Back in 2011 — before that actually — I was asked to write the introduction to an edited book on assessing nanoparticle health risks to human health.
In 2016 a second edition of the book was published, with with a spruced up introductory chapter.
This is one of the few places that I’ve written broadly about the nature of nanoparticle health risks and provided a historic context that tends to be overlooked. Sadly–and as all too often happens with edited books–that chapter is virtually inaccessible to most readers, being lodged in a book that costs well over $100.
So I thought I’d replicate it here–for free.
This is based on the final draft of the chapter and so doesn’t match it precisely. But hopefully it’s still of use. And if you’re interested in the original, as of writing this, you can download it here–although this may not last!
1 INTRODUCTION
In 1990, two consecutive papers appeared in the Journal of Aerosol Science asking whether inhaled particles smaller than 100 nm in diameter are more harmful than an equivalent mass of larger particles (Ferin, Oberdörster et al. 1990, Oberdörster, Ferin et al. 1990). On a mass for mass basis, nanometer-scale particles of TiO2 and Al2O3 were shown to elicit a significantly greater inflammatory response in the lungs of rats compared to larger particles with the same chemical composition. At the time, this research was little more than a curiosity – a novel response to relatively benign materials. But with the advent of the field of nanotechnology, the importance of understanding how the physical form and chemical composition of increasingly sophisticated nanoscale materials influence human health risks has escalated. Now, the ability to identify, assess and address potential impacts from intentionally engineered nanomaterials is seen by many as critical to the success of an increasing range of nanotechnology-based products.
Ferin, Oberdörster, and colleagues attributed the size-specific effects they observed by to an increased rate of interstitialization of nanometer-scale particles in the lungs. They concluded “Phagocytosis of particles in the alveoli counteracts the translocation of particles into the interstitial space. Alveolar macrophage death or dysfunction promotes translocation from alveoli into interstitium. Particles of about 0.02 – 0.03 µm in diameter penetrate more easily than particles of ca. 0.2 – 0.5 µm. Small particles usually form aggregates. Their aerodynamic size determines the deposition in the airways. After deposition, they may deagglomerate. If the primary particle size is ca. 0.02 – 0.03 µm, deagglomeration may affect the translocation of the particles more than for aggregates consisting of larger particles.” (Ferin, Oberdörster et al. 1990). This simple statement outlined two emerging aspects of materials that potentially mediated their impact: particle size and dynamic behavior. In follow-up studies, further associations between material composition and form and effects were uncovered – most notably the role of particle surface area in mediating pulmonary toxicity. Using TiO2 samples consisting of two distinct sizes of primary particles, Oberdörster et al. showed that, while inflammatory response following inhalation in rats depended on particle size, normalizing by surface area led to a common dose response function (Oberdörster 2000). What is more, this response seemed to depend only weakly on the composition of chemically inert materials: using surface area as the dose metric instead of the more conventional mass concentration, Maynard and Kuempel for instance showed that a range of insoluble materials typically classified as “nuisance dusts” followed a similar dose-response curve for pulmonary inflammation in rats. However, more chemically active materials such as crystalline quartz demonstrated a markedly different dose-response relationship (Maynard and Kuempel 2005).
This early research was largely driven by occupational aerosol exposures. There were concerns that the hazards associated with fine dusts ranging from welding fume to metal and metal aerosol powders were not predictable from the chemical composition of these materials alone. What began to emerge was an understanding that the physicochemical nature of inhaled particles was more relevant than previously thought in eliciting a response following exposure, and that materials with a nanometer-scale biologically accessible structure (whether they were discrete nanometer-scale particles, or had a nanometer-scale surface structure, as in the case of aggregates of nanoparticles) had the potential to show previously unanticipated biological behavior. That this new research on what were termed “ultrafine aerosols” was associated with occupational health is perhaps not surprising, given the field’s long history of addressing hazards associated with exposure to aerosol particles with varying sizes, shapes and compositions (Maynard 2007).
At the same time as research into occupational exposure to ultrafine aerosols was developing, environmental epidemiology studies were also beginning to uncover associations between ambient aerosol particle size and morbidity and mortality. Starting with the six-cities study (Dockery, Pope et al. 1993), evidence emerged suggesting that ambient particles smaller than approximately 2.5 µm (PM2.5) had an elevated impact on human health (Schwartz and Morris 1995, Pope 1996, Schwartz, Dockery et al. 1996). As small particles were implicated in being associated with pronounced pulmonary and cardiovascular effects following inhalation exposure (e.g. Seaton, MacNee et al. 1995), researchers began to correlate impacts with exposure to ultrafine particles (Wichmann and Peters 2000, Brown, Zeman et al. 2002, Pekkanen, Peters et al. 2002, Chalupa, Morrow et al. 2004). Although clear associations between ultrafine particle exposure and health impacts remained uncertain, this research hinted at a link between aerosol inhalation and health impacts that was mediated by particle size as well as chemistry, with smaller particles exhibiting a higher degree of potency.
In the late 1990’s, toxicology and epidemiology research on ultrafine aerosols began to come together. But it was the formal advent of the field of nanotechnology towards the end of the 1990’s that galvanized action toward developing a more complete understanding of how material physicochemical characteristics impact on material hazard, and how nanoscale materials might lead to previously unanticipated health impacts. In the 1990’s, federal research agencies in the United States began looking to identify and nurture a new focus for science, engineering and technology that would stimulate research funding and lead to economic growth. At the time, advances across the physical sciences were leading to breakthroughs in understanding how material structure at the near-atomic scale influenced functionality, and how this nanoscale structure might be intentionally manipulated. Recognizing the potential cross-disciplinary and cross-agency significance of these breakthroughs, an Interagency Working Group on Nanotechnology was established within the United States’ Federal Government to promote the science and technology of understanding and manipulating matter at the nanometer scale (IWGN 1999) – the scene was set for the global emergence of nanotechnology.
Although not fully realized until late in the 20th century, the field of nanotechnology had its roots in twentieth century advances in materials science and high-resolution imaging and analytical techniques. As techniques such as X-ray diffraction and Transmission Electron Microscopy (TEM) began to illuminate the structure of materials at the atomic scale – and how this structure influences functionality – interest grew in improving materials through manipulating this structure. The fields of materials science and synthetic chemistry began to explore how small changes in structure at the atomic and molecular level could alter behavior at the macroscale. But it was perhaps the physicist Richard Feynman who first articulated a grander vision of nanoscale engineering. In a 1959 lecture at Caltech titled “There’s plenty of room at the bottom” Feynman speculated on the revolutionary advances that could be made if scientists and engineers developed increasingly sophisticated control over how substances were built up at the nanoscale (Feynman 1960) – a level of control which at the time remained largely out of reach. Despite Feynman’s lecture often being considered the foundation of modern nanotechnology, there is little evidence that it had much impact at the time (Toumey 2008, Toumey 2010). However, the advent of Scanning Probe Microscopy in 1982 (Binnig, Rohrer et al. 1982), together with advances throughout the physical and biological sciences in imaging and understanding matter at the nanometer scale, began to open up the possibility of altering the functionality of a wide range of materials through nanoscale engineering.
Some of the more extreme and speculative possibilities of building materials and even devices molecule by molecule were captured by Eric Drexler in his book “Engines of Creation”, inspired by shrinking human-scale materials engineering down to the nanoscale (Drexler 1986). While many of the ideas put forward by Drexler were treated with caution and sometimes skepticism by the scientific community, there was a ground-swell of excitement through the 1980’s and 1990’s over the possibilities that emerging techniques were enabling systematic manipulation of matter at the nanoscale, allowing nanoscale structure-mediated functionality to be exploited at the macroscale. This excitement was buoyed up by the formal discovery of carbon nanotubes (Iijima 1991) – a new and functionally unique allotrope of carbon – and the demonstration of single-atom manipulation using Scanning Probe Microscopy (Eigler and Schweizer 1990). Working at this scale, new opportunities began to arise, including enhancing the structure of materials; engineering materials tailored to exhibit specific physical, chemical and biological behavior; exploiting novel electron behavior in materials; and building increasingly sophisticated materials that could demonstrate multiple and context-specific functionality. The door was being opened to a new era of enhancing existing materials and products and creating innovative new ones by intentionally manipulating the composition and physical form of substances at the nanoscale.
Riding the wave of this cross-disciplinary “revolution” in science, engineering and technology, President Clinton announced a new US initiative to explore and exploit the science and technology of the nanoscale on January 21 2000 (Clinton 2000). In an address at Caltech on science and technology, he asked his audience to imagine “materials with 10 times the strength of steel and only a fraction of the weight; shrinking all the information at the Library of Congress into a device the size of a sugar cube; detecting cancerous tumors that are only a few cells in size”, and laid the foundation for the US National Nanotechnology Initiative (NNI). Since then, the NNI has been at the forefront of national and international research and development in nanoscale science and engineering.
As nanotechnology began to gain ground however, it didn’t take long for concerns to be raised over the potential health and environmental implications of the technology. In 2000, the co-founder of Sun Microsystems Bill Joy wrote an influential essay for Wired Magazine titled “Why the Future Doesn’t Need Us” in which he raised concerns about the impacts of nanotechnology (Joy 2000). This was followed by calls for a moratorium on research until more was known about the possible adverse impacts by one Civil Society group (ETC Group 2003). Concerns were also raised by the reinsurance company Swiss Re in 2004 (Hett 2004), and later that year the UK Royal Society and Royal Academy of Engineering launched a highly influential report on the opportunities and uncertainties of nanotechnology (RS/RAE 2004). At the center of the Royal Society and Royal Academy of Engineering report were concerns that engineered nanoscale materials with unique functionality may lead to unexpected exposure routes; may have access to unanticipated biological compartments; and may exhibit unconventional biological behavior associated with their size. In particular, concern was expressed over materials intentionally engineered to have nanoscale structure – nanomaterials – and particles and fibers with nanometer-scale dimensions – nanoparticles and nanofibers.
The Royal Society and Royal Academy of Engineering report marked a move toward a more integrated approach to the potential risks associated with nanotechnology. As global investment in nanotechnology research and development has grown (it has been estimated that global research and development investment in nanotechnologies exceeded $18 billion as far back as 2008), so has interest in identifying, understanding and addressing potential risks to human health and the environment (e.g. Luther 2004, Chemical Industry Vision 2020 Technology Partnership and SRC 2005, Oberdörster, Maynard et al. 2005, SCENIHR 2005, Maynard, Aitken et al. 2006, Nel, Xia et al. 2006, ICON 2008, Klaine, Alvarez et al. 2008, RCEP 2008, SCENIHR 2009, NNI 2010, PCAST 2010, NRC 2012, Westerhoff and Nowack 2013). This interest has been stimulated by concerns that novel materials have the potential to lead to novel hazards and risks. But fuelling it has been the research noted earlier on the role of particle size, physical form and chemistry in mediating biological interactions and responses. With the advent of nanotechnology and the production of increasingly sophisticated engineered nanomaterials, research strands developing an understanding of the potential human health impacts of fine particles were thrust into the mainstream, and became the basis of new thinking about how potential risks associated with new materials can be addressed.
2 THE NATURE OF THE NANOMATERIAL CHALLENGE
As awareness has grown over the emerging human health issues raised by engineered nanomaterials, questions have revolved around potential impacts at every stage of a material’s life cycle – from production to transport to use to disposal, and even to recycling (Klöpffer, Curran et al. 2007, Gottschalk and Nowack 2011, Westerhoff and Nowack 2013). This has been stimulated by increasing awareness over the need for a life-cycle approach in addressing any human/environmental health risk from physical, chemical or biological agents. But it has also been forced by the dynamic nature of many engineered nanomaterials. Where potential impact depends on physical form as well as chemistry, changes in physicochemistry – along with availability or exposure potential – across a material’s life cycle, can have a profound impact on risk within different contexts. Thus the risk presented by just-generated carbon nanotubes for instance may be markedly different from the risk presented by processed/purified nanotubes, which not only represent an altered physicochemistry but also a different exposure potential. Likewise, once these carbon nanotubes have been incorporated into a product – an epoxy resin matrix say – the exposure potential and the physicochemical nature of any material that is released is profoundly different from that of the starting material (Harper, Wohlleben et al. 2015). And as the resulting product is used and eventually disposed or recycled, the hazard and exposure potential differ yet again. Thus the risk profile of a nanomaterial over its life cycle is complex – even if that material is relatively stable. However, when nanomaterials undergo transformations through their lifecycle – as many do – through processes such as agglomeration, dissolution, surface adsorption/desorption, chemical reaction, or other interactions with close-proximity materials, the challenges of evaluating and addressing risk become commensurately more difficult.
Within this complex challenge, much attention has been placed on exposure potential as a first order determinant of potential risk. And this in turn has led to the workplace being an area of particular concern, as an environment where inhalation of, dermal contact with and possibly ingestion of engineered nanomaterials before they are incorporated into products could be significant (Maynard and Kuempel 2005, NIOSH 2010). Much of this concern has focused on nanoparticles – nominally particles smaller than 100 nm in diameter – as being most likely to enter the body and cause unanticipated harm. However, this is an environment where airborne nanostructured materials that are micrometers in diameter can be inhaled and enter the upper airways and lungs, placing an onus on understanding interactions with relatively large aggregates and agglomerates of nanoscale particles, as well as micrometer-scale particles with biologically accessible nanoscale features (Maynard 2007).
The importance of workplace exposures to engineered nanomaterials is reflected in a growing literature and expanding research initiatives on occupational exposure, hazard and potential risk (e.g. Maynard 2007, Schulte, Murashov et al. 2010, Schulte, Geraci et al. 2014). In the US for example, the National Institute for Occupational Safety and Health (NIOSH) has developed a detailed research strategy addressing the evaluation, characterization and management of workplace health risks associated with engineered nanomaterials (NIOSH 2012). This has been developed in response to growing concerns over the safety of workers as nanotechnology and the production and use of engineered nanomaterials continues to grow. But it has also been prompted by a number of evaluations that highlight the workplace as a critical area where further research on potential risks and their mitigation is needed.
Research that is now being pursued is beginning to help address the safe handling of nanomaterials in the workplace. Yet more generally, there is a sense that the key human health questions associated with engineered nanomaterials remain elusive. Numerous reports have listed specific research gaps regarding engineered nanomaterial safety (e.g. SCENIHR 2005, Maynard 2006, EPA 2007, ICON 2008, NNI 2008, RCEP 2008, Aitken, Hankin et al. 2009, EFSA 2009, SCENIHR 2009, ENRHES 2010, UK House of Lords 2010, NNI 2011, NRC 2012). However, few of these manage to establish key research gaps within a compelling strategic framework that relates research challenges to real-world decision-making. This was perhaps most obvious in the 2008 engineered nanomaterials risk-research strategy published by the US National Nanotechnology Initiative (NNI 2008) that was criticized by a National Academies of Science review panel for failing to be strategic enough (National Research Council 2009a). Although the criticisms were hard hitting, the NNI report was not unique in failing to clearly identify the nature of the problem being addressed or a viable route to its resolution (The NNI also responded to the critique in the follow-up 2011 strategy (NNI 2011)). This lack of clarity is indicative of a nanomaterial safety research community as a whole that is struggling to formulate the problems assumed to be presented by these new and often novel materials. In effect, although problem formulation is the first step to assessing and addressing risks (National Research Council 2009b), many years of efforts to develop an understanding of the potential risks presented by engineered nanomaterials attests to the difficulties of characterizing the problem, never mind the solution, when dealing with complex and novel materials. There is a possibility though that these difficulties have been compounded by an adherence to definitions of nanotechnology and engineered nanomaterials that are not directly relevant to human health risks. To understand how definitions may have obfuscated research into potential risks, and to explore possible roots out of the resulting definition rut, it is worth examining what is generally meant by the term “engineered nanomaterial”.
3 THE PROBLEM WITH DEFINITIONS
“Engineered nanomaterial” is often used as shorthand for describing in qualitative terms a group of materials that have certain features in common. These materials typically have a physical structure that is of the order of nanometers in scale; they are intentionally engineered to have structure at this scale; and they are designed to allow product developers and producers to take advantage of this structure. They are a subset of the broader field of nanotechnology, defined by the National Nanotechnology Initiative (NNI) as “the understanding and control of matter at dimensions between approximately 1 and 100 nanometers, where unique phenomena enable novel applications. Encompassing nanoscale science, engineering, and technology, nanotechnology involves imaging, measuring, modeling, and manipulating matter at this length scale.” (NSET 2010) From this (and similar) definitions, engineered nanomaterials are often defined as materials with structures having at least one dimension between approximately 1 – 100 nm which exhibit unique or substantially enhanced properties, including scale-specific electrical, optical and mechanical behavior. These scale-specific properties are at the center of current government and commercial investment in engineered nanomaterials: If a substance can be engineered to behave in different ways, it can potentially be used to add value to a product, or even as the basis of a completely new product. This in turn extends the toolbox available to scientists and technologists to make new products and to explore new ways to address the challenges of providing people with water, food, energy, healthcare and a host of other pressing societal needs. Yet these same scale-specific properties are also at the center of concerns over possible new risks associated with engineered nanomaterials – if a new material behaves in novel ways (goes the argument), what are the chances of this novel behavior leading to unexpected and unanticipated harm to people and the environment?
As concerns over potential adverse impacts of engineered nanomaterials on human health and the environment have arisen, common definitions of engineered nanomaterials have been used to try and identify new materials that may present unanticipated or poorly understood risks to human health. However, since biological systems respond to a variety of physical and chemical stimuli that do not necessarily map directly onto those characteristics encapsulated in definitions of engineered nanomaterials, these attempts have run into difficulties. As a case in point, the scale range usually used to describe engineered nanomaterials – 1 – 100 nm – has relatively little bearing on its own in determining the risk a substance presents to people or the environment (Auffan, Rose et al. 2009, Drezek and Tour 2010). In effect, risk “problems” associated with engineered nanomaterials have been formulated in terms of established “technological” definitions of nanotechnology and engineered nanomaterials, which do not reflect adequately the potential of a material to cause harm. This is not to say that efforts to date have been wasted. Framing the potential risks associated with engineered nanomaterials in terms of established definitions does provide some insight into emergent risks. For example, potential human exposure to particles may well be enhanced as their size decreases to the nanoscale. But at the same time, this framing runs the danger of highlighting issues that may not be relevant, while obscuring others that are
The problem with definitions has been highlighted in particular in Europe in recent years. In 2010, the Scientific Committee on Emerging and newly-Identified Health Risks (SCENIHR) explored the scientific basis for the definition of the term “nanomaterial” (SCENIHR 2010). As a result, on October 18 2011, the European Commission adopted a Recommendation on the definition of a nanomaterial – a move that didn’t garner support in some quarters (Maynard 2011). In 2014, the European Commission Joint Research center published an extensive review of the definition, running to over 300 pages (EC 2014, EC 2014). Despite this evaluation, there remains no widely accepted, scientifically grounded definition of engineered nanomaterials for the purposes of identifying and managing potential risks.
If future research and action on risks presented by engineered nanomaterials is to be relevant and responsive, careful consideration is needed on what leads to a new material presenting a new, unusual or ill-defined human health risks. In effect, the challenge is how to develop an approach to differentiating between materials that present conventionally understandable and addressable risk from those that present novel risks which require new understanding and methods to ensure their safe use.
4 PRINCIPLES-BASED PROBLEM FORMULATION FOR ENGINEERED NANOMATERIALS
One approach to this challenge is to use a set of principles rather than definitions to identify engineered nanomaterials where new research is needed to ensure their safe and responsible development and use. Three possible principles that might be of use here are principles encapsulating emergent risk, plausibility, and impact (Maynard, Warheit et al. 2011).
4.1 Emergent risk.
Emergent risk in this context captures the likelihood of a new material causing harm in a manner that is not apparent, assessable or manageable based on current approaches to risk assessment and management. This might include the ability of small particles to penetrate to normally inaccessible places, the failure of certain established toxicology assays to respond in expected ways to some materials, scalable material behavior that is not addressed by conventional approaches to assessing hazard (such as surface-area mediated responses where mass is the exposure metric of choice), or the possibility of abrupt scale-dependent changes in material interactions with biological systems. This understanding of “emergence” depends on the potential of a material to cause harm in unanticipated or poorly understood ways, rather than its physical structure or properties per se. As such, it is not subject to rigid definitions of nanotechnology or nanomaterials. Instead, it allows engineered nanomaterials that potentially present unanticipated risks to human health and the environment to be distinguished from those that probably do not.
Many of the engineered nanomaterials that have been raising concerns in recent years have shown potential to lead to emergent risks, and would be classified as requiring further investigation under this criteria. But the concept also embraces more complex nanomaterials that are either in the early stages of development, or have yet to be developed; including active nanomaterials and self-assembling nanomaterials.
4.2 Plausibility.
“Plausibility” provides an indication of the likelihood of a new material, product or process presenting a risk to humans or the environment. It is dependent on the possible hazard of a material and the potential for exposure or release to occur. But it also addresses the likelihood of a new material being developed and commercialized, and it leading to emergent risks. For example, the “gray goo” of self-replicating nanobots envisaged by Bill Joy in the 2000 Wired article (Joy 2000) might legitimately be considered an emergent risk, but it is far from being a plausible risk. In this way, plausibility acts as a crude filter to distinguish between speculative risks – which are plentiful – and credible risks – which are not.
4.3 Impact.
“Impact” in this context is an indicator of the extent of the harm a poorly managed engineered nanomaterial might cause. It provides a qualitative reality-check to guard against extensive efforts to address risks that are unlikely to have a significant impact on human health, while ensuring that research and actions having the potential to make a significant difference is identified and supported. Of course, evaluating impact before a material or product has been fully developed or commercialized is not trivial, and there is a significant chance that predictions will not pan out. However, this is an area where scenario-planning methodologies may help explore more and less likely impacts from different engineered nanomaterials.
These three principles provide a basis for developing an informed approach to addressing potential risks from engineered nanomaterials. They are tools that allow, in principle, new materials that raise safety concerns to be differentiated from those that, while they may be novel from an applications perspective, do not present undetected, unanticipated or enhanced risks. In particular, they are technology-independent, and therefore can be used as long-term drivers of research into potential nanoscale material risks. Whether dealing with early or late generations of nanotechnology-based products, they provide a means of identifying which products require closer scrutiny from a risk perspective. And while the principles are not a substitute for clear definitions of materials and products that are needed to underpin regulatory decision-making, they provide a framework within which specific classes of material and product might be better-identified and defined for the purpose of regulation. More significantly, they enable the potential human health risks of engineered nanomaterials risk to be approached from a position that is informed by relevant and scientifically plausible concerns, rather than being constrained by material definitions that emphasize physical and chemical function rather than potential to cause harm.
5 APPLYING THE PRINCIPLES TO ENGINEERED NANOMATERIALS
These principles can be applied across the life cycle of materials and products to identify where context-specific risks may arise that need further research to assess and manage them. Here, the concepts of plausibility, emergence and impact can help differentiate between what may be more or less significant in addressing risk. For instance, generating and handling multi-walled carbon nanotubes in a workplace may present a plausible and emergent risk to workers, given that production and use of the material is a relatively new area, there are indications that some forms of the material are more hazardous than their chemical makeup alone might indicate, and the potential exists for human exposure to occur through inhalation and possibly ingestion. However, handling a baseball bat made of a multi-walled nanotube-containing composite material, or driving an electric car powered by a nanotube-enabled battery presents a very different scenario. While the emergent risk associated with the raw material might exist under each scenario, the plausible risk – the likelihood of people or the environment being exposed during product use to sufficient quantities of material in a form that can cause substantial harm – is much reduced. Finally, when products containing multi-walled carbon nanotubes are disposed of or prepared for recycling, a plausible and potentially high impact risk may re-emerge, depending on the volume of material in circulation, as the material once again becomes potentially dispersible and biologically available.
In this example, the principles of plausible and emergent risk and impact allow potentially significant risk “hot spots” to be identified over the life cycle of a material. In doing so, they provide a systematic basis for identifying and prioritizing areas where further research is needed to address risks appropriately. It’s an approach that has been explored further in the context of developing “prospective” case-studies around speculative yet highly plausible applications of engineered nanomaterials (Maynard 2014). Here and elsewhere, using principles rather than definitions to determine “action points” when addressing the safety of engineered nanomaterials is similar to the approach previously proposed in the Nano Risk Framework developed by DuPont and the Environmental Defense Fund (DuPont and Environmental Defense 2007).
Applying these three principles to existing and emerging engineered nanomaterials, a number of groupings of materials begin to emerge that may require deeper study (Maynard, Warheit et al. 2011). These include:
5.1 Materials demonstrating abrupt scale-specific changes in biological or environmental behavior
These are materials that undergo abrupt size-dependent changes in physical and chemical properties which in turn affect biological behavior, may present a hazard that is not predictable from larger scale materials of the same composition. In this case, size and form at the nanoscale may increase or decrease hazard in a way that is currently not well understood.
5.2 Materials capable of penetrating to normally inaccessible places
These are materials that, by nature of their size, surface chemistry or both, are able to persist in or penetrate to places in the environment or body that are not usually accessible based on current understanding, may present emergent risks. Where there is a credible possibility of accumulation of, exposure to, or organ/system-specific dose associated with a nanoscale material that is not expected from how either the dissolved material or larger particles of the material behave, a plausible and emergent risk is potentially arises.
5.3 Active materials.
These are materials that undergo a significant change in their biological behavior in response to their local environment or an external stimulus (Subramanian, Youtie et al. 2010) potentially present dynamic risks that are currently not well understood within the context of quantitative and chemical identity-based risk assessment.
5.4 Materials exhibiting scalable hazard that is not captured by conventional risk assessments
Where hazard scales according to parameters other than those normally associated with a conventional risk assessment, emergent risks may arise as dose response relationships are inappropriately quantified. For instance, if the hazard presented by an inhaled material scales with the surface area of the material yet the risk assessment is based on mass, the true hazard may not be identified. In this case, the material has the potential to cause unanticipated harm. Where a material’s chemical composition and physical form combine to determine biological behavior, there is increasingly likelihood of response scaling with non-standard measures of dose. In each of these examples (they are not exclusive), there are key research questions that need to be addressed if emergent and plausible risks are to be identified, characterized, assessed and managed.
Used in this and similar ways, the principles of emergent risk, plausibility and impact can help underpin a science-based approach to addressing the environmental, health and safety implications of engineered nanomaterials through strategic research.
6 RESPONSIBLE RESEARCH AND INNOVATION
In June 2004, experts from twenty-five countries convened in Alexandria, Virginia, to discuss responsible research and development of nanotechnology (Tomellini 2004). Driving them was a shared concern that, without proactively taking into account the potential environmental, health and social impacts of nanotechnology, its promise could be jeopardized. This early global interest in responsible development led in part to Organization on Economic Cooperation and Development (OECD) efforts to coordinate activities on nanomaterial safety testing and evaluation internationally. It also stimulated work in Europe on developing a “code of conduct” for responsible nanosciences and nanotechnologies research (EC 2013) and similar work amongst businesses and other stakeholders on a “responsible nano code” (NIA 2008).
This early interest in responsibility and innovation has evolved into the broader field of Responsible Innovation (or Responsible Research and Innovation). In Europe for instance, there is now a growing emphasis on Responsible Research and Innovation within the European Commission (EC 2012), while in 2014, the new Journal of Responsible Innovation was launched (Taylor-Francis 2015). And internationally, the Virtual Institute for Responsible Innovation is coordinating activities across eleven countries (VIRI 2015).
In 2011, René von Schomberg defined responsible innovation as “A transparent, interactive process by which societal actors and innovators become mutually responsive to each other with a view to the (ethical) acceptability, sustainability and societal desirability of the innovation process and its marketable products (in order to allow a proper embedding of scientific and technological advances in our society).” (von Schomberg 2011). The ideas encapsulated here were clarified further by Stilgoe, Owen and McNaughten in their seminal 2012 paper on responsible innovation, where they defined responsible innovation as “taking care of the future through collective stewardship of science and innovation in the present” (Owen, Macnaghten et al. 2012).
While no longer being anchored specifically in nanotechnology, responsible innovation begins to lay the philosophical and ethical foundations for making practical decisions within nanomaterial production and use. It challenges researchers and businesses alike to think through future consequences of their actions, and to make early-on decisions that have the potential to avoid significant risk-liabilities further down the line. But it also provides tools that help guide informed decisions that lead to more sustainable products, by factoring in societal and environmental factors early in the development process that reduce the chances of innovations becoming locked into potentially detrimental trajectories.
In 2008 the European Commission made recommendations on a “code of conduct for responsible nanosciences and nanotechnologies research” (EC 2008). These recommendations foreshadowed current interests around responsible research and innovation, and begin to flesh out ideas on what responsibility means for researchers engaged in nanoscale science and engineering (Jones 2009). They did however stop short of providing a framework for responsible innovation for business. Here, there was some resistance to the idea that businesses need an explicit set of guidelines that defined “responsibility” – partly under the assumption that few businesses set out to be “irresponsible”, and so aim to be responsible by default. At the same time, the business community has long been aware of the potential impact of societal concerns on economic success, and the need to ensure responsible behavior (as well as being seen to be responsible) through formal initiatives. Corporate Social Responsibility, Responsible Care and, more recently, sustainable business practices, all reflect this undertstanding. With growing uncertainty over the governance and impacts (both real and perceived) of technologies such as nanotechnology (Hodge, Bowman et al. 2010), emerging ideas around responsible innovation are a natural extension of this trend.
In 2006, the Nanotechnologies Industries Association partnered with Insight Investment and the UK Royal Society to convene a workshop focusing on the technical, social and commercial uncertainties of nanotechnology within a business context. The Responsible Nano Code emerged out of the multi-stakeholder dialogue that followed (NIA 2008). This code is built around seven foundational principles that together create a sound framework for understanding what “responsibility” means from the perspective of a nanotech businesses. The principles cover the bases of accountability and stakeholder engagement, environmental health and safety, wider societal and ethical impacts, and transparency and disclosure. They create the basis of a framework for responsibility in nanotechnology innovation that compliments other initiatives.
Yet between frameworks such as the Responsible Nano Code and Code of Conduct for Responsible Nanosciences and Nanotechnologies Research, there remains a need to translate the ideas behind Responsible Innovation to a growing community of entrepreneurs (Maynard 2015). As progress toward designing, producing and using increasingly sophisticated engineered nanoparticles continues to move forward, it will become increasingly necessary to understand how the concepts of responsible innovation can be embedded within this community.
7 LOOKING FORWARD
Engineered nanomaterials clearly present a new set of challenges to evaluating and avoiding potential human health impacts, and developing safe, beneficial and sustainable products. However, formulating problems in ways that render these challenges tractable from a scientifically sound and societally responsive basis is not a simple task. Nearly two decades of emphasis on nanotechnology – and more recently the environmental, safety and health implications of nanotechnology – has opened up new discussions on identifying and addressing emergent risks as, and even before, new materials and products come to market. Yet it is clearer now than ever that we need to be increasingly sophisticated in how we frame the problems that need to be solved. The principles outlined above, together with relevant applications of Responsible Innovation, represent some first steps toward this. But more is needed. Even at a basic level, there needs to be a language of engineered nanomaterial risk that clarifies rather than obfuscates the challenges being faced (Maynard, Bowman et al. 2010) – starting with the distinction between nanotechnologies, nanomaterials and nanoparticles, which are too often used interchangeably and inappropriately. Beyond this, new approaches are needed to addressing the human health impacts of materials where biologically-relevant behavior is mediated by physical form as well as chemistry, where relevant material characteristics are dynamic and context-specific, and where uncertainty over risk abounds. This is where the greatest challenges presented by nanoparticles and engineered nanomaterials lie, and they are not ones that are easily constrained by narrow definitions of what “nano” means, or what “responsibility” entails.
As was alluded to earlier in this chapter, a growing number of analyses have grappled with this challenge, with varying degrees of success. In 2006, a group of researchers published five high-level research “grand challenges” to ensuring the safety of engineered nanomaterials in the journal Nature (Maynard, Aitken et al. 2006). These included:
- Developing instruments to assess exposure to engineered nanomaterials in air and water.
- Developing and validating methods to evaluate the toxicity of engineered nanomaterials
- Developing models for predicting the potential impact of engineered nanomaterials on the environment and to human health
- Developing robust systems for evaluating the health and environmental impact of engineered nanomaterials over their entire lifetime
- Developing strategic programmes that enable relevant risk-focused research.
These five challenges still stand as markers of where we need to be, rather than where we are, in ensuring the safe use of engineered nanomaterials. Progress continues to be made toward each challenge. But there is still a long way to go before the potential health impacts of new nanomaterials can be predicted and assessed effectively. At the same time, understanding on the knowledge-gaps that need to be addressed if safer uses of nanomaterials are to result continue to evolve. A 2010 review of where we are and where we need to be on nanomaterials environmental, safety and health impacts highlighted many of the issues raised in the 2006 Nature commentary (Nel, Grainger et al. 2010). But it also placed a strong emphasis on innovative and multidisciplinary approaches to predicting, assessing and managing potential impacts that go beyond the 2006 “grand challenges”. In effect, the field of addressing potential risks associated with engineered nanomaterials is developing, as the generation, production and use of the materials themselves develops. This in turn places a meta-challenge on problem formulation; ensuring that the process of identifying the challenges that need to be met and the data gaps that need to be filled is grounded in science and precedent, yet remains sufficiently flexible to respond to new information and not to get bogged down in misconceptions, preconceived ideas and outmoded understanding.
In other words, addressing the human health impacts of engineered nanomaterials is a complex challenge. But it is nevertheless an important one. Without a doubt, the next one to two decades will see the introduction of increasingly complex materials to the workplace, people’s lives and the environment, which can cause harm in unexpected ways, and which potentially slip through the net of established management and governance frameworks. Addressing this challenge is vital for the continued health of people exposed to these new materials. But it is also essential to the long-term sustainability of new technologies that could prove vital to addressing global issues such as disease treatment, provision of plentiful and nutritious food, access to clean water and energy, and so on. In moving forward, a delicate balance will be needed between addressing emerging challenges and re-assessing the framework within which those challenges are defined. Within this complexity, there are five themes that are likely to pin the course of future research and action:
- Synergisms between the physical form and chemical composition of materials will continue to influence hazard, exposure and risk;
- Human health and environmental impacts of engineered nanomaterials will be both time and context-dependent;
- Risk management approaches will have to deal increasingly with decision-making in the face of uncertainty; and
- Integrative approaches to risk assessment and management will become increasingly necessary as materials become increasingly complex.
- Responsible Innovation will need to be applied in practical ways to the challenges of designing and engineering new materials; translating innovations into entrepreneurial ventures; growing nano-enabled businesses; and ensuring the long-term sustainability of commercial applications of nanotechnology.
Irrespective of whether the current buzz-word is “nanotechnology”, “nanomaterial”, “nanoparticle” or something else, increasing control over matter at the level of atoms, molecules, and small clusters of molecules, is leading to the generation of new and sophisticated materials that lie outside current understanding of how materials potentially impact on human health. Rising to the challenge of ensuring these sophisticated new materials are as safe and as useful as possible will depend on new thinking and new research on how potential risks are identified, assessed and addressed. And in this endeavor, perhaps the two biggest dangers are ignoring the past – and the vast wealth of knowledge we already have on potentially harmful materials – and getting bogged down in technology frameworks that do not support science-based problem formulation. If we can avoid the technology hype and build on what is already known though, there is every chance that new knowledge, tools and methodologies will be developed that will enable us to assess – and manage – the potential human health impacts of nanometer-sized particles and nanometer-scale materials.
References
Aitken, R. J., S. M. Hankin, B. Ross, C. L. Tran, V. Stone, T. F. Fernandes, K. Donaldson, R. Duffin, Q. Chaudhry, T. A. Wilkins, S. A. Wilkins, L. S. Levy, S. A. Rocks and A. Maynard (2009). EMERGNANO: A review of completed and near completed environment, health and safety research on nanomaterials and nanotechnology. Edinburgh, UK, Institute for Occupational Medicine.
Auffan, M., J. Rose, J. Y. Bottero, G. V. Lowry, J. P. Jolivet and M. R. Wiesner (2009). “Towards a definition of inorganic nanoparticles from an environmental, health and safety perspective.” Nature Nanotechnology 4(10): 634-641. DOI: 10.1038/nnano.2009.242
Binnig, G., H. Rohrer, C. Gerber and E. Weibel (1982). “Surface Studies by Scanning Tunneling Microscopy.” Phys. Rev. Lett. 49: 57-61. DOI: 10.1103/PhysRevLett.49.57
Brown, J. S., K. L. Zeman and W. D. Bennett (2002). “Ultrafine particle deposition and clearance in the healthy and obstructed lung.” Am. J. Respir. Crit. Care Med. 166: 1240-1247. DOI: 10.1164/rccm.200205-399OC
Chalupa, D. C., P. E. Morrow, G. Oberdorster, M. J. Utell and M. W. Frampton (2004). “Ultrafine particle deposition in subjects with asthma. .” Environ. Health Perspect. 112(8): 879-882. DOI: 10.1289/ehp.6851
Chemical Industry Vision 2020 Technology Partnership and SRC. (2005). “Joint NNI-ChI CBAN and SRC CWG5 Nanotechnology research needs recommendations.” Retrieved 10/20/10, from http://www.chemicalvision2020.org/pdfs/chem-semi ESH recommendations.pdf.
Clinton, W. J. (2000). “President Clinton’s Address to Caltech on Science and Technology. Remarks by the President at Science and Technology Event, California Institute of Technology Pasadena, California.” Retrieved 9/24/10, from http://pr.caltech.edu/events/presidential_speech/pspeechtxt.html.
Dockery, D. W., C. A. Pope, X. Xu, J. D. Spengler, J. H. Ware, M. E. Fay, B. G. Ferris and F. E. Speizer (1993). “An association between air pollution and mortality in six U.S. cities.” N. Engl. J. Med 329(24): 1753-1759. DOI: 10.1056/NEJM199312093292401
Drexler, E. (1986). Engines of creation: The coming era of nanotechnology. New York, Anchor Books.
Drezek, R. A. and J. M. Tour (2010). “Is nanotechnology too broad to practise?” Nature Nanotechnology 5: 168-169. DOI: 10.1038/nnano.2010.37
DuPont and Environmental Defense (2007). Nano Risk Framework, DuPont and Environmental Defense. https://nanotech.law.asu.edu/Documents/2011/06/6496_Nano%20Risk%20Framework_534_2973.pdf
EC (2008). COMMISSION RECOMMENDATION of 07/02/2008 on a code of conduct for responsible nanosciences and nanotechnologies research. Brussels, Commission of the European Communities.
EC (2012). Responsible Research and Innovation. Europe’s ability to respond to societal challenges, European Commission.
EC (2013). Final Report Summary – NANOCODE (A multistakeholder dialogue providing inputs to
implement the European code of conduct for Nanosciences and nanotechnologies
(N&N) research) European Commission. https://cordis.europa.eu/project/id/244521/reporting
EC (2014). Towards a review of the EC Recommendation for a definition of the term “nanomaterial” – Part 2: Assessment of collected information concerning the experience with the defintion, Publications Office of the European Union. DOI: 10.2787/97286
EC (2014). Towards a review of the EC Recommendation for a definition of the term “nanomaterial”; Part 1: Compilation of information concerning the experience with the definition, Publications Office of the European Union. DOI: 10.2788/36237
EFSA (2009). “SCIENTIFIC OPINION: The Potential Risks Arising from Nanoscience and Nanotechnologies on Food and Feed Safety.” The EFSA Journal 958: 1-39. DOI: 10.2903/j.efsa.2009.958
Eigler, D. M. and E. K. Schweizer (1990). “Positioning single atoms with a scanning tunneling microscope.” Nature 344: 524-526. DOI: 10.1038/344524a0
ENRHES (2010). Engineered nanoparticles: Review of health and environmental safety. Edinburgh, UK, Edinburgh Napier University. https://cordis.europa.eu/project/id/218433/reporting
EPA (2007). U.S. Environmental Protection Agency Nanotechnology White Paper. EPA. [link]
ETC Group (2003). No Small Matter II: The Case for a Global Moratorium. Size Matters! Winnipeg, Canada, ETC Group. https://www.etcgroup.org/content/size-matters
Ferin, J., G. Oberdörster, D. P. Penney, S. C. Soderholm, R. Gelein and H. C. Piper (1990). “Increased Pulmonary Toxicity of Ultrafine Particles .1. Particle Clearance, Translocation, Morphology.” Journal of Aerosol Science 21(3): 381-384. DOI: 10.1016/0021-8502(90)90064-5
Feynman, R. P. (1960). “There’s plenty of room at the bottom.” Engineering and Science 23(5): 22-36. https://resolver.caltech.edu/CaltechES:23.5.1960Bottom
Gottschalk, F. and B. Nowack (2011). “The release of engineered nanomaterials to the environment.” Journal of Environmental Monitoring 13(5): 1145-1155. DOI: 10.1039/c0em00547a
Harper, S., W. Wohlleben, M. Doa, B. Nowack, S. Clancy, R. A. Canady and A. Maynard (2015). “Measuring Nanomaterial Release from Carbon Nanotube Composites: Review of the State of the Science.” J. Phys.: Conf. Ser. 617 012026 DOI: 10.1088/1742-6596/617/1/012026
Hett, A. (2004). Nanotechnology. Small matter, many unknowns. Zurich, Switzerland, SwissRe. https://www.nanowerk.com/nanotechnology/reports/reportpdf/report93.pdf
Hodge, G., D. Bowman and A. D. Maynard, Eds. (2010). International Handbook on Regulating Nanotechnologies. Cheltenham, England, Edward Elgar.
ICON (2008). Predicting nano-biointeractions: An international assessment of nanotechnology environment, health, and safety research needs. Houston TX, International Council On Nanotechnology.
ICON (2008). Towards Predicting Nano-Biointeractions: An International Assessment of Nanotechnology Environment, Health and Safety Research Needs. Houston, TX, International Council On Nanotechnology.
Iijima, S. (1991). “Helical Microtubules of Graphitic Carbon.” Nature 354(6348): 56-58. DOI:
IWGN (1999). Nanotechnology Research Directions: IWGN Workshop Report. Vision for Nanotechnology R&D in the Next Decade. Washington DC, National Science and Technology Council Committee on Technology Interagency Working Group on Nanoscience, Engineering and Technology (IWGN). https://obamawhitehouse.archives.gov/sites/default/files/microsites/ostp/NanoResearchDirections1999.pdf
Jones, R. (2009). “Are you a responsible scientist?” Nature Nanotechnology 4: 336. DOI: 10.1038/nnano.2009.127
Joy, B. (2000). Why the future doesn’t need us. Wired Magazine. https://www.wired.com/2000/04/joy-2/
Klaine, S. J., P. J. J. Alvarez, G. E. Batley, T. F. Fernandes, R. D. Handy, D. Y. Lyon, S. Mahendra, M. J. McLaughlin and J. R. Lead (2008). “Nanomaterials in the environment: Behavior, fate, bioavailability, and effects.” Env. Toxicol. Chem. 27(9): 1825-1851. DOI: 10.1897/08-090.1
Klöpffer, W., M. A. Curran, P. Frankl, R. Heijungs, A. Köhler and S. I. Olsen (2007). Nanotechnology and Life Cycle Assessment. Synthesis of Results Obtained at a Workshop. Washington DC, Project on Emerging Nanotechnologies. https://backend.orbit.dtu.dk/ws/portalfiles/portal/3374746/NanoLCA_3.07.pdf
Luther, W., Ed. (2004). Technological Analysis. Industrial application of nanomaterials – chances and risks. Düsseldorf, Future Technologies division of VDI Technologiezentrum GmbH. https://www.researchgate.net/publication/246012217_Industrial_Application_of_Nanomaterials_-_Chances_and_Risks
Maynard, A., D. (2007). “Nanotechnology: The next big thing, or much ado about nothing?” Ann. Occup. Hyg. 51: 1-12. DOI: 10.1093/annhyg/mel071
Maynard, A. D. (2006). Nanotechnology: A research strategy for addressing risk. Washington DC, Woodrow Wilson International Center for Scholars, Project on Emerging Nanotechnologies. https://www.pewtrusts.org/en/research-and-analysis/reports/2006/07/19/nanotechnology-a-research-strategy-for-addressing-risk
Maynard, A. D. (2011). “Regulators: Don’t define nanomaterials.” Nature 475: 31. DOI: 10.1038/475031a
Maynard, A. D. (2014). Exploring boundaries around the safe use of advanced materials: A prospective product-based case studies approach. Second Edition. Nanotechnology environmental health and safety. Risks, regulations and management. M. Hull and D. Bowman. Kidlington, Oxford, William Andrews.
Maynard, A. D. (2015). “Responsible Innovation – the (nano) entrepreneur’s dilemma.” Nature Nanotechnology 10, 199–200 (2015). DOI: 10.1038/nnano.2015.35
Maynard, A. D., R. J. Aitken, T. Butz, V. Colvin, K. Donaldson, G. Oberdörster, M. A. Philbert, J. Ryan, A. Seaton, V. Stone, S. S. Tinkle, L. Tran, N. J. Walker and D. B. Warheit (2006). “Safe handling of nanotechnology.” Nature 444(16): 267-269. DOI: 10.1038/444267a
Maynard, A. D., D. M. Bowman and G. A. Hodge (2010). Conclusions: Triggers, gaps, risks and trust. International Handbook on Regulating Nanotechnologies. G. A. Hodge, D. M. Bowman and A. D. Maynard. Cheltenham, Edward Elgar.
Maynard, A. D. and E. D. Kuempel (2005). “Airborne nanostructured particles and occupational health.” Journal Of Nanoparticle Research 7(6): 587-614. DOI: 10.1007/s11051-005-6770-9
Maynard, A. D., D. Warheit and M. A. Philbert (2011). “The New Toxicology of Sophisticated Materials: Nanotoxicology and Beyond.” Tox. Sci. 120(Suppl 1): S109-S129. DOI: 10.1093/toxsci/kfq372
National Research Council (2009a)”Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research.” Washington, DC: The National Academies Press. DOI: 10.17226/12559.
National Research Council (2009b). “Science and Decisions: Advancing Risk Assessment.” Washington, DC: The National Academies Press. DOI: 10.17226/12209
Nel, A., D. Grainger, P. Alverez, S. Badesha, V. Castranova, M. Ferrari, H. Godwin, P. Grodzinsky, J. Morris, N. Savage, N. Scott and M. R. Wiesner (2010). Nanotechnology Environmental, Health and Safety Issues. Nanotechnology Long Term Impacts and Research Directions: 2000 – 2020. http://www.cein.ucla.edu//file_uploads/chapter04.pdf
Nel, A., T. Xia, L. Madler and N. Li (2006). “Toxic potential of materials at the nanolevel.” Science 311(5761): 622-627. DOI: 10.1126/science.1114397
NIA (2008). The Responsible Nano Code – Update May 2008, Nanotechnology Industry Association. http://www.aznano.org/uploads/Friedrichs_NIA_ArizonaTalk_10042008.pdf
NIOSH (2010). Strategic plan for NIOSH nanotechnology research and guidance, National Institute for Occupational Safety and Health. https://www.cdc.gov/niosh/docs/2010-105/default.html
NIOSH (2012). Filling the Knowledge Gaps for Safe nanotechnology in the Workplace. A Progress Report from the NIOSH Nanotechnology Research Center, 2004 – 2011, National Institute for Occupational Safety and Health. https://www.cdc.gov/niosh/docs/2013-101/pdfs/2013-101.pdf
NNI (2008). Strategy for nanotechnology-related environmental, health and safety research. Washington DC, National Nanotechnology Initiative. https://www.nano.gov/NNI-EHS-Research-Strategy
NNI (2010). National Nanotechnology Initiative 2011 Environmental, Health, and Safety Strategy – Draft. Washington DC, NNI. https://www.nano.gov/sites/default/files/pub_resource/tinkle_-_march_10.pdf
NNI (2011). National Nanotechnology Initiative Environmental, Health, and Safety Research Strategy. Washington DC, National Science and Technology Council Committee on Technology, Subcommittee on Nanoscale Science, Engineering, and Technology https://obamawhitehouse.archives.gov/sites/default/files/microsites/ostp/nni_2011_ehs_research_strategy_final.pdf
NRC (2012). A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials, The National Academies Press. DOI: 10.17226/13347
NSET (2010). The National Nanotechnology Initiative. Research and Development Leading to a Revolution in Technology and Industry. Supplement to the President’s FY 2011 Budget. Washington DC, Subcommittee on Nanoscale Science, Engineering and Technology, Committee on Technology, National Science and Technology Council. https://obamawhitehouse.archives.gov/sites/default/files/microsites/ostp/nni_2011_budget_supplement.pdf
Oberdörster, G. (2000). “Toxicology of ultrafine particles: in vivo studies.” Phil. Trans. Roy. Soc. London Series A 358(1775): 2719-2740. DOI: 10.1098/rsta.2000.0680
Oberdörster, G., J. Ferin, G. Finkelstein, P. Wade and N. Corson (1990). “Increased Pulmonary Toxicity of Ultrafine Particles .2. Lung Lavage Studies.” Journal of Aerosol Science 21(3): 384-387. DOI: 10.1016/0021-8502(90)90065-6
Oberdörster, G., A. Maynard, K. Donaldson, V. Castranova, J. Fitzpatrick, K. Ausman, J. Carter, B. Karn, W. Kreyling, D. Lai, S. Olin, N. Monteiro-Riviere, D. Warheit and H. Yang (2005). “Principles for characterizing the potential human health effects from exposure to nanomaterials: elements of a screening strategy.” Part. Fiber Toxicol. 2(8): DOI:10.1186/1743-8977-1182-1188.
Owen, R., P. Macnaghten and J. Stilgoe (2012). “Responsible research and innovation: From science in society to science for society, with society.” Science and Public Policy 39(6): 751-760. DOI: 10.1093/scipol/scs093
PCAST (2010). Report to the President and Congress on the Third Assessment of the National nanotechnology Initiative. Washington DC, President’s Council of Advisors on Science and Technology. https://www.nano.gov/node/623
Pekkanen, J., A. Peters, G. Hoek, P. Tiittanen, B. Brunekreef, J. de Hartog, J. Heinrich, A. Ibald-Mulli, W. G. Kreyling, T. Lanki, K. L. Timonen and E. Vanninen (2002). “Particulate air pollution and risk of ST-segment depression during repeated submaximal exercise tests among subjects with coronary heart disease – The exposure and risk assessment for fine and ultrafine particles in ambient air (ULTRA) study.” Circulation 106(8): 933-938. DOI: 10.1161/01.cir.0000027561.41736.3c
Pope, C. A. I. (1996). “Particulate pollution and health: A review of the Utah valley experience.” J. Exposure Anal. and Environ. Epi. 6(1): 23-34. https://pubmed.ncbi.nlm.nih.gov/8777371/
RCEP (2008). Novel Materials in the Environment: The case of nanotechnology. London, UK, Royal Commission on Environmental Pollution. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/228871/7468.pdf
RS/RAE (2004). Nanoscience and nanotechnologies: Opportunities and uncertainties. London, UK, The Royal Society and The Royal Academy of Engineering: 113 pp. https://royalsociety.org/~/media/Royal_Society_Content/policy/publications/2004/9693.pdf
SCENIHR (2005). Scientific Committee on Emerging and newly Identified Health Risks (SCENIHR) Opinion on The appropriateness of existing methodologies to assess the potential risks associated with engineered and advantitious products of nanotechnologiues, Scientific Committee on Emerging and newly Identified Health Risks. https://ec.europa.eu/health/ph_risk/committees/04_scenihr/docs/scenihr_o_003b.pdf
SCENIHR (2009). Risk Assessment of Products of Nanotechnologies. Brussels, Scientific Committee on Emerging and Newly-Identified Health Risks (SCENIHR). https://ec.europa.eu/health/ph_risk/committees/04_scenihr/docs/scenihr_o_023.pdf
SCENIHR (2010). Scientific Basis for the Definition of the Term “nanomaterial”. Brussels, Scientific Committee on Emerging and Newly-Identified Health Risks (SCENIHR). https://ec.europa.eu/health/scientific_committees/emerging/docs/scenihr_o_032.pdf
Schulte, P. A., C. L. Geraci, V. Murashov, E. D. Kuempel, R. D. Zumwalde, V. Castranova, M. D. Hoover, L. Hodson and K. F. Martinez (2014). “Occupational safety and health criteria for responsible development of nanotechnology.” J. Nanopart. Res. 16(1). DOI: 10.1007/s11051-013-2153-9
Schulte, P. A., V. Murashov, R. Zumwalde, E. D. Kuempel and C. L. Geraci (2010). “Occupational exposure limits for nanomaterials: State of the art.” Journal of Nanoparticle Research 12(6): 1971-1987. DOI: 10.1007/s11051-013-2153-9
Schwartz, J., D. W. Dockery and L. M. Neas (1996). “Is daily mortality associated specifically with fine particles?” Journal of the Air & Waste Management Association 46(10): 927-939. DOI: 10.1080/10473289.1996.10467528
Schwartz, J. and R. Morris (1995). “Air-Pollution and Hospital Admissions for Cardiovascular- Disease in Detroit, Michigan.” Am. J. Epidemiol. 142(1): 23-35. DOI: 10.1093/oxfordjournals.aje.a117541
Seaton, A., W. MacNee, K. Donaldson and D. Godden (1995). “Particulate air pollution and acute health effects.” Lancet 345: 176-178. DOI: 10.1016/s0140-6736(95)90173-6
Subramanian, V., J. Youtie, A. Porter and P. Sharipa (2010). “Is there a shift to “active” nanostructures?” J. Nanopart. Res. 12(1): 1-10. DOI: 10.1007/s11051-009-9729-4
Taylor-Francis. (2015). “Journal of Responsible Innovation.” from http://www.tandfonline.com/loi/tjri20 – .VMJqcXB4pfE.
Tomellini, R. (2004). “International dialogue on responsible research and development of nanotechnology.” Retrieved 1/21/15, from ftp://ftp.cordis.europa.eu/pub/nanotechnology/docs/alexandria062004.pdf.
Toumey, C. (2008). “Reading Feynman into Nanotechnology: A Text for a New Science.” Techné 13(3): 133-168. DOI: 10.5840/techne20081231
Toumey, C. (2010). Tracing and disputing the story of nanotechnology. International Handbook on Regulating Nanotechnologies. G. Hodge, D. Bowman and A. D. Maynard. Cheltenham, England, Edward Elgar: 46-59.
UK House of Lords (2010). Nanotechnologies and food. London, UK, House of Lords Science and Technology Committee. https://publications.parliament.uk/pa/ld200910/ldselect/ldsctech/22/2205.htm
VIRI. (2015). “The Virtual Institute for Responsible Innovation (VIRI).” from https://cns.asu.edu/viri.
von Schomberg, R. (2011). Prospects for Technology Assessment in a framework
of responsible research and innovation. Technikfolgen abschätzen lehren: Bildungspotenziale transdisziplinärer Methoden. M. Dusseldorp and R. Beecroft. Wiesbaden, Vs Verlag. DOI: 10.2139/ssrn.2439112
Westerhoff, P. and B. Nowack (2013). “Searching for Global Descriptors of Engineered Nanomaterial Fate and Transport in the Environment.” Accounts of Chemical Research 46(3): 844-853. DOI: 10.1021/ar300030n
Wichmann, H. E. and A. Peters (2000). “Epidemiological evidence of the effects of ultrafine particle exposure.” Philos. Trans. R. Soc. Lond. Ser. A-Math. Phys. Eng. Sci. 358(1775): 2751-2768. DOI: 10.1098/rsta.2000.0682
