Scratching The Surface Of Nano-Regulation

Thursday, March 1, 2007 - 00:00

Introduction

In the world of medical research, as in many other sectors, the use of nanotechnology has excited much interest. Manipulation of materials at an atomic level may allow for a diverse and extraordinary range of possibilities, particularly advances in medical diagnoses and treatments. For instance, nanoparticle coatings can allow implants to adhere more readily to biological tissue which can improve the useful life of a prosthesis, and devices are already being developed to allow for immediate diagnoses of illnesses, including the detection of cancer cells. The use of nano-pharmaceuticals might even make drug therapies more stable and targeted. Nanotechnology has even been postulated in the treatment of brain tumours where iron nanoparticles placed in the tumour could be activated when the patient is placed in an external magnetic field, causing localised heating. Already, silver nanoparticles are being used as an antibacterial and antimicrobial coating.

However the technological advances in this area have left a trail of concern about the safety of nano-products and the sufficiency of regulatory structures and safety processes. On 17 January 2007, the European Group on Ethics in Science and New Technologies to the European Commission (the "European Group") issued an "Opinion on the ethical aspects of nanomedicine."1 The European Group recognised the enormous potential of nanotechnology in the healthcare and other industries but reinforced the need for adequate safety processes to be put in place.

What Is A Nano?

The prefix nano is derived from the Greek meaning dwarf with a nanometre (nm) being classified as one thousand-millionth of a metre. Nanoscience is the name given to the study of phenomena and manipulation of materials at the level of the atom or molecule. In some respects, nanoscience and nanotechnology are not new applications. Chemists and engineers have been working at the nanolevel for decades. One way to generate nanoparticles is by use of high impact forces. In fact, a recent Nature article has suggested that medieval swordsmiths fighting the Crusaders, albeit unwittingly, were creating nanotubes and nanowires when they fashioned their Damascus blades from their steel-forging process.2 But it is only very recently that we have started to investigate and manipulate matter at the nanolevel as our technology has become more and more sophisticated.

Is Nanotechnology Safe?

As particles become smaller their relative surface area increases making them more reactive than the same material existing at a larger scale. The consequence of this is that products containing manufactured nanoparticles may be inert (and therefore safe) in their normal existing state but these same products may become toxic when they are broken down into their component nanoparticles.

Initial evidence suggests that at least some manufactured nanoparticles will be more toxic per unit of mass than larger particles of the same chemical. In the UK, the Royal Society and the Royal Academy of Engineering have suggested that analogies can be drawn with studies on exposure to other small particles such as pollutant nanoparticles known to be present in the smoggy airs of some cities. In addition, nanoparticles might gain an increased level of toxicity when inhaled, due to changes in surface structure.

Nanoparticles might also be absorbed into the bloodstream or become more toxic due to the changed chemical composition or structure of the molecule. Ultimately however, little is known about the potential effects of the use of nanotechnology in the domains where it is presently being explored. In its 2005 report entitled, "The National Nanotechnology Initiative at Five Years: Assessment and Recommendations of the National Nanotechnology Advisory Panel," the National Nanotechnology Advisory Panel (the "NNAP") noted that the greatest likelihood of exposure to nanomaterials is during their manufacture. Accordingly, NNAP members have agreed to support research on the potential hazards of nanomaterials from workplace exposure. Last year, the National Nanotechnology Initiative stated that it planned to invest about 4% of the total year's budget on research aimed primarily at understanding and addressing the potential risks posed by nanotechnology to health and the environment.

Is More Regulation Needed?

Developers of nanotechnology are not working in a regulatory vacuum. In the European Union (the "EU"), directives exist which relate to:

1. the placing of medical devices and medicinal products on the market: medical devices do not require authorisation but they must be the subject of a conformity assessment procedure which requires the conduct of a risk assessment and the adoption of a risk management strategy;

2. the conduct of clinical trials: all medicinal products marketed in the EU require product authorisation. Clinical trials, which are assessed by an ethical review committee, must be conducted prior to any authorisation. The Clinical Trials Directive also requires that, prior to the commencement of the trial, there is a weighing of predictable risks and drawbacks with regard to the therapeutic benefits for both individuals and society, respect for the trial subject's right to physical and mental integrity and informed consent; and

3. the use of chemicals: manufactures are also required to conduct risk assessments under the newly adopted Registration, Evaluation and Authorisation of Chemicals (REACH) regulations.

In their "Nanoscience and nanotechnologies" report published in July 2004, the Royal Society and the Royal Academy of Engineering stated that the evidence suggests that current EU and UK regulatory frameworks were sufficiently broad to deal with the current stage of nanotechnological development. This conclusion was reiterated by the European Group in their January 2007 report although the most recent report does advise that overlapping regulatory structures could create uncertainty about the application of particular regulations.

One Size Fits All?

Whether existing regulatory structures are able to be applied in a coherent and meaningful fashion to nanotechnology is a difficult issue. The definition of nanotechnology is not based on the product itself, merely its size. Indeed, an individual product may be both a medical device and a medicinal product.

Recently, the Environmental Protection Agency (the "EPA") applied existing regulatory mechanisms to nanotechnology employed in a washing machine; the machine is now considered to be a "pesticidal device." The EPA initially advised Samsung Electronics that the silver ion generating washing machine, which Samsung was marketing with claims that it would kill bacteria on clothing, was a device and therefore not required to be registered under the Federal Insecticide, Fungicide, and Rodenticide Act ("FIFRA"). However the EPA decided to change its position, making the washing machine subject to registration requirements as a pesticide as the machine incorporates a pesticidal substance (silver). Under FIFRA, a product that uses only physical or mechanical means to trap, destroy or repel a pest (including microbial pests) is a device and is not required to be registered, though its production and labelling are regulated. However, if the product incorporates a substance or mixture of substances intended to prevent, destroy or repel pests, then it is considered to be a pesticide and is required to be registered. The EPA advised that it would issue a notice in response to questions about whether Samsung's silver ion generating washing machines are pesticidal products; however it has made it clear that it does not represent an action to regulate nanotechnology.

However, the basis for the EPA notice was not the use of nanotechnology, as such, but the claims that the product operated as a pesticide. The focus on the application of the product rather than the technology itself would be one way in which to address legislative concerns but the reality is that nanotechnology stretches our understanding of the potential uses of products and their precise categorisation is uncertain. In the event that Samsung decides not to market the product as having pesticidal properties, it will cease to be regulated by the EPA.

Also, what constitutes an adequate risk assessment is not entirely clear. In the context of clinical trials, how can the consent of an individual be properly informed when little is known about the effects of nanomedicine?

In addition to overlapping regulatory structures, questions still remain about how to meaningfully comply with existing requirements. Workplaces in which nanoparticles are developed will need to consider occupational health surveillance and measures to minimise worker exposure. The prime objective of a risk assessment is to calculate the measures for the protection of health and safety that are reasonably practicable for that business. This requirement is present in European health and safety directives3 and has been incorporated into the domestic law of Member States. For example, in the UK, Regulation 3 of the Management of Health and Safety at Work Regulations 1999 requires employers to make a suitable and sufficient assessment of, in part:


the health and safety risks that an employee is exposed to whilst at work; and


the health and safety risks to others arising out of or in connection with activities carried out by the undertaking.

For a risk assessment to be suitable and sufficient it must:


identify the significant risks arising from the work;


enable the employer to identify and prioritise the measures which need to be taken to comply with relevant statutory provisions; and


be appropriate to the nature of the work and remain valid for a reasonable period of time.

Clearly at the present time, in the context of nanotechnology, risk assessments relating to the workplace must be mainly limited to the use of standard protective personal equipment, even where it is not clear that such equipment would be sufficient. It may be adequate to use high grade filter masks in the development and manufacturing processes but it is unclear what, if any, protective equipment might be needed by healthcare workers working with nanomaterials.

The Precautionary Principle

The Precautionary Principle (the "Principle") is a guide for decision making when confronted by "difficult to predict" or uncertain events. The Principle originally emerged in the context of environmental harm; however, there is now broad acceptance that it can be properly applied in relation to the health and safety of individuals and in relation to harm to flora and fauna.4 There is no single definition of the concept; however, the UK government's Better Regulation Commission defines the Principle as follows:

"The Principle says that when an activity raises threats of harm to human health or the environment, and the current state of scientific evaluation doesn't allow the level of risk to be determined with sufficient confidence, then precautionary measures should be taken." 5

The Principle is based on three specific concepts:

1. The need for the fullest possible scientific evaluation. As far as possible this evaluation should determine the degree of scientific uncertainty at each stage;

2. Any decision to act or not to act pursuant to the Principle must be preceded by a risk evaluation and an evaluation of the potential consequences of inaction; and

3. Once the results of the scientific evaluation and/or the risk evaluation are available, all the interested parties must be given the opportunity to study the various options available, whilst ensuring the greatest possible transparency.

The European Group consider in their report that the Principle would provide a useful guide on how to approach nanotechnology.

Future Research

Significant funding is being devoted to further research. The U.S. National Science Foundation's 2008 budget request includes $390 million for nanotechnology. The Seventh Framework Programme is the EU's largest research and development funding programme; it was launched on 1 January 2007, injecting some $4.5 billion into nanotechnology-related research between 2007 and 2013. In addition, joint-research initiatives are on the agenda for the EU and the U.S. and under a bilateral research framework concluded on 9 February 2007, scientists and researchers in both jurisdictions will engage in joint efforts to address common environmental challenges. Over time, these initiatives should generate a far greater understanding of the potential toxicity of nanomaterials and also produce methods of assessing risk, enabling an evidence-based assessment of the regulatory structure and, if appropriate, supplementary legislation to be issued.

However, in the interim, businesses seeking to research nanomaterials and introduce new, nanotechnology-based products to the market may be faced with an avalanche of regulations that may not sit comfortably in the tiny worlds where they will need to be applied.1 Opinion No.21

2 Nature, Vol. 444, No 7117, pg 286

3 On the introduction of measures to encourage improvements in the safety and health of workers at work. 4 Article 9 of Directive 89/391/EEC

5 Better Regulation Commission "Imaginative Thinking for Better Regulation September" 2000

Diana Newcombe is a Senior Associate at the London office of Eversheds LLP. Diana specialises in regulatory compliance, the implementation of legal risk management systems and best practice in corporate governance. She also provides advice in relation to corporate criminal defence and civil proceedings relating to regulatory breaches. She is qualified as a barrister and solicitor in England and Australia. She may be contacted by telephone +44(0) 845 497 0861. Alan McBride is a Trainee Solicitor in the Regulatory group at the London office of Eversheds LLP. A former biochemist, his interests lie in intellectual property rights and the regulation of scientific and pharmaceutical products and technologies. He may be contacted by telephone +44(0) 845 497 0705.

Please email the authors at diananewcombe@eversheds.com or alanmcbride@eversheds.com with questions about this article.