Research Progress on Environmental, Health, and Safety Aspects of Engineered Nanomaterials (2013)

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4 Getting to Green INTRODUCTION The research enterprise that is investigating potential risks to human health and ecosystems posed by engineered nanomaterials (ENMs) engages a broad and multidisciplinary array of stakeholders, including researchers, the industrial sector, and the public at large. The success of research in this domain, as in oth- ers, depends on identifying—through stakeholder engagement—the most critical questions that need to be addressed; networking in the United States and interna- tionally among investigators in government, academe, and industry; developing standards for analyses and reference materials; using uniform terminology and data descriptions; capturing data in an accessible, quality-assured database; and continuing to refine research methods. Figure 4-1 represents the committee’s construct for a successful research enterprise in the potential environmental, health, and safety (EHS) risks posed by ENMs. The figure describes the interre- lated and interdependent research activities that are driven by the evolving pro- duction of ENMs. A critical output is an evaluation of risk that informs decision- making on ENMs. The diagram is aspirational, offering a vision for an integrat- ed and strategic system for developing data that will provide for the characteri- zation of ENMs, refinement of experimental methods, and support for model development to predict and then prevent and manage risks associated with new ENMs. Many of the elements are already in place, but such an overall frame- work has not yet been articulated. The committee considers that the develop- ment and integration of the elements of such a framework are essential for ad- vancing the progress necessary to “get to green” on the committee’s identified research priorities. Similar frameworks have been articulated for other research endeavors; for example, a recent report on “precision medicine” by the National Research Council provided a theoretical framework for translating advances in biomedical research into clinical practice (NRC 2011; Figure 3-1). 83 

84 Research Progress on EHS Aspects of Engineered Nanomaterials INVENTORIES MATERIALS REFERENCE ENM RELEASES LABORATORY KNOWLEDGE REAL  WORLD COMMONS WORLD VALIDATION SCREENING TOOLS METHODS/INSTRUMENTS MODELS METHODS/INSTRUMENTS RISK DECISION MAKING FIGURE 4-1 Nanotechnology environmental, health, and safety research enterprise. The diagram shows the integrated and interdependent research activities that are driven by the production of ENMs. The production of ENMs is captured by the orange oval, labeled “materials”, which includes reference materials, ENM releases, and inventories. (An inventory is a quantitative estimate of the location and amounts of nanomaterials pro- duced or current production capacity, including the properties of the nanomaterial.) The knowledge commons (red box) is the locus for collaborative development of methods, models, and materials, and for archiving and sharing data. The “laboratory world” and “real world” (green boxes) feed into the knowledge commons. The laboratory world comprises process-based and mechanism-based research that is directed at understanding the physical, chemical, and biologic properties or processes that are most critical for as- sessing exposures and hazards and hence risk (NRC 2012, p. 55). The “real world” in- cludes complex systems research involving observational studies that examine the effects of ENMs on people and ecosystems. The purple boxes capture the range of methods, tools, models, and instruments that support generation of research in the laboratory world, the real world, and the knowledge commons. Of necessity, Figure 4-1 provides a simplified vision of a complex system of knowledge creation and use, but each of its elements is critical. The system places research into two broad domains: “laboratory world”, process-based or mechanism-based research directed at the “critical elements of nanomaterial interactions” (a central component of the committee’s conceptual framework; see Chapter 1); and “real world”, systems research involving observational stud- ies that examine the effects of ENMs on complex experimental models of hu- man health and ecosystems. The research is supported by the availability of ma- terials (reference materials, materials from inventories developed with industry input, and materials released and modified through their value chain and life 

Getting to Green 85 cycle), analytic methods and instrumentation, and a “knowledge commons”, which is central to this schema. The knowledge commons incorporates a stand- ard nomenclature, data classifications, and storage of data with sufficient detail to facilitate informed modeling. The success of the research enterprise requires that all researchers place their data (in a compatible form) in a data-management commons that is supported by appropriate hardware and software. “Models” of many types are inherent in Figure 4-1. For example, some models will be used to estimate exposures of human populations and ecosystems to ENMs across their value chains and life cycles. Predictive models need to be developed to anticipate risks posed by ENMs. Such models require validation, which will be facilitated by an iterative process that involves data access through the knowledge commons. “Screening tools” will be needed to generate data that can be used to establish priorities for knowledge creation that in turn can be used to formulate models to predict risks posed by new ENMs. Such knowledge gen- eration will be developed in an iterative fashion that draws on research results from mechanistic and complex systems of research. Figure 4-1 shows the relationship between the research activities and risk, which in turn inform a broad range of decision-making by diverse stakeholders, including regulators, manufacturers, and the public. Models provide the bridge from research findings to risk estimation and characterization of uncertainty. The estimation of risk is iterative. The overall research process provides feed- back to materials generation with the goal of reducing the potential risk present- ed by ENMs and the products that they enable. Several features of Figure 4-1 merit emphasis. The relationships among its components are dynamic, and there are multiple feedbacks (represented by the arrows) among them. The success of the research enterprise hinges on the crea- tion of a knowledge commons and engagement of the broad community of re- searchers who are addressing potential risks to human health and ecosystems. It also requires stakeholder engagement, particularly of the manufacturing sector, to ensure that the materials studied reflect those in use and that the most critical research questions are addressed. Leadership in its development and stewardship of its maintenance are also essential. In the discussion below, the committee analyzes the findings of Chapter 3 in the context of the flow of activities in the nanotechnology EHS research en- terprise (Figure 4-1), examining pathways to advance research and mechanisms to improve implementation of the enterprise with an eye to “getting to green” on the committee’s indicators (Boxes 3-1 and 3-2). First, research progress is con- sidered, and the steps needed to advance the research are described. The discus- sion is divided into six major subjects as reflected in the research enterprise: nanomaterial processes and mechanisms, material sources and development of reference materials, model development, methods and instrumentation, the knowledge commons, and nanomaterial interactions in complex systems. Then, 

86 Research Progress on EHS Aspects of Engineered Nanomaterials progress on mechanisms to ensure implementation of the research is evaluated, and the steps needed to advance implementation of the research are discussed. FUNDAMENTAL PROCESSES THAT AFFECT NANOMATERIAL EXPOSURE AND HAZARD The committee’s first report identified the need for research on cross- cutting processes that affect both exposure and hazard (see Figure 1-1). The re- search entails identifying fundamental processes, typically through laboratory experiments. A description of the processes is needed to develop general and predictive capabilities to assess risks that move beyond case-by-case evaluations of ENMs. The process-based activities described in Figure 4-1 are enabled by continual development of methods and instrumentation. The experimental ap- proach is updated through understanding of material properties and the evolving physical, chemical, and biologic processes that affect exposure and hazard. Hy- pothesized properties or mechanisms can be scrutinized in well-defined labora- tory experiments and in observations of ENM behavior in complex systems, from in vivo experiments to models of ecosystem interactions in microcosms, mesocosms, and field observations. Boundaries between well-defined laboratory and complex systems may be blurred, but the key contrast is that between a re- ductionist approach to unraveling elements that may affect organisms, popula- tions, and ecosystems and holistic examination of ENMs in complex systems. Both approaches are needed, and they are complementary. Ideally, the agenda for process-based research is influenced in part by findings on the extent to which research reduces uncertainty in the understand- ing of potential risks. Reducing uncertainty requires updating of models to in- crease our understanding of risks to human health and ecosystems, motivated in part by needs of stakeholders (whether workers producing ENMs or consumers of ENM-enabled products). Information generated from process-based research influences how ENMs are produced, including considerations of life-cycle risks and relevant reference materials for conducting studies. Substantial progress (green) has been made in exploring mechanisms that control the dynamics and transformation of ENMs. However, only moderate (yellow) progress has been achieved in development of methods to quantify ef- fects of ENMs in experimental systems; this level of progress may reflect the complex nature of in vivo experiments and the need for model development and verification. The roles of methods and instrumentation in understanding mecha- nisms of ENM transformations, distribution, and effects highlight the state of progress in developing methods for ENM characterization and detection in rele- vant media; and this indicator has been noted as green. That stands in strong contrast with the relatively limited progress made in translating methods to read- ily available instrumentation for characterizing ENM properties and their trans- formations; this indicator was denoted as red, and the lack of progress represents a key impediment to advancing understanding of processes and mechanisms. 

Getting to Green 87 Steps to Ensure Progress Toward Elucidating Mechanisms Continued, vigorous activity to elucidate mechanisms of ENM interactions with organisms and ecosystems is critical for reaching the long-term goal of predicting ENM effects. The ability to make such predictions will allow evalua- tion of risks posed by ENMs at the design stage, in model predictions, and in validated screening assays. The interdependences described in Figure 4-1 and the state of research progress indicated in Box 3-1 imply that continued progress in understanding mechanisms of ENM behavior will require advances in instru- ment development and increased availability of up-to-date instrumentation to researchers. Another key impediment to progress is the relative lack of a data- integration infrastructure and of validated models that reflect field-tested theo- ries. NANOMATERIAL SOURCES AND DEVELOPMENT OF REFERENCE MATERIALS The committee’s nanotechnology EHS research strategy is driven by the need to assess potential risks associated with the accelerating production of new ENMs and materials that are present in an increasing number of products. As shown in Figure 4-1, ENMs are the central element of nanotechnology-related research studies in the knowledge commons, the laboratory world (mechanism- driven research), and the real world (investigations in complex systems). Three primary types of ENMs (shown in the figure) are the focus of these studies: ref- erence materials, nanomaterial-enabled products (inventories), and released na- noscale species (ENM releases). Reference materials were described in the committee’s first report and include individual ENMs and libraries of ENMs that are used to conduct targeted studies to answer EHS-research questions. Na- nomaterial-enabled products are ENMs found in the inventory of substances being incorporated into commercial products. ENM releases are materials that come from products that may be transformed as they are released. The need for appropriately designed and adequately characterized ENMs was highlighted in the first report (NRC 2012, pp. 181-182). That report called for Developing nanomaterials and libraries:  Extent of development of libraries of well-characterized nanomaterials, including those prevalent in commerce and reference and standard materials. Providing feedback to inform the design of appropriate nanomaterials: 

88 Research Progress on EHS Aspects of Engineered Nanomaterials  Development of inventories of current and near-term production of na- nomaterials.  Development of inventories of intended use of nanomaterials and val- ue-chain transfers.  Identification of critical release points along the value chain.  Identification of benchmark (positive and negative) and reference mate- rials, for use in such studies and measurement tools and methods to estimate exposure and dose in those complex systems.  In addition to those direct calls for action, the need for nanomaterials to support other research priorities was implicit as described elsewhere in this chapter. Appropriate ENMs are needed to carry out research that will generate data needed to populate the knowledge commons, to develop new methods and instruments, to conduct mechanistic studies, and to perform investigations in complex media.  Research to characterize ENM production and releases along the value chain was generally considered to show moderate progress (yellow). However, very little progress was considered to have occurred in modeling releases along the value chain (denoted as red). Moreover, the lack of a systematic process for collecting information on the production of ENMs and the lack of a process for providing feedback from the research enterprise to improve the sustainability of ENMs together limit the pace of the entire research enterprise.  As discussed in Chapter 3, progress in developing ENMs for study was evaluated as some to little (rated either yellow or red). In particular, little to no progress was considered to have occurred in developing benchmark (for positive and negative controls) and reference materials for metrology. The nanotechnol- ogy EHS-research enterprise has mostly relied on commonly available nanopar- ticles to conduct most studies. These particles, typically produced to evaluate their use in specific applications or produced as commercially available research samples, are largely categorized by core material. The vast majority of the stud- ies have been conducted on a relatively small number of core species, including carbon nanomaterials (tubes, fullerenes, and graphene), metals (primarily silver and gold), metal oxides (primarily zinc oxide, titanium dioxide, cerium oxide), and polymeric materials. There is no process to determine which nanomaterials should have high priority for development on the basis of the needs for mecha- nistic studies or investigations of materials in complex systems. To move high- priority research toward green, additional effort and coordination are required to develop appropriate nanomaterial libraries. Similarly, the lack of a systematic process for collecting information needed to create a picture of nanomaterial production along the value chain limits the pace of research required to conduct risk evaluations and the feedback needed to improve nanomaterial properties from EHS and sustainability perspectives. 

Getting to Green 89 Steps to Ensure Progress Toward Providing Reference Materials The lack of availability of ENMs for research and the limits of our knowledge of commercial ENM production quantities and formats create a criti- cal-path challenge in advancing nanotechnology EHS research. Important ele- ments for advancing the development and distribution of reference nanomateri- als for research and analytic purposes include  A mechanism to identify and set priorities among nanomaterials and li- braries for development. Developing precisely defined and characterized refer- ence materials is expensive and time-consuming. Sustainable approaches are needed to set priorities among materials for development and distribution to researchers.  Material descriptors and other nomenclature to distinguish properly between different nanomaterial samples. Appropriate and standardized material descriptors need to be adopted and used. Without such descriptors, the specifici- ty or precision with which nanomaterials are designed, developed, and shared will not be sufficient, particularly for developing the knowledge commons. This is one aspect of the ontology that needs to be developed for ENMs.  Improved synthesis and purification methods. Once nanomaterials are identified for research purposes, the synthesis and purification methods to pro- duce them may need to be developed. Although some methods have been devel- oped for synthesis of specific classes of nanomaterials, new methods need to be developed for other nanomaterials that have been identified for development.  Collaborations among scientists who are studying mechanisms and complex systems so that materials for these studies can be optimized. The pro- duction of a reference material or library is only the beginning of its develop- ment. Reference nanomaterials require further optimization through collabora- tion among material developers and users (for example, to optimize handling protocols or for in situ monitoring of the nanomaterials).  Instrumentation for rapid characterization of reference materials. Alt- hough there has been progress in developing instrumentation and protocols for characterization of pristine, synthesized nanoparticles in the laboratory, new methods and approaches are needed to accelerate routine characterization. For example, laboratory-scale, small-angle x-ray scattering can be used to reduce the number of artifacts during analysis and reduce the time for characterization from hours (or days) to minutes relative to transmission electron microscopy.  Instrumentation to characterize complex nanoscale species (that is, ma- terials of unknown origin, mixtures, and released materials). Each of these ma- terial classes presents challenges to characterizing their structure, composition, and purity—substantial barriers to studying their effects on health and the envi- ronment. Those barriers reflect the lack of information on the starting composi- tion and structure of the materials and the lack of knowledge of their history. 

90 Research Progress on EHS Aspects of Engineered Nanomaterials  Mechanisms and incentives for collecting information. Information management plans and appropriate research infrastructure are needed to create a process for collecting information on nanomaterial production and uses along the value chain. Steps to Ensure Progress Toward Characterizing Commercial Sources of Nanomaterials  Greater investment in research at the interface between the physical sciences, social sciences, and business. A full understanding of potential risks along the value chain requires broad and multidisciplinary expertise that will bridge physical and social sciences and engage the commercial sector. The criti- cal topics include trends in nanomaterial production, value-chain analysis, and human behavior in relation to use of products that contain ENMs and the poten- tial for exposures along the value chain and throughout the life cycle. An im- proved understanding of those factors is needed as a starting point for modeling nanomaterial exposure along the value chain. MODEL DEVELOPMENT A key outcome of the integration of data and information contained in the knowledge commons is development of a suite of models. The models allow the application of new methods and instruments that reflect thinking regarding hy- pothesis testing and assessment. Such models may be used to predict physical characteristics of ENMs, outcomes of toxicity testing, and exposure potential in complex systems. In their initial forms, the models represent working assump- tions that are refined with additional data. As confidence in a model increases, validation studies that involve comparisons of model outputs with results from experimental systems that use benchmark or unknown ENMs can be conducted. The process of data integration and model formulation and validation informs risk assessment. Given adequate knowledge, refined and validated models allow prediction of potential hazards associated with exposure to ENMs throughout their life cycle and value chain. Mechanistic models should provide the greatest long-term benefit to the EHS nanotechnology research community with regard to anticipating risks. However identifying the critical elements of nanomaterial-environment and na- nomaterial-biota interactions is a significant undertaking and will take time to develop. There is a near term need to predict behaviors of nanomaterials in rele- vant environmental and biologic matrices. Empirical predictive models that are parameterized appropriately (for example, partition coefficients between nano- materials and bacteria in wastewater treatment plants or approximate dissolution rates and half times in specific media) may be sufficient to approximate behav- iors of ENMs in selected matrices. The forms of these predictive models, their 

Getting to Green 91 parameters, and appropriate assays to measure the values for these parameters in selected environmental and biologic media are still needed (Hou et al. 2013; Westerhoff and Nowack 2013). As described in Chapter 3, several indicators of research progress involve successful model development. They include qualitative and quantitative models to characterize the origins and releases of ENMs into the environment. The abil- ity to address potential releases, transformations, environmental concentrations, and exposures was highlighted previously. Efforts appear to be focused on spe- cific release points and routes of exposures (see examples in Chapter 3); pro- gress in this indicator is considered to be minimal (red in Table 3-1). Progress is hampered by a lack of information on ENMs in the value chain for particular ENM-containing products and a lack of data from experimental studies to in- form modeling efforts on fate and transport in the environment. In another re- search indicator in Chapter 3, progress toward the use of experimental research results in initial modeling efforts for predicting ENM behavior in complex bio- logic and environmental settings was considered minimal (red). Because ENM behavior will be influenced by the characteristics of the material and the proper- ties of the system into which it is released, development of integrated models will be important. Those efforts have been limited by the lack of resources for conducting long-term fate and transport studies in complex environmental sys- tems, such as mesocosms, or in in vivo studies. An additional limitation is the absence of a knowledge commons in which research data from multiple studies can be integrated with other information and model outputs to be used in these complex, initial models. Some individual efforts were identified, but they lack the consistency in approaches and interoperability of data that is needed to sup- port effective model development. The efforts also suffer from a focus on a small number of ENMs, which hinders the development of more widely appli- cable predictive models. Steps to Ensure Progress Toward Validated Models for Nanomaterial Risk Getting to green in the development of predictive models requires substan- tial development of data from mechanistic and complex system studies and characterization of physical properties of a variety of ENMs in different com- plex environments. Initial working models will require iterative development as data emerge. Early outputs of the models can determine future data needs and influence decisions about experimental approaches and instrumentation needs. Data should be collected with consideration of future data integration and mod- eling efforts. Input of the data into a knowledge commons is needed to allow a wide array of investigators to engage in modeling efforts. Validation studies that use families of materials in various complex environments will be required. Models for assessing hazard, exposure, and risk will depend on the data sources, and appropriate information management and integration will help to produce a more coordinated and focused approach for addressing EHS aspects of ENMs. 

92 Research Progress on EHS Aspects of Engineered Nanomaterials METHODS AND INSTRUMENTATION The need for methods and instrumentation to characterize ENMs in rele- vant media is pervasive in the nanotechnology EHS research enterprise. Meth- ods and instrumentation are defined here as the tools required to detect and to characterize ENMs and their properties in relevant media. Toxicity testing and other screening assays are discussed later in this chapter. Not surprisingly, the need for characterization and detection methods is apparent in the four primary cross-cutting research categories identified in the committee’s first report: adap- tive research and knowledge for accelerating research progress and providing rapid feedback, quantifying and characterizing the origins of nanomaterial re- leases, processes affecting hazard and exposure, and nanomaterial interactions in complex systems. Progress in the development and validation of the methods and instrumentation needed for those categories ranged from green to red. That range reflects the different characterization needs and scenarios identified. For example, methods and instrumentation needed to characterize newly manufac- tured ENMs and their important properties (with a few notable exceptions dis- cussed below) in a well-characterized and relatively simple medium (such as deionized water or simple physiologic buffer) are well established. The varia- tions in ENM properties (such as size) measured with different techniques are recognized and can be documented with appropriate methods and metadata. Therefore, progress toward development of methods and instrumentation in well-controlled, simple media is designated green. However, there are fewer reliable methods for characterizing ENMs in in- creasingly complex and less well-characterized media (such as blood and natural waters) because complex nonequilibrium interactions between the ENMs and the components of the medium can lead to measurement artifacts or even pre- clude measurement. For example, measuring the size of ENMs in fluid with light-scattering methods and identifying a specific material with electron mi- croscopy are difficult in the presence of other background particles. Some re- search has been initiated to modify existing techniques (for example, x-ray ab- sorption spectroscopy [Lombi et al. 2012]) or to develop new ones (for example, hyperspectral imaging [Badireddy et al. 2012] and single-particle ICP-MS [Mi- trano et al. 2012]) to address the shortcomings. Thus, the committee designated progress in developing methods and instrumentation as yellow in “quantifying and characterizing nanomaterial releases” (NRC 2012, p. 181) and “processes affecting both hazard and exposure” (p. 149). Progress in those research catego- ries depends on the ability to measure ENM properties in complex media and progress in the development of methods and instrumentation to track, detect, and characterize ENMs in complex environments (such as soil or wastewater in which the origins of ENMs and the composition of the solution are unknown and ENMs are present in very low concentrations) has been particularly poor. New instrumentation for single-particle measurements has also seen little pro- gress, so this indicator was denoted red. 

Getting to Green 93 In summary, there has been progress in adapting existing tools for use in well-defined systems, but considerably less progress has been achieved as the complexity of the medium has increased or in understanding the properties of individual particles. The lack of adequate methods and instrumentation for tracking, and for detection and characterization of ENMs in complex systems hinders research progress in many critical research fields. The inability to isolate single-particles also constrains our ability to determine mechanistically how ENM properties affect their behavior. Steps to Improve Progress in Methods and Instrumentation Development Advancing research requires methods and instrumentation for measuring key properties of ENMs, particularly in complex media. There are several criti- cal needs. First, the average properties of the ENMs in relevant complex biolog- ic and environmental media and in the matrices in which they will be used need to be quantified and characterized. Second, the properties of single particles need to be measured so that specific ENM properties can be associated with observed behavior and effects. Third, there needs to be an ability to track ENMs in complex media and organisms (for example, using isotopic signatures or ra- dio-labeled materials). Fourth, methods to extract ENMs from complex matrices or to perform in-situ measurements are needed. Finally, the methods developed need to be sensitive enough to be operable at the very low concentrations of ENMs expected in the biologic and environmental samples. There are two principal challenges in quantifying and characterizing the average properties of ENMs in complex biologic and environmental matrices: the low concentrations of the ENMs in the matrices and the unknown history of the ENMs before analysis. That is important because ENMs in samples taken from organisms or the environment may undergo transformations that change their properties and make it difficult to quantify and laborious to characterize them with existing methods. Released materials in their environments cannot be characterized without appropriate measurement and characterization methods. Appropriate methods to isolate nanoparticles from complex matrices (such as field-flow fractionation or liquid extractions) and appropriate detectors for measuring chemical composition, speciation, and other relevant properties (such as charge) need to be developed. Spectroscopic methods, such as x-ray absorp- tion spectroscopy and near infared fluorescence spectroscopy, that eliminate the need to isolate ENMs from complex matrices (such as soil and tissue), also need additional development. Spectroscopic methods require greater spatial resolution and sensitivity to characterize and quantify ENMs at low environmental and in vivo concentrations. The ability to monitor the transformations of ENMs direct- ly in a matrix in real time would improve our understanding of the critical pro- cesses that affect ENM behavior. That will probably require instrumentation that has not been and is not being developed. 

94 Research Progress on EHS Aspects of Engineered Nanomaterials Single-particle characterization techniques are needed to determine how specific ENM properties affect their behavior. Most ENMs are polydisperse and have varied properties, such as size, crystal defects, and chemical composition. Exposure to ENMs is typically to a distribution of ENMs with known average properties. Single-particle characterization methods would allow one to isolate how the specific features of an ENM affect its behavior. Such methods as tether- ing ENMs to a transmission electronic microscopy grid can enable tracking be- havior of individual particles. Better spatial resolution of microscopy and spec- troscopy methods will also allow characterization of individual ENMs. A critical research need that cuts across exposure and effects research is the characterization of the properties of adsorbed macromolecules on ENMs, including the structure of the macromolecule and the outer surface layers of the ENMs. That information is needed to describe properties and changes of ENMs in relevant biologic and environmental media. It is also a prerequisite to devel- opment of appropriate models for predicting ENM behavior in complex systems (such as biouptake models) and effects. It is an extremely challenging task, es- pecially in complex media, and will probably require new instrumentation with spatial resolution adequate for focusing on single particles and initial develop- ment in well-characterized systems before application in more complex media. Another important component of this research is the ability to determine critical release points along the value chain and to identify exposed populations. Therefore, characterization in relevant complex matrices requires methods for characterizing ENMs and transformations in the matrix in which the ENMs are used. The matrix may affect the ENM properties that are used to measure pris- tine ENMs (such as fluorescence or absorption at a specific wavelength); there- fore, development of new methods or validation of existing methods is needed to detect and characterize ENMs released from their matrices. It is important that the measured properties and characteristics of trans- formed ENMs be captured in the knowledge commons. That requires an ontolo- gy for describing such properties as the adsorbed macromolecular layer. Placing such data in the knowledge commons will allow the community to share them and to develop and update models for describing the behavior of the ENMs in complex environments. INFORMATICS: THE KNOWLEDGE COMMONS In Figure 4-1, the knowledge commons performs three functions. The first is to broaden participation in the development and validation of predictive mod- els, particularly risk models. To accomplish that, more effective communication is needed among those engaged in reductionist science (the laboratory world) at the left of the figure, those engaged in integrative science (the real world) at the right, and the information on materials at the top of the figure. Model develop- ment via the knowledge commons would be hosted in a collaborative environ- ment with access to both processed and raw experimental data and data from 

Getting to Green 95 other, lower-level computations and simulations. The iterative model validation process would lead to publication of validated models with any run-time param- eters, files, sample data, baseline results, and metadata regarding the range of validity of the model. Such information would help to accelerate the use and improvement of the model. The second function of the knowledge commons is to provide a collabora- tive environment for methods development, including access to the results of ruggedness testing and interlaboratory testing for a method, amplification re- garding sample preparation and additional controls for different ENM types, and comments regarding modifications to improve reproducibility. Additional bene- fits for collaborative methods development include better understanding of the method, its range of validity, available instrumentation, and user facilities sup- porting the method. In addition, the knowledge commons would establish a means to publish, access, and annotate issues regarding analytic methods and their reproducibility. The third function of the knowledge commons is to establish a means of collaboratively designing new ENMs by using models to encapsulate and quan- tify a material’s characteristics and effects and potential risks associated with different manufacturing processes and controls. Because this function would provide useful results for manufacturers, regulators, and users of the materials, additional governance would be required to allow collaboration for precompeti- tive projects and continued use of modeling tools in a secure environment. Although the knowledge commons would provide a new mechanism and environment for collaborative development of methods, models, and materials, many of the core functions have been initiated elsewhere. The Nanomaterial Registry (Nanomaterialregistry 2013) and NanoHUB (NanoHUB.org 2013) are two examples—the registry for sharing and annotating nanomaterial data and the NanoHUB for providing facilities for accessing, running, and annotating mod- els. The underlying strength of the knowledge commons would be in linking these existing capabilities and others in a new environment focused on providing quantitative, reliable estimates of uncertainty for risk estimation and method validation and for establishing a vital missing link between the reductionist and integrative branches of research on the EHS aspects of nanotechnology. New programs, such as NanoRelease (ILSI 2013a) and NanoCharacter (ILSI 2013b), have similar aims, and the knowledge commons would aid in supporting gov- ernment, industry, and academic participation in such programs. Such new initi- atives as the Nanotechnology Knowledge Infrastructure (NSET 2012a; NNI 2013) and the Materials Genome Initiative (MGI) (NSTC 2011; EOP 2012; Warren and Boisvert 2012) could provide additional linkage and informatics expertise in augmenting the knowledge commons for different users and pro- grams. Researchers involved in those initiatives are aware of each other’s goals and progress because there is much overlap in membership, participation in each other’s workshops, occasional briefings, and coordination through the National Nanotechnology Coordination Office (NNCO). However, discussions on an 

96 Research Progress on EHS Aspects of Engineered Nanomaterials overarching framework that would knit their separate resources, capabilities, and objectives into the knowledge commons presented here have not yet taken place. Initiation of a series of pilots to integrate data and knowledge generated from the several activities and other informatics efforts would provide both a core plan- ning group and an initial effort to set appropriate informatics requirements rele- vant to all activities whether private or public. It is important to note that many other activities could provide valuable in- put into establishment of the knowledge commons and the present report is not intended to be comprehensive. Although this report is primarily focused on inte- grating research data, methods, and models relevant to the properties and effects of nanomaterials and nanomaterial-containing products in biologic and envi- ronmental systems, other related fields such as epidemiology and nanomedicine have not been the focus. However, the goals and structure of the knowledge commons are sufficiently broad to accommodate the integration of data, meth- ods, and models used by stakeholders in these related fields. First, the evaluation of both EHS risk and product-design risk involves uncertainty propagation and the documentation and sharing of errors, uncertainties, sensitivities, and expert opinion through the knowledge commons and the informatics systems (see NRC 2012, pp.175-178 and Appendix B). Second, the emphasis on the need for data, method and model validation, curation, and sharing applies to all relevant fields, and reflects similar concerns and goals of other programs (for example, Big Da- ta1 and the MGI) as well as goals of the Network and Information Technology Research and Development (NITRD) program (NITRD 2013a). Third, as dis- cussed in NRC 2012 (pp.175-178), existing nanoinformatics are compatible with National Cancer Institute and National Institutes of Health biomedical systems and applications, and recent progress, such as with the ISA-TAB-Nano data format capability extend that commonality to data exchange nomenclature and formats, including both genomics and clinical studies. Finally, there is evidence of convergence in vision among different informatics activities with examples, including US NanoHUB (NanoHUB.org 2013) and European Union NANOhub (JRC 2013), whose focus and goals overlap substantially, and collaborations involving EU-US CoRs and the NanoSafety Cluster (NanoSafety Cluster 2013). Steps to Improve Progress in Developing the Knowledge Commons Steps that could be taken to improve progress in development of the knowledge commons have been foreshadowed in the preceding pages and in Chapter 4 of the committee’s first report (NRC 2012). The brief summary below broadly outlines the type of coordination that is needed to initiate development of a viable and vibrant knowledge commons that is responsive to the changing needs of the research and translational communities. The common theme under- 1 For additional details see the workshop on Data Sharing and Metadata Curation: Ob- stacles and Strategies (NITRD 2013b). 

Getting to Green 97 lying model, method, and material development is the need to provide data and knowledge to improve the reproducibility of the models, methods, and materials. To achieve reproducibility of models, there must be a means for publish- ing models with their run-time parameters, files, sample data, baseline results, and metadata concerning the range of validity. Virtual collaborative environ- ments associated with each model or model type would allow focused scientific discussion of a particular model, its submodels, and algorithms; comparisons with similar models; and a means of establishing provenance concerning both model development and authorship. During model development (which accesses public data) the collaborative spaces should be open, permitting easy access for annotating and curating model development, the model’s theoretical underpin- nings, numerical methods and algorithms, and model validation. Access may be restricted for a number of reasons, but provision should be made for eventual publication of the model because scientific publication would be a primary mo- tivator for placing it in the knowledge commons and would allow faster model improvement and adoption through an open-development infrastructure. As not- ed above, open development would be particularly suited to risk models in that modeling risk involves uncertainty propagation, whether the uncertainties arise from models, data, or expert opinion. Through use of the models to focus re- sources on reducing the largest uncertainties, the reproducibility of risk esti- mates could be improved systematically. The use of virtual collaborative environments would also be key for meth- ods development, creating a single focus for a method—its documentation and range of validity, accompanying video for adding detail or providing training, current instrumentation and later improvements, links to data obtained from the method and links to data and models derived from the data, annotation on the method and datasets, information on sample preparation and controls for differ- ent ENMs, and metadata and information regarding method curation and prove- nance. The primary advantages of the collaborative environments for analytic methods would be a common focus for all aspects of method development, ro- bustness testing and capture of sensitivity data, interlaboratory testing and data capture, use of reference materials for calibration, suggestions for improvements and extensions, method revision and retesting, and provenance concerning all uses of the data. Standard methods could be developed, validated, adapted, im- proved, and revised on an abbreviated timescale while linkage to all raw, de- rived, and modeled data related to that method, its instrumentation, and sample preparation procedures is provided. Virtual collaborative environments would also accelerate the development of nanomaterials. The collaborative environment could focus on a particular ENM designated by a production lot number; document the production, separa- tion, and purification processes used and any initial characterization of the lot’s properties; and create a data aggregation point for all uses of the particular na- nomaterial, how samples were prepared, what methods were used, and whether the method’s data were associated with any models or modeling efforts. Sample history could also be recorded; this would provide data necessary for both in- 

98 Research Progress on EHS Aspects of Engineered Nanomaterials formal and formal interlaboratory testing of the materials with different meth- ods. As data from different researchers using different methods are accumulated, comparisons can be made with greater validity because there would be a basis for “apple to apple”2 comparisons, given the association among all samples that have common parentage. In addition, informed decisions concerning the struc- ture or distribution of structures of particular ENM samples would be possible, and structural models of the samples could be deposited in a repository, such as the Collaboratory for Structural Nanobiology, for use in developing detailed predictive models of ENM effects in different environments. Collaboration spaces would also support aggregation of data on ENMs from different lots or from similar materials. Analysis of those data would allow correlation of ENM sample structures with their properties and effects and aid in formulating hy- potheses of possible underlying mechanisms. Perhaps the most important effect of the knowledge commons is the crea- tion of a new literature based primarily on data from the application of validated methods to identified lots of nanomaterials. Raw data would be linked to derived data—whether on nanomaterial structure, their properties, or their effects in dif- ferent experimental tests and environments—and to data from appropriate pre- dictive and structural models. The correlation of data on ENM lot, structure, properties, and effects would help in the creation and incremental improvement of an evidence-based nomenclature and ontology that are consistent with known structural, experimental, and modeling data and that can be used to organize and track the use, annotation, curation, and provenance of the data and models in the knowledge commons. In addition, the informatics system could be implemented with different levels of security to accommodate both open exchanges with precompetitive data and models and privileged access for more restricted col- laborative efforts. NANOMATERIAL INTERACTIONS IN COMPLEX SYSTEMS RANGING FROM SUBCELLULAR SYSTEMS TO ECOSYSTEMS As discussed in Chapter 3, the committee evaluated progress in a set of in- dicators related to ENM interactions in complex systems and found some pro- gress. The indicators included extent of initiation of studies to relate in vitro to in vivo observations, extending research from simplified laboratory studies to more complex assays, and going from organisms to ecosystems; steps toward development of models for ecologic exposures and effects in complex systems; extent of refinement of a set of screening tools that reflect toxicity pathways; adapting existing system-level tools; and identification of benchmark or refer- 2 The use of the phrase “apple to apple” comparisons conveys the importance of com- paring sufficiently similar nanomaterials in studies (including such information as the material size, physical and chemical structure and properties, purity, and processes used to manufacture, store, and prepare the materials for analyses). 

Getting to Green 99 ence materials for use in development of tools for estimating exposures and dos- es and for providing positive and negative controls—useful for hazard ranking of ENMs. Perhaps one of the biggest gaps is the lack of mechanistic data—an increasing volume of toxicity data is being generated, but the ability to use the data to predict ENM risks with any certainty is constrained because of the types of studies conducted. Many of the published studies incorporate high-dose (overload) acute exposures to single cells or simplified single-organism mortali- ty assays involving a single postexposure time and do not consider that underly- ing mechanisms are dose-dependent (Slikker et al. 2004). To provide more use- ful information, studies need to focus on more complex experimental design issues—such as relevant dose and dosimetry; dose response and time course characteristics; appropriate target cells, tissues, and organisms; and examination of more biologic pathways—concomitantly with better characterization of ENM test substances and incorporation of standardized reference materials as controls. The development and availability of standardized reference materials or bench- mark (positive and negative) controls are essential because these materials are integral to study design. For example, use of ENM positive control material pro- vides a reference for comparing the effects of ENM test materials being studied, and studies using ENM test materials and positive reference controls can facili- tate comparisons of results among research laboratories, an essential component of the validation process. In addition, consensus on the interpretation of hazard data is more readily achieved when the mechanism of action is known for the reference material. Useful comparisons are toxicity studies of endocrine disruption and 2,3,7,8- tetrachlorodibenzodioxin (TCDD); mechanisms are well known for the refer- ence material (Eadon et al. 1986; Safe 1987, 1998; Van den Berg et al. 1998; Silva et al. 2002). Toxicity tests of potential estrogens or dioxins are done in reference to that of estrogen or TCDD and provide a comparison with the toxici- ty of the agent of interest, and they ensure that a study has a positive control. In contrast, for the development of validated assays for ENMs, no positive controls exist, partly because of the sparseness of information on potential mechanisms of action of ENMs. However, having available toxicologic data for ENMs once they have been more thoroughly studied, including an understanding of potential mechanisms, would help to advance the science. Thus, ENM reference and benchmark materials are needed for use by all researchers. A consistent set of reference and benchmark ENMs is also needed for each category, such as metal oxides, silver, gold, and carbon nanotubes (CNTs). Additional shortcomings in available ENM toxicity data are related to the need to shift experimental study designs and models to gain more realistic and useful data for mechanistic understanding of ENMs. The preponderance of pub- lished studies provides information of questionable relevance to the health and environmental effects of realistic ENM exposures. Many findings are based on acute, high-dose exposures of single cells under in vitro conditions and so pro- vide little or no information on relevant dose or dosimetry (for humans), on po- tential sustained effects (key to understanding potential toxicity vs short-term 

100 Research Progress on EHS Aspects of Engineered Nanomaterials injury resulting from reactive oxidation species or an inflammatory response), on dose–response characteristics that provide mechanism insights, and on issues related to route of exposure or to life cycle. Similarly, many of the animal bioas- say data come from studies involving high-dose acute exposures with limited time-course information or data on mechanisms or important end points, such as development and reproduction. In addition, there are minimal studies of com- munity-level or ecosystem effects. Studies are limited to a few organisms, but uptake and mechanisms of action may differ among species. Those issues need to be explored further in relation to establishing standardized assays. To generate study results that can provide useful information on potential health and environmental risks associated with ENMs and that can be validated by other researchers in the field, it will be important to expand and redirect the focus of experiments to provide greater relevance on EHS issues, considering the chronic low-dose exposure scenarios that prevail for people and ecosystems. The results should be shared with other investigators, and results of in vivo stud- ies (at relevant concentrations) should be compared with results of in situ and in vitro screening assays to foster development of more expedient testing strate- gies. However, there is a paucity of useful in vivo data to establish a foundation for development of better screening tools. Consequently, the committee graded progress in experimental research in organisms that is relevant to community or ecosystem level effects as yellow. Research is ongoing in Environmental Protec- tion Agency–National Science Foundation (EPA–NSF) centers, but there is little emphasis on the effects of ENM exposures on interactions among organisms (community-level effects) or on the interactions of multiple communities with the abiotic environment, including how ENMs may change such interactions and how ENMs may be changed when interacting within the ecosystem (ecosystem- level effects). There is an absence of validated screening tools that are needed to apply data gained from experiments to challenging risk-related questions in humans and ecosystems (that is, transitioning from the laboratory world to the real world). There is a need to scale from laboratory systems to whole organisms and to the full ecosystem. Progress may need to be tied to a federal effort, inasmuch as individual laboratories may not have the incentive to participate in this meth- ods development. One way to begin to address that shortcoming may be to use the data generated in the comprehensive Organisation for Economic Co- operation and Development program that involves 12 ENMs (representative of materials found in commerce). This program collects extensive in vivo health effects data in accordance with robust scientific guidelines (OECD 2013); the results could be used as benchmarks for toxicologic evaluation of unknown ENMs. New assays under development could be compared with that rich data- base. The lack of mechanistic understanding is a further barrier that limits cer- tainty as to which types of assays should be developed. Supporting more mech- anistic research and giving individual laboratories the opportunity to build on the few existing assays that have been tried with a subset of ENMs is necessary to bridge this gap. 

Getting to Green 101 Steps to Improve Progress in Understanding Nanomaterial Interactions in Complex Systems Ranging from Subcellular Systems to Ecosystems The development of relevant in vivo hazard data based on appropriate routes of exposure and realistic exposure concentrations is an excellent starting point for understanding ENM interactions in complex systems. The ENM test material should be well characterized, and concentrations or doses administered to the organism should be based on data obtained from exposure-assessment studies and appropriate dose metrics (if available). Dose–response and time- course (temporal) characteristics should be built into the experimental design of these in vivo studies, and benchmark materials should be used as references for better interpretation of results. Time-course studies should initially focus on acute and subchronic responses to determine whether measurements of early (acute) injury are transitory. It would be important to have multiple laboratories conduct studies with similar or identical experimental protocols and end points to demonstrate whether interlaboratory experimental protocols and findings can be validated for a particular ENM or end point. When a more complete toxico- logic profile of an ENM has been developed, in vitro models that use relevant cell types, end points, doses, and time-course results can be constructed. Well- designed, in vitro mechanistic studies can provide important insights into rele- vant toxicity pathways of a particular ENM response, but only when these crite- ria are established: there is a relevant in vivo end point for comparison, time- course studies are undertaken for both in vivo and in vitro investigations, appro- priate doses and dose metrics are relevant for simulating human or ecologic ex- posures, temporal (time-course) effects are investigated (that is, not simply acute, high-dose effects), and appropriate benchmark reference materials are integrated into the experimental design to foster appropriate interpretation of the data. The successful establishment of adequate in vivo models should be fol- lowed sequentially by corresponding and validated in vitro toxicity tools; only then can the development of high-throughput toxicity screens informed by in situ and in vitro data represent a realistic approach. ANALYSIS OF PROGRESS TOWARD ADDRESSING IMPLEMENTATION NEEDS Indicators of Progress in Implementation and Their Link to the Nanotechnology Environmental, Health, and Safety Research Enterprise The committee identified mechanisms to ensure implementation of the EHS research strategy, including enhancing interagency coordination, providing for stakeholder engagement in the research strategy, conducting and communi- cating results of research funded through public–private partnerships, and man- aging potential conflicts of interest (NRC 2012, p. 183). Each of those repre- sents a high but achievable objective, and together they make up the support 

102 Research Progress on EHS Aspects of Engineered Nanomaterials needed for implementation of a successful nanotechnology EHS research enter- prise (Figure 4-1). For example, without strong and effective interagency coor- dination, a comprehensive knowledge commons is compromised. Robust inter- agency coordination minimizes overlap in research in the laboratory world and real world and maximizes the opportunity to identify research gaps and aggres- sively fund research needed to close them. Closing such gaps in turn supports the integration of all the elements in Figure 4-1; for example, with more and better data, modeling efforts can be improved, risk assessment can be enhanced, and decisions can be better informed. Engagement of stakeholders in the research enterprise requires participa- tion of all sectors, including government and academic researchers, nongovern- ment organizations (NGOs), regulators, industry, nanotechnology workers, and consumers. Stakeholder involvement maximizes the breadth of input needed to generate a comprehensive knowledge commons. Perhaps most important, stake- holders include workers and consumers who make up the populations that have the greatest exposures in the real world; these stakeholders not only have inter- est, expertise, and perspective in providing input that may help to shape research but are the most likely to be affected by the decisions made. The role of public–private partnerships in the research portfolio for EHS aspects of ENMs has proved more difficult to define and implement. Funding and policy issues limit formation of such partnerships in that federal agencies involved in nanotechnology EHS research may have expended their allocated research budget and industry may have only modest interest in joint funding because of competitive business concerns. However, there are examples of suc- cessful public–private partnerships in the environmental-health arena. The most notable example has been the congressionally mandated Health Effects Institute (HEI), which operates through equal cofunding from EPA and the automobile industry. In the nanotechnology realm, examples include partnerships between the National Institute for Occupational Safety and Health (NIOSH) and industry, and the multistakeholder Nano Release Initiative, which provide collaboration and interaction beyond simply joint funding. Such partnerships can support fo- cused research needs and could be well suited to develop inventories of ENMs and of their intended uses. Public–private partnerships also provide opportuni- ties for development of instrumentation or methods to monitor or measure na- nomaterial characteristics in laboratory and real-world research environments, which will enhance the knowledge commons. Well-structured and carefully governed public–private partnerships can provide unique credibility as they pro- vide insulation against conflicts of interest. The management of the potential for conflicts of interest between the dual roles of the National Nanotechnology Initiative (NNI) in both promoting and overseeing nanotechnology has special implications in Figure 4-1. Conflict of interest not only puts the knowledge commons at risk but has the potential to invalidate the models that are critical for assessing risk and supporting regulato- ry decisions. Management of conflict of interest can provide distinct lines of budget and management authority for applications-directed and implications- 

Getting to Green 103 directed research. It can be facilitated by engaging a broad group of stakeholders with responsibility for helping to develop laboratory and real-world research. As noted previously, where feasible, appropriately structured public–private part- nerships may offer unique opportunities for controlling and potentially eliminat- ing conflict of interest in the data-collection process. As described above and illustrated in Figure 4-1, all four implementation issues are central to the development of a successful nanotechnology EHS re- search enterprise. The discussion below addresses steps needed to “get to green” in the implementation indicators. Steps to Ensure Progress Toward Enhancing Interagency Coordination In Chapter 3, the committee recognizes the progress that the NNI has made in coordination of EHS research among federal agencies but reiterates the need for accountability for implementation of the NNI’s EHS research strategy and the need for the strategy’s integration with research undertaken by other entities, both domestically and internationally. The committee considers that little or no progress (red) has been made in “establishing a mechanism to ensure sufficient management and budgetary authority to implement the NNI’s EHS research strategy” (NRC 2012, p. 183). However, it determined that some pro- gress (yellow) had been made by the NNCO in annually identifying funding needs for interagency collaboration. Greater effort is needed specifically to ac- celerate and enhance high-priority research. The need for a stronger, central convening authority to direct EHS re- search efforts conducted under the NNI has now been raised in at least four sep- arate reviews of the NNI and its strategy (NRC 2009; GAO 2012; NRC 2012; PCAST 2012). As noted in Chapter 2, the latest President’s Council of Advisors on Science and Technology (PCAST) review of the NNI identified “significant hurdles to an optimal structure and management” (p. 17), reiterating a concern that PCAST had raised in its 2010 review of the NNI (PCAST 2010): that NNI agency representatives on the Nanoscale Science, Engineering, and Technology Subcommittee (NSET) of the National Science and Technology Council Com- mittee on Technology lack authority to influence budget allocations, even within their own agencies, that are needed to meet NNI objectives. In particular, PCAST called on the NSET to establish “high-level, cross-agency authoritative and accountable governance” (p. 22), noting that one effect of the absence of such a governance framework is a continuing gap between funded research and the information needed by decision-makers to manage potential risks effectively. The present committee’s first report (NRC 2012, pp. 166–169) proposed several options for establishing such authority, either inside or outside the NNI and the Nanotechnology Environmental Health Implications working group (NEHI) structure. Implementing those or other options need not require new legislation, but there may be advantages in pursuing such authority in any reau- thorization of the 21st Century Nanotechnology Research and Development Act, 

104 Research Progress on EHS Aspects of Engineered Nanomaterials as was considered but not enacted by the 111th Congress. Whatever the mecha- nism used, the committee reiterates the conclusion of its first report that “to im- plement [the NNI’s] strategy effectively an entity with sufficient management and budgetary authority is needed to direct development and implementation of a federal EHS research strategy throughout NNI agencies and to ensure its inte- gration with EHS research undertaken in the private sector, the academic com- munity, and international organizations. Progress in implementation of the strat- egy will be severely limited in the absence of such an entity” (NRC 2012, p. 169). Short of addressing that fundamental need, the committee suggested other means by which the NNI could enhance and extend interagency coordination. The NNI has identified a number of activities aimed at improving interagency coordination and stakeholder engagement, both in its 2011 EHS research strate- gy (NEHI 2011) and in its 2013 budget supplement (NSET 2012b), that are promising but do not appear to have been implemented. The 2011 strategy (NEHI 2011, p. 96) indicates plans to use “webinars, workshops, and other mechanisms for information exchange to assess the state of the science and cur- rent research, and to reassess areas of weakness and gaps”; however, despite proposing to host two or three webinars each year, it appears that the NNI has held but one such webinar, “Public Engagement through Nano.gov” (NNI 2012a), and at the time of this writing none is planned. The NNI’s 2011 strategy also identified its signature initiatives (NNI 2012b) as offering NEHI “a new mechanism through which to organize and leverage interagency efforts” (NEHI 2011, p. 96). Those initiatives are all fo- cused on nanotechnology development, however, not on EHS issues, and the committee has not seen any indications of NEHI’s use of the signature initiatives for the indicated purpose. Similarly, the NNI’s 2013 budget supplement (NSET 2012b, p. 61) notes plans for NEHI to host “monthly meetings, public work- shops and webinars and other social media”, but the committee is not aware that such activities have taken place. The committee encourages NEHI and the NNCO to implement those plans, which promise the dual benefit of enhancing interagency coordination and stakeholder engagement. Another option would be the formal assignment of responsibility for man- agement of the knowledge commons shown in Figure 4-1 to the NNCO. The NNCO would then be accountable for ensuring both that EHS-relevant infor- mation generated by research in individual NNI agencies is efficiently trans- ferred to the knowledge commons and that it is widely shared. Such responsibil- ity in itself might support and spur a greater role for the NNCO in enhancing interagency coordination. The committee puts this example forth to illustrate the role that enhanced interagency coordination could play in increasing the overall effectiveness and efficiency of the nanotechnology EHS research enterprise. At the committee’s November 2012 workshop, representatives of two fed- eral agencies indicated that they were undertaking a mapping of their own re- search activities onto the 2011 NNI strategy’s objectives. The NNCO could re- 

Getting to Green 105 quire all NNI agencies to conduct such mapping, compile the results, and use them to indicate how they intend to address overlaps and gaps in their activities. Finally, to address PCAST’s criticism directly, the NNCO could reconsti- tute the NSET to require that NNI agencies designate senior officials who have budgetary authority in their agencies as members of the NSET. Improving interagency coordination requires tracking of research that is being conducted by the agencies and of how much is being spent on specific projects. Since publication of the committee’s first report, two reviews of the NNI have raised concerns about the need for the NNI to develop and implement better performance metrics that can be used to track progress toward core objec- tives. That need was a central theme of the 2012 Government Accountability Office (GAO) report, which has as one of its two “recommendations for execu- tive action” that “the Director of OSTP [Office of Science and Technlogy Poli- cy] coordinate development by the NNI member agencies of performance measures, targets, and time frames for nanotechnology EHS research that align with the research needs of the NNI, consistent with the agencies’ respective statutory authorities, and include this information in publicly available reports” (p. 51). GAO (2012, p. 46) noted that earlier reviews had also flagged that need, including a 2010 review by the National Nanotechnology Advisory Panel (PCAST 2010) and NRC (2009). Similarly, PCAST’s 2012 review of the NNI (pp. vi, 17) notes that “the lack of clear metrics for assessing the impacts of Federal investments in nano- technology remains a concern” and that it had raised a similar concern in its 2010 review of the NNI. PCAST calls on agencies to develop “mission- appropriate” (p. 21) metrics and on the NNCO to track the development of ap- propriate metrics and implement them to assess NNI outputs. (PCAST’s call for such metrics is not limited to EHS concerns; it is related to all aspects of the NNI.) Metrics are needed specifically for identifying the levels, types, and sources of funding needed to ensure that interagency research efforts have suffi- cient funding to meet specific goals and to complete research in fields identified as having high priority.3 As noted earlier, the committee continues to believe that accountability for fostering interagency collaboration in implementing a research strategy requires more than what the NNI has done to date—identifying what collaborative research is under way or contemplated—namely, putting into place a means of estimating periodically (ideally at least once a year) funding needs and of tracking and reporting progress toward meeting the needs. GAO (2012, p. 51) reached a similar conclusion: “We also recommend that, to the extent possible, the Director of OSTP coordinate the development by the NNI member agencies of estimates of the costs and types of resources necessary to meet the EHS research needs.” 3 The absence of available funding data prevented the committee from revisiting the resource estimates presented in its first report (NRC 2012). 

106 Research Progress on EHS Aspects of Engineered Nanomaterials The committee is not aware of any effort by the NNCO to develop such a set of metrics for estimating funding needs and tracking whether they are met. We renew our call for the NNCO to do so. Steps to Ensure Progress Toward Addressing Stakeholder Involvement In Chapter 3, the committee rated progress toward “actively engaging di- verse stakeholders in a continuing manner” (NRC 2012, p. 183) as yellow and noted some specific examples of progress toward meeting this goal. Getting to green in stakeholder engagement means encouraging the bright spots where there is some momentum, simultaneously expanding on existing programs and creating new ones. The NIOSH forum (NIOSH 2012) should be supported as an annual event, not where the research and development (R&D) community is located but where the opportunity for the greatest stakeholder engagement can be found, and should be marketed directly to the stakeholder groups that were underrepresented in the “first annual” event. Similar forums should be created, perhaps aligned with the EHS categories of worker–consumer–environment or value chain (raw materials–intermediates–final products). The forums could be extended into standing bodies to ensure that stakeholder-engagement processes are ongoing and inform all aspects of strategy development, implementation, and revision. The public forums and standing bodies are critical for generating and building engagement among the various stakeholders and will lead to more buy-in at the outset of and throughout these processes. In addition, the committee recommends the creation of a new Stakeholder Advisory Council by the NNCO. It would help the NNCO to assess the effec- tiveness of such efforts as those described in the previous paragraph and identify opportunities to expand such forums to include other stakeholder groups and all aspects of the research strategy. The members of the Stakeholder Advisory Council would become key points of contact for the stakeholders that they rep- resent that might be underserved, marketing such programs directly to their peers, and collecting responses from them regarding better ways to engage. There are models for such an advisory council. In its 2012 report (NRC 2012, pp. 170-171), the committee described NIOSH’s National Occupational Research Agenda (NORA), specifically its establishment of both sector-specific councils and a cross-sector council. Council members assist the institute in de- veloping, implementing, and revising national and sector research agendas and strategies, and in facilitating communications to and from their respective stake- holder groups. The Stakeholder Advisory Council of Australia’s National Ena- bling Technologies Strategy offers another model (Australian Government 2013). This standing council with diverse stakeholder representation meets regu- larly to advise the government on nanotechnology and other enabling technolo- gies. Its focus is broader than NORA but includes research strategies, including policy issues, funding needs and priorities, sector and community communica- tions and engagement, and information dissemination. 

Getting to Green 107 Steps to Ensure Progress Toward Development of Public–Private Partnerships The committee determined that little or no progress had been made in cre- ating well-defined effective partnerships as measured by execution of partner- ship agreements, issuance of requests for proposals, and the establishment of governance structure—hence, it denoted this indicator as red. Although there have been few nanotechnology-based public–private partnerships, blueprints from other scientific fields exist, such as the HEI. Founded in 1980, the HEI is a nonprofit corporation chartered to provide scientific research on the health ef- fects of air pollution. Its mission is to identify and fund high-priority research, to provide independent review of HEI-based research, and to communicate HEI’s results. The HEI has funded and published or presented public reports on more than 250 studies on a variety of topics, including carbon monoxide, air toxics, nitrogen oxides, diesel exhaust, ozone, particulate matter, and other pollutants. Its board of directors includes leaders of corporations, academe, NGOs, and policy groups. EPA and representatives from the motor-vehicle industry—Ford Motor Company, General Motors Corporation, and Chrysler LLC—fund the organization, each with about a 50% share. In addition to NIOSH’s nanotechnology-focused public–private partner- ships discussed in Chapter 3, a nanotechnology EHS–focused public–private partnership that could serve as a model was the Europe-based Nanotechnology Capacity Building NGOs (NanoCap) (NanoCap 2009). The European Commis- sion, under the FP6 Science and Society programme, funded the 3-year project (2006–2009) which was organized to increase understanding of EHS risks and ethical aspects of nanotechnology. IVAM is an independent research and con- sulting firm of the University of Amsterdam Holding in the Netherlands that conducts technologic, environmental, and occupational-health projects with trade unions, environmental NGOs, industry, and government organizations. It led a consortium of environmental NGOs (for example, the Baltic Environmen- tal Forum, the European Environmental Bureau, and the Mediterranean Infor- mation Office for Environment, Culture and Sustainable Development), trade unions (such as European Trade Union Institute, Health and Safety Department), and academic researchers (such as at the University of Aarhus interdisciplinary Nanoscience center, Katholieke Universiteit Leuven, the Department of Public health, the University of Amsterdam, and the Institute for Biodiversity and Eco- system Dynamics). NanoCap developed and publically presented recommenda- tions that enabled public authorities to address EHS risks related to nanotech- nology. In addition, NanoCap’s goal was to encourage academe and industry to focus on reduction of sources of nanoparticles and the inclusion of risk assess- ment in their work. The NNI signature initiatives are additional examples of public–private partnerships, albeit not focused on EHS. The signature initiatives are collabora- tions intended to spur the advancement of nanotechnology in the service of na- 

108 Research Progress on EHS Aspects of Engineered Nanomaterials tional economic, security, and environmental goals. For example, the signature initiative Nanotechnology Knowledge Infrastructure: Enabling National Leader- ship in Sustainable Design is a multistakeholder group of scientists, engineers, and federal agencies charged with developing a multidisciplinary collaboration that integrates basic research, modeling, applications development, and ultimate- ly a nanotechnology data infrastructure to support data-sharing and collaboration (NNI 2013). Overall, getting to green on “conducting and communicating the results of research funded through public–private partnerships” may require a public– private partnership approach similar to the HEI but with a focus on nanotech- nology EHS issues, such as NIOSH’s efforts or the European-based NanoCap. Five critical elements for an effective public–private partnership are a strong independent and accountable governance structure, adequate and shared fund- ing, specific and agreed-on goals, transparent sharing of results and information, and appropriate confidentiality agreements. To that end, the committee recom- mends that NNI government agencies, individually and jointly, spur the organi- zation of well-focused public–private partnerships; however, the governance structure needs to extend well beyond the agency. For example, HEI’s Board of Directors is a recommended governance model. However, unlike the HEI’s au- tomotive-industry focus, no single market or industry binds all nanotechnology research, so there may be a need to establish multiple sector-specific or material- based public–private partnerships (for example, a CNT-based public–private partnership that includes CNT manufacturers, researchers, and other key stake- holders). Partners should share in the funding of the public–private partnerships; this would help to ensure active participation of all parties in moving toward clearly articulated and agreed-on goals. Although the goals will depend on the nature and scope of the specific partnership, some basic goals modeled on those of HEI would provide direction applicable to all public–private partnerships. Public–private partnerships should foster open sharing of information, both internally among partners and externally with a broader audience, via reports, con- ferences, and other media. Public–private partnership agreements should take into account the confidentiality concerns of industrial partners. It is understood that the organization of an effective and well-run public–private partnership takes time, but NNI agencies should increase their efforts to initiate partnership programs because they are critical for the implementation of the research strategy; without them, research progress will be slower and more limited. The committee recognizes that there are mechanisms that allow agencies to share and pool resources for collaborative projects. An example is the joint funding of federally funded research and development centers (FFRDCs), such as the EPA- and NSF-funded University of California Center for Environmental Implications of Nanotechnology and the Center for Environmental Implications of Nanotechnology. 

Getting to Green 109 Steps to Ensure Progress Toward Addressing Conflict of interests Conflict of interest is an issue of public concern that affects many societal sectors and institutions, both public and private. From government agencies, aca- demic institutions, and professional organizations to industry, financial insti- tutions, and nonprofit organizations, that concern has resulted in the proliferation of conflict-of-interest policies, reporting and disclosure requirements, and training programs meant to restore or ensure public confidence and trust. In one widely used definition, conflict of interest is described as “a set of circumstances that creates a risk that professional judgment or actions regarding a primary interest will be unduly influenced by a secondary interest” (Lo and Field 2009, p. 46). By statute, the NNI was established with dual functions—promoting the development and commercialization of nanotechnology applications and un- derstanding and mitigating their EHS implications—and that created a set of cir- cumstances in which conflict of interest is almost inherent. The current allocation of its research dollars ($105 million requested for EHS research in 2013 of a total NNI request of $1.8 billion) is perhaps the most visible manifestation of the conflict. It is clear that applications R&D takes pri- ority over EHS risk research, so it is understandable that some stakeholders may question or have concerns about the NNI’s ability to pursue research on EHS implications with vigor and integrity. The tension between the dual roles of NNI is exacerbated in that the results of EHS research may inform regulatory deci- sions and affect the developers and users of nanotechnology applications. Given the almost inherent conflict, it is critical that the NNI focus particu- lar attention and energy on ensuring that all stakeholders—including workers and the consuming public—trust the integrity of its EHS research enterprise. As noted in the committee’s first report, the separation of nuclear-power R&D (as- signed to the Department of Energy) from risk research and risk management (assigned to the Nuclear Regulatory Commission) is one model for addressing the inherent conflict between the federal government’s interest in developing a new technology and managing the associated risks. In Chapter 3, the committee assessed progress toward addressing two in- dicators for managing conflicts of interest. The committee determined that little progress had been made 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” (NRC 2012, p. 183), and this indicator was designated red. Some progress was deemed to have been made in the “continued separate tracking and reporting of EHS research activi- ties and funding” (NRC 2012, p. 183), so this indicator was yellow. To move those indicators toward green, actual or perceived conflicts that arise from the NNI’s dual mission could be addressed through structural and managerial changes—driven by changes in the NNI’s authorizing statute or by changes that the NNI and its participating agencies could implement themselves. Such changes do not seem to be forthcoming; indeed, in its 2013 budget sup- 

110 Research Progress on EHS Aspects of Engineered Nanomaterials plement (NSET 2012b), the NNI noted that such actions are “unlikely or not needed”. The committee continues to believe that the NNI writ large would ben- efit from a clearer separation of authority and accountability for its EHS re- search enterprise. It would not only advance stakeholder trust and confidence in the seriousness of the NNI’s commitment to responsible development, especially the integral importance of its EHS research mission, but would help to address the need for better integration and coordination of EHS research throughout the NNI. The committee urges the NNI to review and reconsider the variety of mod- els, mechanisms, and managerial processes noted in the committee’s first report. Until such changes in structure, management, and budgetary processes are made, greater transparency will be key in getting to green. Even within its current remit, greater transparency can help to address concerns about possible conflicts of interest and real or perceived bias within the NNI research community.4 The NNI has already made some progress in enhanc- ing transparency for its EHS research, for example, by improving the tracking and reporting of EHS research activities and funding and by providing narrative information on agency-specific EHS research activities and projects in the NNI supplement to the president’s FY 2013 budget. Further efforts to enhance the timeliness, specificity, and accessibility of information about EHS research pro- jects are needed, including development of clearer guidance on how agencies should differentiate between research directly relevant to EHS risk and applica- tions-oriented research with EHS implications. Transparency and trust can be further advanced through creation of and adherence to strong scientific-integrity policies at the agency level. Following a presidential memo on the topic, OSTP issued guidelines for scientific-integrity policies in 2010 (Holdren 2010), and most departments have developed policies and plans in response.5 The NNI should periodically review the scientific- integrity policies of its participating agencies to ensure continued attention and adherence to the key principles of scientific integrity—a cornerstone of public trust in the scientific enterprise of public agencies. The NSET, the NNCO, and NNI agencies should explore additional mechanisms to foster transparency and thus minimize and manage any concerns about conflicts of interest and bias. For example, the NNCO or NNI agencies could create an ombudsman position to receive, investigate, and resolve com- plaints or concerns about bias and conflicts of interest in the NNI’s research portfolio. The NNCO could also develop and disseminate best practices for 4 For definitions of conflict of interest and bias, see Appendix B in the Keystone Cen- ter’s report from the Research Integrity Roundtable, Improving the Use of Science in Regulatory Decision-making: Dealing with Conflict of Interest and Bias in Scientific Advisory Panels and Improving Systematic Scientific Reviews (Keystone Center 2012). For hypothetical examples of conflict of interest and bias, see Appendix 1 in the Biparti- san Policy Center report Improving the Use of Science in Regulatory Policy (Bipartisan Policy Center 2009). 5 For an assessment of and link to agency scientific-integrity policies, see UCS (2012). 

Getting to Green 111 identifying, managing, and preventing conflicts of interest and bias in the plan- ning, conduct, and reporting of research—especially for entities engaged in re- search on both nanoscience applications and their EHS implications. Identifica- tion of best practices, with appropriate checks and balances, should be informed by input provided through a multistakeholder process that includes workers, consumers, health and environmental NGOs, large and small businesses, and researchers in the public and private sectors. Attention to frequency, timeliness, substance, and inclusivity of stakeholder engagement activities can also enhance trust and transparency. REFERENCES Australian Government. 2013. National Enabling Technologies Strategy: A National Approach. Department of Industry, Innovation, Climate Change, Science, Re- search and Tertiary Education [online]. Available: http://www.innovation.gov.au/ Industry/Nanotechnology/NationalEnablingTechnologiesStrategy/Pages/National EnablingTechnologiesStrategyANationalApproach.aspx [accessed June 20, 2013]. Badireddy, A.R., M.R. Wiesner, and J. Liu. 2012. Detection, characterization, and abun- dance of engineered nanoparticles in complex waters by hyperspectral imagery with enhanced darkfield microscopy. Environ. Sci. Technol. 46(18):10081-10088. Bipartisan Policy Center. 2009. Improving the Use of Science in Regulatory Policy. Sci- ence for Policy Project [online]. Available: http://bipartisanpolicy.org/sites/default/ files/BPC%20Science%20Report%20fnl.pdf [accessed Dec. 27, 2012]. Eadon, G., L. Kaminsky, J. Silkworth, K. Aldous, D. Hilker, P. O’Keefe, R. Smith, J. Gierthy, J. Hawley, N. Kim, and A. DeCaprio. 1986. Calculation of 2, 3, 7, 8-TCDD equivalent concentrations of complex environmental contaminant mixtures. Environ. Health Perspect. 70:221-227. EOP (Executive Office of the President). 2012. Fact Sheet: Progress on Materials Ge- nome Initiative, May 14, 2012. Executive Office of the President [online]. Availa- ble: http://www.whitehouse.gov/sites/default/files/microsites/ostp/mgi_fact_sheet_ 05_14_2012_final.pdf [accessed Mar. 12, 2013]. GAO (U.S. Government Accountability Office). 2012. Nanotechnology: Improved Per- formance Information Needed for Environmental, Health, and Safety Research. GAO-12-427. Washington, DC: U.S. Government Accountability Office [online]. Available: http://www.gao.gov/assets/600/591007.pdf [accessed Dec. 5, 2012]. Holdren, J.P. 2010. Scientific Integrity. Memorandum for the Heads of Executive Depart- ments and Agencies, from John P. Holdren, Assistant to the President for Science and Technology and Director of the Office of Science and Technology, Washington, DC. December 17, 2010 [online]. Available: http://www.whitehouse.gov/sites/de fault/files/microsites/ostp/scientific-integrity-memo-12172010.pdf [accessed Apr. 8, 2013]. Hou, W.C., P. Westerhoff, and J.D. Posner. 2013. Biological accumulation of engineered nanomaterials: A review of current knowledge. Environ. Sci. Process. Impacts 15(1): 103-122. ILSI (International Life Sciences Institute). 2013a. NanoRelease Consumer Products [online]. Available: http://www.ilsi.org/ResearchFoundation/RSIA/Pages/NanoRel ease1.aspx [accessed Mar. 12, 2013]. 

112 Research Progress on EHS Aspects of Engineered Nanomaterials ILSI (International Life Science Institute). 2013b. NanoCharacter [online]. Available: http://www.ilsi.org/NanoCharacter/Pages/NanoCharacter.aspx [accessed Mar. 12, 2013]. JRC (Joint Research Centre Institute). 2013. JRCNANOhub. European Commission, Joint Research Centre Institute, Institute for Health and Consumer Protection (IHCP), Ispra [online]. Available: http://www.napira.eu/ [accessed Mar. 12, 2013]. Keystone Center. 2012. Improving the Use of Science in Regulatory Decision-Making: Dealing with Conflict of Interest and Bias in Scientific Advisory Panels, and Im- proving Systematic Scientific Reviews. A Report from the Research Integrity Roundtable [online]. Available: https://www.keystone.org/images/keystone-cent er/spp-documents/Health/Research%20Integrity%20Rountable%20Report.pdf [ac- cessed Dec. 27, 2012]. Lo, B., and M.J. Field, eds. 2009. Conflict of Interest in Medical Research, Education, and Practice. Washington, DC: National Academies Press. Lombi, E., E. Donner, E. Tavakkoli, T.W. Turney, R. Naidu, B.W. Miller, and K.G. Scheckel. 2012. Fate of zinc oxide nanoparticles during anaerobic digestion of wastewater and post-treatment processing of sewage sludge. Environ. Sci. Tech- nol. 46(16):9089-9096. Mitrano, D.M., A. Barber, A. Bednar, P. Westerhoff, C.P. Higgins, and J.F. Ranville. 2012. Silver nanoparticle characterization using single particle ICP-MS (SP-ICP- MS) and asymmetrical flow field flow fractionation ICP-MS (AF4-ICP-MS). J. Anal. At. Spectrom. 27(7):1131-1142. NanoCap. 2009. NanoCap Project. European FP6 Capacity Building Project [online]. Availa- ble: http://www.nanocap.eu/Flex/Site/Page4662.html?PageID=%26Lang= [accessed Apr.8, 2013]. NanoHUB.org. 2013. NanoHUB [online]. Available: http://nanohub.org/ [accessed Mar. 12, 2013]. Nanomaterialregistry.org. 2013. Nanomaterial Registry [online]. Available: https://www. nanomaterialregistry.org/ [accessed Mar. 12, 2013]. NanoSafety Cluster. 2013. About NanoSafety Cluster [online]. Available: http://www. nanosafetycluster.eu/ [accessed July 11, 2013]. NEHI (Nanotechnology Environmental Health Implications Working Group). 2011. Na- tional Nanotechnology Initiative 2011 Environmental, Health, and Safety Strategy, October 2011. Nanotechnology Environmental Health Implications Working Group, Subcommittee on Nanoscale Science, Engineering, and Technology, Committee on Technology, National Science and Technology Council [online]. Available: http:// www.nano.gov/sites/default/files/pub_resource/nni_2011_ehs_research_strategy.pdf [accessed Dec. 27, 2012]. NIOSH (National Institute for Occupational Safety and Health). 2012. Prevention through Design: Safe Nano Design Workshop, August 14-16, 2012, Albany, NY [online]. Available: http://www.cdc.gov/niosh/topics/ptd/nanoworkshop/default.html [ac- cessed Feb. 2, 2013]. NITRD (The Networking and Information Technology Research and Development). 2013a. Networking and Information Technology Research and Development Pro- gram, NITRD Subcommittee [online]. Available: http://www.nitrd.gov/nitrdgrou ps/index.php?title=Subcommittee_on_Networking_and_Information_Technology_ Research_and_Development_(NITRD_Subcommittee) [accessed July 12, 2013]. NITRD (The Networking and Information Technology Research and Development). 2013b. Data Sharing and Metadata Curation: Obstacles and Strategies: Future Strategies for Managing Scientific Data and Metadata for Basic and Applied Re- 

Getting to Green 113 search, May 29, 2013, Natural Science Foundation, Arlington, VA [online]. Avail- able: http://www.nitrd.gov/nitrdgroups/index.php?title=Data_Sharing_and_Meta data_Curation:_Obstacles_and_Strategies [accessed July 12, 2013]. NNI (U.S. National Nanotechnology Initiative). 2012a. Public Engagement through Nano.gov. Webinar. Nano.gov [online]. Available: http://www.nano.gov/node/873 [accessed Dec. 27, 2012]. NNI (U.S. National Nanotechnology Initiative). 2012b. Nanotechnology Signature Initia- tives. Nano.gov. [online]. Available: http://www.nano.gov/signatureinitiatives [ac- cessed Dec. 27, 2012]. NNI (U.S. National Nanotechnology Initiative). 2013. NSI: Nanotechnology Knowledge Initiative (NKI) – Enabling National Leadership in Sustainable Design [online]. Available: http://www.nano.gov/node/829 [accessed Mar. 12, 2013]. NRC (National Research Council). 2009. Review of the Federal Strategy for Nanotechnolo- gy-Related Environmental, Health, and Safety Research. Washington, DC: National Academies Press. NRC (National Research Council). 2011. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease. Washington, DC: National Academies Press. NRC (National Research Council). 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: National Acad- emies Press. NSET (Nanoscale Science, Engineering, and Technology). 2012a. Nanotechnology Sig- nature Initiative. Nanotechnology Knowledge Infrastructure: Enabling National Leadership in Sustainable Design. Subcommittee on Nanoscale Science, Engineer- ing, and Technology, National Science and Technology Council. May 14, 2012 [online]. Available: http://nano.gov/sites/default/files/pub_resource/nki_nsi_whi te_paper_-_final_for_web.pdf [accessed Jan. 22, 2013]. NSET (Nanoscale Science, Engineering, and Technology Subcommittee). 2012b. The National Nanotechnology Initiative: Research and Development Leading to a Rev- olution in Technology and Industry: Supplement to the President's FY 2013 Budg- et. Subcommittee on Nanoscale Science, Engineering, and Technology, National Science and Technology Council. February 2012 [online]. Available: http://www. nano.gov/sites/default/files/pub_resource/nni_2013_budget_supplement.pdf [ac- cessed Nov. 27, 2012]. NSTC (National Science Technology Council). 2011. Materials Genome Initiative for Global Competitiveness. Interagency Group on Advanced Materials, National Sci- ence Technology Council. June 2011 [online]. Available: http://nano.gov/node/829 [accessed Mar. 12, 2013]. OECD (Organisation for Economic Co-operation and Development). 2013. Current Devel- opments in Delegations on the Safety of Manufactured Nanomaterials – Tour de Ta- ble. Series on the Safety of Manufactured Nanomaterials No. 37. ENV/JM/MONO (2013)2. Organisation for Economic Co-operation and Development [online]. Avail- able: http://search.oecd.org/officialdocuments/displaydocumentpdf/?cote=env/jm/ mono%282013%292&doclanguage=en [accessed Mar. 11, 2013]. PCAST (President’s Council of Advisors on Science and Technology). 2010. Report to the President and Congress on the Third Assessment of the National Nanotechnol- ogy Initiative. March 2010 [online]. Available: http://www.whitehouse.gov/sites/ default/files/microsites/ostp/pcast-nano-report.pdf [accessed Dec. 20, 2012]. PCAST (President’s Council of Advisors on Science and Technology). 2012. Report to the President and Congress on the Fourth Assessment of the National Nanotech- 

114 Research Progress on EHS Aspects of Engineered Nanomaterials nology Initiative. April 2012 [online]. Available: http://nano.gov/sites/default/files/ pub_resource/pcast_2012_nanotechnology_final.pdf [accessed Dec. 5, 2010]. Safe, S. 1987. Determination of 2,3,7,8-TCDD toxic equivalent factors (TEFs): Support for the use of the in vitro AHH induction assay. Chemosphere 16(4):791-802. Safe, S.H. 1998. Hazard and risk assessment of chemical mixtures using the toxic equiva- lency factor approach. Environ. Health Perspect. 106(suppl. 4):1051-1058. Silva, E., N. Rajapakse, and A. Kortenkamp. 2002. Something from “nothing”: Eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects. Environ. Sci. Technol. 36(8):1751-1756. Slikker, W., Jr., M.E. Andersen, M.S. Bogdanffy, J.S. Bus, S.D. Cohen, R.B. Conolly, R.M. David, N.G. Doerrer, D.C. Dorman, D.W. Gaylor, D. Hattis, J.M. Rogers, R.W. Setzer, J.A. Swenberg, and K. Wallace. 2004. Dose-dependent transitions in mechanisms of toxicity: Case studies. Toxicol. Appl. Pharmacol. 201(3):226-294. UCS (Union of Concerned Scientists). 2012. Agency-specific Solutions. Union of Con- cerned Scientists, Cambridge, MA [online]. Available: http://staff.nationalacademi es.org/academynet/informationresources/researchcenter/index.htm [accessed Apr. 8, 2013]. Van den Berg, M., L. Birnbaum, A.T. Bosveld, B. Brunström, P. Cook, M. Feeley, J.P. Giesy, A. Hanberg, R. Hasegawa, S.W. Kennedy, T. Kubiak, J.C. Larsen, F.X. van Leeuwen, A.K. Liem, C. Nolt, R.E. Peterson, L. Poellinger, S. Safe, D. Schrenk, D. Tillitt, M. Tysklind, M. Younes, F. Waern, and T. Zacharewski. 1998. Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environ. Health Perspect. 106(12):775-792. Warren, J.A., and R.F. Boisvert. 2012. Building the Materials Innovation Infrastructure: Data and Standards. A Materials Genome Initiative Workshop, May15-15, 2012, Washington, DC. NISTIR 7898. National Institute of Standards and Technology [online]. Available: http://nvlpubs.nist.gov/nistpubs/ir/2012/NIST.IR.7898.pdf [ac- cessed Apr. 5, 2013]. Westerhoff, P., and B. Nowack. 2013. Searching for global descriptors of engineered nanomaterial fate and transport in the environment. Acc. Chem. Res. 46(3):844- 853.