Nanomedicine and Risk: Further Perspectives

DESIGN

Defining risk

To further consider how best to frame risk management in the context of medical nanotechnology, it is probably necessary to briefly revisit the definition of risk as normally applied in the medical technology industry:

Risk: combination of the probability of occurrence of harm and the severity of that harm.

Harm: physical injury and/or damage to the health of people or damage to property or the environment.²

It is useful to remember the difference between a risk as defined above and a hazard:

Hazard: potential source of harm.²

It can be seen from the above that a risk is generally considered to have two elements, namely probability (how likely something is to happen) and severity (if it does happen, what are the importance of the consequences). In the context of medical nanotechnology, these two elements remain critical.

Levels of complexity in nanosystems

Although it is important to avoid generalisations on risk issues, because every technological situation is unique with a different range of hazards and causal factors, generally, the combination of the probability of occurrence of harm and the potential severity of that harm rises as the level of complexity of a system increases. In addition, the definition of a nanomaterial is one where one dimension is below 100 nm.

Looking at this from a medical nanotechnology perspective, it may be possible to derive a tiered categorisation of risks, as recently suggested by the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR)³ and the International Risk Governance Council (IRGC).⁴ In particular, this would make a distinction between risks presented by passive and active nanostructures.

Passive nanostructures. Most currently available medical nanotechnology products incorporate passive nanostructures. In passive nanostructures, behaviour is usually passive or reactive and materials tend to have relatively simple steady structures, and stable mechanical behaviour and chemical reactivity.⁴ Examples of these structures in medical technology include nanopatterned materials such as those used on implant surfaces, nanostructured materials used in tissue engineering scaffolds, nanowires used in novel biosensors, and nanotubes used in regenerative medicine and some types of simple nanoparticles and quantum dots used in diagnostics.

Although there may be new hazards presented by passive nanostructures, generally speaking their risks may be evaluated and managed using conventional risk management procedures such as EN ISO 14971.²

Active nanostructures. Here, the state of the structure itself changes during operation. Examples include in vivo biosensors, nanoactuators, nano-based cardiac or neural stimulation devices, targeted nanostructures for drug delivery, paramagnetic nanoparticles for theranostic use, and nanobio interface systems. In all of these applications, the intended function derives from some change, whether chemical or physical, in the nanostructure or nanoparticle itself. In the IRGC White Paper, Renn and Roco⁴ further subdivide products based on active nanostructures into second-generation (such as the examples mentioned), third-generation (integrated nanosystems and systems of nanosystems) and fourth-generation (heterogeneous molecular nanosystems). Examples of third generation medical nanotechnology products include artificial organs and other regenerative medicine therapies. Examples of fourth generation products include medical interventions at the subcellular level and nanoscale-mediated stem cell therapies.

Because of the increasing level of complexity in active nanosystems, new hazards may emerge and risk may become increasingly difficult to quantify. For example, as the size of nanostructure decreases, characteristics such as dispersion and dissolution, and physical and chemical properties may change markedly. Increased surface area effects may also play a critical role in relation to some hazards, for example, toxicological ones.

In relation to hazard characterisation, the SCENIHR Opinion³ recommends investigating, over time and under various conditions, a wide range of physical and chemical properties. These would include elemental composition, density, crystal structure, solubility, charge, conductivity, melting point, hardness, magnetic and optical properties, morphology, size and size distribution, surface area and surface layer composition, and chemical reactivity. For medical nanomaterials, characterisation should ideally be performed under conditions that will mimic their predicted human exposure. For toxicological risks, toxicology data from bulk materials, particularly where nano-particulate formulations are insoluble/poorly soluble may not be reliable and, in general, it may be difficult to extrapolate risk characterisation from bulk materials to nanomaterials. The SCENIHR Opinion goes on to recommend, “that a tiered approach is developed in order to set out a rationale framework for assessing the potential risks from engineered nanoparticles. The intention is to produce a scientifically valid, cost-effective framework that enables a scientific judgement to be made on the risks to human health and to the environment from nanoparticles.”³

This is broadly comparable with the distinction of risks proposed in the IRGC White Paper and outlined above.

Practical tools

The author considers that the overall framework or “backbone” for risk management as set out in well-proven and widely used standards such as EN ISO 14971 could also be applicable to medical nanotechnology, with the additional requirements and guidance on hazard identification, risk evaluation, risk reduction, risk–benefit decision making and risk communication as appropriate to materials and processes at the nanoscale. There is a precedent for this approach with the development of EN ISO 22442-1, Risk Management in Relation to Medical Devices Containing Animal Products, which is primarily designed to control risks arising from transmissible prions such as Bovine Spongiform Encephalopathy (BSE) and based on EN ISO 14971.

Most certainly it is important that risk management follows an integrated and iterative approach in this product sector. It is essential that the results of risk management activities are presented in a form that is transparent to all interested parties in view of the increased sensitivity in the public perception of risk in new areas such as nanotechnology following high-profile issues including BSE, genetically modified foods and contaminated blood. It is also important that practical support on risk management is established quickly to prevent a void in which industry is unsure what measures to apply. For this reason, a rapidly developed tool such as a British or preferably European or ISO Technical Specification may be preferable to a full consensus standard in the short term, with the possibility to review and amend the document within a short timeframe.

Public perception

The public perception of nanotechnology has been influenced by a number of high-profile statements drawing on often rather remote risks such as the fear of self-replicating nanomachines as represented in Michael Crichton’s 2002 novel “Prey.” Self-assembling molecular nanosystems are on the horizon according to some expert commentators,⁴ however, their development is still some way off and many fears apply solely to the realm of science fiction. One big advantage in the health care sector is that the public is used to balancing risk and benefit in therapy. Examples include X-rays, chemotherapy, cardiac resuscitation devices such as defibrillators, cardiac and vascular implants and radical surgery, to name but a few. In all of these cases, patients know there is a risk involved, but are prepared to accept that risk, in consultation with medical professionals, in view of the potential benefit to be gained. The same should certainly be true for medical nanotechnology, particularly if it can be seen that a rigorous process of risk management has been applied and that any “residual risks” have been communicated clearly.

Richard Moore is Manager, Nanomedicine and Life Sciences, at The Institute of Nanotechnology, 6 The Alpha Centre Innovation Park, University of Stirling, Stirling FK9 4NF, UK, tel. +44 1786 447 520, e-mail: richard.moore@nano.org.uk [6], www.nano.org.uk [7].