Nanotechnology and safety

Five years ago, little was known about nanotechnology outside specialist circles. Yet it is now being touted as a major technological breakthrough, heralding the next industrial revolution. Researchers and developers are talking about how nanotechnology might be used to develop lighter, stronger materials, better batteries and improved solar cells in the near-term with applications such as targeted cancer treatments, microscopic sensors and even life-mimicking devices in the mid to distant future.

This enthusiasm is backed by serious r&d funding from government and industry — estimated at nearly US$10 bn globally for 2005.1

At the same time, there are concerns that nanotechnologies will bring new risks to human health and the environment, which we are not equipped to deal with.2 The previous industrial revolution taught us many hard lessons about how rapid technological advances can impact on society. Even so, preventing disease and injury from industrial processes and products with their roots in the industrial revolution still presents many challenges. Relatively recent technologies such as nuclear power and genetically modified organisms have led to increased scepticism within society over the ability of industry and governments to ensure their safety.

Against this backdrop comes nanotechnology. Early concerns over the possible dangers were voiced by civil society groups such as the ETC Group and Greenpeace.3,4 In 2004, the Royal Society and Royal Academy of Engineering published a milestone report addressing the opportunities and potential challenges presented by different nanotechnologies.5 Since then, a steady stream of reports and papers from groups that include academia, government, non-government organizations and industry have emerged, that consider the dangers of not balancing the benefits of emerging nanotechnologies against potential and novel risks. 6-12

Are the promises of nanotechnology and the potential risks real? Or is the current flurry of interest little more than hype? And how should the occupational hygiene community respond — as it represents and protects the first line of people to face possible risks?

Perhaps one of the best known of the "new" nanomaterials was carbon nanotubes — discovered in the 1990s.13-14 Single-walled carbon nanotubes (SWCNT) are in essence a single sheet of graphite (graphene), wrapped into a tube of about 1.5 nm in diameter.

This unique atomic configuration leads to a material with an exceptionally high strength-to-weight ratio; that is an excellent thermal conductor; that is highly electrically conductive and yet, may be an insulator or semiconductor if the atomic configuration is marginally altered. Many other materials show unique properties that are dependent on their nanostructure. These range from size-specific fluorescence in semiconductors such as cadmium selenide due to quantum confinement, altered optical properties in nanoscale TiO2 and a whole host of surface area and surface chemistry-dependent behaviours in a wide range of materials. But these are relatively simple nanomaterials.

Current research is leading to the development of more sophisticated and heterogeneous materials and devices — based on an increasing ability to engineer in functionality at the nanoscale.15 For instance, multicomponent nanoscale particles are being developed for cancer treatment that will have the ability to attach to diseased cells, enable their position to be tracked, and destroy the cell while leaving surrounding tissue intact when signalled to do so. 16

Further out, there is interest in replicating biological functions with engineered molecules and systems. For example, researchers at Rice University in Houston have developed "nano-cars"—four Carbon-60 molecules (the wheels) connected by organic molecules (the chassis), that demonstrate directional motion on a surface.17 These are seen as proof-of-concept for "nanoscale transporters", able to move materials around in a controlled manner at the nanoscale.

In many ways, nanotechnology more closely represents a way of thinking or doing things, than a discrete technology. And this makes it particularly difficult to discuss potential risks in general terms.

Already, investment in research and development has led to over 300 allegedly nanotechnology-based consumer products entering the global market.18 These range from computer chips to sports goods and clothing to cosmetics and dietary supplements. By 2014, it is estimated that the global value of nanotechnology products will exceed US$2.5 trillion.19 The presence of engineered nanomaterials in the workplace now presents an immediate challenge to how occupational safety and health is managed effectively. Little is known about what the immediate risks might be, or how to handle them.

Health hazards

There will never be a one-solution-fits-all approach for working safely with nanotechnologies and nanomaterials in the workplace, but this association between structure and functionality provides a useful handle for beginning to explore occupational health risk.

The significance of structure — as well as chemistry — in engineered nanomaterials is demonstrated by the research of Professor Z. L. Wang.20 A number of purposely made nanostructured materials. Can be produced in which the chemistry is the same (ZnO), but the physical form is very different. Structure, as well as chemistry, at the nanoscale will determine the behaviour of these materials, in much the same way that both structure and chemistry determine the properties of engineered products at the macro scale — including everything from powders to hand tools to buildings.

At the visible scale, it is obvious that structure and chemistry act together to make a product work; the danger is that we ignore the same association when we cannot physically see a nano-engineered material or product. The concept that both chemistry and structure are important in determining health risk is not new to occupational hygiene: Lung diseases resulting from aerosol exposure are associated with particle size and composition for instance.21 In the extreme case, asbestos represents a substance where both chemistry and structure conspire to construct a highly hazardous material in the lungs: change either the composition or the morphology, and the hazard is reduced.

If we are to address the potential risks presented by engineered nanomaterials, this concept of structure and chemistry acting together to determine impact needs to be developed and applied.

Kreyling et al. have studied nanoparticle translocation from the lungs of rats, using 192Ir particles that are both insoluble and easily traced. 22 Introducing 80 nm diameter particles into the animals’ lungs, they found a significant mass of material translocating to the liver. However, the translocation rates were low — of the order of 0.1%. When the experiment was repeated with 15 nm diameter particles, translocation rates were significantly higher — between 0.3 and 0.5%. Although still low, the data strongly suggest discrete nanometre-diameter particles can leave the lungs by a nonconventional route. Looking to another part of the respiratory system, recent research using rodents has suggested that deposited discrete nanometre-diameter particles are capable of being transported from the nasal region of the respiratory tract to the brain, via the olfactory bulb, thus circumventing the blood–brain barrier.23,24

While it is by no means certain that this particle size-dependent exposure route is significant in humans, it raises a number of intriguing possibilities when exploring possible associations between exposure and disease.

Staying with particle size but moving to the outside of the body, the skin is traditionally thought of as providing a highly effective barrier against particles. But the inclusion of nanometre-scale particles in cosmetics and sunscreens in recent years has led to this assumption coming under some scrutiny. Research has demonstrated the potential for submicrometer particles to penetrate the outer layers of mechanically flexed skin in laboratory tests.25 Nanometre-diameter particles may be able to penetrate the skin where larger particles cannot, but the probability of penetration will depend on chemistry as well as size.

Despite clear evidence for an association between inflammatory response and particle structure, it would be naïve to ignore the possible significance of chemistry. What happens if particle surface chemistry is altered — does the hazard potential remain the same, increase or decrease?

A further piece of evidence to be considered addresses the significance of structure in more complex materials in determining biological response in lungs. SWCNT have their own distinct morphology, but also assemble into complex larger structures. Studies examining tissue thickening in the lungs of mice have demonstrated a unique response to purified SWCNT aggregates. But they have also indicated a structure-specific response. Purified SWCNT material introduced to mice through pharyngeal aspiration showed rapid tissue thickening in the proximal and distal regions of the lungs, at doses as small as 20 mg per mouse. 26

It appears that the response in the alveolar region was associated with SWCNT aggregates having a very open structure. Not only were these able to deposit and elicit a response in a different region of the lungs to the compact aggregates: they were not detectable using standard histopathology techniques. These examples are just a few of many that strongly suggest an association between nanomaterials structure and hazard potential.

These and other studies do lend substantial weight to the hypothesis that the heath hazard of some engineered nanomaterials will be dependent on chemistry and structure. What published research does not indicate yet is how this potential hazard might relate to risk.

To address possible health impact, we need to understand the risk to human health, and how this might be controlled and managed. It has already been noted that the diversity of nanotechnologies will most likely prevent a one-solution-fits-all approach to risk. To address risk rationally, nanotechnologies presenting a clear threat to health must be distinguished from those less likely to cause harm.

Under conventional risk assessment paradigms, understanding the risk presented by these materials will be a function of both hazard (incorporating toxicity and health outcomes) and exposure (including exposure routes and dose). There is also a third component that deserves specific attention when addressing engineered nanomaterials: Characterization.

Unlike many conventional materials, the relevant characteristics of engineered nanomaterials may be non-obvious, and non-trivial to quantify. In constructing a framework for nanomaterials toxicity testing, Oberdörster et al.11 recommend 16 physico-chemical parameters that should be evaluated in toxicity tests — a far cry from the two or three usually measured. These range from surface area and surface chemistry to particle size distribution and particle charge. Engineered nanomaterials are notoriously difficult to characterize — even two materials that are notionally the same may have subtle but significant differences that determine their behaviour.

For instance, introducing a small percentage of impurities to the surface of nano-TiO2 particles may fundamentally alter their propensity to generate free radicals under UV radiation.27 And changes over time such as coagulation, sintering and chemical transformations can likewise alter behaviour. Without rigorous nanomaterials characterization, it will be near-impossible to interpret toxicity studies, compare similar studies and develop predictive models of nanomaterials hazard.

Characterization is just as important for evaluating exposure. In an ideal world, the same parameters of interest to determining hazard would also be used in evaluating exposure. Of course, this would place an impossibly high burden on occupational hygienists. Instead, it is more practical as a first step to consider the three key physical exposure metrics — number concentration, surface area concentration and mass concentration.

While developing a sound understanding of hazard and exposure will allow the occupational risks of engineered nanomaterials to be quantified, safe workplaces will depend on controlling exposures. Here there are two challenges: How do we know the efficacy of conventional control approaches for airborne nanomaterials, and how can we define appropriate levels of control if there is insufficient information available for a quantitative risk assessment?

We are a long way from having enough information on the risks presented by many emerging nanomaterials to evaluate what levels of control are appropriate.

It may be possible to assign an "impact index" to engineered nanomaterials, based on their composition-based hazard, and perturbations associated with their nanostructure (for instance, surface area, surface chemistry, shape, particle size, etc.). A corresponding "exposure index" could, in turn, represent the amount of material used, and its propensity to become airborne (dustiness). As with conventional control banding, the combination of the two indices could then be conceivably linked to specific control bands.

While we are beginning to develop ways of approaching engineered nanomaterials in the workplace, we cannot avoid the fact that there is an overwhelming level of uncertainty over what materials and technologies present a potential risk, why they do, and how risk might be assessed and managed effectively. In the long-run, safe nanotechnologies will not become a reality unless these uncertainties are addressed systematically. And this means conducting strategic research.

Investment in longer-term priorities is needed now, if we are to build sufficient knowledge and capacity to address future challenges. Identified longer-term priorities include establishing associations between nanomaterials exposure and disease, and developing methods of predicting hazard of new engineered nanomaterials.

To achieve the necessary level of knowledge to support "safe" nanotechnologies, the PEN report12 emphasizes the need for targeted research addressing specific and well-defined issues. It also recognizes the need to identify and use risk-relevant research within the broader sphere of nanoscience and nanotechnology. This research, it is argued, must be conducted within and through partnerships if it is to be successful — between researchers, governments, industries and others with a stake in ensuring the safety of emerging nanotechnologies.

Inevitably, there is a certain amount of hype surrounding nanotechnology. And yet, our ability to manipulate matter at the smallest scales will continue to improve, leading to increasingly sophisticated materials and devices that are engineered at the nanoscale. But the benefits will inevitably bring with them new risks that need to be identified and managed.

As people working within emerging nano-industries will be some of the first coming into contact with the new materials, the challenge we face is how to ensure these people remain safe — how to stay ahead of the curve, and assess and manage risk where existing knowledge can only be pushed so far.

With foresight, sound science and strategic research, we have the opportunity to ensure that emerging nanotechnologies are as safe as possible, while reaching their full potential.