Summary

Nanotechnology relies on the ability to design, manipulate, and manufacture materials at the nanoscale.¹ Investments in nanotechnology and in the production of engineered nanomaterials (ENMs) continue to grow; the global market for nanotechnology is expected to exceed $3 trillion by 2015. The novel physical and chemical characteristics of ENMs are being exploited in new applications and have motivated research on the potential human health and environmental risks associated with these materials because of concerns about their behavior in biologic systems. Given the global use of ENMs, research on their environmental, health, and safety (EHS) aspects necessarily extends globally and involves a multidisciplinary and international group of stakeholders, including academic researchers, the industrial sector, nongovernment organizations (NGOs), and the public.

Over the last decade, there has been more funding for research and a corresponding increase in peer-reviewed publications on EHS aspects of ENMs. However, in spite of progress in understanding some aspects of risks posed by ENMs, uncertainty persists about the potential implications of the materials for consumers, workers, and ecosystems. In that context, the US Environmental Protection Agency (EPA) asked the National Research Council to perform an independent study to develop and monitor an integrated research strategy on EHS risks posed by ENMs.

In response to EPA’s request, the National Research Council convened the Committee to Develop a Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials, which produced its first report in 2012, A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. In this second report, the committee evaluates the trajectory of research progress on the basis of indicators or criteria established in its first report. (See Appendix B for complete statement of task.) This report expands on the need for a strategic approach for developing the research infrastructure for addressing uncertainties regarding the potential EHS risks associated with ENMs that was begun in the first report. The approach hinges on the vision put forth in Figure S-1, which describes the nanotechnology EHS research enterprise and shows the interrelated and interdependent research activities that are driven by the production of

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¹ Nanoscale refers to materials on the order of one billionth of a meter.

ENMs. The diagram presents an integrated and strategic system for developing data that will provide for characterization of ENMs, for refinement of experimental methods, for support of model development, and for storage and retrieval of information through the “knowledge commons”. The potential success of the enterprise rests on involvement of the global community of stakeholders, including researchers, manufacturers of ENMs, regulators, and components of civil society that are invested in addressing potential health and environmental risks posed by ENMs. Many of the elements of this enterprise are in place, but the committee concludes that their further development and integration are essential for advancing progress.

The committee’s second report considers findings that were presented in its first report and other recently released US and European Union efforts that provide global perspectives for advancing nanotechnology EHS research. It examines trajectories of research and implementation progress and identifies barriers to progress and steps to ensure progress. To advance the concepts described in the research enterprise (Figure S-1), the committee envisions a time beyond its current research recommendations to consider how questions about risk can be best approached in an adaptive fashion with the goal of generating information needed to design materials and processes so as to avoid and control potential risks.

ASSESSMENT OF PROGRESS

This report is released a short time after of the committee’s first report. Using indicators developed based on priorities from that report (see Boxes S-1 and S-2 for indicators of research and implementation progress, respectively), the committee evaluated progress in this second report.

For its evaluation, the committee developed a color scheme to categorize progress qualitatively by considering new activities since preparation of its first report and the trajectory of research progress. Because of the many concomitant nanotechnology EHS reviews and planning efforts, the committee did not attempt to attribute progress to any particular effort. Rather, it classified progress on the basis of committee consensus whereby green implies substantial progress (there are new activities, and sustained progress is expected), yellow implies moderate or mixed progress, and red implies little progress (there is minimal activity, and little change is expected). (The committee’s assessment of progress is indicated in the color circles in Boxes S-1 and S-2.)

In the following sections, the committee provides a brief evaluation of the research and implementation indicators, together with the steps needed to speed progress to a pace at which “getting to green”² is achievable. (Additional details regarding the evaluation of progress are described in Chapters 3 and 4.)

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² “Getting to green” is the title of Chapter 4, and indicates the steps needed to achieve progress in the research and implementation indicators identified in Boxes S-1 and S-2.

FIGURE S-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 produced, 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 assessing exposures and hazards and hence risk (NRC 2012, p. 55). The “real world” includes 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.

Research Progress

Adaptive Research and Knowledge Infrastructure for Accelerating Research Progress and Providing Rapid Feedback to Advance Research

In the first report, the committee identified a need for an adaptive infrastructure for research and knowledge generation to accelerate and advance nanotechnology EHS research. The components of the infrastructure include characterized materials for reference and research purposes; nanomaterial libraries;

instruments and methods for measuring nanomaterials and their transformations; methods or assays for quantifying the effects of nanomaterials; databases, ontologies³, and tools for sharing research results; and models for uncovering relationships among the data. In this second report, the committee determined that research progress ranges from green for detecting and characterizing ENMs in relatively well-characterized media to yellow for development of libraries of well-characterized ENMs, development of methods for quantifying effects of ENMs in experimental systems, and the extent of joining existing databases and advancing systems for sharing research results.

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³ Ontologies—specifications of the terms and their logical relationships used in a particular field—are used to improve search capabilities and allow mapping of relationships among databases and informatics systems.

⁴ The wording and ordering of some indicators have been modified from NRC (2012, pp. 181–182). Details of the modifications are noted in the descriptions of the indicators in Chapter 3.

Quantifying and Characterizing the Origins of Material Releases

Knowledge of human and ecosystem exposures requires detailed information on the quantities and characteristics of ENMs produced and the products in which they are used, on how they are introduced into the environment, on how they are transported and transformed in humans and ecosystems, and on the populations exposed.

Progress in this research priority ranged from yellow to red. Yellow was assigned for the extent of progress in developing inventories of ENMs, in identifying critical release points along the value chain, in identifying critical populations or systems exposed, and in characterizing released materials in complex environments. Because those are prerequisites for model development, the ability to model releases along the value chain was denoted as red.

Processes that Affect Both Exposure and Hazard

In its first report, the committee highlighted the need to identify the critical nanomaterial interactions that affect ENM behaviors and recommended identifying cross-cutting processes common to assessing exposure and hazard. This topic includes cataloging the types of ENM transformations in complex matrices, developing instrumentation for monitoring transformations in vivo or in complex environmental media, and developing models for predicting ENM behaviors. There is a need for an infrastructure for archiving data on ENM behavior for model development. Progress ranged from yellow for initiation of studies to characterize ENM transformations and for studies that relate ENM properties

to observed effects in more complex systems to red for development of new instrumentation for measuring transformations in situ, in vivo, or in single particles.

Nanomaterial Interactions in Complex Systems Ranging from Subcellular Systems to Ecosystems

In its first report, the committee recognized the need to improve understanding of interactions of ENMs in a variety of complex systems—from single cells to subcellular organelles to individual organisms to ecosystems. A first step is to identify relevant exposure sources, concentrations, and cellular, organismal, and ecologic targets so that potential effects on complex systems can be addressed. Research progress indicators for this category ranged from yellow to red with none denoted as green. Indicators were yellow for initiation of studies that address effects of ENMs in complex systems, adaptation of system-level tools to support studies of these systems, and steps toward development of models for assessing ecologic exposures and effects. Indicators were red for developing screening tools that reflect important toxicity pathways and for identifying benchmark and reference ENMs for use in studies to characterize exposure or dose.

Research Progress Indicators: Getting to Green

The research enterprise (Figure S-1) provides a means of capturing the flow of activities and examining the pathways needed to advance research progress to get to green. As such the figure provides a means of illustrating barriers to research progress. The discussion focuses on six major categories: nanomaterial sources and development of reference materials, processes that affect nanomaterial exposure and hazard, the knowledge commons, model development, methods and instrumentation, and nanomaterial interactions in complex systems.

Nanomaterial Sources and Development of Reference Materials

Relevant ENMs include reference materials, materials from inventories, and materials released and modified across their value chain and life cycle. ENMs form the central element of research studies in the knowledge commons, the laboratory world, and the real world. The appropriate design and characterization of ENMs are needed for developing libraries, informing the design of future ENMs, developing the data to populate the knowledge commons, developing new methods and instrumentation, and conducting mechanistic studies and studies in complex media.

The nanotechnology EHS research community has relied on commonly available ENMs to conduct most studies. There is no process for determining

which nanomaterials should have high priority for development on the basis of research needs. Elements for advancing the development and distribution of reference nanomaterials for research and analytic purposes to get to green include the following:

• A mechanism for identifying and setting priorities among nanomaterials and libraries for development.

• Adoption and use of appropriate and standardized material descriptors for the design, development, and sharing of ENMs.

• Improved synthesis and purification methods for ENMs.

• Collaboration among the scientists who are studying mechanisms and complex systems to optimize materials for study.

• New methods and approaches for rapid characterization of reference materials.

• Instrumentation for characterizing complex nanoscale species (materials of unknown origin, mixtures, and released materials).

• Information-management plans and appropriate research infrastructure for collecting information on nanomaterial production and uses along the value chain.

Fundamental Processes That Affect Nanomaterial Exposure and Hazard

Research in this category occurs both in the laboratory world and the real world (Figure S-1) and involves experimental approaches to understand the physical, chemical, and biologic processes that affect exposure and hazard. Hypothesized ENM properties are scrutinized in well-defined laboratory experiments and in observations of ENM behavior in complex systems, from in vivo experiments to models of ecosystem interactions. The research is informed by development of methods and instrumentation that are needed for understanding ENM transformations, distribution, and effects.

Continued efforts to elucidate mechanisms of ENM interactions with organisms and ecosystems are critical for achieving the long-term goal of predicting ENM effects. The ability to make such predictions will allow evaluation of risks posed by ENMs at the design stage, in model predictions, and in validated screening assays. Continued progress in understanding mechanisms of ENM behavior will require advances in instrument development and an improved data-integration infrastructure.

Informatics: The Knowledge Commons

The knowledge commons, the focal point of Figure S-1, is the locus for collaborative development of methods, models, and materials, and its success requires increased integration with research in the laboratory world and the real world and with development of materials. The knowledge commons serves three

functions: a collaborative environment for the development and validation of predictive models, a collaborative environment for methods development, and a collaborative environment for the design of ENMs with the objective of improving manufacturing processes to reduce risks.

The strength of the knowledge commons is its ability to knit existing and new capabilities together in an overarching framework that provides a means of linking the various components of nanotechnology EHS research; such integration has not yet occurred. In addition, such new initiatives as the National Nanotechnology Initiative (NNI) Nanotechnology Knowledge Infrastructure (NKI) and the Materials Genome Initiative could augment the knowledge commons by providing additional linkages and informatics expertise. The knowledge commons would also have a key role in integrating participation of all sectors—including government and academic researchers, NGOs, regulators, and industry—to generate the data and knowledge that are required as inputs.

Model Development

An important outcome of the knowledge commons will be the development of a suite of models for predicting physical characteristics of ENMs, outcomes of toxicity testing, and exposures. There has been some progress in development of some types of models, but there is a lack of consistency in approaches and interoperability of data to support effective model development. Development of integrated models is needed to link behavior of ENMs to their characteristics and to properties of systems into which they are released.

Getting to green in the development of predictive models will require substantial data development from mechanistic and complex-system studies and characterization of physical properties of a variety of ENMs in different environments. Initial models will need to be developed iteratively using emerging data. Early outputs of the models can inform data needs and influence decisions about experimental approaches and instrumentation needs.

Methods and Instrumentation

Methods and instrumentation are defined as tools required for detecting and characterizing ENMs and their properties in relevant media. Progress in development of methods and instrumentation has varied because of the different applications of the tools; there has been some progress in characterizing newly manufactured ENMs in well-understood, simple media but little in detecting and characterizing ENMs in complex environments.

Progress in developing methods and instrumentation will require characterization and quantification of the properties of ENMs in complex biologic and environmental media and measurement of the properties of single particles so that specific ENM properties can be associated with observed behaviors and effects.

Nanomaterial Interactions in Complex Systems Ranging from Subcellular Systems to Ecosystems

Research on nanomaterial interactions in complex systems cuts across the laboratory world and the real world (Figure S-1). A critical barrier to advancing understanding of ENM interactions in complex systems is the lack of mechanistic data: an increasing volume of toxicity data is being produced, but the ability to use the data to predict ENM risks with any certainty is constrained because of the types of studies conducted. To provide more useful information on potential human and environmental risk, studies need to focus on more complex experimental-design issues—such as relevant dose and dosimetry; dose–response relationships 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 data, in a common format, should be shared among investigators, and results of in vivo studies (at relevant concentrations) should be compared with results of in situ and in vitro screening assays to foster development of these more expedient testing strategies. Validated screening tools also need to be developed so that information can be compared across experiments and used in modeling efforts to predict potential effects on humans and ecosystems.

Implementation Progress and Steps Needed to Get to Green

In the committee’s first report, it identified mechanisms to ensure implementation of the EHS research strategy: enhancing interagency coordination; providing for stakeholder engagement in the research strategy; conducting and communicating results of research funded through public–private partnerships; and managing conflicts of interest. Collectively, those mechanisms represent support needed for the nanotechnology EHS research enterprise (Figure S-1), given the broad potential reach of nanotechnology in our society and economy and the EHS issues that span the missions of many stakeholders. Progress in addressing implementation indicators ranged from yellow to red; no indicators were denoted as green (see Box S-2).

Enhancing Interagency Coordination

In its first report, the committee acknowledged the value of the coordinating role played by NNI and pointed to changes that have enhanced interagency coordination, including the naming of an EHS coordinator to the National Nanotechnology Coordination Office (NNCO) and the NNI’s release of its 2011 EHS research strategy. However, the committee concluded that accountability for implementation of the NNI’s EHS research strategy is hampered by the absence of an entity that has sufficient management and budgetary authority to direct

implementation among NNI agencies and to ensure integration of the strategy with EHS research being undertaken nationally and abroad. Ensuring implementation of the strategy and gauging progress in high-priority research also require an assessment of the effectiveness of available mechanisms for interagency collaboration and frequent review of funding needs.

The committee determined that some progress had been made by the NNI in increasing collaborations in EHS research and in tracking how research aligns with its broader goals and strategy. In spite of increased collaboration among federal agencies, the committee did not discern substantial progress toward establishing a mechanism to ensure sufficient management and budgetary authority to develop and implement an EHS research strategy among NNI agencies, and it designated this indicator red. The need for a stronger, convening authority to direct EHS research efforts conducted under the NNI has been similarly raised in several independent reviews of the NNI and its strategy (for example, by the President’s Council of Advisors on Science and Technology and the Government Accountability Office).

The committee gave a yellow rating to the extent to which the NNCO is identifying funding needs for collaborative efforts between agencies to accelerate high-priority research progress. To move this indicator toward green will require processes to estimate funding needs periodically and to track and report progress toward meeting the needs.

Providing for Stakeholder Engagement in the Research Strategy

The committee determined that some progress had been made toward actively engaging diverse stakeholders in a continuing manner in all aspects of strategy development, implementation, and revision (indicator yellow). The committee notes recent examples, including the NIOSH-sponsored Safe Nano by Design Conference in Albany, NY, in 2012.

To advance progress in this indicator, the committee considers that additional effort is needed to foster engagement with stakeholders, including supporting the NIOSH forum as an annual event. Similar forums should be created, perhaps around other EHS themes, including consumers, the environment, or the value chain. Such forums could be expanded to standing bodies to ensure continued engagement. In addition, the committee recommends creation of a Stakeholder Advisory Council by NNCO to help to assess the effectiveness of and opportunities for stakeholder engagement.

Conducting and Communicating the Results of Research Funded Through Public–Private Partnerships

Public–private partnerships are needed to expand and enrich EHS research through focused collaborations with stakeholders (for example, ENM manufacturers) and to expand and leverage federal funding. The committee determined

that little or no progress had been made in creating well-defined effective partnerships, as measured by execution of partnership agreements, issuance of requests for proposals, and the establishment of a governance structure; it designated this indicator red. NIOSH provides the closest current example: exposure surveys conducted at nanomaterial-manufacturing facilities.

Other examples of public–private partnerships are the European-based Nanotechnology Capacity Building NGOs (NanoCap) that addressed nanotechnology EHS risks and the NNI’s signature initiatives⁵. Another blueprint outside the realm of nanotechnology is the Health Effects Institute (HEI); a nonprofit organization chartered to provide science on the health effects of air pollution and funded 50:50 by EPA and the motor-vehicle industry.

Getting to green on the establishment of public–private partnerships may require an approach similar to the model of HEI but with a focus on nanotechnology EHS issues. Critical elements of such a public–private partnership would need to include an independent and accountable governance structure, adequate and shared funding, specific and agreed-on goals, transparent sharing of results and information, and appropriate confidentiality agreements that balance the proprietary needs of industry participants with the public need to share information and make decision-making processes transparent.

Managing Potential Conflicts of Interest

In its first report, the committee noted that the NNI’s dual functions—developing and promoting nanotechnology and its applications and mitigating risks arising from such applications—pose tension or even actual conflict between its respective goals. The clearest manifestation of the tension is the disparate allocation of resources between the two functions and the inadequacy of EHS risk research funding. The risks of early-stage technology development are intrinsically riddled with uncertainties; the science needed to provide definitive answers is highly complex and integrative and takes many years to develop. When faced with those nuances, an organization that is evaluated largely according to its success in technology development may not be perceived as able to set EHS research priorities among either resources or study topics effectively.

The committee determined that little progress had been made in establishing 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, and this indicator was designated red. Some progress was made in continued separate tracking and reporting of EHS research activities and funding as evidenced in the research-project funding data in the NNI’s EHS research

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⁵ The signature initiatives, although not focused on EHS issues, are collaborations that are intended to spur the advancement of nanotechnology. The NKI is one of the signature initiatives.

strategy and in the NNI’s supplement to the president’s 2013 budget. This indicator was designated yellow.

The committee maintains that the NNI would benefit from a clearer separation of authority and accountability for its EHS research enterprise in relation to its mandate to promote nanotechnology development and commercialization. But it acknowledges that absent a change in the NNI’s statutory mandate, establishment of wholly separate management and budgetary structures and authorities for the dual functions may not be realistic. Nonetheless, other steps could be taken at both the agency level and across the NNI as a whole to address this concern. Agencies should create and adhere to strong scientific-integrity policies governing both intramural and extramural research and should consider creating an ombudsman position to receive, investigate, and resolve complaints or concerns about bias and conflicts of interest related to nanotechnology research. The NNCO should develop and disseminate best practices for identifying, managing, and preventing conflicts of interest and bias in the planning, conduct, and reporting of research.

GOING BEYOND GREEN

Beyond advancing progress on the indicators, the committee projects to a time beyond the domain of its current research recommendations to consider how questions about risk can be best approached in an adaptive and continuing manner so as to update priorities for research and identify concerns.

The committee has repeatedly concluded that more engaged and broadly reaching governance is needed for nanotechnology EHS research. Unlike other “big science” initiatives, such as the Human Genome Project, the applications of nanotechnology permeate every sector of our society and economy; this means that the research spans the missions and jurisdictions of many diverse government agencies and intersects with activities and interests of many stakeholders. Also unlike some initiatives that focus principally or exclusively on technology development and applications, the NNI and its associated agencies are involved in research touching on both applications and implications. Governance processes must actively engage all relevant groups in the process of managing nanotechnology EHS research while addressing perceived or actual conflicts of interest. An integrated and well-coordinated program on both national and global scales would help to ensure that research findings provide the evidence needed to inform EHS decisions so that risks can be effectively managed and, ideally, prevented. Such governance requires empowered leadership: if all agencies are responsible, to some degree, for nanotechnology EHS research, no single agency can be held clearly accountable for its management and progress. The gap in empowered nanotechnology EHS research leadership at the federal level has made coordination and communication challenging and left the enterprise open to perceptions of conflicts between technology development and risk-related research. The committee considers that progress could be accelerated if one of

the NNI agencies that has EHS in its mission were designated as the lead agency for directing EHS research throughout the federal government. Alternatively, a new entity could serve that function.

Whatever organization oversees the nanotechnology EHS research strategy, among its most important functions will be to secure and maintain adequate funding for the program, inasmuch as the research strategies outlined by the NNI and the present committee cannot be accomplished without a sustained commitment over at least the next decade. In addition to funding, it is critical that the best researchers nationally and abroad be engaged in this effort and that incentives be established to encourage joint planning and information exchange to address the multidisciplinary research.

An essential element of effective governance and sustenance of the research is a means of ensuring that all stakeholders have access to the growing and evolving body of knowledge—the knowledge commons. Such a resource will provide information relevant to nanotechnology EHS research at multiple levels of detail and thus can improve public understanding, inform policymakers, offer data for future researchers, and shape the focus of future research. For researchers, the knowledge commons will provide access to existing data and will add mechanisms to curate, annotate, and link datasets, so that it will be possible to “bank” the data for consideration by future researchers. The availability of such an inventory would also facilitate oversight of the nanomaterial research program itself and provide greater accountability for research progress. The knowledge commons would provide a context for addressing the recognized need for improved taxonomies of ENM structures, experiments, characteristics, models, effects, and uses. A pragmatic approach would be the development of ontologies that map one set of defined terms onto other commonly used sets to permit data to be fully shared even if researchers adopt different conventions for nomenclature, formatting, and reporting.

CONCLUDING REMARKS

Characterization of the risks posed by ENMs across their life cycles is a scientific challenge that requires integrated, quantitative, and systems-level scientific approaches. It is also an institutional challenge that stretches the conventional roles of agencies and researchers and that looks to how future concerns can be addressed and anticipated. Strong governance is vital if effective, timely, and actionable research is to be ensured. Empowered leadership at the federal level with oversight by a single agency would begin to address many of the organizational barriers. There should be sustained funding for this research and for the infrastructure needed to support data-sharing. The necessary ideal of responsible development of nanotechnology is both daunting and important, but there is no doubt that it is attainable if we plan well for research and for the management of the infrastructure needed to shape and disseminate its findings.