3

Assessment of Progress

INTRODUCTION

The committee’s first report identified indicators of research progress and implementation that could be used as benchmarks for gauging the extent of research and implementation in response to the report. In developing the indicators, the committee acknowledged that given the short timeframe between that report and this second one, there would not be measurable, long-term progress that could be assessed with the indicators. It considered, however, that there would be ample time for initiation of research and for initial development of the infrastructure needed for implementing the research strategy.

In examining the extent of progress that has occurred, the committee is aware that many concomitant environmental, health, and safety (EHS) nanotechnology reviews and planning efforts have occurred within the same period as its own work, including publication of the National Nanotechnology Initiative (NNI) EHS research strategy, other government assessments, international initiatives, and continuing research efforts in general (see Chapter 2). It is neither possible nor useful to try to attribute progress to any particular effort, including this committee’s first report. Rather, we examine the trajectories of research and implementation to gauge whether steps have been made toward addressing the indicators identified by the committee and, if not, what efforts are needed to achieve progress.

The committee used a color scheme for categorizing progress: green for substantial progress, yellow for moderate or mixed progress, and red for little progress. It adopted that qualitative approach as suitable for gauging progress given the scope and types of information available. It classified progress on the basis of a consensus of the committee. The assessment considered new activities since preparation of the committee’s first report and the trajectory of research progress. Thus, green implies that there are new activities and that sustained progress can be expected, red refers to a situation of limited activity and little expectation of change, and yellow refers to mixed scenarios. The committee recognizes that its assessment is not an exhaustive compilation and evaluation of



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3 Assessment of Progress INTRODUCTION The committee’s first report identified indicators of research progress and implementation that could be used as benchmarks for gauging the extent of re- search and implementation in response to the report. In developing the indica- tors, the committee acknowledged that given the short timeframe between that report and this second one, there would not be measurable, long-term progress that could be assessed with the indicators. It considered, however, that there would be ample time for initiation of research and for initial development of the infrastructure needed for implementing the research strategy. In examining the extent of progress that has occurred, the committee is aware that many concomitant environmental, health, and safety (EHS) nano- technology reviews and planning efforts have occurred within the same period as its own work, including publication of the National Nanotechnology Initiative (NNI) EHS research strategy, other government assessments, international ini- tiatives, and continuing research efforts in general (see Chapter 2). It is neither possible nor useful to try to attribute progress to any particular effort, including this committee’s first report. Rather, we examine the trajectories of research and implementation to gauge whether steps have been made toward addressing the indicators identified by the committee and, if not, what efforts are needed to achieve progress. The committee used a color scheme for categorizing progress: green for substantial progress, yellow for moderate or mixed progress, and red for little progress. It adopted that qualitative approach as suitable for gauging progress given the scope and types of information available. It classified progress on the basis of a consensus of the committee. The assessment considered new activities since preparation of the committee’s first report and the trajectory of research progress. Thus, green implies that there are new activities and that sustained progress can be expected, red refers to a situation of limited activity and little expectation of change, and yellow refers to mixed scenarios. The committee recognizes that its assessment is not an exhaustive compilation and evaluation of 41

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42 Research Progress on EHS Aspects of Engineered Nanomaterials progress, rather it is intended to provide illustrative examples of progress. Chap- ter 4, “Getting to Green”, describes additional efforts and the pathways that are needed to achieve progress in the research and implementation indicators identi- fied by the committee in the context of the vision for the EHS nanotechnology research enterprise (Figure 1-2). The discussion below addresses advances made with regard to research and implementation progress indicators identified in the first report. The com- mittee considers that the indicators remain appropriate for evaluating progress. However, in certain cases (as noted), it has clarified the wording or modified the order of the indicators. Boxes 3-1 and 3-2 summarize the indicators, including the committee’s assessment of progress—green, yellow, or red. The following text identifies the indicators, discusses progress, and presents the rationale for selection of a particular assessment. BOX 3-1 Status of Indicators of Research Progress1 Adaptive Research and Knowledge for Accelerating Research Progress and Providing Rapid Feedback to Advance the Research  Extent of development of libraries of well-characterized nanomaterials, including those prevalent in commerce and reference and standard materials  Development of methods for detecting, characterizing, tracking, and monitoring nanomaterials and their transformations in simple, well-characterized media  Development of methods to quantify effects of nanomaterials in experimental systems  Extent of joining of existing databases, including development of common informatics ontologies  Advancement of systems for sharing the results of research and fostering development of predictive models of nanomaterial behaviors Quantifying and Characterizing the Origins of Nanomaterial Releases  Developing inventories of current and near-term production of nanomaterials  Developing inventories of intended uses of nanomaterials and value-chain transfers  Identifying critical release points along the value chain  Identifying critical populations or systems exposed  Characterizing released materials in complex environments  Modeling nanomaterial releases along the value chain (Continued) 1 The wording and ordering of some indicators have been modified from NRC (2012, pp. 181-182). Details of the modifications are noted in the descriptions of the indicators in this chapter.

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Assessment of Progress 43 BOX 3-1 Continued Processes That Affect Both Exposure and Hazard  Steps taken toward development of a knowledge infrastructure able to describe the diversity and dynamics of nanomaterials and their transformations in complex biologic and environmental media  Progress in developing instrumentation to measure key nanomaterial properties and changes in them in complex biologic and environmental media  Initiation of interdisciplinary research that can relate native nanomaterial structures to transformations that occur in organisms and as a result of biologic processes  Extent of use of experimental research results in initial models for predicting nanomaterial behavior in complex biologic and environmental settings Nanomaterial Interactions in Complex Systems Ranging from Subcellular Systems to Ecosystems  Extent of initiation of studies that address the impacts of nanomaterials on a variety of end points in complex systems, such as studies that link in vitro to in vivo observations, that examine effects on important biologic pathways, and that investigate ecosystem effects  Extent of adaptation of existing system-level tools (such as individual species tests, microcosms, and organ-system models) to support studies of nanomaterials in such systems  Development of a set of screening tools that reflect important characteristics or toxicity pathways of the complex systems described above  Steps toward development of models for exposure and potential ecologic effects  Identification of benchmark (positive and negative) and reference materials for use in studies and measurement tools and methods to estimate exposure and dose in complex systems INDICATORS OF RESEARCH PROGRESS Adaptive Research and Knowledge for Accelerating Research Progress and Providing Rapid Feedback to Advance the Research In the committee’s 2012 report (NRC 2012), the first set of research pri- orities involved establishing an adaptive infrastructure for research and knowledge generation to accelerate and advance EHS nanotechnology research. The components of this infrastructure include study and reference materials; nanomaterial libraries; instruments and methods for measuring nanomaterials and their transformations; methods or assays to quantify the effects of nano- materials; databases, ontologies, and tools for sharing research results; and mo-

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44 Research Progress on EHS Aspects of Engineered Nanomaterials dels to uncover relationships among the data. Progress toward those short-term and medium-term research priorities ranged from green for detecting and char- acterizing engineered nanomaterials (ENMs) in relatively well-characterized media to yellow for development of libraries of well-characterized ENMs, de- velopment of methods for quantifying effects of ENMs in experimental systems, and the extent of joining of existing databases, including the elements of an in- formatics infrastructure. It is expected that the integrated components of the infrastructure will need to be continuously improved to adapt to the growing needs of the research enterprise.  Extent of development of libraries of well-characterized nanomaterials, including those prevalent in commerce and reference and standard materials BOX 3-2 Status of Indicators of Progress in Implementation (NRC 2012, p. 183) Enhancing Interagency Coordination  Progress toward establishing a mechanism to ensure sufficient management and budgetary authority to develop and implement an EHS research strategy among NNI agencies  Extent to which the NNCO is annually identifying funding needs for interagency collaboration on critical high-priority research Providing for Stakeholder Engagement in the Research Strategy  Progress toward actively engaging diverse stakeholders in a continuing manner in all aspects of strategy development, implementation, and revision Conducting and Communicating the Results of Research Funded Through Public–Private Partnerships  Progress toward establishment of effective public-private partnerships, as measured by such steps as completion of partnership agreements, issuance of requests for proposal, and establishment of a sound governance structure Managing Potential Conflicts of Interest  Progress toward achieving a clear separation in management and budgetary authority and accountability between the functions of developing and promoting applications of nanotechnology and understanding and assessing its potential health and environmental implications  Continued separate tracking and reporting of EHS research activities and funding distinct from those for other, more basic or application-oriented research

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Assessment of Progress 45 The committee’s first report emphasized that libraries of well-characterized nanomaterials were needed to accelerate EHS nanotechnology research and that the libraries should include nanomaterials that meet the evolving needs of the re- search community. There has been progress in developing specific nanomaterials that have been appropriately characterized for nanotechnology EHS studies, in- cluding gold, silver, and carbon standards developed by the National Institute of Standards and Technology (NIST 2013a), Organisation for Economic Co- operation and Development reference materials characterized by the National In- stitutes of Health (NIH) Nanotechnology Characterization Laboratory (NCL) for the National Institute of Environmental Health Sciences Nanotechnology Consor- tium (AZoNano.com 2010), and materials developed in individual research groups and centers. Some of those materials are now available through commercial chan- nels (NanoComposix 2012). However, the composition, structure, properties, im- purities, and contaminants of a nanomaterial sample depend on the production, refinement, separation, and purification processes used to make them and can ex- hibit substantial lot-to-lot variation. In addition, the sample-preparation techniques used for different characterization methods are generally not well documented or reported. For example, the NCL reports (McNeil 2012) that up to 40% of samples submitted to it for characterization were contaminated with endotoxin even though they had been vetted for possible use in therapeutics. It will continue to be difficult to correlate published research results with nanomaterial types unless more detail is provided in publications or documentation of datasets regarding the manufactur- ing process, lot number, and sample-preparation and characterization methods used. For the last few years, it has been recognized that nanomaterials for EHS re- search need to be well characterized in the media in which they are used (Richman and Hutchison 2009; von der Kammer et al. 2012; Pettit and Lead 2013). Alt- hough there has been progress in that respect (for example, use of the same well- characterized materials in various studies to allow comparison of results), there still are no recommended standard materials for characterization. Nanomaterials produced for fundamental or applied research are rarely characterized adequately for EHS research. Therefore, new nanomaterials that are produced and developed for applied research typically cannot be used more broadly for EHS research, be- cause of the different types of characterization needed, which depend on the in- tended uses. With respect to developing materials libraries to support nanotechnology EHS research, the committee concludes that much work is needed. There has been an emphasis on nanomaterials that have been documented to be most prev- alent in commerce—including nanosilver, carbon nanotubes (CNTs), and zinc oxide (ZnO) (OECD 2008; PEN 2013)—although a recent survey of the patent literature suggests that there is probably a more diverse set of materials that are being and will be incorporated into products (Leitch et al. 2012). To accelerate research, a larger set of nanomaterials is needed to identify the structural fea- tures responsible for potential biologic and environmental effects. Specifically, ENMs should be selected to address hypotheses regarding the influences of in-

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46 Research Progress on EHS Aspects of Engineered Nanomaterials dividual structural parameters (for example, surface coating, surface functionali- ty, ion release rates from core material, core sizes, and material purity). Thus far, there has been little progress in producing structurally analogous sets (or librar- ies) of well-characterized nanomaterials (Harper et al. 2011). As a result, it is not possible to conduct systematic studies of families of structurally related na- nomaterials to determine how structure influences effects. Not surprisingly, the structural diversity of the materials that have been produced does not yet support the needed breadth of nanotechnology EHS studies. Thus, although there has been some progress in producing and characteriz- ing new nanomaterials to support EHS research, there are large gaps, and pro- gress toward this goal is categorized as yellow.  Development of methods for detecting, characterizing, tracking, and monitoring nanomaterials and their transformations in simple, well-characterized media In its first report, the committee gave high priority to research that pro- motes development of critical supporting tools, including methods of character- izing how the properties of ENMs affect their interactions with humans and the environment (NRC 2012). Those capabilities need to be developed in the short term and ramped up to become sustainable in the longer term. In simple and relatively well-characterized media (such as deionized water and physiologic buffer with known composition), substantial progress has been made in develop- ing analytic tools and methods for detecting and characterizing nanomaterials. (Detection and characterization of ENMs in more complex environmental media are discussed later in this chapter.) Several agencies—including NIST, the US Army Corps of Engineers Engineer Research and Development Center, and the NCL—have active research programs in place that are aimed at developing and validating the tools (NSET 2012a). Some components of activities in two re- search centers funded by the Environmental Protection Agency (EPA) and the National Science Foundation (NSF) are aimed at developing and validating ENM detection and characterization methods; in most cases, these are applica- tions of, or adaptations of, existing tools, including x-ray spectroscopy (Ma et al. 2012; Lawrence et al. 2012), spectrometry (Mitrano et al. 2012), and optical methods (Fatisson et al. 2012). Some new methods are being developed to measure important ENM properties, such as surface hydrophobicity of nanopar- ticles (Xiao and Wiesner 2012) and chirality of single-walled CNTs (Khan et al. 2013). In addition, the nanotechnology EHS research community now recogniz- es the dynamic nature of nanomaterials and the need to characterize nanomateri- al transformations and the transformed materials (Levard et al. 2012; Liu et al. 2012; Lowry et al. 2012a; Nowack et al. 2012). The committee classifies this indicator as green because of the number of programs initiated or under way in various agencies and the progress evident in the peer-reviewed literature (as described above). However, characterization

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Assessment of Progress 47 efforts are generally (not exclusively) limited to studies in well-controlled model media, and more work is needed to extend understanding to more complex sys- tems (discussed later in this chapter). Some ENM properties are still difficult to measure, such as the properties of adsorbed macromolecules and the structure of the outer surface layers of nanomaterials. Techniques for routine monitoring of nanomaterials in environmental media (for example, wastewater treatment-plant effluent) are not available (as discussed later). Finally, although there are many data on ENM characteristics and likely transformations, cross-validation and synthesis of the data to provide knowledge about ENM properties and the envi- ronmental properties that lead to the transformations have not occurred.  Development of methods to quantify effects of nanomaterials in experi- mental systems The committee’s first report identified the need for standardized methods for assessing environmental effects of nanomaterials in the environment and the need for markers for assessing toxicity. It also identified a lack of information on effects, especially ecosystem effects, of longer-term nanomaterial exposures of organisms and human populations. Studies have been published on the poten- tial effects of acute nanomaterial exposures of various organisms in aquatic and terrestrial environments. However, it is difficult to integrate the data to develop the information needed to predict the effects of ENMs, because of the lack of standardized assays, the variety of ENMs, the variety of organisms and experi- mental conditions used, and the fact that many studies have examined primarily acute mortality outcomes. More toxicity information on a greater variety of na- nomaterials is needed so that different ENM properties and different end points can be examined. Standardization of assays and development of reference mate- rials for positive and negative controls are also needed to ensure that the data gathered for toxicity assays are comparable and useful. The EPA, the Food and Drug Administration (FDA), and the National In- stitute for Occupational Safety and Health (NIOSH) have not identified assays targeted at specific outcomes to assess nanotoxicity. There is a need to standard- ize toxicity assays, both in vitro and in vivo, to reduce variability within and between laboratories and to improve consistency of results among different la- boratories. For example, a round-robin in vitro study involving 10 laboratories in the United States and Europe to characterize nanoparticles before toxicity testing revealed that although there was improved reproducibility between la- boratories because of adherence to strict protocols for shipping, measurement, and reporting, measurements of polydisperse suspensions of nanoparticle aggre- gates or agglomerates were not reproducible (Roebben et al. 2011). The use of ultrasonication increased variability among polydisperse suspensions. With re- spect to quantifying effects of nanomaterials in vivo, a 2013 round-robin study (Bonner et al. 2013) by four laboratories in the United States investigating pul- monary responses in mice and rats to three forms of nano-titanium dioxide

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48 Research Progress on EHS Aspects of Engineered Nanomaterials (nano-TiO2) and three forms of multiwalled CNTs (MWCNTs) showed some interlaboratory variability of the inflammatory response to TiO2, but the relative potency of the MWCNTs was similar among all laboratories. Although some agencies, such as NIST, are evaluating different protocols (NIST 2013b), the need for standard operating procedures has not been fully met. Establishing such procedures for all phases of ENM preparation and toxicity testing is required to increase consistency of results among laboratories. Several studies have identified acute ecotoxic effects of ENM exposures and issues associated with traditional nanotoxicity assays (see Klaine et al. 2008 and above references for review). However, there is little information on effects on ecologically relevant species or on ecosystem-level effects of the chronic low-dose exposures to ENMs that are expected in the environment (Bernhardt et al. 2010; Gottschalk and Nowack 2011). Investigations of perturbations in whole-organism systems are also lacking. Efforts have concentrated on oxida- tive stress, which may be a fleeting reaction of an organism to ENM exposures and may not be the sole mechanism of effects. The committee’s 2012 report called for targeted assays for assessing nanotoxicity. Efforts to assess toxicity by using high-throughput assays at the EPA–NSF funded centers (Lin et al. 2013; Nel et al. 2013) may provide some standard acute-toxicity information on se- lected nanomaterials. The relevance of those assays to more realistic chronic low-dose exposures and population-level effects has not been established. The committee specifically suggested development of a standard battery of assays and novel assays that may be required to describe the various effects of many types of nanomaterials, including ones that have new biologic activities. Stand- ardized assays for ecosystem effects of even standard chemicals are lacking. The EPA–NSF funded centers may be an indication of support for those types of assays, but this is the only direct support identified for this topic. The committee considered that there was some research progress in this category, but the progress was marked yellow because of the lack of identifica- tion of a set of methods to determine effects. More information on the variety of potential mechanisms and research that elucidates these mechanisms will move this indicator toward green.  Extent of joining of existing databases, including development of com- mon informatics ontologies Some progress has been made toward the development of informatics on- tologies and sharing of databases. For example, the Big Data Initiative was an- nounced in March 2012 “to greatly improve the tools and techniques needed to access, organize, and glean discoveries from huge volumes of digital data” with support from NSF, NIH, the Department of Energy (DOE), the Department of Defense (DOD), the Defense Advanced Research Projects Agency, and the US Geological Survey (OSTP 2012). The new program defines data as including data, publications, samples, physical collections, software, and models (NSF

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Assessment of Progress 49 2010). The same comprehensive definition underpins the new NSF Nanotech- nology Signature Initiative for a Nanotechnology Knowledge Infrastructure (NKI) with participation by the Consumer Product Safety Commission (CPSC), DOD, DOE, EPA, FDA, the National Aeronautics and Space Administration, NIH, NIOSH, NIST, NSF, and the Occupational Safety and Health Administra- tion (OSHA). In addition, the NKI will support the new Materials Genome Initi- ative (MGI) (NSET 2012b) so that informatics approaches, data curation work- flows, protocols, and standards developed through MGI activities may initially be explored for nanoscale activities by the NKI effort. Coordination of activities in the United States and the EU has been estab- lished through the Communities of Research (CoRs) by the National Nanotech- nology Coordination Office (NNCO) and the EU. The CoRs include “predictive modeling for human health, ecotoxicity testing and predictive models, exposure through the life cycle, databases and ontology, risk assessment, and risk man- agement and control” (Finnish Institute of Occupational Health 2012). The on- tology CoR is responsible for coordinating informatics needs for all the CoRs, and its databases provide a mechanism for developing prototype systems and applications to support information-sharing, annotation, validation, and curation for experimental, computational, and theoretical efforts in nanotechnology. The EU–US CoRs represent an important opportunity for international collaboration to develop an infrastructure that can serve both communities. Although those new programs are promising, progress in developing ele- ments of an informatics infrastructure has been less encouraging. The foregoing examples show the need for libraries of nanomaterials; for improved reporting on nanomaterial production processes and sample-preparation techniques; for new methods for characterizing, tracking, and monitoring nanomaterials and their transformations; for methods for quantifying the effects of nanomaterials; and for systems for sharing research results and the development of predictive models for nanomaterial behaviors. Core systems, services, and applications are not yet available or have been insufficiently adopted, and this gap impedes re- search and the translation of research findings into products. For example, a harmonized nomenclature system that facilitates and informs nanomaterial clas- sification and development does not exist; data and metadata standards are not established; reproducibility of methods (ruggedness testing) has not been estab- lished; and the sensitivity data are not shared and therefore cannot be used to improve the reproducibility of methods or to inform error propagation in risk analyses. The same general limitations are present for model development: fur- nishing accurate nanomaterial and nanoproduct structural models on the appro- priate scales; developing and validating the models and their sensitivity to input parameters, computer programs, the choice of run-time parameters, computer architectures, and compilers at the relevant dimensions and time scales; and ac- cessing and validating models for the physical, chemical, and biologic systems of interest, also at the appropriate dimensions and time scales. In that regard, NanoHUB constitutes a substantial and important start, providing a stable code for different users and assuming the burden of hosting the code; providing com-

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50 Research Progress on EHS Aspects of Engineered Nanomaterials puters, storage, and user services; archiving and sharing data, metadata, and in- formation about results; and comparison with related model results. Finally, there is an overarching need for informatics to augment collabora- tion and accelerate research and translation by facilitating access to data. Exam- ples of the need for informatics include the accelerated adoption of models through NanoHUB and the increased amount of interlaboratory testing of meth- ods by various organizations (NIEHS 2012; ILSI 2013a). There are abundant examples of data that are not available through the publication process and that in many cases are not accessible on any database—such as sensitivity data on methods and validation data on models—but there are several areas of particular interest and activity. For example, high-throughput methods are increasingly used in nanotechnology-EHS research, and applications from EPA–NSF funded centers (Thomas et al. 2011; Mandrell et al. 2012) promise to generate large, correlated datasets obtained with standardized screening methods. ISA-TAB- Nano2, a new standard for data exchange, is emerging; its harmonized data for- mats incorporate high-throughput screening assays and methods for nanomateri- al characterization. Metadata capture will be possible through the NanoParticle Ontology (NPO) that builds on NIH’s Enterprise Vocabulary System. However, most important are the increasing informatics efforts (mentioned above) that promise new support and substantially increased collaboration—the NKI, col- laboration with the MGI, and the other NNI signature initiatives, particularly the EU-US CoRs. Those developments collectively signal heightened interest in increasing data quality throughout nanotechnology and nanoscience and height- ened activity in establishing a coherent infrastructure for increased collaborative research among all the disciplines. Additional data inputs are possible if databases are compiled from other studies. One potential mechanism, as mentioned in the committee’s first report, is NSF’s requirement that all grant proposals include a two-page plan for how data will be managed and shared publicly. However, modifications of that re- quirement through creation of a data commons could allow the collection of all nanotoxicity data from NSF-funded studies rather than siloed storage and re- trieval sites established by each researcher. On the basis of the still unmet need for more data-integration mechanisms, the committee has characterized this indicator as yellow.  Advancement of systems for sharing the results of research and foster- ing development of predictive models of nanomaterial behaviors 2 This format is an extension of the Investigation-Study-Assay (ISA) Tabular formats used for genomics and high-throughput screening (for example, MAGE-TAB) and adds a material file to permit transmission, linkage, and provenance of data on the nanomaterial samples being studied. This publication represents an initial step to providing one aspect of the needed infrastructure for sharing research data, and it is not yet clear how it will be received by the research community.

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Assessment of Progress 51 In its first report, the committee identified the need to develop predictive models for ENM behaviors and risk. However, the development of models can- not occur in isolation from data generation. Coordination is needed in the short term to ensure that experimental, modeling, and informatics efforts contribute to a coordinated, functional infrastructure. There is a need to collect, store, archive, and share data related to assessing the potential effects of ENMs (as described in the previous section) so that these data can be used to develop predictive models of ENM behavior. The goals of advancing systems for sharing and developing models of behavior are intimately related in that the models and data structures are both influenced by the specific questions related to exposure to ENMs and the resulting effects that need to be addressed. Therefore, the needs for models and infrastructure to support the models are assessed together. There has been some progress in development of models to predict nano- material exposures and toxicity (Gottschalk et al. 2011; Nel et al. 2013). Several government agencies have instituted specific programs to develop and test dif- ferent models to assess ENM behavior (for example, fate in the environment, releases from consumer products, plant uptake, and occupational exposure), including EPA, NIST, FDA, DOD, the US Department of Agriculture, and NIOSH (NSET 2012a). Efforts are also in place to develop computational mod- els for toxicity (for example, EPA’s ToxCast program). Finally, there has been progress towards the development of empirical predictive models as opposed to fully mechanistic models for behavior (Hou et al. 2013; Westerhoff and Nowack 2013). These models rely on empirical correlations (for example, partition coef- ficients) rather than complete mechanisms. The models can be developed in less time than fully mechanistic models, and can predict approximate behaviors (for example, in a wastewater treatment plant) and may be used to support regulatory decisions. The committee classifies progress in this category as yellow because, de- spite the development and use of the models in the nanotechnology-EHS com- munity, there is not yet a central repository for sharing the models (although NanoHub may be appropriate), and many needed models have not yet been de- veloped, such as models to predict the structure of ENM surfaces in various en- vironments. Most important, there is a paucity of data for calibrating and vali- dating models that have been developed; for example, there are very few data on ENM concentrations and speciation in environmental and biologic media that can be used to calibrate fate and transport or biodistribution models. The ab- sence of metadata and validation data for most models hampers their broad ac- ceptance and use because they are not deemed reliable and accurate. Some progress is being made in the collection, storage, and archiving of ENM physical and chemical properties. For example, the Nanomaterials Regis- try (NR) has been developed by the Research Triangle Institute with funding from NIH (Nanomaterialregistry 2013). The NR will provide a curated reposito- ry of ENM information (for example, ENM properties) from a wide array of studies that used the materials. The repository would allow researchers to com- pare model results for behaviors and effects of ENMs by using data on the na-

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72 Research Progress on EHS Aspects of Engineered Nanomaterials public and private entities, insufficient funding commitments from both gov- ernment and industry, and confidentiality concerns. In Chapter 4, the committee provides recommendations and examples of best practices to alleviate those road blocks. Managing Potential Conflicts of Interest In its first report, the committee noted that the NNI’s dual functions— developing and promoting nanotechnology and its applications and mitigating risks arising from such applications—pose tensions or even actual conflicts be- tween its goals. Manifestations of the tension previously noted by the committee included the vastly disparate allocation of resources between the two functions, the inadequacy of EHS risk research funding, and the NNI’s classification of research projects with respect to their “EHS relevance”. The committee believes that the tension can also affect the extramural research community, especially EHS risk researchers in large centers, the bulk of whose research funding is fo- cused on applications. To address what it saw as an inherent conflict, the com- mittee concluded that a clear separation in the management and budgetary au- thority and accountability between the functions was needed, and it identified two indicators for tracking progress in managing conflicts of interest. That con- clusion echoed that of a previous National Research Council report (2009), which noted that “a clear separation of accountability for development of appli- cations and assessment of potential implication of nanotechnology would help ensure that the public health implications has appropriate priority” (NRC 2009, p. 11).  Progress toward achieving a clear separation in management and budgetary authority and accountability between the functions of developing and promoting applications of nanotechnology and understanding and assessing its potential health and environmental implications The committee sees little progress in establishing clear and discernibly separate management and budgetary structure between the two potentially con- flicting functions in the NNI itself or the agencies that pursue or fund research on both applications and EHS risk implications of engineered nanomaterials. Therefore, this indicator is red. Both functions continue to operate under the same management and budget structures in the NNI and in its member agencies. In its first report, the committee noted possible models and mechanisms that could be used to separate accountability for the NNI’s dual functions, for exam- ple, elevating oversight of the EHS research portfolio in OSTP (NRC 2012; pp. 166–169), assigning responsibility and comparable authority for the two func- tions to different offices or to senior staff members in individual agencies or in the NNI itself (NRC 2012; pp.167, 173–174), or separating the two functions into independent entities—a model used elsewhere to address potentially con- flicting issues related to nuclear power (p. 174). The committee acknowledges

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Assessment of Progress 73 that in the absence of a change in its statutory mandate, the NNI would be hard- pressed to establish wholly separate management and budgetary structures and authorities for its dual functions. In the absence of such a change, the committee encourages the NNI and participating agencies to consider other approaches for managing perceived or actual conflicts of interest and biases. If not adequately addressed, such perceptions could undermine public trust and confidence in the research, technology, and government processes that are meant to ensure the health, and safety of ENMs.  Continued separate tracking and reporting of EHS research activities and funding distinct from those for other, more basic or application-oriented research The NNI has made considerable progress on this issue, commencing be- fore the committee issued its first report. That progress constitutes an impressive step toward creating the transparency noted above. The Office of Management and Budget (OMB) call to NNI agencies for detailed information on FY 2009 EHS research project funding facilitated easier identification of research projects most directly relevant to EHS risk. That data call helped to inform the NNI’s Environmental, Health, and Safety Research Strategy (NSET 2011). The NNI supplement to the president’s 2013 budget (NSET 2012a) also provides narra- tive information on agency-specific EHS research activities and projects. Despite the impressive progress, the tracking of EHS research progress and performance between and within NNI agencies remains challenging. As noted by GAO in its May 2012 report, performance information— such as out- comes, outputs, quality, timeliness, customer satisfaction, and efficiency—can inform such critical management decisions as priority-setting and resource allo- cation. Without project-specific information, researchers and other stakeholders have only a vague understanding of the research questions, methods, materials, and study populations being addressed through the NNI. Although periodic OMB data calls for EHS research project funding are helpful and could be made even more helpful if they included clearer guidance on how agencies should differentiate research directly relevant to EHS risk from applications research with EHS implications, they cannot address the need for a continuing (ideally annual) system for identifying and tracking EHS research projects and their per- formance. REFERENCES Aitken, R.J., S.M. Hankin, C.L. Tran, K. Donaldson, V. Stone, P. Cumpson, J. Johnstone, Q. Chaudhry, S. Cash, and J. Garrod. 2008. A multidisciplinary approach to the identification of reference materials for engineered nanoparticle toxicology. Nan- toxicology 2(2):71-78.

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