5


Research Priorities and Resource Needs

OVERVIEW

Chapter 2 developed a conceptual framework (Figure 2-1) for considering environmental, health, and safety (EHS) risks related to nanomaterials and to help prioritize activities within a strategic research plan. Three overarching principles were developed to guide the development of strategic research and to identify ENMs requiring particular attention; emergent risk, plausibility and severity. In addition, specific criteria were established as a basis for assigning research priorities:

•  Research that advances knowledge of both exposure and hazard wherever possible.

•  Research that leads to the production of risk information needed to inform decision-making on nanomaterials in the market place.

•  Research efforts to address short-term needs that serve as a foundation for moving beyond case-by-case evaluations of nanomaterials and allow longer-term forecasting of risks posed by newer materials expected to enter commerce.

•  Research that promotes the development of critical supporting tools, such as measurement methods, limitations of which hinder the conduct of research in processes that control hazards and exposure.

•  Research on ecosystem-level effects that addresses exposure or hazard scenarios that are underrepresented in the current portfolio of nanotechnology-related EHS research; for example, impacts on ecosystem processes and on organisms representing different phyla and environments.

Chapter 3 reviewed what is known about the EHS aspects of nanomaterials in the context of the conceptual framework and identified critical research questions that remain unanswered, focusing on processes most likely to affect exposure and hazards related to engineered nanomaterials (ENMs) (circle in Figure 2-1). Chapter 4 addressed tools needed for characterizing how the proper-



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5 Research Priorities and Resource Needs OVERVIEW Chapter 2 developed a conceptual framework (Figure 2-1) for considering environmental, health, and safety (EHS) risks related to nanomaterials and to help prioritize activities within a strategic research plan. Three overarching prin- ciples were developed to guide the development of strategic research and to identify ENMs requiring particular attention; emergent risk, plausibility and severity. In addition, specific criteria were established as a basis for assigning research priorities:  Research that advances knowledge of both exposure and hazard wher- ever possible.  Research that leads to the production of risk information needed to in- form decision-making on nanomaterials in the market place.  Research efforts to address short-term needs that serve as a foundation for moving beyond case-by-case evaluations of nanomaterials and allow longer- term forecasting of risks posed by newer materials expected to enter commerce.  Research that promotes the development of critical supporting tools, such as measurement methods, limitations of which hinder the conduct of re- search in processes that control hazards and exposure.  Research on ecosystem-level effects that addresses exposure or hazard scenarios that are underrepresented in the current portfolio of nanotechnology- related EHS research; for example, impacts on ecosystem processes and on or- ganisms representing different phyla and environments. Chapter 3 reviewed what is known about the EHS aspects of nanomateri- als in the context of the conceptual framework and identified critical research questions that remain unanswered, focusing on processes most likely to affect exposure and hazards related to engineered nanomaterials (ENMs) (circle in Figure 2-1). Chapter 4 addressed tools needed for characterizing how the proper- 143

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144 Research Priorities and Resource Needs ties of ENMs affect their interactions with humans and the environment (bottom of Figure 2-1). In approaching the charge to develop research priorities, the committee applied the framework developed in Chapter 2 to the research and development needs identified in Chapters 3 and 4, and in doing so, identified four broad, cross-cutting research priority categories. These mirror the larger elements of the conceptual framework described in Chapter 2 and map directly to the critical research needs identified in Chapters 3 and 4. At the chapter’s end, the commit- tee discusses the resources needed to implement a strategic research plan within the context of these priority categories. The research categories are  Adaptive research and knowledge infrastructure for accelerating re- search progress and providing rapid feedback to advance research.  Characterizing and quantifying the origins of nanomaterial releases.  Processes affecting both potential hazard and exposure.  Nanomaterial interactions in complex systems ranging from subcellular systems to ecosystems. Given the diversity of nanomaterials and the breadth of their potential ap- plications, the committee considered that a prescriptive approach to addressing the EHS aspects of nanomaterials would be short-sighted and would probably fail to anticipate the rapid evolution of this field and its potential impacts. Rather, in selecting the four broad categories, the committee envisioned a risk- based system that is iteratively informed and shaped by the outcomes of research and new findings. Thus, its approach addresses one goal in particular as described in Chapter 1: to generate scientific evidence that provides approaches to environmental and human health protection even as our knowledge of ENMs is expanding and the research strategy is evolving. Furthermore, as the research strategy is evolving, an adaptive and integrated knowledge infrastructure will be developed to iden- tify and enable prediction of risks posed by nanomaterials with sufficient cer- tainty to enable informed decisions on how the risks should be managed or miti- gated. The knowledge infrastructure also will provide evidence that helps to identify and evaluate the merits of various risk-management options, including measures to reduce inherent hazard or exposures to nanomaterials. The committee proposes a strategy to address the EHS aspects of nanoma- terials that sets priorities for research efforts that bridge complex and model systems, exposure and hazard, and immediate and long-term concerns, thus re- flecting the need for systems integration described in Chapter 3. The strategy also favors the development of supporting measurement and modeling tools to advance the study of nanomaterial interactions among the risk-assessment do- mains of exposure, hazard, and risk characterization. Such broad, overarching priorities were deemed important by the committee, given the relevance of nanomaterials to numerous scientific and technical disciplines—including elec-

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Environmental, Health, and Safety Aspects of Engineered Nanomaterials 145 tronics, energy, and medicine—and the array of exposure and hazard scenarios. The committee also identified commonalities in the research tools (for example, measurement methods and data infrastructure) throughout multiple levels of organization (for example cellular, organismal, or ecosystem) that can be capi- talized on in addressing research priorities. In the sections below, the committee expands on each of the four research priority categories and describes their relationship to the data gaps and key re- search questions in Chapters 3 and 4. The four categories are of equal priority and interconnected; their ordering does not imply a priority, and some research components are common to all four priority categories. In some cases, the com- mittee describes components of the categories that need to be addressed in the short term and components that will evolve. A short-term timeframe is consid- ered to be within 5 years. The priorities are activities that can be readily organ- ized, resourced, and accomplished with available knowledge and tools. They need to be accomplished because they are fundamental to informing or enabling other activities. Furthermore, many topics on which research is expected to be initiated in the short term will continue to be addressed in the longer term as new tools and approaches are developed; this emphasizes the iterative nature of the research strategy. Because of the iterative and sequential nature of the research process, the committee demarcated short-term and long-term research only when there was an evident distinction in timing. The committee describes the logical sequence of the research within each of the priority categories with recognition that timing will depend on the knowledge gained from previous research efforts. ADAPTIVE RESEARCH AND KNOWLEDGE INFRASTRUCTURE FOR ACCELERATING RESEARCH PROGRESS AND PROVIDING RAPID FEEDBACK TO ADVANCE RESEARCH An adaptive knowledge infrastructure is essential for supporting and pro- viding rapid feedback on integrative research. Broadly, the infrastructure must support the generation of inputs (materials, methods, and end points), the devel- opment of relationships and models based on data-sharing and validation of the models, and the development of hypotheses and predictions from the models. The infrastructure encompasses tools, including materials, characterization methods, models, and informatics. The infrastructure should also  Identify emerging data gaps and highlight those that need to be ad- dressed.  Provide rapid feedback to inform research and design of new materials with reduced hazards or exposure potential.  Be accessible to the public and to scientists.

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146 Research Priorities and Resource Needs The outcomes needed from the research and knowledge infrastructure in- clude making characterized nanomaterials widely available, refining analytic methods continuously to define the structures of the materials throughout their life span, defining methods and protocols to assess effects, and increasing the rate of generation and the quality of the data and models available. Stakeholders should be engaged in developing best practices, in sharing information, and in collaborating in developing methods and models. Informatics should be fostered through the joining (“federating”) of existing databases, the encouraging and sustaining of curation and annotation of the data, and the assigning of credit to those who share datasets and models. Joined knowledge bases need to be inter- operable and provide for mapping or translation of related ontologies (descrip- tions of the concepts and relationships among a set of agents or elements; Gru- ber 2011) to allow for searching similar concepts to identify appropriate data. Because the knowledge infrastructure will integrate the research agenda, it comprises activities that connect the other research categories. Each activity described below is an integral part of the infrastructure and has both short-term and long-term components. The relative emphasis placed on each activity will change as the foundational components of the infrastructure are established; however, to ensure coordination of the infrastructure, some emphasis on each activity is needed from the outset. The activities are binned into three areas, in descending order of their importance in the short term. Short-term priority requiring immediate emphasis followed by a sustained effort:  Produce and make available material libraries (characterized nanomate- rials in commerce, reference materials, and standard materials) that have the structural definition and systematic variation needed for advancing key research (see Chapter 4). Building these capabilities in the short term and ramping them up to a sustained effort in the longer term:  Develop and validate the analytic tools and methods needed to relate nanomaterial properties to system responses, including methods for detecting, characterizing, and tracking nanomaterials in relevant media and for monitoring transformations (including surface modifications) in complex media and on the timescale of experiments. A multi-tiered approach will be needed to develop methods so that the fate of ENMs in all relevant media can be understood.  Refine and validate methods needed to characterize and quantify the ef- fects of ENMs in experimental systems, considering the identity and dose of a nanomaterial at the target or in the system. Develop and validate methods, in- cluding high-throughput screening, to examine the sensitivity of effects to struc- tural motifs and descriptors.

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Environmental, Health, and Safety Aspects of Engineered Nanomaterials 147  Create and support mechanisms for data-sharing to advance research and to generate understanding of relationships among data using models. Data- sharing systems should be collaborative and nimble; should engage the broad array of stakeholders in producing materials, instruments, and models; and should provide mechanisms for sharing raw data and results (negative and posi- tive). The findings should support continuing research and the design of safer nanomaterials. Longer-term efforts that require consideration and coordination in the short term to ensure that experimental, modeling, and informatics efforts contribute to a coordinated, functional infrastructure  Advance and validate models for nanomaterials, nanomaterial trans- formations, and target systems that test specific and systemwide effects of ENMs.  Encourage collaboration between experimentalists and computer mod- elers and develop descriptors to compare materials, models, and model results.  Establish and evolve an informatics framework that begins by federat- ing and supporting existing data repositories and connecting them through shared or translatable ontologies. CHARACTERIZING AND QUANTIFYING THE ORIGINS OF NANOMATERIAL RELEASES Characterizing the quantity and nature of nanomaterials to which human populations and ecosystems are exposed is critical for evaluating the EHS risks posed by nanomaterials. Exposure to a nanomaterial in any setting (for example, in the workplace, in domestic use, or in the environment) is a result of condi- tions associated with the initial state of the nanomaterial (for example, as indi- vidual particle vs embedded in a synthetic or biologic matrix), the potential pathways of exposure, and the influences of environmental conditions (such as temperature, sunlight, and flow of air or water) on the nanomaterial released. An understanding of release scenarios across the life cycle and value chain of the material is needed, including in production, in use, and at the end of life. For example, as discussed in Chapter 3, characterizing the nature and relevance of exposure requires information on the sources of exposure (including nanomate- rials and contaminants), the nature of nanomaterials in products, the condition of the material released, the release points where nanomaterials may enter the envi- ronment (for example, in transportation, waste-handling, product recycling, and disposal), and the environmental conditions in which releases occur. Just as complex systems in nature (such as organisms and ecosystems) present chal- lenges for detection and characterization of nanomaterials across the value chain, so do human activities. Moreover, socioeconomic drivers, proprietary considerations, and complex networks of products and information dissemina-

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148 Research Priorities and Resource Needs tion support the need for an integrative-research structure. Industry involvement in this research to understand trends in manufacturing and “horizon materials” will probably be a key input to advancing this priority category. In summary, research activities in this category would  Identify and characterize what is being released and who is exposed: o Identify critical release points and quantities along the life cycle, including the waste streams, and characterize materials being re- leased. o Identify human and ecosystem populations exposed. o Characterize releases and exposures of workers and consumers of high-production nanomaterials currently in the market and in use down the value chain (for example, carbon nanotubes).  Define the range of materials to o Develop inventories of current and expected production of nano- materials1. o Develop inventories of current and expected use of nanomaterials and value-chain transfers.  Measure the quantity and nature of released materials in associated re- ceptor environments to o Quantify exposures. o Model nanomaterial releases along the life cycle. Short-term activities address materials in commerce and in the environ- ments that nanomaterials will enter along the value chain and lifecycle. Expo- sure routes and transformations can be determined on the basis of uses of com- mercially available nanomaterials and their properties and formats (for example, their presence in emulsions or polymer matrices). Longer-term activities address trends in nanomaterial markets and in nanomaterial development; new materials and new markets create greater uncertainty regarding the nature of the nanoma- terials, production quantities, uses, and routes of exposure. Longer-term activi- ties also will consider other life-cycle impacts of nanomaterial production, such as material and energy use and the wastes produced. Short-Term Activities  Inventories of current and near-term production of nanomaterials. 1 The committee identified the need for better understanding of ENMs that are in or about to enter commerce, and the development of inventories of nanomaterial production and use to that end is warranted. To the extent that reporting by industry would contribute to such an effort, the entities and nanomaterials subject to reporting would need to be defined with some precision. Those issues were addressed in establishing the inventory reporting systems developed for conventional chemicals (for example, EPA’s Toxic Sub- stances Control Act Chemical Data Reporting Program [EPA 2011]).

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Environmental, Health, and Safety Aspects of Engineered Nanomaterials 149  Inventories of intended use of nanomaterials and value-chain transfers.  Identification of critical release points along the value chain.  Identification of populations or systems exposed.  Characteristics of released materials and associated receptor environ- ments.  Modeling of nanomaterial releases along the value chain. Middle-Term to Long-Term Activities  Development of models to anticipate trends in production and use of nanomaterials and characteristics of future releases.  Development of a more sophisticated understanding of the release of and exposure to more complex “new-generation” nanomaterials, such as those involving composite materials, active-bioactive nanomaterials, and composites of biologic materials and nanomaterials.  Life-cycle analysis of nanomaterial production, use, and disposal with an accounting of energy and material inputs and the wastes produced. PROCESSES AFFECTING BOTH EXPOSURE AND HAZARD Because nanoscale properties have a profound influence on biologic, physical, and chemical processes that control nanomaterial releases, transforma- tions, and effects in various levels of biologic organization, from organisms to ecosystems, it is advantageous to assess exposure to and hazards of nanomateri- als together. The conceptual framework for the EHS research strategy (Figure 2- 1) emphasized the investigation of processes common to exposure and hazard as a basis for advancing risk assessment in a predictive and generalizable fashion, thereby laying a foundation for informing decision-making on current and future nanomaterials. Research in this category is focused on the nanoscale where ad- vances in information technologies, the life sciences, physical chemistry, mate- rials science, and other disciplines converge. The common ground for interdisci- plinary research at the nanoscale should be exploited through development of fundamental knowledge that advances our understanding of both exposures and hazards. As discussed in Chapter 2, an approach that simultaneously addresses ex- posure and hazard enables decision-making in the short to long term related to comparing risks among materials and providing criteria for establishing priori- ties for research on nanomaterials that are currently on the market, to providing feedback on research needs and priorities, and to providing information needed to reduce the risks posed by nanomaterials that are on the market or are under development. One example of the importance of understanding both hazards and expo- sures is the role of nanoparticle-macromolecular interactions in regulating and

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150 Research Priorities and Resource Needs modifying nanoparticle behavior at scales ranging from genes to ecosystems. Such interactions result from nanomaterial properties that originate during their creation with adsorbed coatings (for example, materials designed to stabilize particles against aggregation, enhance their association with targeted cells in drug delivery, improve their dispersion in emulsions, or contain their reactivity, as in sun- screens). Physiologic and ecologic environments may modify the material sur- faces, for example, through adsorption of proteins in blood or naturally occurring polyelectrolytes in surface waters. Studying nanoparticle-macromolecular interac- tions as a unified topic rather than separately as an investigation of hazard or ex- posure can lead to a better understanding of the processes controlling nanoparticle mobility, environmental partitioning, biodistribution, bioaccumulation, protein folding, and changes in the conformation of RNA or DNA with associated changes in gene expression. The cross-disciplinary interactions among physical chemists, toxicologists, geochemists, molecular biologists, and other scientists are critical for the study of processes at the nanoscale, such as particle aggregation, deposition on surfaces, reactivity, persistence, and biokinetics. Topics in this research category include the effects of particle surface modification on aggregation and nanoparticle bioavailability, reactivity, and toxicity potential; processes that affect nanomaterial transport across biologic or synthetic membranes; and the development of structure-activity relationships of nanomaterials with their transport, fate, and effects. For example, surface modi- fication of zero-valent iron [Fe(0)] nanoparticles with polyelectrolyte or natural organic matter reduces their aggregation and deposition and enhances their transport in soils (Saleh et al. 2008; Johnson et al. 2009). Decreasing ag- gregation and increasing mobility in the environment increases the potential for exposure to those materials. However, the same surface modifications decrease the toxicity of the materials to bacteria (Li et al. 2010) and to neurons and cen- tral nervous system microglia cells (Phenrat et al. 2009a) compared with un- modified particles. Despite the decrease in toxicity based on the end points stud- ied, coated particles were able to enter the cells’ nuclei, and uncoated (aggre- gated) Fe(0)/Fe3O4 core-shell nanoparticles were not (Phenrat et al. 2009a). Similarly, the oxidation of Fe(0)/Fe3O4 core-shell to Fe-oxide increases the mo- bility of the nanoparticles in the environment but dramatically decreases their toxicity to multiple receptors (Auffan et al. 2008; Phenrat et al. 2009b). Thus, such processes as surface modification, aggregation, and oxidation can in this case increase the potential for exposure but decrease hazard. Ultimately, under- standing how those fundamental processes affect risk will inform risk- management decisions about nanomaterial compositions, modifications, and application scenarios. Research in this category is necessarily broad. Some examples of activi- ties are  Development of instrumentation and standard methods for characteriz- ing releases and exposures to ENMs in relevant biologic and environmental me-

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Environmental, Health, and Safety Aspects of Engineered Nanomaterials 151 dia, including ENM size, surface character, and composition dynamically (from seconds to hours) and single particles.  Studies that specify and characterize trends in how ENM transforma- tions influence the biologic effects of ENMs on organisms and ecosystems.  Cross-cutting research that systematically describes ENM transforma- tions that occur in organisms or as a result of biologic processes.  Examination of how native ENM structures influence the dynamic ENM structures that develop in environmental and biologic settings.  Research that provides a generalized and quantitative understanding of ENM transformations through the development of predictive models.  Further development of a knowledge infrastructure that can describe and allow for the diversity and dynamics of ENM structure in relevant biologic and environmental media. Instrumentation to measure ENM properties in various matrices is needed to relate their properties to the potential for exposure and effects and to deter- mine the types and extent of ENM transformations in environmental and bio- logic systems. Because unique properties of a subset of ENMs may cause them to behave differently from other nanomaterials, methods for characterizing sin- gle-particle features of the ENMs are needed. All the activities discussed are considered to have high priority, but initial investigations should be weighted toward the development of characterization methods, including for single particles, so that the methods will be available for addressing issues related to ENM structure and activity and to transformations in environmental and bio- logic media. NANOMATERIAL INTERACTIONS IN COMPLEX SYSTEMS RANGING FROM SUBCELLULAR SYSTEMS TO ECOSYSTEMS EHS research on ENMs is unified by the need to understand their interac- tions with complex systems, whether subcellular components, single cells, or- ganisms, or ecosystems. Each of those systems has a level of complexity with many embedded, interrelated processes that may interact synergistically, an- tagonistically, and often unpredictably in response to the introduction of nano- materials. The scientific community has recognized the need for system-level approaches to understand the potential for ENM effects on human health and the environment. That recognition encompasses the notion of indirect consequences of direct interactions. For example, effects on environmental geochemistry can affect the viability of key components of the ecosystem food web that ultimately may affect ecosystem integrity. In addressing responses to ENMs, whether at the cellular level or the ecosystem level, there are common challenges, including a need to re-examine “default” assumptions and scenarios. The challenges include classic examples from ecosystem science and toxicology, such as extrapolation

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152 Research Priorities and Resource Needs from high-dose effects to low-dose effects, temporality of response, generaliza- bility from one animal model (or ecosystem) to another, and variability within populations (or habitats). Transformations that occur in physiologic or environ- mental systems, such as weathering (ecosystems) and metabolism (organisms and ecosystems), and interactions with macromolecules (for example, blood serum proteins, DNA, humic materials, and polysaccharides) introduce com- plexity that must be considered in performing research. Traditional end points and associated metrics (for example, LD50) may not capture more subtle effects that occur in the context of development, reproduc- tion, repair, adaptation, and behavior, given population characteristics and indi- vidual variability. Indeed, there are probably ecosystem effects that cannot be predicted from single-organism toxicity tests; this is analogous to the failure to predict human toxicologic effects from single responses, such as inflammation, particularly when such effects are measured at a single time or at an unrealisti- cally high dose. In this priority category, research includes efforts to relate in vitro to in vivo observations, predicting such system-level effects as nutrient cycling, and at the organism level, assessing effects on the endocrine or devel- opmental systems. This category also encompasses the need to develop a more rigorous, con- ceptual, and complex model of effects of exposure and potential effects along the ecologic food chain concomitantly with corresponding development of in- strumentation and protocols for nanomaterial measurement, and detection and development of assays for isolating ENM effects and reactivity in complex me- dia. Lessons learned from complex systems, such as the relevance of character- istics and interferences for predicting physiologic and environmental effects of nanoparticles, must be systematically fed back into experimental-design efforts, such as high-throughput screening. Research in this category therefore must be supported by the development of informatics tools and the knowledge infrastruc- ture. At some point, models and physicochemical data must be validated with experimental data. To identify the most productive subjects for research, a matrix approach that takes advantage of the development of tools for nanomaterial characteriza- tion and systems effects should be considered. The matrix elements would in- clude in one dimension screening tools for determining nanomaterial effects, ranging from subcellular to ecosystems, and in the other dimension a set or li- brary of standard nanomaterials characterized by specific properties, such as composition, surface charge, size, and shape. From those complex, system level models or screening approaches would be derived nanomaterial and system characteristics. These characteristics would indicate directions for exploration of mechanisms of effects to develop predictive methods for assessing effects that depend on the combinations of nanomaterial and system properties. Nothing in this approach would impede research that is successfully exploring known inter- actions of nanomaterials in complex systems from subcellular systems to eco- systems.

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Environmental, Health, and Safety Aspects of Engineered Nanomaterials 153 Short-Term Activities  Refinement of a set of screening tools (high-throughput and high- content) that reflect important characteristics and toxicity pathways of the com- plex systems described above.  Adaptation of system-level tools (for example, individual species tests, microcosms, and organ-system models) to support in vitro to in vivo correlations for nanomaterials, including exposure route, dose, and mechanisms of effects.  Development of approaches for comparing standardized reference nanomaterials with a variety of traditional toxic substances to understand such issues as bioavailability, metabolism, and relative potency.  On the basis of results of the above activities, identification of refer- ence materials that can be used as positive or negative controls for a variety of high-throughput and high-content test systems.  Development of tools and methods for estimating exposure and doses in complex systems, including approaches to address portal of entry, kinetics of toxicity, and mechanisms of effects.  Identification of potentially exposed, susceptible human and ecosystem populations with a focus on end points identified through previous studies and development of surveillance tools for detecting and characterizing effects of nanomaterials in these populations and ecosystems. Long-Term Activities Long-term priorities will depend on the successful completion of some of or all the short-term activities detailed above. An example of a longer-term priority is research on complex human health effects, in which it is possible that low-dose inhalation exposures to nanomaterials over a long term could have pathologic sequelae from sustained (low-level) pulmonary inflammation to pulmonary fibrosis. In that example, it would be critical to identify nanomaterial-specific dose-related and time-course-related mechanisms of action in vivo to understand toxicokinetic and toxicodynamic characteristics of nanomaterials in order to facili- tate development of high-throughput testing and high-content screening with in vitro and in silico methods. The development of those approaches could be ex- pedited by inclusion of standard reference nanomaterials in experimental testing designs, but such approaches must await the development of short-term data to support testing strategies to advance system-level understanding of the potential EHS effects of nanomaterials. Research in the four broad priority categories will address the goals of the research agenda articulated in Chapter 1 by generating scientific evidence that  Provides for approaches to environmental and human health protection even as our knowledge of ENMs is expanding and the research strategy is evolv- ing.

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154 Research Priorities and Resource Needs  Identifies and predicts risks posed by nanomaterials with sufficient cer- tainty to enable informed decisions on how the risks should be prevented, man- aged, or mitigated.  Identifies and evaluates the relative merits of various risk-management options, including measures to reduce the inherent hazard or exposure potential of nanomaterials. RESOURCES FOR ADDRESSING RESEARCH PRIORITIES In addition to identifying the four research priority categories, the commit- tee considered the resources needed to address its recommendations, consistent with its charge. In making these recommendations, the committee recognizes the current funding situation and the overall inadequacy of the funding available. Given this constraint, the committee provided pragmatic and general recom- mendations for funding. While it mentions specific amounts, the guidance should not be construed as reflecting the priority that should be given to a par- ticular category, as we considered all categories of equal priority. There is, how- ever, a sequencing to these categories that is reflected in the resource recom- mendations. In making its resource recommendations, the committee examined past funding levels, but did not conduct a more formal analysis of funding. In its sec- ond report, the committee will revisit its funding recommendations, based on further analysis and changes in the funding context. Overall, there has been concern as to whether the level of federal funding devoted to EHS research related to nanomaterials is sufficient (Denison 2005a; GAO 2008; Maynard 2008; Sargent 2011). That concern was echoed in the NRC (2009) review of the federal strategy (NEHI 2008). However, as in all ar- eas of research, placing a dollar investment value on needed research is a neces- sarily complex and qualitative approach, made more difficult by uncertainties in potential adverse impacts in the absence of research investment, in the potential for reducing adverse impacts with findings from research investments, and in the application of research findings in associated fields (for example, the use of in- formation resulting from nanoscale-medical applications to address the EHS impacts of other ENMs). In 2006, The Project on Emerging Nanotechnologies conducted an as- sessment of nanotechnology-related EHS research gaps and recommended a minimum EHS R&D investment of $100 million over the following 2 years to address highly targeted risk-based research (Maynard 2006). That estimate was lower than an estimate made by the Environmental Defense Fund (Denison 2005b) that called for an annual investment of $100 million per year by the fed- eral government in nanomaterial-related EHS R&D. Denison (2005b, p. 1) ac- knowledged that “there is, of course, no single ‘magic number’ nor a precise means to determine the right dollar figure, given the wide-ranging set of re- search issues needing to be addressed and the significant associated uncertainty

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Environmental, Health, and Safety Aspects of Engineered Nanomaterials 155 as to the anticipated results.” Nevertheless, he proposed a rationale based on research gaps, nanotechnology R&D investment and market impact, and expert assessment and benchmarking, including the recommended and actual Environ- mental Protection Agency expenditures on airborne particulate-matter research. Other organizations, such as the NanoBusiness Alliance (Murdock 2008), have argued that 10% of the federal nanotechnology-related R&D budget should be focused on EHS research. In testimony before the U.S. House of Representa- tives Committee on Science and Technology in 2008, Sean Murdock, executive director of the NanoBusiness Alliance, stated (Murdock 2008, p. 29): The NanoBusiness Alliance believes that environmental, health, and safety research should be fully funded and based on a clear, carefully-constructed research strategy. While we believe that 10 percent of the total funding for nanotechnology research and development is a reasonable estimate of the resources that will be required to execute the strategic plan, we also be- lieve that actual resource levels should be driven by the strategic plan as they will vary significantly across agencies. From 2006 to 2010, absolute and relative federal funding for nanotechnol- ogy-related EHS R&D increased substantially (see Table 5-1). In FY 2006, the federal government invested an estimated $37.7 million in nanotechnology- related EHS R&D (2.8% of the nanotechnology R&D budget). In contrast, in FY 2010, nanotechnology-related EHS R&D accounted for 5.1% of the federal nanotechnology R&D budget, or $91.6 million. In 2011, nanotechnology-related EHS funding showed a marked decrease; however, the President’s FY 2012 budget request proposes $123.5 million for nanotechnology-related EHS R&D—5.8% of the total nanotechnology R&D budget and the highest annual budget to date (NSET 2011). This figure does not include a substantial body of research on the biologic interactions and impacts of materials designed to enter the body for medical purposes – therapeutics, therapeutic delivery vehicles, and medical devices. While there is some disagreement over the direct applicability of research in this area to understanding the health and environmental risks as- sociated with ENMs (NRC 2009), this is a research area that undoubtedly con- tributes to mechanistic understanding of how certain ENMs interact with bio- logic systems potentially causing harm. Therefore current overall federal investment in EHS-relevant R&D is likely substantially greater than $123.5 mil- lion. However, it remains unclear how this investment translates into actionable information on potential EHS risks. Although there has been concern that accounting of nanotechnology- related EHS R&D investment has been overinflated (GAO 2008; NRC 2009), the committee finds that current investments, as reported in the supplement to the President’s federal budget request (NSET 2011), represent a reasonable indi- cation of federal R&D funding specifically directed at EHS R&D. However, on the basis of the analysis of research needs presented in this chapter and in

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156 Research Priorities and Resource Needs TABLE 5-1 National Nanotechnology Initiative EHS Research Funding, FY 2006-2012 EHS Percentage of Total Federal Nanotechnology-Related Federal Nanotechnology R&D Investment EHS R&D Investment FY 2006 (actual) $37.7 million 2.8% FY 2007 (actual) $48.3 million 3.4% FY 2008 (actual) $67.9 million 4.4% FY 2009 regular (actual) $74.5 million 4.4% a FY 2009 ARRA (actual) $12.0 million — FY 2010 (actual) $91.6 million 5.1% FY 2011 (requested) $116.9 million 6.6% FY 2011 (continuing $85.6 million 4.6% resolution) FY 2012 (requested) $123.5 million 5.8% a The American Reinvestment and Recovery Act of 2009. Source: Adapted from Sargent 2011; NSET 2010, 2011. Chapters 3 and 4, the committee considers that there is still a gap between the research and associated activities currently funded and the level of activity that would foster greater and more responsive progress toward providing information and tools to support the safe development of nanotechnologies. In general, the committee considers the predominant challenge to closing this gap is one of strategic realignment rather than additional funding. Based on the analysis conducted, the committee concludes that the research needs and research priorities addressed in this report provide an opportunity for strategi- cally realigning the substantial federal resources being dedicated to ENM EHS R&D, based on the priorities outlined above. Such realignment will require fed- eral-agency cooperation and resource leveraging. In addition, modest resource increases in the five areas described below could have a substantial effect on building infrastructure that is critical for sup- porting an effective R&D program. The committee recognizes that such re- source increases are not likely to be met by the budget requests of any one agency or institute but need to be garnered through a coordinated effort on the part of the nanomaterial community to leverage additional resources from pub- lic, private, and international initiatives to support critical cross-cutting research. These critical cross-cutting activities are encompassed within the research priority categories described above and would be supported by greater coordi- nated investment in nanotechnology-related EHS informatics, investment in

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Environmental, Health, and Safety Aspects of Engineered Nanomaterials 157 translating advanced measurement and characterization approaches to EHS- accessible methods, additional investment in developing and providing bench- mark nanomaterials, investment in identifying and characterizing nanomaterial sources across the value chain and life cycle of products, and investment in de- veloping and maintaining research networks that provide human infrastructure for collaborative research, information-sharing, and translation. Without budget- ary increases in each of these areas, the committee anticipates that the federal government’s ability to derive the maximum strategic value from investments in nanotechnology-related EHS research will remain insufficient. Initial funding estimates made by the committee for these cross-cutting ac- tivities were based on anticipated costs of addressing specific challenges over the next five years, and where possible drew from similar examples from other fields (for instance, the development of informatics programs in areas outside nanotechnology). The results, however, were considered to be unrealistic within the current economic climate, representing an anticipated investment in excess of $200 million over the next five years. Instead, the committee considered from an expert perspective what levels of funding would enable substantial advances in research infrastructure, allowing significant value to be added to existing and emerging research programs, while working within realistic budgetary con- straints. The resulting dollar amounts are based on expert judgment that is in- formed by the research priorities outlined above, the committee’s grasp of the cost of research activities, and a consensus on the most appropriate balance be- tween anticipated impact and realistic investment. To ensure the development and implementation of a strategic nanotech- nology-related EHS R&D program that is proportionate to overall nanotechnol- ogy R&D funding, that is commensurate with nanotechnology’s economic and societal importance, that addresses critical knowledge gaps, and that maximizes the beneficial influence of federal R&D investments, the committee offers the following resource recommendations:  On the assumption that core nanotechnology-related EHS R&D fund- ing by federal agencies remains at about $120 million per year over the next 5 years, over time, funded research should be aligned with strategic priorities identified here and in the National Nanotechnology Initiative nanotechnology- related EHS strategy. Any reduction in this total would be a setback to EHS re- search and slow progress in addressing the committee’s priorities.  Additional multi-agency funding should be made available for five cross-cutting activities that are critical for providing needed infrastructure and materials to support a strategic and effective R&D program and for ensuring that research findings can be readily translated into practical action by stakeholders. The guidance on funding levels is general, and not indicative of priority order. The specified amounts are the minimums that should be available, and for each of the areas funding is critically needed in the short term:

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158 Research Priorities and Resource Needs Informatics: $5 million per year in new funding for the next 5 o years should be used to support the development of robust infor- matics systems and tools for managing and using information on the EHS effects of ENMs. The committee concluded that develop- ing robust and responsive informatics systems for ENM EHS in- formation was critical to guiding future strategic research, and translating research into actionable intelligence. This includes maximizing the value of research that is EHS-relevant but not nec- essarily EHS-specific, such as studies conducted during the devel- opment of new therapeutics. Based on experiences from other ar- eas of research, investment in informatics on the order of $15 million is needed to make substantial progress in a complex and data rich field. However, within the constraints of nanotechnology R&D, the committee concluded that the modest investment pro- posed would at least allow initial informatics systems to be devel- oped and facilitate planning for the long-term. Instrumentation: $10 million per year in new funding for the next 5 o years should be invested in translating existing measurement and characterization techniques into platforms that are accessible and relevant to EHS research and in developing new EHS-specific measurement and characterization techniques for assessing ENMs under a variety of conditions. The committee recognized that the proposed budget is insufficient for substantial research into devel- oping new nanoscale characterization techniques—especially con- sidering the cost of high-end instruments such as analytic electron microscopes—in excess of $2 million per instrument. However, the proposed budget was considered adequate to support the trans- lation of techniques developed or deployed in other fields for the EHS characterization of ENMs. Materials: Investment is needed in developing benchmark ENMs o over the next 5 years, a long-standing need that has attracted little funding to date. The scope of funding needed depends in part on the development of public-private partnerships. However, to assure that funding is available to address this critical gap, the committee recommends that $3-5 million per year be invested initially in de- veloping and distributing benchmark ENMs. While more funds could be expended on developing a library of materials, this amount will assure that the most critically needed materials are de- veloped. These materials will enable systematic investigation of their behavior and mechanisms of action in environmental and bio- logic systems. The availability of such materials will allow bench- marking of studies among research groups and research activities. The committee further recommends that activities around materials development be supported by public-private partnerships. Such

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Environmental, Health, and Safety Aspects of Engineered Nanomaterials 159 partnerships would also help to assure that relevant materials are being assessed. Sources: $2 million per year in new funding for the next 5 years o should be invested in characterizing sources of ENM release and exposure throughout the value chain and life cycle of products. The committee considered that this was both an adequate and rea- sonable budget to support a comprehensive inventory of ENM sources. Networks: $2 million per year in new funding for the next 5 years o should be invested in developing integrated researcher and stake- holder networks that facilitate the sharing of information and the translation of knowledge to effective use. The networks should al- low participation of representatives of industry and international research programs and are a needed complement to the informatics infrastructure. They would also facilitate dialogue around the de- velopment of a dynamic library of materials. The committee con- cluded that research and stakeholder networks are critical to realiz- ing the value of federally funded ENM EHS research and considered this to be an area where a relatively small amount of additional funding would have a high impact—both in the devel- opment of research strategies and in the translation and use of re- search findings. Given the current absence of such networks, the proposed budget was considered adequate. REFERENCES Auffan, M., W. Achouak, J. Rose, M.A. Roncato, C. Chaneac, D.T. Waite, A. Masion, J.C. Woicik, M.R. Wiesner, and J.Y. Bottero. 2008. Relation between the redox state of iron-based nanoparticles and their cytotoxicity toward Escherichia coli. Environ. Sci. Technol. 42(17):6730-6735. Denison, R.A. 2005a. Getting Nanotechnology Right the First Time. Statement to the National Research Council Committee to Review the National Nanotechnology Initiative, 25 March 2005, Washington, DC [online]. Available: http://sei.nnin.org/ doc/resource/balbus.pdf [accessed May 25, 2011]. [Pp. 172-174 in A Matter of Size: Triennial Review of the National Nanotechnology Initiative (2006). Wash- ington, DC: National Academies Press]. Denison, R.A. 2005b. A Proposal to Increase Federal Funding of Nanotechnology Risk Research to at least $100 Million Annually. Environmental Defense Fund, Wash- ington, DC [online]. Available: http://www.environmentaldefense.org/documents/ 4442_100milquestionl.pdf [accessed May 26, 2011]. EPA (U.S. Environmental Protection Agency). 2011. Inventory Update Reporting and Chemical Data Reporting [online]. Available: http://www.epa.gov/oppt/iur/ [ac- cessed December 21, 2011].

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