanomaterials used in dentistry although it is not yet commercially available52. Regenerative medicine Risks associated with regenerative Regenerative medicine comprises a number nanomedicine not only include health of technical approaches, ranging from tissue and safety considerations such as toxicity engineering and wound repair to various and carcinogenicity, but also the long- futuristic visions of full-scale cell therapy. term stability and excretion pathways of It focuses on the improvement, repair or

Box 5 | Nanomaterials in dentistry BIOFILMS 55. NANOMATERIAL-BASED FILLERS lesions55 56 . 55. 55 55 55.

14 to identify the hazards associated with narrowing of the blood vessel within the stent. novel nanotechnology-based therapies A number of manufacturers have addressed and characterise the associated risks, while involving relevant stakeholder groups such hydroxyapatite, polymer or nanoporous as health professionals and patients. Key ceramic to inhibit re-narrowing46. questions are whether the materials used are Retinal implants to treat retinitis pigmentosa themselves toxic and their fate when they have become available in clinical settings, are released from the product. Inevitably, using silicon photodiodes or a series of release may occur even when compounds are platinum electrodes on a silicon plate. Both tightly bound in a matrix, for instance through treatments are considered medical devices abrasion and during waste disposal53. and have CE labelling52, a declaration of conformity with EU standards. Implants Nanomaterials used for implants fall into the The application of nanotechnology may also categories of metals, ceramics, polymers lead to improvements in the ability, control and composites. Nanocomposites and and precision of neuro-stimulation to the nanomaterial coatings have been developed brain. Brain implants may be usefully applied commercially for both bone and dental to neurodegenerative diseases such as implants46. Typical examples include Parkinson’s disease, movement disorders such composites for dental restoration and self- as dystonia or tremors, psychiatric disorders such as depression, obsessive disorders and silanised zircon46. Synthetic bone replacement pain54. Risks associated with implants are products with a similar calcium and similar to regenerative nanomedicine and phosphate composition as bone, i.e., as include health and safety considerations such hydroxyapatite and tricalcium phosphate, as toxicity and carcinogenicity, but also the are also becoming available in nano form46 long-term stability of the implant. Safe waste (and see Box 5). Nanostructured metallic disposal may also be an issue. alloy implants – for instance hip prostheses made of titanium – are thought to overcome problems of chemical contamination that may occur with conventional prostheses BENEFITS ¬ and offer mechanical advantages. Different nanocoatings, e.g., nanosilver, are thought ¬ to further enhance these products and that occur with conventional prostheses. ¬ items such as bone cement due to their when compared to conventional prostheses. antimicrobial properties46. The use of silver ¬ material properties when compared to conventional nanoparticles with antimicrobial properties in materials. 46 ¬ bone cements may also become feasible . conventional materials.

Coronary heart disease associated with RISKS ¬ narrowing of the vascular network (stenosis) is environment. often treated with the implantation of a stent ¬ device to keep the artery open. The main nanomaterials used in implants. ¬ complication is intra-stent restenosis, a re- and in relation to wear and tear or disposal.

15 2.3 Nanotechnology-based diagnostics, heart disease by identifying biomarkers medical instruments and imaging tools such as the levels of certain protein enzymes which may indicate that a patient has had an A number of nanotechnology-based undetected heart attack25. Carbon nanotubes diagnostics, including imaging tools and have been used in a subcutaneous device some nanoscale medical instruments, are for monitoring blood sugar levels in vivo46. already well developed and are available While many of these applications are still in in clinical and healthcare settings. This the research or preclinical stage, a lab-on-a- area of nanomedicine enables the early chip the size of a postage stamp is already diagnosis of diseases, decentralisation of commercially available and is used to monitor healthcare and more effective treatment medication levels for manic depressive methods. The overall economic impact of patients at home at much lower cost and with the use of nanotechnology in these areas greater convenience25. can be considerable, as the application of nanotechnology to diagnostics has resulted, Other diagnostic applications using for example, in high throughput screening, nanotechnology and already on the market and will ultimately lead to point-of-care include: colloidal gold particles which, due diagnostics and personalised medicine57. to their stability, have been widely used to rapidly test for pregnancy, ovulation, HIV and Diagnostic tools other indications35; magnetic nanoparticles Currently in vitro diagnostics are costly and used for cell sorting applications in clinical 35 it is hoped that new generation “lab-on- diagnostics ; and superparamagnetic iron a-chip” with nanoscale componentry will oxide nanoparticles for magnetic resonance 35 offer advantages including reduced costs, . portability, and shorter and faster analysis. Magnetic iron oxide nanoparticles also show Applications may include point-of-care great promise in the detection of Alzheimer 58 measurements of saliva for periodontitis, plaques . heart disease, insulin detection and improving The toxicity risks both for humans and the healthcare accessibility38. For example, gold environment are as yet unclear and will of particles can be used in vitro to detect early

16 nanomaterials in use. For instance, the use of quantum dots to illuminate organs and the ensuing metabolism of the burst cells). detect tumours may pose additional toxicity risks should they diffuse into surrounding Imaging tools 59 organs and disrupt cellular function . It is also Nanomaterials are being used extensively unclear whether diagnostic tests could have as contrast agents in non-invasive medical adverse effects on medical staff applying the imaging tools, including computed tests and how disposal of diagnostic tests will tomography, magnetic resonance, positron be undertaken safely. emission tomography, single photon- emission computed tomography, ultrasound, Medical instruments and optical imaging. The use of nanosized Medical instruments are also being metal oxides, dendrimers, quantum dots, increasingly miniaturised, with nanomaterials etc., as contrast agents may lead to better understanding of biological processes at carbon nanotubes may be used instead the molecular level, as well as having the of glass pipettes for delivery into cells46. advantage of better photo-stability, higher Nanosilver is increasingly incorporated into quantum yield and increased in vitro and in catheters and other instruments as a coater vivo stability. However, the inevitable issues because of its antimicrobial effects46,60. Wound of waste management and potential toxicity dressings may also incorporate some sort of issues have rarely been discussed60, despite nanosilver, either in the form of silver salts, the need to address them with some urgency. metallic silver nanocrystals or nanoparticles for the same purpose46.

Another area of great development in medical devices is that of thermotherapy, a form of cancer treatment that uses heat to destroy cancer cells. By using nanoparticles to generate the heat, the treatment can be more successfully localised and result in fewer side effects. A number of devices are either at the clinical study stage or are already on the BENEFITS ¬ market. The devices use a number of different and produce less waste. nanomaterials including nanosized iron ¬ oxides, gold-coated silica nanoparticles and ¬ hafnium oxide nanoparticles. For instance, diseases. iron oxide nanoparticles are interstitially ¬ alternatives to chemical cancer treatments. or intravenously delivered then heated by ¬ medical devices. provide hyperthermia treatment localised RISKS ¬ to a tumour59. Iron oxide nanoparticles are also used for magnetic detection of cells in ¬ vitro59. A key question will be if this therapy devices. ¬ constitutes a device (for bursting the tumour overused.

17 For example, quantum dots are extensively therapy and diagnostics? can also act simultaneously as drug delivery At the more visionary end of the scale are the vehicles. In this dual role, i.e., as imaging plans for “theranostics,” a fusion of therapy agents and drug delivery vehicles, they have and diagnostics. Rather than wait for a disease played a key role in theranostics61. However, to manifest itself on a more conventional time questions have been raised regarding the use scale, nanomedicine raises the possibility of quantum dots in their current form due to of using ultra-sensitive diagnostic abilities their potential acute toxicity. combined with treatment at a very early stage. Theranostic platforms envisage the targeting of a disease, diagnosis and administration of a treatment in one single step. Much work in this area has focused on cancer treatment, especially in the utilisation of electromagnetically-activated nanoparticles. Several of these platforms are currently nearing or are progressing through clinical development.

Theranostics may in the future predict risks of contracting a disease, diagnose disease, assist in stratifying patients, and monitor therapeutic responses and hence enable earlier and more effective treatment. But this approach also raises ethical issues surrounding the starting point of “disease” and the use of treatments before “illness” begins. Some of the materials used are also potentially acutely toxic and there are risks of environmental contamination and unintentional exposure.

BENEFITS ¬ ¬

RISKS ¬ ¬ ¬

18 CASE STUDY: NANOSILVER IN NANOMEDICINE 3

The fungicidal, bactericidal and algicidal in medical devices include in infusion properties of silver have been known for a long time. For centuries silver has been known devices, endovascular stents, urological to be effective in killing harmful bacteria stents, endoscopes, electrodes, peritoneal contaminating various commodities, including dialysis devices, subcutaneous cuffs and milk and water. In recent years, nanosilver in surgical and dental instruments62. Silver has increasingly been used in consumer nanotechnologies are also claimed to and industrial products. It has become one improve battery performance in implantable of the most commonly used nanomaterials in consumer products, predominantly as a and so protecting conductivity62. bactericide. It can be found in a range of products, including disinfectants, cleaning Nanosilver is a more effective antimicrobial agents, powder coatings (e.g., on door than bulk silver knobs), wall paints, air conditioning, clothes The comparatively large surface area of especially sportswear, toothbrushes, baby silver nanoparticles increases their reactivity, bottles, etc. The biocidal effect is used not which increases their toxicity, typically from only for preservation of materials but more oxidative stress caused by the release of often against the real or supposed risk of silver ions66. Given the rate of ion release is infection or only against unpleasant odours generally proportional to the surface area caused by bacteria. than bulk silver at generating silver ions and In hospital settings, nanosilver is used 62. extensively for wound management, Additionally, increased toxicity to bacteria particularly for the treatment of burns, results from the ability of nanosilver to cross ulcers (rheumatoid arthritis-associated leg many biological barriers, increase production ulcers, diabetic ulcers, etc.), toxic epidermal of reactive oxygen species and its capacity to necrolysis, healing of donor sites and for meshed skin grafts62, with claims of bacteria67. improved infection management63. Silver- coated catheters are also used to prevent Induction of bacterial resistance that encourage bacterial infection64. For A number of concerns have been raised instance, silver-coated urinary tract catheters regarding the use of nanosilver including reduce the frequency of urinary tract the possibility of adverse effects on patient infection64. Nanosilver is also used in textiles cells which could delay wound healing or 68 and other essential medical equipment65. pose localised toxicity . A bigger concern is Other proposed applications of nanosilver that the overuse of nanosilver in consumer

19 products may induce bacterial resistance and 69. All exposure routes may ultimately lead to silver applications. Several reports describing resistance in environmental bacteria73. And, resistance to silver in hospital settings have once in the environment, exposure to humans already emerged, especially in hospital burn or non-target organisms may occur through wards63. A recent study reported for the a variety of mechanisms including inhalation, Bacillus spp. could develop dermal contact and ingestion74. For instance, resistance to nanosilver cytotoxicity upon nanosilver used in some clothing has been exposure69. A key issue here is the problem shown to leak rapidly and quickly into the that selection of bacteria with the ability to water during washing and easily reach resist silver also selects for other antimicrobial wastewater treatment plants75. resistance genes. Resistance genes to silver In addition to induced bacteria resistance, have been found on a range of plasmids, notorious for containing multiple antibiotic soil microbes depending on the soil resistance genes70,71. The widespread and type76. Changes in microbial community indiscriminate use of nanosilver in healthcare composition, biomass and extracellular settings may further contribute to the enzyme activity, as well as effects on some induction of resistance. above-ground plant species, have been Environmental risks observed after the application of sewage The distribution of silver nanoparticles into biosolids containing low doses of nanosilver the environment and the possibility of adverse environmental effects have only recently 77 been researched in some detail. Key routes (N2 into the environment are through elevated oxide is a notorious greenhouse gas, with 296 times the global warming potential of carbon through the use of sewage sludge as fertiliser dioxide. It is also the dominant stratospheric or as organic soil improver72. The sludge or ozone-depleting substance. A number of biosolids from wastewater treatment can also studies have also investigated nanosilver’s reach the environment through dumping in toxicity to aquatic organisms. For instance, nanosilver particles have been shown to

20 accumulate inside algal cells, where they toxicity81. The clinical use of nanosilver should exerted toxic effects78. They have also been be limited to applications of most value observed to aggregate and be transferred (wound management, medical devices) where transgenerationally in nematodes79 and to alternative disinfectants or antimicrobials accumulate in fathead minnow embryos80. are not effective. Hospitals and healthcare providers should establish guidelines to There are considerable human health restrict the clinical use of nanosilver to critical and environmental risks associated with applications and patients. Nanosilver textiles the indiscriminate use of nanosilver in should only be used where substantial consumer and health products. Evidence to therapeutic effect can be demonstrated. date suggests that precautionary action is advisable due to nanosilver’s environmental

21 POTENTIAL RISKS FOR HUMAN HEALTH AND THE ENVIRONMENT 4

The potential risks for human health and the environment of nanomedicine products predict or to include in existing environmental will depend on the nanomaterial that is risk assessment schemes83. Table 2 provides used, as well as on the environmental a summary of nanomaterials commonly used processes and exposure routes that control in medicine, their applications and their the fate, transport and transformation of the potential toxicity and ecotoxicity. nanomaterial41 to nanomaterials in nanomedicine products 4.1 Human health concerns is intentional. However, the desirable effects may also lead to unintentional exposure to A vital question in considering the toxicology other organs in the patient’s body, other of nanomaterials to human health is how they people, non-target organisms and the environment51. biological compartment (in the body or within

A key issue for nanomaterials toxicity is their ability to bind and interact with biological one of the key features of nanomaterials and matter and as a result change their own 46 properties . However, in the case of Box 6 | Toxicity of dendrimers nanomaterials the interaction mechanisms between nanomaterials and living systems are 46 not yet fully understood . Furthermore, one of the greatest potential dangers may be the propensity of some nanomaterials to cross biological barriers in a manner not predicted 23. from studies of larger particles of the same chemical composition82. in vitro The common assessment paradigm for toxicological assessment is that there is a correlation between mass and toxicity, but a 23. number of studies have shown that this may not be the case for nanomaterials. Other properties such as surface area, surface chemistry, etc., may give a better indication of 83 toxicological endpoints . Furthermore, given that bioavailability may be enhanced in some nanomaterials, particularly those devised for 23. medical purposes, this will result in a change

22 one of their greatest potential dangers may evidence that nanomaterials can translocate be their ability to cross biological barriers, not from the lung into the liver, spleen, heart seen in studies of larger particles of the same and possibly other organs103. Access via the chemical composition82. This also highlights a olfactory bulb has also been reported104. key paradox for nanomedicine: the desirable Another potential exposure route in humans effects observed in nanomedicines may at the is through the skin. Access by fullerenes and same time be highly toxic to other persons, quantum dots has been reported, dependent the environment or non-target organisms51. on size and surface coatings105. Gastro- intestinal assimilation and movement from particles are well documented. For example, there into the blood stream has also been the industrial pollutant carbon black is known demonstrated106. Nanomaterials have been to cause cancer through inhalation in rats and found to accumulate in low concentrations under certain circumstances in humans101. in the liver, spleen, heart and the brain107. Similar concerns have been raised in relation The possible effects of nanomaterials on the to certain carbon nanotubes102. A further developing foetus are of special concern, with major concern is whether nanoparticles can gold nanoparticles108 and quantum dots98 cross the air-blood barrier in the lungs and having been shown to cross the maternal- gain access to the rest of the body7. There is foetal barrier.

NANO COMPONENT HUMAN AND MAMMALIAN TOXICITY ECOTOXICITY

84 5. on CNT structure85.

in vitro 86. 50.

Dendrimers . 87. 88. 89. communities90. 91. 92.

Cucurbita maxima 93. nanoparticles94. Ceriodaphnia dubia 95. Nanosilver 68. 59. 60. and plasmids. Quantum dots 82. 98. 97. 97.

99. 93. 100.

Table 2 | Example of potential human health and environmental toxicity risks of selected nanomaterials used in nanomedicine

23 The key pathways through which humans may The generation of reactive oxygen species be unintentionally exposed to nanomaterials has been shown to be greatly affected by are through inhalation, ingestion and catalytic effects at the nanoparticle surface11. dermal exposure, with possibility for further The presence of other contaminants, mode translocation to secondary organs7. For of action of the chemical and differences in instance, dental procedures may involve 112. the milling, drilling, grinding and polishing A further complication is that nanomaterials of applied medical materials containing may also acquire new “biological identities” nanomaterials, which may then be inhaled (and thus new properties) via the adsorption inadvertently, make contact with skin or be of biomolecules onto their surface, giving ingested109. what is termed a “bio-corona”. Toxicological A number of parameters will affect the overall studies need to assess the interaction between toxicity of nanoparticles. In general, it has the bio-corona and the nanomaterials and been observed that size is very important, in how they might interact with each other, as particular for cellular uptake of nanoparticles. well as assessing the physiological response Additionally, the greater the intracellular of the organism to the bio-corona82. dose of nanoparticles, the greater the effect generated (whether toxic or otherwise). 4.2 Occupational Health and Safety issues Shape, and perhaps more importantly in healthcare facilities surface charge, can also have a determining effect on toxicity97. Other physiochemical Nanomedicine can pose a risk to others characteristics that may have toxic effect in beside patients. The manufacture, use of and cells depending on the nanomaterial include exposure to nanomaterials in any workplace is agglomeration82, the Trojan horse-type a recognised matter for concern, but as yet not uptake mechanism110 and zeta potential111. resolved. The European Agency for Safety and nanomaterials – such as silver, gold and Box 7 | Toxicity of quantum dots titanium nanoparticles and carbon nanotubes

– as posing potential health hazards and 61 occupational health and safety (OHS) risks115. While the application of nanotechnology 61 arsenide semiconductor materials and nanomaterials has the potential to offer cadmium ions into culture medium113. Various methods to what risks healthcare workers are exposed 113. to in the process of using, administering or involuntarily coming into contact with nanomedicine products. Many healthcare workers are unaware that they may be handling these materials on a day-to-day basis 114. Their complicated and of the potential toxicity of nanomaterials. For healthcare workers, accidental exposure to 114. nanomaterials may occur through a number

24 of exposure scenarios. While inhalation of particles that are used in a liquid matrix may airborne nanoparticles may be the most be present in the atmosphere in the factory, common exposure route in the workplace, presenting inhalation rather than topical ingestion through unintentional hand-to-mouth exposure hazards. Manufacturing sites may transfer from contaminated materials is also also generate wastes with high concentrations possible. Dermal exposure is another possible of nanoparticles, which differ in nature and pathway for entry into the human body, in effects from the products, being by-products particular via cuts and damaged skin or through of the synthesis procedures. These all need to unintentional needle-stick injuries. Exposure be considered in the overall assessment of the can occur in a variety of situations, such as nanomaterials before licensing. disposal of excreta from patients receiving nanoscale drugs, handling of nanomaterial- Key OHS issues include a lack of data on the contaminated items and spillages, consumption health impacts of nanomaterials and their of food and beverages that have come into potential environmental toxicity, combined contact with nanoscale drugs, and cleaning and with a continuing inability to monitor any 115 maintenance of areas where nanoscale drugs adverse effects . The lack of technologies are handled34,109,115. Healthcare workers with a and protocols for environmental and health particularly high risk of exposure are those that monitoring, detection and remediation is prepare or administer medicines containing still considerable, despite some efforts being 109 nanomaterials or who work in the areas where made to address the problem . For instance, these medicines are used. Safety Data Sheets (SDS) generally contain little or no information about nanomaterials, Although some particular health issues including whether they are present, what their characteristics and risks are, nor how to exposure), more generally there are gaping prevent exposure115. holes in the available information concerning OHS issues. Despite the focus of this report in Preventive measures are therefore currently healthcare environments, workers involved in the only available tools to protect the health the manufacturing of nanomaterials may also of workers. To minimise risks of exposure to suffer substantial exposures. The nature of their nanomaterials in workplaces in the healthcare exposure may also be different; for example, sector the European Agency for Safety

25 and Health at Work suggests the following participation in the management and risk measures115: assessment processes of nanomaterials is fundamental to elimination or reduction of Substitution the risks posed by nanomaterials. Doctors, ¬ Avoiding the presence of nanomaterials nurses and other healthcare professionals that could become airborne by using less need to know the risks involved in their work hazardous forms or modifying their surface and be able to contribute to improvements in properties. workplace practices at all levels.

Workplace design and monitoring procedures Box 8 | Ethical issues

¬ Instituting engineering controls such particulate air (HEPA H14) or ultra-low ¬ Supplying separated, clearly signed and dedicated workplaces for handling nanomaterials. ¬ Minimising the number of personnel being exposed and the duration of exposure. ¬ Prohibiting access by unauthorised what point does one intervene? personnel. Collective preventive measures 54. ¬ Instituting a health surveillance program for workers handling nanomaterials.

Personal protective equipment ¬ Using personal protective equipment 4.3 Environmental concerns when exposure cannot be reduced Globally, hundreds of thousands of tonnes effectively enough. Equipment should be of nanomaterials are being released into adequate to prevent exposure and minimise the environment, both intentionally and the risk while being suitable for the worker. unintentionally, throughout the lifecycle of This can include respiratory protection, nanomaterial production, use and disposal. gloves and protective clothing. Possible entry routes for nanomaterials into Given the general lack of coordinated, the environment include waste disposal (waste water treatment, storm water run-off, nanomaterials, including who produces them, where they are being produced and such as through abrasion and wear as well as used and what their potential risks may be, emissions from manufacturing and accidental it is not clear that the risks are being taken spills34. A 2013 study into the global lifecycle into consideration in healthcare facilities. of engineered nanomaterials estimated Provision of information to workers and their that, in 2010, 260,000–309,000 tonnes of

26 the food chain119. Simulated experiments soils (8–28 %), water bodies (0.4–7 %), and have shown that physicochemical properties the atmosphere (0.1–1.5 %)116. Nanomedicine of the aquatic environment such as pH, ionic is increasingly, albeit on a small scale, strength, salinity, mineral content, natural contributing to this problem. organic matter and extracellular polymeric For components of nanomedicine products, bioavailability of nanomaterials120,121. a major route of entry into the environment is through human metabolism and excretion A recent review of toxicological research into the sewage system. The fate and ultimate on nano metal oxides (silver, copper and removal of these compounds depends very zinc oxide) reported that they are extremely much on the appropriate design of waste water treatment facilities and it is at present unclear to freshwater aquatic organisms including whether these will be able to adequately remove nanomedicines. Unsatisfactory affected122. Freshwater may stabilise nano removal of emerging contaminants in metal oxides and make them more persistent general is a recognised worldwide problem and nanomedicines may exacerbate this issue. Other possible transfer routes into the to facilitate aggregation and settling and environment include the improper disposal hence reduce toxicity123 of nanomedicine products at end-of-life the need for strict assessment and regulation (especially of in vitro diagnostic materials)34. of the use and disposal of nanomaterials in general and nanomedicines in particular. Environmental impacts are uncertain Nano metal oxides have also been shown to When nanomedicine products enter the contaminate soils and enter the food chain environment it becomes crucial to understand via plant uptake. Recent studies reported their fate and effects in terms of bioavailability, that different plant communities experience bioaccumulation, toxicity, environmental reduced growth or biomass after taking up transformation and interaction with other nanosilver from soil124,77. Soya beans, a major environmental contaminants. A key question human and animal food source, have been is whether current environmental fate and shown to absorb and be adversely affected transport models are even applicable83. What by nano zinc oxide and nano cerium oxide happens to nanomaterials once they reach from contaminated soils125. Cerium oxide the environment depends on numerous in vitro and environmental conditions, including their in vivo toxicity data) are viewed as having aggregation, dissolution, oxidisation/ great potential as a cancer treatment and reduction and adsorption properties117. treatment for other diseases such as macular 50 Nanodrugs in particular may present degeneration and hepatitis . Yet at the bioaccumulation issues as many are stable same time their interaction with important in aqueous solution118. This implies that they food crops raises serious issues about how will be able to travel for long periods in the and when they should be used and, very 123 external environment, will contaminate soils importantly, their disposal . via sewage and spills and ultimately migrate A recent review concluded that risk into groundwater and river systems and into assessment of nanoparticles in soil will

27 engineered nanoparticles was conducted conditions120. However, nanosilver, nano in 2010, as part as the EU’s 7th Framework copper oxide and zinc oxide nanoparticles ENRHES project128. This review recognised that understanding of the environmental microbes to varying extent depending on the exposure risk of engineered nanomaterials soil type76. Exposure to carbon nanoparticles was hampered by the general lack of data may harm earthworms by slowing population relevant to their soil and sediment behaviour, growth, increasing mortality and damaging especially in relation to metal oxides and tissue126. Data for many other nanoparticles carbon nanotubes129 . A further key issue used in nanomedicine is still lacking or sketchy. research due to different functionalisation Possible synergistic effects of nanomaterials, different experimental An often overlooked aspect of environmental approaches and different levels of attention contaminants is that they usually exist as part given to the characterisation of the 129 of a complex mixture of chemicals in the nanomaterials used . environment. The composition of this mixture Given the novel properties and the novel may increase or decrease the bioavailability ways that nanomaterials interact with living of individual components and hence toxicity organisms and the environment, it is clear that to organisms. For instance, the presence all nanomaterials must be considered new of nano titanium dioxide may increase the chemicals. accumulation of cadmium in carp (Cyprinius carpio)127. To date, little research has been done in the area of ecotoxicological effects of 4.4 Nanomedicine waste management engineered nanoparticles in chemical mixtures Nanomaterials may occur in a variety of and more research is urgently needed127. products that are used in healthcare settings and that ultimately have to be disposed of, Lack of knowledge is hampering assessment including not only nanomedicine products, of ecotoxicity Ascertaining the ecotoxicity of nanomaterials well as various items contaminated with and how they are distributed in the nanomaterials (e.g., wipes and syringes). environment and the effect they may have on It is inevitable that some of the new organisms is currently not only challenging, nanotechnologies will end up in waste water but also beset with limitations due to a lack of suitable monitoring equipment and extensive either as deliberate or accidental waste. knowledge gaps128. Currently no actual The minimisation of the amount and toxicity environmental monitoring of nanomaterials of waste generated by the healthcare sector, proper management and segregation change in the near future. In the interim, of medical waste and the elimination of environmental models of the effect of medical waste incineration by promoting and nanomaterial release into the environment are implementing alternatives has been one of being calculated and reported34. the major campaign goals (and successes) An extensive review of the potential of Health Care Without Harm. Unfortunately, health impact and environmental safety of the introduction of nanomedicines and nanomaterials in the healthcare sector

28 introduces many of the old but also new waste management issues. meet the criteria of hazardous waste132. Key questions pertaining to the waste disposal of Current regulatory guidance on nanowaste nanomedicines and medical nanowaste will management is minimal, whole lifecycle data revolve around their potential intrinsic toxicity, is largely unavailable, and the application their recyclability, their fate and transport in of industrial waste treatment methods the environment upon disposal, as well as to nanowaste is problematic, due to the general safety and hazard factors130. EU waste management regulations and directives will of nanomaterials130. Available research need to be updated appropriately. comparing methods used to treat nanowaste from research and manufacturing facilities Solid waste treatment concluded that “ options for solid waste. The incidental or hazardous waste, and as a minimum, known disposal of nanomaterial waste as double-bagged, enclosed in a rigid solid waste raises concern about its effects on impermeable container and preferably anaerobic (waste degradation and leachate 130 bound within a solid matrix” . treatment) and aerobic (leachate treatment) Health Care Without Harm recommends a processes, as well as issues with the potential lifecycle approach to deal with nanomaterial release of these nanomaterials into the 133 waste, with special emphasis on end-of- . A life management. Nonetheless, virtually no recent study focusing on the effect of water- guidelines on how this can be achieved are soluble nano zinc oxide, nano titanium dioxide currently available. A report, funded by the UK 133 Department for Environment, Food and Rural provided inconclusive preliminary results . Affairs (June 2010), on lifecycle assessment of Waste water treatment consumer products with carbon nanotubes Waste water treatment plants will provide (CNTs), concluded that urgent research is key entry points of nanomaterials into soil needed (via sludge) and freshwater. Some research “to address the almost total lack of on the effect of engineered nanomaterials exposure data for CNT-containing consumer on waste water treatment is starting to products, and the appropriateness of end- emerge. For instance, when sewage, biosolids of-life treatments” 131. The report went on to suggest that wastewater reclamation facility were analysed, appropriate treatment should include separate engineered nano titanium particles in a collection of (spent) CNT-containing products range of sizes were detected119. This clearly under controlled conditions, and that disposal demonstrates the need to monitor waste methods should ensure their complete destruction, which the report suggested could nanoparticles119. Furthermore, research that only be achieved by incineration. observed the release of silver ions from silver

Currently, neither European Directive 2008/98/EC nor Directive 1991/689/EEC, conditions found that the particles persisted 134 which govern waste management, mention even after 4 months . The exact nature of nanomaterials at present as it is still too the particles is likely to be crucial however -

29 for example, a polymer coating appeared to environment132. The interactions are likely to affect the fate and behaviour of nanomaterials be dependent on the particle composition in waste water treatment plants, with coated and available surface area. The limited experimental evidence shows that formation than uncoated nano silica135. of pollutants can increase in some cases and decrease in others132. Some research Incineration reported that the total PAH (polycyclic Incineration has been suggested as one of the aromatic hydrocarbons) emission factors methods to deal with nanowaste. Incineration were on average 6 times higher for waste of solid waste is still a common way of treating spiked with nanomaterials (i.e., titanium, waste in many European countries, either nickel oxide, silver, cerium, iron oxide, directly into incinerators or via wastewater fullerene and quantum dots) versus their bulk and then sludge incineration. Incineration is counterparts136. Chlorinated furans were also known to produce many toxic by-products formed at elevated concentrations when silver including polycyclic aromatic hydrocarbons and titanium nanomaterials were part of the (PAHs), polychlorinated dibenzo-p-dioxins waste136. and polychlorinated dibenzofurans (PCDD/ Recent experiments, conducted on the fate of Fs)136. The toxic by-products may then be nano cerium oxide in a full scale incineration emitted into the atmosphere either in their plant, showed that while incineration did not gaseous and/or particulate phase. release the nanomaterials into the atmosphere, The effect that nanomaterials contained in the residues to which they bound ended up the waste may have on the hazardousness in the solid waste fraction137. Further disposal of these emissions is largely unknown. of the nanomaterials bound to the bottom ash However preliminary evidence suggests nanomaterials may undergo physical or prevent release into the environment. chemical transformations, may catalyse the formation and destruction of other pollutants (e.g., dioxins) and may affect the effectiveness of control technology to remove them, as well as affect their transport and impact in the

30 CLARIFYING THE REGULATORY PATHWAY 5

The regulation of nanomaterials will remain 5.2 Nanomaterials under REACH a complex issue for the next couple of years. The European Commission has adopted Currently, nanomaterials are not explicitly a so called “incremental approach”, which mentioned in REACH, the EU’s regulation on focuses on adapting existing laws to include chemicals and their safe use (EC 1907/2006). nanomaterials, including the regulations Nanomaterials are clearly covered by the pertaining to medical devices and human 138 medicines. Key issues currently include itself does not mention nanomaterials . nanomaterials, safety data and access to which make the regulation wholly unsuitable information, including labelling and the for the regulation of nanomaterials and fatally establishment of registries of nanomaterials weaken its capacity to ensure proper safety and products. For nanomedicine, one of the for humans and the environment: big issues will be how to regulate crossover ¬ Given its silence on the subject, REACH or borderline products, i.e., products that does not insist that nanomaterials are integrate medicines and devices. Finally, the separately registered. If considered manufacturing and production of medicines equivalent to the bulk material, a and medical devices at the nanoscale will also manufacturer does not have to present a include worker OHS issues, contamination dossier of hazard information including of the environment and waste management questions, which need careful consideration acknowledge any novel properties. and may need additional regulations. ¬ REACH applies only to materials produced in total quantities of over 1 tonne/year, which would exclude the majority of nanomaterials from having to As discussed earlier, the nanomaterial be registered139. Furthermore, because nanomaterials usually occur in low 2011 (2011/696/EU) will not be appropriate exclusion could occur since no registration nanomedicine products. The key limitation is required when the concentration of a developed will have a size above the rather arbitrary limit of 100 nm in one or more to determine for nanoformulations. dimensions, while still having the essential A further issue is the general lack of properties of nanomaterials. access to information due to commercial 138.

31 ¬ Finally, establishing the ecotoxicology of researchers, NGOs, consumer organisations nanomaterials is fraught with limitations and and workers’ representatives have disagreed 23. An overarching problem with with this position on the basis that a revision EU legislation is that current test guidelines in REACH use conventional methodologies all the issues that REACH should properly for assessing chemical risks that are most encompass36,37,38,39,40,146 likely inappropriate for risk assessment of nanomaterials140. For example, some of 5.3 Medicinal product or medical device? the standard tests for assessing the risk As mentioned previously, a key question for of bioaccumulation of medical products nanomedicine is whether nanomedicines may not be appropriate141,142. Similarly, are to be regulated as a medicinal product environmental concentration thresholds may or as a medical device (see Box 9). EU be inappropriate. Further risk assessment legislation differentiates between medicinal is triggered if surface water concentrations products and medical devices, with different are predicted to equal or exceed 0.01 parts regulatory approaches for risk assessment. per billion, but this threshold is neither Preliminary market authorisation for medicinal science-based nor can it be interpreted products for human use is only issued after as a safe concentration143. Given their suitable clinical trials (Directive 2001/83/EC), increased reactivity and other novel while a medical device can be introduced properties, a mass-based concentration may with lesser degrees of testing depending be the wrong approach to describing the on the risk category the device falls into 142,144. (Directives 90/385/EEC, 93/42/EEC, 98/79/ EC and 2007/47/EC currently under revision: the European Commission concluded that In the new proposal for a regulation on medical devices, and taking into new legislation145. The Commission is of some technical provisions in REACH used in medical devices, the European Annexes. Several European Member States, Commission proposes that

Box 9 | Medicinal products or devices? A MEDICINAL PRODUCT: and which does not achieve its principal intended action in or on Directive 2004/27/EC A MEDICAL DEVICE: (Directive 2007/47/EC

32 “All devices incorporating or consisting tumour cells are mechanically destroyed by of nanomaterial are in class III unless the nanoparticles (a device) but which is followed nanomaterial is encapsulated or bound in by later metabolism (medicine)46. The such a manner that it cannot be released into the patient’s or user’s body when the device is used within its intended Risks (SCENIHR) considered (without coming purpose”147. to a conclusion) that “the immediate effect is mechanical as Class III triggers the most severe conformity the tumour cells burst. On the other assessment procedure. At the time of writing, hand, one might regard the legislation on medicines applicable as the burst cells are questioned at the European Parliament level metabolised at a later point in time”148. and might be rewritten in the new Regulation to cover only devices which intentionally release nanomaterials. exhibit characteristics of both, i.e., combining mechanical, chemical, pharmacological and Some nano products have already been immunological properties, and/or combining registered in Europe as medical devices, diagnostic and therapeutic functions, a many clearly with mechanical functions potential third category might be needed to such as carbon nanotubes in bone cements, regulate these products149. nanopaste hydroxyapatite powder for bone It is also unclear at this point whether the with nanoparticles in dental cements46. currently required toxicological studies are However, nanosilver or other nanomaterials used as coatings on implants and catheters nanomedicines require new testing and as wound dressings can be argued to models in vitro and in vivo at the preclinical 150 combine mechanical (protecting a wound) stage and pharmacological functions, and could is standardising and conducting preclinical be construed as both a medical device and a medicinal product. The same could be argued for nanoparticles and devices through its of thermo cancer therapy (see above) where Nanotechnology Characterization Laboratory

33 in order to prepare products for US clinical stating the quantity and information on use. approval. The EU has also indicated the The aim is to better understand how and intention of establishing such a centre, but this has as yet not progressed any further151. traceability; improve knowledge of the market and volume of nanomaterials involved; and collect available information on the toxicology 5.4 Mandatory EU register and labelling and ecotoxicology of nanomaterials152. The A number of EU member countries and NGOs nano register received more than 3400 have recently proposed the establishment registrations in 2013. In the French system, of an EU Register of nanomaterials used in nanomaterials which are intentionally released products, and/or of products containing under normal or reasonably foreseeable nanomaterials. The purpose of such a register conditions due to washing, abrasion or wear is to assure maximum transparency of the use do not need to be registered154. of nanomaterials in all products, including Belgium is proposing a system in line with the French that would require all manufacturers, a number of purposes: monitoring of the distributors or importers of substances at potential adverse health and environmental the nanoscale (>100 g/year) to register their impacts of nanomaterials; improving products via an online portal from 2015. companies’ knowledge of the substances Unfortunately, cosmetics, biocides, medicines they are manufacturing and using; increasing for humans and animals, food contact information and traceability throughout the materials and animal feed would be excluded. supply chain for all stakeholders; and increasing knowledge of toxicity and ecotoxicity and In the new proposal for a regulation on resources invested in risk assessments for medical devices, the European Commission nanomaterials. Overall, this would increase advanced with mandatory labelling for the sustainability of nanotechnology while medical devices containing nanomaterials (as noted above): general public and workers. “unless the nanomaterial is encapsulated or bound in such a manner that it cannot be While the Commission is not advancing released into the patient’s or user’s body with a EU level register, and has delayed a when the device is used within its intended consultation on this topic to evaluate the purpose”149 potential costs of operating such a system and This would limit the scope of labelling its impacts on health and the environment, provisions, ignoring materials which might give several European countries are initiating or rise to accidental or unintentional releases. considering national projects. France was the (January 2013), while Belgium is proposing 5.5 Improving worker safety to start one in 2015 and Denmark is currently There are a number of Directives in place and consulting interested stakeholders. a Health and Safety Strategy implemented The French nano register requires companies in the EU-28 Member States that should that manufacture, import and distribute in principle provide a measure of OHS preventative measures. Employers are submit to the authorities an annual declaration obliged to conduct regular workplace risk

34 assessments and put in place adequate 5.6 Nanowaste prevention measures (EU Directive 89/391/ EEC). Chemical agents at work are stringently At present, EU waste management legislation regulated according to Directive 98/24/ EC. And of course, if a nanomaterial, or nanowaste. The European Commission the macro-scale material of the same believes that the current legislation also composition, is recognised as a carcinogen applies to nanowaste. However, this is not or mutagen, then Directive 2004/37/EC on always the case and the European Parliament carcinogens and mutagens at work must be has asked the Commission to review its waste followed. how to manage nanowaste to avoid health The European Commission has assumed and environmental issues, particularly from that these pieces of legislation also protect 36. workers from the risks of nanomaterials. However, these EU Directives do not substances per se according to REACH. Furthermore, methodologies to identify nanomaterials are lacking and, with no labelling requirements at European level, information on their presence in products and the possible risks are not available to workers. As such, these Directives do not protect workers, and Trade Unions (namely the European Trade Union Confederation) and the European Parliament have already asked from the risks of nanomaterials36,40,155.

35 CONCLUSIONS AND RECOMMENDATIONS OF HCWH 6

Nanomedicine is already a reality and has the potential to deliver many advantages remains largely unproven. Nanomaterials for the diagnosis and treatment of many are essentially new and largely untested health problems. A number of technologies chemicals and little is known about their are already on the market or being tested persistence, bioaccumulation and toxicity, in clinical studies, using a myriad of although many would fall into the category nanomaterials. Health Care Without Harm of toxic materials. Therefore, in view of the recognises that nanomedicine can bring potential risks of nanomaterials to human health and the environment and the lack professions. However, there are many reasons of knowledge, preventive action should be to consider that new risks may arise to affect taken and the precautionary principle must human health and the environment. be applied. Without a clear knowledge of the risks involved for human health and The basis for these concerns lies with the the environment, products should not be different properties of nanomaterials, allowed into the market. This is particularly the many gaps in knowledge, the lack of important for dispersive applications such methodologies and tools for assessment and as disinfectants, which do not have a clearly management of any risks, and our conclusion other products. protect human health and the environment. The risks will of course be dependent on the Address limitations of EU regulatory frameworks routes, but cannot be dismissed while they Nanomaterials are new chemicals and Health Care Without Harm believes that EU legislation, placing the burden of proof legislators have an important role to play in for safety in the hands of nanotechnology protecting human health and the environment producers and distributors. One of from the potential risk of exposure to the biggest issues is that of regulating nanomedicine and nanomaterials. A strong nanomedicine products, as many will be crossover or borderline products with the use of nanomedicine, and a number of mechanical and chemical functions. Therefore, policy recommendations from Health Care it is important to: Without Harm follow below. ¬ Improve the current nanomaterial Apply the precautionary principle threshold to 100 nanometres in one or The potential of nanotechnology to bring more dimensions, in accordance with

36 ¬ Toxicological properties; and Agency. ¬ Environmental fate and behaviour ¬ Amend REACH, maintaining the dictum including ecotoxicological properties. “no data, no market” and taking into In order for appropriate testing to be carried consideration: A need for different threshold terms of: requirements for registration of ¬ crystal structure nanomaterials. ¬ primary particle size distribution ¬ agglomeration/aggregation state information should be required to ensure ¬ that the manufacture, marketing and ¬ morphology/shape/aspect ratio use of nanomaterials in nanomedicine ¬ products or others have no harmful effects ¬ catalytic properties on human health or the environment ¬ free radical formation potential during the entire life cycle. ¬ ¬ Specify clear provisions for nanomedicine ¬ dustiness (i.e., the propensity of a products that exhibit characteristics material to generate airborne dust during its combining pharmacological and mechanical functions so that they are regulated as a ¬ the fate and properties of nanomaterials third category which acknowledges the in water, and risks of both intentional and non-intentional ¬ photo-degradation potential. release of nanomaterials into patients and healthcare professionals. Prioritise research to address safety concerns regarding ¬ Review EU waste management legislation the risks of nanomedicine products in human health and the environment properties and characteristics of nanowaste Research into nanomaterials and and to provide guidance on management of nanomedicine has continued to increase in recent years, but it has been focused whilst avoiding health and environmental towards improving technological innovation consequences. and, unfortunately, the potential risks of nanoproducts have remained poorly Identify and categorise nanomaterial characteristics to assessed. When nanomedicine products enter ensure appropriate testing methodologies into the environment it is crucial to understand Testing methods for nanomaterial toxicity their fate and effects in terms of bioavailability, are still very much under development, bioaccumulation, toxicity, environmental hence knowledge on toxicological and transformation and interaction with other environmental contaminants. Also current test to conduct proper risk assessment140. The guidelines use conventional methodologies recommended testing requirements to that are unlikely to be appropriate for ensure the safe use of nanomaterials can be the assessment of risks associated with grouped into: nanomaterials. Therefore it is important to: ¬ ¬ characterisation based on physicochemical safety, fate and persistence of nanomaterials in humans and the environment.

37 ¬ guidelines and tools to detect, monitor and measure nanomaterials in the Patients, workers and communities need full access environment and the effects of exposure of to information and to be part of the decision-making these materials on human health and the process environment. Transparency, despite numerous stakeholder dialogues and other public relation exercises Consider the entire lifecycle of products when pertaining to nanotechnology, has not been a hallmark of the emerging nanotechnology The entire lifecycle (including the industry. In many of the “dialogues” there manufacture, transport, use, environmental has been a heavy emphasis on convincing impacts and end-of-life management) of the public of the potential (but as yet mostly nanomaterials needs to be addressed when very little information on the potential risks nanomedicine. For example it is important to: associated with substantially unregulated and ¬ Develop guidelines to assess end-of-life untested products that have been introduced management options for nanomaterials that into the market. In terms of nanomedicine, include: very little stakeholder involvement The potential intrinsic toxicity of has occurred. Perhaps this is because nanomedicine waste and the hazardous nanomedicine has been perceived primarily effects of incineration emissions. as the domain of the medical profession, Prediction of the fate and transport rather than a range of “products” that has the of nanowastes in the environment upon potential to affect not only patients but also disposal. healthcare workers, the wider community and Assessment of whether nanowaste the environment. It is therefore important to: should be listed as hazardous waste. ¬ Create a mandatory EU register for Research into the current handling, of the production, import and use of treatment, storage and disposal nanomaterials and nanomedicine products. practices for bulk materials and their ¬ Introduce compulsory labelling of all appropriateness for the respective nanomedicine products, so patients and nanoform. healthcare workers can take informed ¬ Discourage the use of nano-based decisions about the use of such products. cleaners and disinfectants in hospitals. ¬ Increase public participation in decisions Nano-based cleaners may act as potent regarding the exposure of patients, workers antibacterials but may also exacerbate and communities to nanomaterials and antibacterial resistance. They should only nanomedicine. be used in the context of treating serious medical conditions.

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Commission of the European Communities. Communication From The Commission To The

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