Nanotechnologies, and nanomaterials as a subset, have a great deal to offer to improve the quality of life. However, as for any emerging technology or development, there are potential downsides. There is no direct link between the nanoscale properties of a material and its possible toxicity, as this property is is strongly dependent on the type of particle and its environment.
The challenge in evaluating toxicological behaviour is to determine the characteristics that are specific to particles of nanoscale size (which is usually considered to be particles with at least one dimension smaller than 100 nm) and try to correlate these to the observed toxicological behaviour. This process is currently ongoing, with among others, the aim to predict possible adverse effects based on these characteristics. In 2009, the EU Scientific Committee SCENIHR already provided an overview of a number of important toxicological findings for non-(water)soluble nano-sized particulate matter.
Toxicological exploratory research has allowed to adress more firmly the questions of what makes nanomaterials different from conventional molecular substances and what are the methods that can be used to determine if effects are still applicable for nanoparticles and materials. Even if there is still a lack of clarity and significant work to be done to resolve the many unanswered scientific and regulatory questions, there has been progress in the application of this toxicological knowledge to a regulatory context. We need now to find further ways to assess and deal with the uncertainties of these risks across time and a number of considerations are offered, that provide useful context for subsequent steps to be taken.
Do we have the tools today to evaluate the potential risks associated to nanomaterials?
There is a continuous development of new nanomaterials to be used in a multitude of products. In parallel, our scientific understanding and ability to explain and describe the observed phenomena associated to nanomaterials is growing, but is still relatively limited. Nanoparticles toxicology, as it is applied in the safety evaluation of nanomaterials, is fundamentally different from the classical toxicology of substances in soluble form. In the meantime, our knowledge of more advanced nanomaterials – e.g. coated particulate matter, bioactive nanomaterials, self-organising particles – is very limited in terms of toxicology and microbiology, and it is not progressing at a pace that keeps up with the technological developments.
Scientific understanding is growing, but has not reached the point that we can provide general descriptive models; more empirical data and mechanistic understanding are necessary to support this process. Potential risks still need to be assessed on the basis of incomplete data and incomplete understanding of the relevant underlying (toxicological) phenomena.
New fields of research with an impact on the current knowledge of toxicology and hazards are still emerging (bionanotechnology – nanotechnology using biological materials – is an example).T hus, the RIVM considers that elementary (eco)toxicological understanding and risk assessment tools for relatively simple nanomaterials are projected to be available not before 2020. There is indeed a considerable and continuous interdisciplinary effort still needed to develop the necessary knowledge and generate all the necessary information and data from a risk assessment point of view.
What are the hazardous properties potentially associated to nanomaterials?
From the hazard1 perspective for humans, an elementary but important observation is that nanomaterials and nanoparticles are in the size range of our biological machinery. Nanomaterials are a class of compounds that is toxicologically ‘new’, that is it may interact with biota in a way which we now only partly understand. It is important to recognize that many of the substances that are the focus of current nano-toxicological studies are relatively ‘simple’ particulate materials (often termed ‘first-generation’ nanomaterials including metals, metal-oxides, SiO2, carbon, carbon nano-tubes (CNT)), mainly on the basis of their high and widespread current production and use. At present, these simpler and better researched nanomaterials and their exposure potential are relatively well understood.
Inhalation exposure to certain nano-sized particulate matter may result in local lung inflammation, possibly resulting in subsequent responses such as allergy and genotoxic effects. Due to their size, shape and persistence in the organism, some specific types of nano-fibres may exhibit asbestos like responses including chronic inflammation.
Additional concerns are related to the internal exposure, as some particles may enter the bloodstream and accumulate in organs like the liver and spleen. In in vitro cell systems, particulate matter is able to enter subcellular compartments, including the nucklear membrane, opening up a possible route for direct and indirect genotoxic effects.
Meanwhile, new generations of complex and sophisticated nanomaterials exhibit specifically designed bio-interactions or have a self-assembling nature. These nanomaterials may show complex dynamical behaviour, which fundamentally complicates the process of scientific understanding.
Among these, nano-encapsulates, developed to be used in food and feed products and already used for medical purposes, are an important novel class of nano-particulates. In food products, the current thinking is that, in the human intestinal tract, the nano-structures quickly degrade back into their individual constituents. There is however some concern about more stable forms of encapsulates that may result, for example, in increased bioavailability of these ingredients.
Regarding the hazards for the environment, the diversity of impact data makes it impossible to form a consistent opinion on the hazards of specific nanomaterials. Most of the available information concerns the aquatic environment and virtually no information exists on the hazards of nanoparticles in soils and sediments. Increasing attention is being paid to the hazards of transformation products, which are formed after the introduction of a nanomaterial into the environment.
What are the risks associated to exposure to some nanomaterials
In essence, the basic philosophy and methodology needed to perform a risk assessment of nanoparticles is the same than for conventional non-nanomaterials: comparing the level of exposure with the level at which a toxic effect (a hazard) is observed.
Here again, the instruments normally used to assess the risks related to the exposure to nanomaterials need to be adapted because of the specific properties of some nanomaterials. Adapting old and developing new instruments is time consuming and requires considerable effort. Existing knowledge focuses on finding more generalized assessment methods. These metyhods are essential in order to assess the continuously and rapidly growing number of increasingly complex nanomaterials that are being developed and potentially applied. However, further understanding of mechanisms of action the development of the methods and tools, and the drafting of standards are well underway.
In the meantime, as a consequence of both the lack of data on the behaviour and effects of a specific nanoparticle and the current lack of scientific and harmonized methods and tools to evaluate them properly, the number of authoritative risk assessments of specific nanoparticle substances performed with a sufficient rigour by acknowledged specialists, is still very limited. Nowadays, these risk assessments are limited to relatively simple nanomaterials:
- For a number of cosmetic ingredients; conclusions were drawn based mainly on the low levels of dermal uptake and therefore the limited internal exposure. Use of spray, resulting in possible inhalation was not recommended.
- For nano-silver, the EU Scientific Committee SCENIHR reviewed the available information and could not rule out adverse effects. Nano-silver and -titane oxide are also subject to an evaluation in which (environmental) aspects are included.
- For a number of other nanomaterials, a more detailed risk assessment is foreseen: silicium oxide (SiO2) is currently under scrutiny because of it accumulating potential in humans combined with its widespread use.
- The possible risks as a result of the established use of nanomaterials as food additives are reevaluated . This evaluation process will include nano-forms of the additives and is scheduled to be finalised in 2020.
- For medicinal products, the greatest challenges are associated with the novel, “next generation” of nanomedicinal products and the generic versions of first generation products, e.g. those based on liposomes or iron oxide nanoparticles, which are termed “nanosimilars”.
More globally, several initiatives might support new ways of efficiently addressing nanomaterial safety in such a way that they do not hamper the innovation potential. Pragmatic reasoning, in which we accept that in some cases protection cannot be 100%, might be worthwhile considering as an interim solution. The report stresses that this is a pragmatic and realistic assessment of the current situation, and an instrument to help prioritise efforts:
- On the one hand, initiatives addressing safety can be distinguished, for example safe innovation or responsible research and innovation;
- On the other hand, there are also initiatives aiming to better tune regulatory approaches to innovations; initiatives like adaptive governance or flexible regulations.
What about the risks associated to occupational exposure to nanomaterials?
In the EU, occupational risk assessments are primarily the responsibility of the employer. Derivation of occupational exposure limits to specific nanomaterials is hampered by the lack of toxicological data. Also, many challenges in exposure measurement techniques need to be overcome.
Here again, pragmatic approaches in order to aid in the assessment and subsequent control of nano-particles exposure in exposure determination and risk management are being developed in the occupational field. ‘Reference values’ are presently derived that, for all practical purposes, act as exposure limits. These values are derived through scientific reasoning, using the best knowledge available at that moment.
What about the environmental risks of nanoparticles?
Development of the fundamentals of models that describe the release, distribution and exposure, as well as the data to validate the models are still scarce. Progress in the development of analytical tools and methods for measuring nano-characteristics in complex media, are needed to gain insights into the presence of and exposure to nanomaterials.
Environmental risk assessment for metallic nanoparticles of zinc shows that the gap between effect levels and exposure levels is relatively large, so that as yet, at EU level, no risk for organisms in the aquatic enviroment waters is anticipated. A similar approach for nanoparticles of silver does not exclude the occurrence of adverse effects on the environment.
Is information available on human exposure to nanomaterials?
Although there is still a serious lack of information on the use and presence of nanomaterials in consumer products, there is increasing knowledge of their presence based on obligatory labelling information, in the case of cosmetics and biocides. There is also increasing knowledge of amounts, number of particles and concentrations in consumer products based on experimental measurements.
However, the speed at which new products with nanomaterials are expected to hit the market and the sheer number of them exceed the pace at which our knowledge on their risks is developing. For a number of product categories, there is no regulatory incentive or otherwise for manufacturers to make data available about the presence of nanomaterials in their product. Experimental measuring techniques still require highly skilled personnel and bring high costs, and thus are not universally available.
What are the main knowledge gaps regarding nanomaterials?
There are four main areas on which progress should be focused :
First of all, there is a serious need for data – i.e. nanomaterial and nanoparticle specific data (physical-chemical, (eco)toxicology, exposure) but also data on the use of nanomaterials/particles in products and the release of these materials/particles from products. These data are needed to be used a.o. in legislative frameworks including occupational health and consumer protection. The many data generated in the numerous European and global projects could for example be shared and combined at a more structured level and developing novel ways to exploit these data may add to the results.
Secondly there is a need for knowledge; we need to improve our current scientific understanding of nano-toxicological behaviour and make the step towards generalisation and abstraction. The question that needs to be addressed is how to deal with assessing the potential risk of pristine nanoparticles versus the potential risk for humankind and the environment during and after use of the product containing these nanoparticles.
As part of this effort, to be able to deal with the growing number of nanomaterials, the step towards scientific understanding and development of models and tools for more generalised approaches (the so- called grouping, read-across, QSARs approaches), is essential. More multidisciplinary approaches and cross-fertilisation with other disciplines are also worthwhile exploring. International processes, which are currently initiated on e.g. OECD-level provide essential support for achieving much needed progress on this topic. These ‘precautionary’ approaches help to identify possible risks and adverse effects at an early – preferably premarket - stage of product development, when also the economic impact is still limited.
Thirdly, we need to broaden the scope to monitor and assess the developments of new generations of nanomaterials (e.g. bioactive and self-assembling materials) and emerging technologies, the so-called 3rd and 4th generation materials. The scientific fundamentals of the interaction of these materials with biota need to be explored and a baseline assessment of potential hazardous impact needs to be made.
Fourthly, we need consider aspects of risk governance and to find ways - scientific, regulatory and societal – to deal with the difference in pace between nanomaterial innovations and our scientific and regulatory capacity to assess the uncertainties and risks, and ways of dealing with these potential risks and uncertainties.
Speeding up the progress in coming to conclusive answers about health risks seems to be inevitable. The current situation is that nanomaterials and materials containing nanoparticles are already on the market while the instruments required to assess their hazards and risks are still in development but not yet sufficiently matured, and the number of products expected to hit the market will most likely show a large increase in a near future.
Therefore, the regulatory-scientific community is exploring options for finding alternative testing strategies to those used for common materials which allow to assess this specific level of concern, and base the subsequent (testing) strategy on this concern.
Such developments will provide policy-makers with additional tools and policy options for decision-making and prioritisation regarding these potential concerns. A similar interesting development can be seen in the field of the evaluation of occupational exposure to nanomaterials .
Is the EU legislation adapted to the management of risks associated with nanomaterials?
At a European level, a recommendation on the definition of nanomaterials was published. This forms the basis for the definition in several newly formulated EU-legislations. A number of product regulations now include a labelling obligation (regulations for cosmetics, food and biocides). Labelling for medical devices is foreseen, but still under discussion at the political level.
The EU regulations on chemicals (REACH Regulation), when adapted, will provide some of data on exposure and on risk reduction measures, albeit at a fairly limited level. But the REACH Regulation only adds limited data relevant for exposure, especially below the 10 ton/year production volume threshold, and adaptation of regulatory frameworks is a slow political process that leaves data gaps. As a consequence, regulation is likely to increasingly lag behind the development of new and innovative materials and products that hit the market. Nevertheless, in general, the European Commission concludes that the current EU-legislative framework to a large extent covers potential risks in relation to nanomaterials.
On the other hand, organisations like the RIVM demonstrated that within the various frameworks like the EU-REACH Regulation and Occupational Safety and Health, legislative gaps still do exist. Therefore, these current legislations may have to be modified in the light of new information becoming available, for example regarding thresholds used in some legislation. Adaptation of the REACH Regulation to include the generation of data and subsequent assessment of the risks is seen as essential.
Owing to the lack of progress in the EU arena, a number of Member States have developed national initiatives for the registration of consumer products containing nanomaterials; each of these initiatives has its own assumptions and content. Ideally, the separate systems will be harmonized over time to achieve a coherent EU registration system, a process expected to become more complex as more national initiatives continue to crystalize. The possibilities for an European approach are now under the scrutiny of the Commission. Finally, there is a need at international level for reliable insights into the application of nanomaterials in consumer products.
Would a better cooperation between scientific inititives and regulatory initiatives be useful?
From a scientific-regulatory perspective, government, society in general, the regulatory-based scientific community, and the business community should cooperatively work to find ways of dealing with fundamentally new and innovative developments in both materials and risk. This would add a firm foundation of increased data available and mutual understanding, as they may provide approaches for policy-makers that support regulatory decision-making at the pre-market stage.
Joint efforts by risk-assessors and industry scientists may help identify possible undesired effects at an early stage, thus allowing for improved pre-market screening of nanomaterials. In this context, both innovation and risk assessment processes may indeed benefit from increased cooperation and data-sharing in which information on composition and underlying data that are fundamental to nanomaterial behaviour and dynamics become available to risk assessors. Sharing and having access to the multitude of data is thus essential for making sufficient progress, a process which, up to now, has been hampered by aspects like confidential business information.
RIVM observed that the emphasis of the scientific nano-safety community is on safety, whereas for fundamental scientists and the scientific business community, innovation is more leading. Joining and combining those viewpoints, focussing on mutual understanding of the underlying concepts will help making a shift towards approaches based on a shared frame of reference.