Jo Anne Shatkin
If I were to survey the membership of the Society for Risk Analysis (SRA) to measure, in our collective expert opinion, which sources of hazards pose the greatest risks to global health, occupational safety, and environmental impacts, it is difficult to envision the risks posed by the use of engineered nanomaterials topping the list, when compared with broad impacts of infectious diseases, resource scarcity, climate change, or conflicts. Yet, the pace of development and breadth of potential applications keep this emerging class of materials in the forefront of numerous international research and governance organizations. This brief overview highlights a few recent developments of note.
In 2010 SRA published a series of papers assessing the state of the science, key uncertainties, and research needs for assessing the risks of emerging nanoscale materials (ENM) and nanotechnologies (Risk Analysis Vol 11 ). In the two-plus years since, there have been many developments in risk science, risk communication, risk analysis, and risk policy for ENM, however fundamental uncertainties remain. Today, risk analysis, risk management, and governance for novel nanoscale materials and technologies remain a dynamic landscape. Notable developments include that there are now several published risk assessments; it is possible, and more common, to find review articles on environmental, health, and safety issues.
Current risk analysis paradigms continue to be affirmed as a valid approach to assessment of nanomaterial risks, yet key uncertainties limit the ability to conduct quantitative assessments, particularly outside of the bounds of occupational inhalation exposures. As new data and tools emerge, this situation is likely to rectify—efforts to develop and standardize comparative data sets, such as the Organization for Economic Cooperation and Development (OECD) Working Party on Nanomaterials, and among the several large research collaborations, are now generating data that could lead to more predictive approaches that inform policy development.
This past year’s National Nanotechnology Initiative Environmental Health and Safety Research Strategy adopted a life-cycle approach to risk analysis. Similarly, the National Research Council’s Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials proposed a conceptual framework that adopts a life-cycle perspective to allow focus on critical research needs (NRC 2012).
Other highlights will be revealed during the 2012 SRA Annual Meeting in December, including several ENM risk symposia, focused on predictive toxicology, research strategies, governance, and perceptions (http://birenheide.com/sra/2012AM/program/sessionlist.php3).
State of the Science
Considerable investment has been made to assess the toxicity profiles, potency, and key attributes of diverse nanomaterials and build a greater understanding of their behavior in biological systems. The volume of studies has increased exponentially in recent years, and while knowledge increasingly links physical and chemical properties (e.g., particle size, surface reactivity, aggregation state) to effects, there remains a limited understanding of key determinants such that predictive toxicology remains elusive.
The situation with regard to data availability has improved considerably, as the number of studies of toxicity, both in vitro and in vivo, continues to grow. The quality of studies, particularly with regard to source material characterization, is better than it was in the mid-2000s. The ratio of published studies on ENM toxicity versus exposure remains high, and risk assessments are few. There are still major gaps in relating material properties to behavior and regarding long-term, or chronic, effects.
Not surprisingly, knowledge is accumulating more quickly for workplace exposure and risk to ENM than for consumer or environmental exposures. The greatest concern is over potential inhalation exposure to unbound nanoparticles during manufacturing. In the United States, the National Institute for Occupational Safety and Health (NIOSH) has assessed workplace exposure to ENMs in dozens of environments and has standardized the measurement of nanoparticles with a suite of instrumentation and measurement methods called Nanoparticle Emission and Assessment Tool (Methner et al. 2009). NIOSH has also conducted occupational risk assessments for two ENM, titanium dioxide (TiO2) and multi-walled carbon nanotubes (CNT). While state of the art, these assessments reflect a continued reliance on mass-based measurement.
Nanoscale TiO2 appears to have greater potency in the lung when inhaled than does conventional TiO2, when compared on the basis of mass. However, since the surface of nanoparticles contains most of the mass, the potency may not be greater for smaller particles if measured on the basis of surface exposure (Warheit 2007). Yet, classical measurement techniques do not report particle surface area, nor do existing standards measure by it. NIOSH has addressed this issue by lowering the mass-based recommended exposure limit (REL) for nanoscale TiO2 for “ultrafine” TiO2 (Peters 2012).
In addition to NIOSH, several organizations have addressed carbon nanotube toxicity and derived risk-based exposure levels. CNT have one or more concentric lengths of carbon forming a tube shape. There are many variations in size, shape, purity, aspect ratio, and surface properties, once calculated to be as many as 50,000 combinations (V. Colvin 2009, pers. comm., May). NIOSH has proposed an REL of 7 µg m-3 for CNT, which is at the limit of quantitation (NIOSH 2010). A few private organizations have also proposed limits: a limit of 2.5 µg m-3 was derived from inhalation toxicity studies for BASF’s Nanocyl, while Bayer’s limit of 50 µg m-3 has also been developed, based on testing for the Baytube product (Shulte et al. 2010). The Japanese New Energy and Industrial Technology Development Organization has proposed a limit of 30 µg m-3 (Nakanishi 2011). These standards reflect differences in data collection, characterization, source material, and interpretation. While there are now recommended exposure levels that form the basis of workplace protection, there is a need to refine the assays used as the basis of the RELs. The need to link specific material properties to toxicity and to identify key material properties for dose-response assessments are needed, as are efforts to standardize the test methods, endpoints, and reported parameters, as well as to validate existing methods for nanomaterials.
Engineered nanomaterials are currently used in a wide variety of products, including paints and coatings, electronics, textiles, batteries, sporting goods, sunscreen and other cosmetics, and some medical applications. In some cases, exposure would be anticipated to be low, for example, when nanomaterials are tightly bound in a composite matrix in a bicycle or tennis racket. However, nanomaterials used as flame retardants or in coatings in consumer products are possible sources of exposure; past experiences with lead and brominated flame retardants indicate elevated blood levels could result. Sunscreen and cosmetics are applied directly to the skin, and medical treatments might be swallowed or injected in the body.
Current requirements for product and ingredient disclosures in consumer products vary widely by geography and class of material. Few market data about the current use of ENM in products are considered reliable, and there is great uncertainty about levels of production or product disposition for most ENM. According to some estimates, there are hundreds of consumer products that contain ENM (e.g., Woodrow Wilson Center).
Production data for ENM are sparce, however, and there is no centralized national or international registry of ENM. The U.S. Environmental Protection Agency has reviewed over 100 submissions of new nanoscale substances under the Toxic Substances Control Act; however, most data submitted with the Pre-Manufacturing Notices has been classified as Confidential Business Information.
In Europe, there is ongoing discussion of disclosure of nanoscale ingredients in certain product classes, including cosmetics. Labeling is highly contentious because it remains unclear whether the specific ENM in products have any associated adverse effects, and disclosing to consumers any nanoscale ingredients, which may be safer than the non-nanoscale alternatives, raises concerns about equity for producers in comparison to other ingredient classes. Further, the European Commission definition of a nanomaterial is not limited to ENM and might be interpreted to include some long-used ingredients.
Use of ENM containing marine coatings and biocidal applications may result in direct environmental exposures. Environmental exposures to ENM otherwise may be low and diffuse, but raise concerns from applications such as packaging or fabric treatments that have direct pathways to environmental receptors. There have been many studies, for example, evaluating the fate of nanosilver, used as an antimicrobial additive, in wastewater and aquatic environments.
The past few years have brought progress on assessing the behavior and effects of ENM in the environment, in soil and aquatic systems. The biggest challenge continues to be the ability to measure nanoparticles in complex environments. The proverbial needle-in-a-haystack analogy applies here, when background levels of nanoparticles are in the low thousands range in clean environments, in the tens or hundreds of thousands in urban and industrial areas and near transport corridors. Equally the case for carbonaceous and elemental materials, identifying ENM from background can be challenging in any environmental media, particularly in the presence of biological components.
Governmental, Standards, and Regulatory Developments
On the regulatory front, most governmental organizations continue on a “case by case” approach to assessing nanoscale material submissions. There is a general recognition that risk assessment remains a sound approach to inform ENM risk management, but that uncertainty and poor measurements suggest modification of some metrics or assays, which may necessitate alternative approaches or endpoint consideration. Various mechanisms are applied to ensure agencies gain access to necessary data for evaluating ENM. For example, Australia’s New Chemicals Program has been amended to ensure that all industrial nanomaterials will undergo a premarket assessment. The European Food Safety Authority released guidance in 2011 for assessing food and feed with ENM. If it is adequately demonstrated that the ENM do not reach the gastrointestinal tract, either because they dissolve or are not in contact with the food, then a traditional assessment is performed. If there is exposure to ENM, detailed physical chemical characterization protocols are used to measure properties, along with absorption, distribution, metabolism, and excretion studies (Shatkin 2012).
A recent report by the European Commission (EC) finds, “The REACH [Registration, Evaluation, Authorisation and Restriction of Chemicals] approach to hazard assessment and risk characterisation, with its built-in flexibility, makes it overall suitable for nanomaterials” (EC 2012). Further: “In the light of current knowledge and opinions of the EU [European Union] Scientific and Advisory Committees and independent risk assessors, nanomaterials are similar to normal chemicals/substances in that some may be toxic and some may not. Possible risks are related to specific nanomaterials and specific uses. Therefore, nanomaterials require a risk assessment, which should be performed on a case-by-case basis, using pertinent information. Current risk assessment methods are applicable, even if work on particular aspects of risk assessment is still required.”
The EC is systematically addressing nanomaterials in all legislation and is developing, in consultation, guidance for ENM submissions. Progress is farthest along for REACH and medical applications, which are considered appropriate frameworks for nanomaterials, while policies are under development for occupational health and safety, consumer product legislation, food, biocides, and cosmetics, including labeling requirements. Environmental legislation is developing, but challenging due to limited ability to measure or control nanomaterials in the environment (EC 2012). An issue raised about REACH is the triggering threshold of 1,000 tons, which might miss many engineered nanomaterials produced at smaller scale. The EC conclusion: “the Commission considers REACH appropriate . . . ” (EC 2012).
While the EC has affirmed its use of risk assessment under REACH for assessing the safety of nanomaterials, “the key remaining question is to what extent data for one form of a substance can be used to demonstrate the safety of another form, due to still developing understanding of e.g. drivers of toxicity” (EC 2012).
Seeking “a balanced, science-based approach to regulating nanomaterials and other applications of nanotechnology in a manner that protects human health, safety, and the environment without prejudging new technologies or creating unnecessary barriers to trade or hampering innovation,” the U.S. Office of Management and Budget, with the White House Office of Science and Technology Policy, described principles for regulatory decision making for ENM. Specifically, the guidance offers, “Nanomaterials should not be deemed or identified as intrinsically benign or harmful in the absence of supporting scientific evidence, and regulatory action should be based on such scientific evidence. . . . In general, however, and to the extent consistent with law, regulation should be based on risk, not merely hazard . . .” (OMB 2011).1
These developments reflect the continued attention across governmental sectors to the issues of nanoscale risks. The development of policies, affirmation of existing regulations, and written guidance all demonstrate progress in ENM risk management, but do not suggest a lack of challenge in assessing and mitigating risks. Legal challenges, for example, to EPA’s conditional approval of a nano-pesticide or to Food and Drug Administration for failure to regulate nanomaterials in cosmetics, indicate otherwise.
Progress continues in developing standards for emerging nanoscale materials. The International Standards Organization (ISO) Technical Committee 229 has published 27 standards addressing terminology, characterization, toxicology, occupational health and safety practices, and risk guidance standards for nanotechnology (ISO 2012).2 The British Standards Institute, ASTM International, TAPPI, the IEEES, NIOSH, and others are working on nanomaterial standards.
Broadly, efforts to standardize terms, methods, and safe handling practices are improving commercial development, risk assessment, and risk management. There is a growing interest in “green” and sustainable nanotechnology development and a continued commitment among those in governance to proactive risk management of emerging technologies. The international meetings continue to convene on a weekly basis. Of greatest interest, the Emerging Nanoscale Materials Specialty Group of SRA is sponsoring several symposia during the 2012 SRA Annual Meeting covering these topics and more.
 “Memorandum for the Heads of Executive Departments and Agencies, Re: Policy Principles for the U.S. Decision-Making Concerning Regulation and Oversight of Applications of Nanotechnology and Nanomaterials” issued on 9 June 2011
 ISO 2012. Standards and projects under the direct responsibility of TC 229 Secretariat. ISO Catalogue. http://www.iso.org/iso/home/store/catalogue_tc/catalogue_tc_browse.htm?c...
European Commission. Communication from the commission to the European parliament, the council and the European economic and social committee. Second regulatory review on nanomaterials. Brussels, COM(2012) 572 final; 2012. Available at: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=COM:2012:0572:FIN:.... Accessed 9 November 2012.
Methner M, Hodson L, Geraci C. Nanoparticle Emission Assessment Technique (NEAT) for the identification and measurement of potential inhalation exposure to engineered nanomaterials part A. Journal of Occupational and Environmental Hygiene 7:3:127–132; 2009. Available at: http://dx.doi.org/10.1080/15459620903476355. Accessed 9 November 2012.
Nakanishi J. Risk assessment of manufactured nanomaterials final report: Overview of approaches and results and executive summaries of three manufactured nanomaterials: Carbon nanotubes (CNT), fullerene (C60), and titanium dioxide. Kawasaki: New Energy and Industrial Technology Development Organization of Japan; 2011.
National Research Council. A research strategy for environmental, health, and safety aspects of engineered nanomaterials. National Academies Press: Washington, DC; 2012. Available at: http://www.nap.edu/catalog.php?record_id=13347#toc. Accessed 9 November 2012.
National Institute for Occupational Safety and Health. Draft NIOSH current intelligence bulletin: Occupational exposure to carbon nanotubes and nanofibers. Atlanta: Centers for Disease Control and Prevention; 2010. Available at: http://www.cdc.gov/niosh/docket/review/docket161A/pdfs/carbonNanotubeCIB.... Accessed 16 November 2012.
Peters TM. Chapter 8: Managing risks in occupational environments. In: Shatkin JA. Nanotechnology health and environmental risks, 2nd ed. In Press. Taylor and Francis: Boca Raton, Florida; 2012.
Shatkin JA. Nanotechnology health and environmental risks, 2nd ed. In Press. Taylor and Francis: Boca Raton, Florida; 2012.
Schulte PA, Murashov V, Zumwalde R, Kuempel ED, Geraci CL. Occupational exposure limits for nanomaterials: State of the art. J Nanopart Res 12:1971–1987; 2010. Available at: http://www.nanoarchive.org/9468/. Accessed 9 November 2012.
Warheit DB, Webb TR, Reed KL, Frerichs S, Sayes CM. Pulmonary toxicity study in rats with three forms of ultrafine-TiO2 particles: Differential responses related to surface properties. Toxicology 230(1): 90–104; 2007.