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Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research 4 Review of High-Priority Research Topics, Research Needs, and Gap Analysis In this chapter, the committee examines the analysis and conclusions presented in Section II (pp. 9-44), “Summary of NNI EHS Research: Portfolio Review and Gap Analysis,” of the National Nanotechnology Initiative document Strategy for Nanotechnology-Related Environmental, Health, and Safety Research (NEHI 2008). That section discusses research categories, research needs, knowledge gaps, and inventories, and it presents the most specific and detailed technical discussion of topics relevant to decision-making for understanding and assessing the environmental, health, and safety (EHS) implications of nanotechnology. Although the committee perceived the NNI document as falling short of its aim of defining a research strategy, elements of Section II would be important for future development of a federal research strategy. The committee approached the evaluation of Section II of the NNI document by asking four questions (see Box 4-1) that were directly responsive to the charge to the committee, which was to review the scientific and technical aspects of the draft strategy and comment in general terms on how the strategy would develop information needed to support the EHS risk-assessment and risk-management needs with respect to nanomaterials. The discussion that follows is framed by the preceding materials in Chapters 2 and 3, on the elements of a research strategy, and the committee’s own collective assessment of federally funded research in FY2006, which allowed the committee to identify and evaluate the strengths and weaknesses of the NNI document. As indicated in Chapter 2, an important challenge in developing a risk-research strategy is defining its focus—in effect, the rationale for project selection. Resources are limited, and they must be deployed to create relevant information as efficiently as possible. Embedded in any strategy document are underlying principles that determine the allocation of resources, mechanisms by which research is funded, and how research is evaluated. In connection with the four questions in Box 4-1, those principles determine what is “appropriate” or “correct.” The committee believes that the value-of-information (VOI) paradigm
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Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research BOX 4-1 Questions that Structured the Committee’s Analysis Is the list of research needs appropriate? Is the gap analysis complete and accurate? Was the priority-setting of needs correct? Does the research support environmental, health, and safety risk assessment and risk management? might have been an excellent approach to informing the development of a research strategy from the outset. The committee recognizes that the 2006 NNI report identified VOI as one of the principles for identifying and setting priorities for EHS research. A VOI approach would help assess what information would be most valuable in improving understanding of the EHS risks of engineered nanomaterials. Its application relies on assessment of both the quality and the relevance of information, and it necessarily weights efforts in favor of the most pressing research needs. One fundamental rule of thumb emerging from this approach is that information that cannot change one’s (or one’s agency’s) decision has no additional value for decision-making. New knowledge could have other favorable social effects and advance our understanding of the natural world and still not have a place in a nanotechnology EHS research strategy. Application of quantitative VOI approaches clearly is premature, but qualitative concepts could be used in the development of an effective EHS research strategy. In the review of Section II of the 2008 NNI document, it was apparent that a number of issues cut across most or all of the research priority topics. They are highlighted in the next section of this chapter and are followed by an in-depth technical evaluation of each of the high-priority research topics in Section II that reflects issues specific to the five research categories (Box 4-2). The last section of the chapter discusses the committee’s assessment of the current distribution of federal investment in nanotechnology-related EHS research; it became clear to the committee when it evaluated the NNI document that its perception of the balance of relevant research among the five research categories differed substantially from the NNI’s perception (see p. 44, NEHI 2008). CROSS-CUTTING CONCLUSIONS ON ANALYSIS OF SPECIFIC RESEARCH CATEGORIES The NNI strategy document organizes EHS research into five overarching topical categories (see Box 4-2), with five research needs in each category. Each category addresses research important to EHS risk assessment. The committee
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Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research BOX 4-2 Environmental, Health, and Safety Research Categories Identified by the National Nanotechnology Initiative Instrumentation, metrology, and analytic methods. Nanomaterials and human health. Nanomaterials and the environment. Human and environmental exposure assessment. Risk-management methods. generally agreed that the five categories are logical, complete, and appropriately weighted in scope. The five categories align with the missions and research programs established within and across the regulatory and research agencies that participate in the NEHI Working Group. They provide an excellent organizational framework for describing research activities. Some committee members questioned the position of risk assessment in the document—whether it should be elevated into a separate category or left as an integrating research theme—and this was the subject of some debate. Otherwise, the committee concluded that the basic topics spanned the diverse and complex space of this problem and provided a good organization for the listing of research needs. The committee found that, with some exceptions, the specific research needs within each category were appropriate for nanotechnology EHS research. The research needs identified substantial aims important for the given research category. However, the committee believed that the lists were incomplete, in some cases missing elements crucial for progress in understanding the EHS implications of nanomaterials or not recognizing common research threads across research categories. For example, the issue of environmental exposure received insufficient emphasis in the exposure-assessment discussion although it was addressed in the nanomaterials in the environment section. The potential for nanomaterials to undergo change within biologic matrices is a common research theme that should be addressed in discussions of nanomaterials and the environment; nanomaterials and human health; and instrumentation, metrology, and analytical methods. Characterization of chemical and biologic reactivity of nanoparticles was not included as a research need in the report. Often, as will become clear, the missing research pieces would have been at an interface between categories, and their absence could have resulted from confusion about where to place them. For example, is environmental exposure a problem best tackled by researchers focused on environmental impact or by those looking at exposure assessment? Missing research needs are detailed in the appropriate sections of the topical reviews that follow.
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Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research The gap analysis is neither accurate nor complete in laying a foundation for a research strategy. As discussed in Chapter 3, the NNI strategy document defines a “gap analysis” as a major input in the development of its research strategy (pp. 6-7). The approach of evaluating the status of a specific technical field at a given time (for example, the snapshot) and comparing it with expected or desired goals is a useful exercise. However, the gap analysis by the NNI embodies perhaps the most important flaw that the committee identified in the document. Issues arising from the ineffective gap analysis led to serious deficiencies in all topical categories described in Section II. The gap analysis was inaccurate because the relevance of existing research projects to the listed research needs was generally overstated. In addition, equating the focus of research projects with research results that address a specific risk-research need is misleading. The document consistently—in every part—assumed that funded projects with only distant links to a research question were indeed meeting that research need. For example, in the measurement and characterization discussion, the development of a subangstrom-resolution microscope was said to fulfill the need “to detect nanomaterials in biological matrices.” In another category, human health, it was the committee’s expert judgment that more than 50% of the inventoried projects1 describe research directly relevant to therapeutics rather than to any of the research needs listed as relevant to potential EHS risks related to nanomaterials. The discussion of risk management, for example, considered economists who were collating the anticipated size of the markets for nanotechnology as addressing needs in risk management. The committee considered that many of the 246 research projects listed in Appendix A were of high scientific value but that they were of little or no direct value in reducing the uncertainty faced by stakeholders making decisions about nanotechnology and its EHS risk-management practices. Thus, NNI (NEHI 2008) significantly overestimates the currently funded general research activity focused on EHS research, and this contributes to the inaccuracy of the gap analysis. The second issue related to the gap analysis is that the approach taken limits the analysis to 1 year (FY 2006) of federally funded research and does not consider EHS research supported by the private sector and elsewhere in the world. Relying solely on U.S. government research has led to a document that lacks the necessary breadth to position our nation’s research on the international scene wisely. A recognition of the large-scale effort in Japan (Thomas et al. 2006), for example, to complete exposure and hazard assessments of aerosols might alter the priorities for nanotechnology EHS funding in this country. A more complete gap analysis would cast a far wider net across the technical peer-reviewed literature and related disciplines. 1 The president’s 2006 budget considered that there were 43 projects in this category; NNI (NEHI 2008) considered that there were 100 projects, the additional 57 projects being ones that are not “primarily aimed at understanding risks posed by nanomaterials” but also include research on medical-application-oriented research (NEHI 2008; Teague, unpublished material, 2008).
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Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research The criteria for priority-setting of research is not clearly stated. Information on priority-setting is only implicit in the graphical timelines (Figures 3, 5, 7, 9, and 11), and rarely explicit in the text. In evaluating each high-priority research need in Section II, the committee consistently observed that there was no clear rationale as to how research priorities were determined. Furthermore, the only representation of research priorities was that implied by the graphical timelines; and the priorities were not discussed at length in the text of NNI (NEHI 2008). The committee assumes that the criteria for priority-setting stem from NNI (NEHI 2007), Prioritization of Environmental, Health, and Safety Research Needs for Engineered Nanoscale Materials: An Interim Document for Public Comment, but that document is cited only once in NNI (NEHI 2008), and then only in the context of establishing the five research categories and 25 research needs. Even if those criteria were the basis of the graphical timelines, the lack of explanation in the text makes it nearly impossible to assess the rationale behind the decisions made by the NNI in constructing the figures. As a consequence, it was generally believed that the absence of more explicit information on priority-setting limits the value and impact of the list of research needs. In addition, there were a few cases in which the committee questioned the validity of priorities of research needs represented in the graphical timelines. For instance, under research need 2 of the instrumentation, metrology, and analytic methods category (“Understand how chemical and physical modifications affect the properties of nanomaterials,” p. 14), it is unclear why “Understanding the effect of surface function on mobility and transformations in water” is considered to have medium-term priority when, given the current production and use of unbound nanoparticles, it must be assumed that nanomaterials are already entering waterways. The document suffers universally from a lack of coherent and consistent criteria for determining the value of information provided by various research activities and for establishing priorities among the research needs. Criteria and a framework for priority-setting of research would ideally be based on an understanding of the value of each of the research needs and the relationships between them. The committee observed that little or no attempt was made to assess how the information that would be generated by addressing the research needs would be used beneficially. Consequently, there is neither a systematic framework within which research needs can be prioritized, funded, and evaluated nor a mechanism for differentiating between high-cost low-value research and lower-cost higher-value research. Both types of research need to be considered in making pragmatic decisions on directing limited resources to address a specific set of challenges. For example, many of the research needs and topics listed in the instrumentation, metrology, and analytic methods category are relevant to EHS risk assessment and management, but without a means of distinguishing research with high and low value in addressing potential risks, projects of questionable
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Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research value are cited as addressing EHS needs. Research listed as relevant to risk in this category includes the National High Magnetic Field Laboratory (National Science Foundation [NSF], project a1-30), Bioabsorbable Membranes for Prevention of Adhesion (National Institutes of Health [NIH], project b2-2), and Using Viral Particles to Detect Cancer (NIH, project b5-6). It is hard to see how such projects will lead directly to information that reduces uncertainty and informs decision-making related to assessing and managing potential risks posed by nanomaterials. If such research is undertaken at the expense of studies of higher value in relation to EHS, it will be indicative of a broken or absent strategy. A similar situation is found in the Nanomaterials and Human Health research category. In the NNI assessment of relevant FY 2006 research projects, a large portion of the research targets human health through therapeutics. Its primary focus is to develop novel strategies for treating cancer and other ailments that deserve the attention of scientists and clinicians. That may accelerate progress in cancer research and will undoubtedly advance knowledge of nanomaterial-biologic interactions that are relevant to potential risks posed by specific nanomaterials, but it will not contribute directly to the body of knowledge needed to ensure protection of public health and the environment from potential risks posed by nanotechnology and its products. In the detailed assessment of the NNI document that follows, the committee concluded that the current research portfolio does not address the most rudimentary problems in environmental, health, and safety. ANALYSIS OF SPECIFIC RESEARCH CATEGORIES The subsections below address the five research categories (see Box 4-2), considering the questions presented in Box 4-1. Each subsection is divided into three parts; the introduction that explains the committee’s approach, the evaluation and assessment, and the conclusions. Instrumentation, Metrology, and Analytic Methods Introduction Because the behavior of nanomaterials depends on their structure at the nanoscale (such as physical shape and size and the location and distribution of chemical components), sophisticated characterization and measurement methods are essential for understanding and addressing potential risks. The potential association between scale-related physicochemical characteristics and biologic effects of nanomaterials challenges conventional approaches to risk. In the past, risk decision-making was typically driven by the chemical constituents of a material, not by physical structure—although there are a few notable exceptions, such as asbestos and the distinctions between in-
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Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research halable and respirable airborne particles. That approach has generally enabled risks associated with materials to be managed reasonably effectively. But the likelihood that some nanomaterials can cause harm by virtue of their nanoscale structure places a much greater emphasis on aspects of nanomaterials not previously considered important. The challenges in instrumentation, metrology, and analytic methods for identifying, assessing, and managing nanotechnology EHS effects are threefold: establishing the usefulness of methods currently used to assess risk, translating existing methods to address risk (a process of method bridging), and developing new methods. Those challenges (once risk parameters are clarified) raise three overarching issues: grouping nanomaterials that have similar risk-relevant characteristics, ascertaining the appropriate tolerances of risk-related measurements, and determining the context of risk-related characterization and measurement. An ability to group nanomaterials according to their biologically relevant behavior is essential if material variants are to be rationalized into a finite number of material classes. Developing methods to assess and to monitor the potential effects of every combination of size, form, chemistry, and other properties of engineered nanomaterials clearly is not feasible. But if materials with similar biologically relevant properties could be grouped, it might be possible to reduce the challenge of characterization to a much smaller set of nanomaterial groups. Tolerance, the accuracy and precision that measurements need to support risk-based decisions, is likely to vary from nanomaterial to nanomaterial and also over time as new information on the importance (or lack thereof) of specific physicochemical characteristics is developed. Without some idea of the tolerance to which measurements should be made, it is not possible to establish a clear research strategy. For instance, if particles of a nanomaterial have similar biologic behavior whether they are 20 nm or 40 nm in diameter (Jiang et al. 2008b), investing tens of millions of dollars on instrumentation with a resolution of 0.05 nm will not advance their risk assessment and management to any important degree.2 Understanding appropriate tolerances will be an iterative process that emerges from a well thought-out and integrated research strategy. If resources are to be assigned appropriately, some initial estimates of what is important are needed. That leads to the third overarching issue: context. Risk-related nanomaterial metrology will depend on the type of material under investigation, the context in which the material is being used (or exposure occurs), and the current level of knowledge on which material characteristics are likely to be important. Metrology requirements for exploratory research on biologic interactions will differ from those for evaluating material toxicity, which in turn will bear only a passing resemblance to measurement and characterization requirements for exposure monitoring and material-dispersion evaluation. Likewise, analytic methods will need to be tied, where possible, to important physicochemical charac- 2 This is a hypothetical example that is loosely based on the Transmission Electron Aberration-Corrected Microscope (TEAM) project discussed in NEHI (2006).
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Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research teristics that may differ between nanomaterials. For example, understanding the interactions between gold nanoparticles and DNA will require a detailed understanding of particle shape, size, and surface chemistry; but in monitoring exposure to the same material in the workplace, it may be sufficient to measure mass concentration or surface area concentration for all particles and aggregates that are smaller than a few micrometers in diameter. In summary, components of an effective research strategy to address nanomaterial instrumentation, metrology, and analytic methods in the context of risk should include An assessment of the current state of the art of nanomaterial analysis. Classification and grouping of nanomaterials that convey the physical and chemical properties relevant to biologic effects. Definition and evaluation of appropriate accuracy and precision (tolerance) for measuring those properties. Identification and clarification of the analytic needs of researchers working with nanomaterials in toxicology, exposure assessment, environmental science, and medicine. Standardization of methods and metrics used in nanotoxicology studies, including standardized approaches for route of administration and dose metrics. Cross-disciplinary translation of established methods to the needs of the nanotechnology-related EHS researchers. Development of new methods that meet the specialized demands of nanotechnology-related EHS research. Evaluation and Assessment Each of the five identified research needs in this category (NEHI 2008, Figure 3, p. 18) is important for nanoscience and nanotechnology generally (see Box 4-3). However, the breadth of many of the research needs is so great that it is difficult to understand how they will be useful in practice for guiding a nanotechnology-related EHS research strategy. There is poor balance between near-term needs for research targeted to immediate issues faced by the EHS community (including characterization of nanomaterials in toxicology studies and monitoring of occupational exposures and environmental releases) and evaluation of the efficacy of control and containment measures. There also appears to be a gap between the identified research needs and the examples of funded research provided in the text that is not clearly resolved (pp. 12-17 and 57-67). Many of the FY 2006 research projects listed in Appendix A as relevant to this research category—although important for the advancement of nanoscience and nanotechnology—have little obvious relevance to EHS issues. There is little effort to address the gap between what is needed and what has been funded.
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Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research BOX 4-3 Research Needs for Instrumentation, Metrology, and Analytical Methods Develop methods to detect nanomaterials in biological matrices, the environment, and the workplace. Understand how chemical and physical modifications affect the properties of nanomaterials. Develop methods for standardizing assessment of particle size, size distribution, shape, structure, and surface area. Develop certified reference materials for chemical and physical characterization of nanomaterials. Develop methods to characterize a nanomaterial’s spatio-chemical composition, purity, and heterogeneity. Source: NEHI 2008. Research need 1, “Develop methods to detect nanomaterials in biological matrices, the environment, and the workplace,” is important but broad and would benefit from being split into three research needs that address biologic matrices, the environment, and the workplace separately. Detecting exogenous nanomaterials in biologic matrices is essential for understanding their movement in the body and doses at the organ, cellular, and subcellular levels. Likewise, detecting nanomaterials in the environment will be essential for both monitoring ecologic exposures and containing possible releases. Workplace exposure is an immediate issue for all of nanotechnology, and methods to address it are necessary. Those three topics underpin much of the research and action needed to understand and address potential environmental and health implications of engineered nanomaterials, and their discussion should be tightly linked to research needs described elsewhere in the document. All the specific aims listed under this research need are useful, but they constitute a collection of research interests that lacks coherence. Creating three new research needs would enable more attention to be given to sequencing relevant measurement and characterization research in the context of what is needed to address potential risks. In common with other research needs, this section is filled with examples of funded projects that bear little relationship to the overall stated goals. For example, several projects mentioned on p. 13 of the NNI document focus on single-molecule fluorescence. Molecular-level interaction of nanomaterials with cells is interesting, but it does not directly concern detection of nanomaterials in biologic matrices and has little relevance to the practical needs for nanotechnology-related EHS research. Likewise, research aimed at developing nanoparticles as contrast enhancers has limited relevance to the general problem of detecting
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Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research exogenous nanoparticles within biologic matrices, given that the aim of such research is specifically to develop nanoparticles that are easy to detect. Similar issues arise in the case of cited research on sensors: the projects described are of a general nature, and their specific value to EHS issues is not clear. Without clearer explanation, it is hard to see how, for example, the following projects are justified as addressing nanotechnology-related EHS research needs: National High Magnetic Field Laboratory (NSF, project A1-30), Bioabsorbable Membranes for Prevention of Adhesion (NIH, project B2-3), Using Plasmon Peaks in Electron Energy-Loss Spectroscopy to Determine the Physical and Mechanical Properties of Nanoscale Materials (Department of Energy, project A2-5), and Using Viral Particles to Detect Cancer (NIH, project B5-6). Research need 2, “Understand how chemical and physical modifications affect the properties of nanomaterals" sits uneasily in this section of the document, as in this area measurement needs cannot be divorced from biological and environmental behavior. It would have been far more effective if research need 2 was directed specifically to issues relevant to biologic and ecologic effects, perhaps by restating it as “biologic” properties. More important, this suggested research need, the correlation of the fundamental structure of a nanomaterial with its biologic properties, does not belong in this research category. Rather, because it is driven primarily by the study of biologic interactions, it should be addressed as a cross-cutting research need between the nanomaterials and human health and the nanomaterials and the environment categories. What does belong in this high-priority group is a discussion of how to characterize the molecular properties of the nanomaterial-biologic and nanomaterial-environmental interface. Information on a nanomaterial’s physical and chemical properties is critical for enabling a general understanding of structure-function relationships that will guide future nanotechnology-related EHS research. It is a long-range and exploratory research need, but it is highly relevant to the potential safety or harmfulness of increasingly sophisticated engineered nanomaterials and should form a key component of a strategic research program. Although the overall need is too broad to be of much use in addressing nanotechnology-related EHS issues, the two specific research subjects identified—“Evaluate solubility in hydrophobic and hydrophilic media as a function of modifications to further modeling of biological uptake” and “Understand the effect of surface function on mobility and transformation in water”—are by contrast too narrowly defined to support strategically relevant progress. These two research areas on their own do not adequately address the studies needed to develop a clearer understanding of how physical and chemical modifications affect the properties of nanomaterials. Research need 3, “Develop methods for standardizing assessment of particle size, size distribution, shape, structure, and surface area,” is based on the fact that such methods are vital for developing a clear understanding of how engineered nanomaterials might affect human health and the environment—and how
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Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research to avoid the effects. Many of the specific aims listed here are relevant to and important for addressing nanotechnology-related EHS issues. This should remain a high priority research need and receive sufficient attention and support to ensure timely and relevant progress. What is missing from the strategy document is an assessment of relative importance: What standardization and metrics are suitable for risk assessment and management? Without that context, the research aims become a vehicle to justify broad metrology research across nanotechnology to the detriment of more targeted risk-relevant research. That is especially the case where the precision and accuracy needed for exposure monitoring or toxicity testing are not as high as those needed for quality control or exploratory research. One emphasis that is essential to this research need but is missing is the importance of community-building activities. Only the broad research community can define and standardize biologically relevant, effective protocols for nanomaterial characterization. The free availability and wide dissemination of methods should be as important an outcome of community-building activities that include round-robin evaluations as the measurement of the accuracy and precision of the methods. Research need 4, “Develop certified reference materials for chemical and physical characterization of nanomaterials,” is important but complex. Standard materials are required to validate the characterization protocols described in research need 3. It is also important to identify metrics with which the standards would be characterized and made available, for example, surface area, size, or chemical activity per unit surface area, such as reactive oxygen species per surface area (Jiang et al. 2008b). Substantial community-building activities (for example, workshops and multistakeholder input) are required to create a pool of useful materials that are relevant to nanotechnology-related EHS research. Efforts to train users to handle and work with the nanomaterials in biologic and environmental testing should also be addressed. In common with other research needs in the category, the question, How much is enough? is important for assessing and managing risk and is not addressed. Without such understanding of the limitations of reference materials, there are no safeguards to prevent inappropriate levels of investment on irrelevant materials. Research need 5, “Develop methods to characterize a nanomaterial’s spatio-chemical composition, purity, and heterogeneity,” is broad, and tolerance and relevance are not addressed in the subtopics. As discussed previously, this research need involves the characterization of nanoscience generally and is ill-suited to the goals of addressing potential EHS effects of nanomaterials. It may be that the intent of this research need was to characterize the nanomaterial-biologic interface. It would be more compelling if it included specific discussion of the critical needs for characterizing this interface and of the tools that could be applied to the needs. Metrology is required that goes beyond nanomaterial detection (research need 1) and nanomaterial gross physical properties (research
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Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research The 2008 NNI document does not address human and environmental exposure potential throughout the life cycle of nanomaterials. It focuses primarily on occupational exposure. The exposure-assessment section is imbalanced and does not adequately connect with research on environmental processes that determine environmental exposures. Understanding metrology and developing tools to characterize and measure attributes of nanomaterials—including particle size, number, and surface area—relevant to exposure is not identified as having high priority, and it is implied that it is adequately addressed by the projects listed in the instrumentation and metrology section. The document does not consider exposure in the context of susceptible populations in humans and the environment, nor does it consider the need to identify such populations. An exposure that may be harmless for a healthy organism may be detrimental to a susceptible population. The NNI document does not address the importance of exposure studies in the design of toxicologic and ecotoxicologic studies. Repeat or chronic studies in relevant experimental animal models and model systems using realistic exposure concentrations should be an essential component of risk assessment of nanomaterials (including considerations of susceptibility, mechanisms, and mode of action). Risk-Management Methods Introduction By including risk-management methods as one of its five research categories, the 2008 NNI document recognizes that research on risk management can not only broaden available options but also inform risk-assessment research. For an emerging set of technologies, such as nanotechnology, with great uncertainties regarding hazards and exposures, the rapid and active development of risk-related information for risk management should have very high initial priority. The NNI document identifies five research needs (see NEHI 2008, Figure 11, p. 42 and Box 4-7) that, with several exceptions, subsume the twenty-four research needs in NEHI (2006). There is no description of the process by which these changes occurred. NEHI (2007) provides a limited description of the combining and prioritization of the 2006 research needs, but does not account for why some identified needs (for example, packaging needs, spill containment methods) are not mentioned. In addition, many of the specific research needs
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Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research subsumed under the five research needs in NEHI (2008) are only evident in the report’s Figure 11 and are not discussed in the text. Responsible nanotechnology-related risk management requires not only research to support risk assessment and to develop new knowledge about risk-management methods and technologies but data collection on trends and practices and dissemination of risk information. A research strategy for risk-management methods should lay out clearly the boundaries between research activities and risk-management data-collection activities. Those boundaries are not defined in the 2008 NNI document. Instead, some essential data-collection and information-dissemination activities are listed as research projects. Such activities are critical for effective risk management, but they do not constitute risk-management research. For example, collecting information on nanoparticle type, composition, and physicochemical characteristics is not research; development of a control banding method3 based on those characteristics would be. Evaluation and Assessment The NNI document lacks a rationale for the selection of research needs and assignment of specific projects related to risk-management methods. That is evident from the statement on p. 41 that indicates that this category has been used as a catchall for projects otherwise not classifiable: “issues not typically thought of as pertaining directly to risk management needs, such as ethics and societal considerations, are included in the projects that fall under this category.” Nearly half the already small number of projects, and 62% of the total funding, could not be assigned to any of the other four categories so were placed here. The text does not describe how the unclassifiable projects contribute to meeting research needs. Ideally, the NNI and the Nanotechnology Environmental and Health Implications Working Group (NEHI) would constitute a useful structure for bringing the needs of risk managers in the regulatory agencies to the attention of scientists in the primary research agencies. The NNI strategy states that “input about the needs of regulatory decision makers expedites the development of information to support both risk assessment and risk management of nanomaterials” (p. 3). That might be true, but there is no description of input from agency risk managers in the 2008 NNI document. Moreover, this section addresses only occupational settings; risk managers for the Food and Drug Administration and EPA would most likely have included environmental and consumer exposure settings as well. The focus of the research may be partly due to NNI’s own data collection methods, as NNI acknowledges on p. 38, “the apparent lack of fund- 3 “Control banding is a qualitative risk-assessment and risk-management approach to promoting occupational health and safety.” For additional information, see NIOSH (2005).
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Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research BOX 4-7 Research Needs for Risk Management Methods Understand and develop best workplace practices, processes, and environmental exposure controls. Examine product or material life cycle to inform risk reduction decisions. Develop risk characterization information to determine and classify nanomaterials based on physical or chemical properties. Develop nanomaterial-use and safety incident trend information to help focus risk management efforts. Develop specific risk communication approaches and materials. Source: NEHI 2008. ing by regulatory agencies for risk management methods research could be due to the data call having been focused primarily at grant-related efforts for a topic that may not always be addressed through research.” There is very little indication of priorities among research needs in this section. Most of the text describes the existing studies that have been placed in this category and the substantial gaps in most of the research needs. There is no textual description of priorities among the many gaps or of how the gaps will be strategically filled. The only indication of priority among the research needs is in Figure 11. Of the 13 subjects in the five research needs, all but two indicate high priority for immediate emphasis. That is appropriate for risk management of an emerging technology, but it is not informative, especially given the poor description of what is involved in the research needs. Moreover, in a research field characterized by uncertain risks and poor-quality information about risks, it is not appropriate to stall the development of essential risk communication, but this is the only research need that is put off to the intermediate term. In reviewing this research category, the committee compared the description of research and research needs in risk-management methods in the 2006 NNI report with the research needs, listed projects, and text discussion on risk-management research in the 2008 NNI document. Research gaps were identified through the comparison and with expert judgment, and the evaluation of priorities was based on the descriptions in the 2008 document. Because the content is explicitly related to risk management, the question of relevance to risk management was not considered separately. Analysis of Individual Risk-Management Research Subjects The strategy briefly describes 14 projects in the risk-management methods
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Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research research category, with a total funding of $3.3 million, primarily from NSF and the National Institute for Occupational Safety and Health. In many cases, it is difficult to discern from the information provided in the 2008 NNI document what is intended by the category; this complicates an independent analysis of the appropriateness of the research needs. For example, research need 3, “Develop risk characterization information to determine and classify nanomaterials based on physical or chemical properties,” implies development of a banding or other screening-level categorization of nanomaterials for risk-management purposes on the basis of readily available physical or chemical characteristics. That is a highly relevant and appropriate research need for risk management that is referred to in the 2006 NNI report. The 2008 document, however, does not describe the research need in any detail or how it is to be met. The text combines the research need with the unrelated research need 4, “Develop nanomaterial-use and safety-incident trend information to help focus risk management efforts,” apparently because one 2006 project was believed to address the two rather disparate research subjects equally. In place of a thorough description of the research needs, the text describes the severe limitations of the one project placed in this grouping. The discussion of research need 3 (risk-characterization information) and research need 4 (trend information) also illustrates the failure of the section to distinguish between risk-management method research and risk-management activities. Compiling information on use, trends, and products is essential for developing appropriate risk-management strategies. However, it is not clear why developing a Web-based library (research need 3, project E3-1 in Appendix A, p. 87) or collection of trend information (research need 4) is considered as filling a “research need” instead of as an infrastructure or surveillance activity, especially when it is only a voluntary activity and therefore unlikely to be comprehensive or representative in its characterization. Moreover, the information collected is stated to be “nanomaterial-characterization” rather than “risk-characterization” information identified as a research need. That is another example of how the document is compromised by its efforts to make existing projects fit into the research needs previously identified as critical even when the projects are neither truly research projects nor designed to develop information pertinent to the research need. Research need 1 (workplace practices and environmental controls) has a primary focus on inhalation exposure; only respirators and personal protective equipment are mentioned. Projects assigned to this research need were relevant and designed to provide essential information. The committee notes, however, that studies of workplace design and other engineering controls, dermal and other routes of exposure, and workplace hygiene and disposal practices should also be discussed in the section. There are large gaps in worker-protection research, and little in this document indicates strategies or priorities for filling them. Research need 2 deals with life-cycle analysis and comprehensively considers, “manufacturing, incorporation into an integrated product, consumer use,
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Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research and recycling or disposal” (p. 4). It is essential that not only the finished product but the materials, byproducts, and waste in producing the materials be considered with regard to EHS. But the description of this research need does little to explain the strategic approach to understanding product or material life cycles. The 2006 portfolio identified only two projects in this category, one of which is a life-cycle analysis of manufacturing technologies rather than products or materials (project E2-2 in Appendix A, p. 87); the other is limited to a small sector of products (project E2-1). The strategy itself identifies a clear research gap in lifecycle analysis for product classes not considered in the two current research projects. The document suggests that the research gap is so large, “a systematic evaluation … is needed to evaluate where the most critical of such gaps would exist” (p. 40). However, there is no further discussion of conducting such an evaluation. Thus, although including life-cycle analysis is appropriate, a clearer description of specific research and of how the extensive gaps are to be filled is needed. Only one project is identified in research need 5 (risk-communication approaches). It is restricted to workplace-related issues, and this indicates a large gap in risk-communication approaches for the general public. In addition, the single project listed describes an information-dissemination project rather than a two-way risk-communication project. The document should consider risk communication as a useful information-gathering process and give higher priority to problem scoping and formulation processes with interested and affected parties (NRC 1996). The section on risk-management methods identifies four gaps on p. 41 of NNI (NEHI 2008): trend information, exposure controls, flammability or reactivity changes due to particle size, and material-safety data sheets. In the broader summary of research needs on p. 46, the 2008 NNI document identifies three major risk-management research gaps to be addressed in the near term: “develop risk characterization information to determine and classify nanomaterials based on physical or chemical properties,” “develop nanomaterial-use and safety-incident trend information,” and “expand exposure route-specific risk management methods research and life cycle analysis research on the basis of nanomaterial use scenarios expected to present greatest exposure and potential for health or environmental effects.” The committee agrees that these seven research priorities, some of which are identical with the research needs mentioned in the document and some not, are reasonable. The lack of concordance between the two lists of identified gaps, however, and the lack of discussion of how the NNI and the NEHI intend to promote research to address them preclude useful evaluation of whether the NNI document provides a useful strategy for filling gaps and meeting short-term and long-term risk-management needs. Risk-management topics and kinds of research areas in addition to the gaps identified by the document should be considered in this section. They include identifying nanotechnology-enabled products that can assist in managing risks posed by conventional hazards, and permitting the replacement of hazardous chemicals with less hazardous materials. For example, the document indi-
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Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research cates that the properties of nanomaterials can be used to “clean contaminated soil and groundwater” (p. 3). That suggests an important risk-management activity for EPA. Although this kind of research was mentioned in the 2006 NNI report and research project C4-8 in Appendix A (p. 82) appears to support it, there is no further discussion of it in the 2008 document. Identifying and developing nanotechnology-enabled risk-management approaches to environmental problems should be addressed as a separate research need. Conclusions The criteria for setting priorities for risk-management methods research were not clearly stated. Information was only implicit in the graphical timelines, not described explicitly in the text. Descriptions of high-priority research needs and how they are to be met are lacking; in their place are descriptions of the FY 2006 projects and their limitations in meeting the needs. There is inadequate description of the process by which the 24 research needs identified in the 2006 NNI report were culled to the five in the 2008 NNI document. The graphical timeline gives high priority to nearly all research needs, providing little strategic guidance for meeting them within resource constraints. The gap analysis for risk-management methods is flawed and limited by the decision to use the 2006 research portfolio as its basis. Major gaps, including management of environmental and consumer risks with emphasis on potential risks to infants and children, are not addressed. The small number of research projects in this category and the smaller number of research projects that actually address the identified research needs underscore the enormous gaps between what is needed and what the agencies are doing. The failure to distinguish carefully between risk-management methods research and risk-management data-collection activities further hampered the gap analysis. The lack of consideration of management of environmental and consumer risks constitutes another considerable gap. It pertains to consideration of risk-management approaches to both general population exposures and specific potential exposure settings, such as accidents and spills, environmental discharges, and exposure through consumer products with the likelihood of exposure of infants and children; it also pertains to the development of life-cycle analyses, which must encompass not just manufacturing processes but the entire product life cycle from resource extraction through disposal. In general, approaches to risk management, such as control banding, that can help to address risks in the absence of completed traditional risk assessments are not adequately addressed in the document. Although the focus on workplace risk management is reasonable given that the occupational setting is likely to be the initial setting where important exposures occur, and the few projects that assess the adequacy of exposure-control measures are critical and appropriate, the overall risk-
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Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research management research portfolio and strategy are inadequate to address societal needs. The document does not provide evidence of a strategic approach to risk-management research. The need for the rapid development and validation of effective risk-management methods is great for a set of rapidly emerging technologies like nanotechnology, but the narrow focus on 2006 studies and failure to describe adequately what is meant by the research categories and how projects are to be given priority constitute a failure to develop a strategic plan to meet the need. COMMITTEE’S ASSESSMENT OF CURRENT DISTRIBUTION OF FEDERAL INVESTMENT IN NANOTECHNOLOGY-RELATED ENVIRONMENTAL, HEALTH, AND SAFETY RESEARCH The NNI comments on the distribution of nanotechnology-related EHS research investment by illustrating the amount of money it was spending on each of the five research categories in FY 2006 (see Table 4-1). It states that “it is appropriate that investments at this time are predominantly in the categories of Instrumentation, Metrology, and Analytical Methods, Nanomaterials and Human Health, and Nanomaterials and the Environment. The balance of spending will evolve in time as research programs mature and efforts that are undertaken sequentially are initiated” (p. 44). On the basis of the breakdown in funding, the NNI concludes that, “in short, the analysis demonstrated that the Federal Government is supporting more EHS research than has been previously identified, and the research is well-distributed across key priority areas” (p. 2). However, the analysis does not address how well the funded studies are addressing the specific research needs for a science-based assessment of the human health and environmental risks posed by the production, use, and distribution of nanoscale engineered materials. In the committee’s opinion, examining what is funded (Appendix A, pp. 55-58) leads to a different research portfolio that is heavily slanted to specific medical-imaging applications, therapeutic nanomaterials, and targeted drug delivery, especially cancer chemotherapeutics, and to studies focused on understanding fundamentals of nanoscience that are not explicitly associated with the EHS aspects of the risks posed by nanomaterials. The nanomedicine projects are not basic toxicologic studies of potential human response to nanomaterials in general. Rather, much of this research focuses on finding new applications of nanotechnology-related therapeutics. That does not lead to the general understanding of factors governing absorption, distribution, metabolism, elimination, and toxicity of manufactured nanomaterials needed for a comprehensive risk assessment of manufactured nanomaterials with respect to environmental, occupational, and consumer exposure (for example, cosmetics).
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Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research TABLE 4-1 NNI Evaluation of Federal Grant Awards in FY 2006 That Are Directly Relevant to EHS Issues Category Number of Projects $ Invested (Millions), FY 2006 Instrumentation, Metrology, and Analytical Methods 78 26.6 Human Health 100 24.1 Environment 49 12.7 Human and Environmental Exposure Assessment 5 1.1 Risk Management Methods 14 3.3 TOTAL 246 67.8 Source: NEHI 2008. Many of the funded projects will not generate the information needed to support EHS risk assessment and risk management or provide critical data for regulatory agencies. It makes no sense to include many of the projects listed in Appendix A only because incidental knowledge, procedures, or techniques obtained from that research might be relevant to one or another aspect of research relevant to EHS needs in nanotechnology. The committee notes that the NNI chose to include an additional 116 projects in Appendix A that were not included in the president’s budget even though they were aimed primarily at medical applications or at characterization and measurement of nanomaterials (NEHI 2008; Teague, unpublished material, 2008). The committee conducted its own informal reassessment of the current balance of nanotechnology-related EHS-research investment by using its professional judgment. The committee reviewed the titles and abstracts of the projects to determine which are primarily aimed at understanding the potential risks posed by engineered nanomaterials or would otherwise be reasonably expected to provide data that are directly relevant to EHS evaluation. The results are presented in Table 4-2. (Only the percentages of projects in each broad category are presented, because the funding of each project was not readily available.) Table 4-2 shows that roughly one-fifth to two-fifths of research projects in the instrumentation, metrology, and analytic methods category and about one-third of projects in the human-health category are directly relevant to understanding the potential risks posed by engineered nanomaterials or would otherwise be reasonably expected to provide data that are directly relevant to EHS evaluation. The ranges in Table 4-2 reflect the variability in professional judgment among committee members; such an evaluation has elements of subjectivity. Nevertheless, what is critical is that fewer than half the projects listed in Appendix A are relevant to understanding of EHS issues related to nanomaterials. Therefore, the amount of money being spent by the federal government specifically to address EHS needs in nanotechnology is certainly far less than the
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Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research TABLE 4-2 NRC Committee’s Estimate of Percentage of FY 2006 Projects That Are Aimed Primarily at Understanding Potential Risks Posed by Engineered Nanomaterials Category Committee’s Professional Judgment Instrumentation, Metrology, and Analytical Methods 18-40% Human Health 30-32% Environment 67-84% Human and Environmental Exposure Assessment 100% Risk Management Methods 57-78% TOTAL 36-48% $68 million indicated in the NNI strategy document. It should be noted that that conclusion is supported by other independent analyses of the issue (for example, GAO 2008; Maynard 2008). CONCLUSIONS Cross-cutting observations that are relevant to all research categories in the 2008 NNI strategy document include the following: generally appropriate research needs are identified, priorities among research needs are not clearly articulated, and the gap analysis contributes to overstating the amount of relevant federal research being conducted to support EHS research needs related to nanomaterials. The organization of research into five topical categories is necessary, but it obscures the interrelationships among research needs and creates the possibility that research needs that fall between categories will be overlooked. It is important that the research categories not be viewed as silos. For example, environmental exposures is a common thread in both research categories; Nanomaterials and the Environment and Human and Environmental Exposure Assessment. An example of a research need that may have been omitted because it falls between categories is the omission of characterization methods that consider specific biologic settings. Additional examples are discussed in Section II. Inventories of the research needs are sufficient for some topical categories, but they are poorly defined and incomplete in risk management and exposure assessment. For example, the discussion of exposure assessment does not address exposures throughout the life cycle of nanomaterials and the discussion of risk-management methods does not cover management of environmental and consumer risks, including specific potential exposure scenarios, such as accidents and spills, environmental discharges, and exposure through consumer products.
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Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research Poor gap analysis is a problem in all sections of the document, but it is particularly severe in the discussions of human health and metrology. Table 4-2 offers the committee’s collective expert judgment of the extent to which the NNI strategy document miscounts research projects in its gap analysis. As is apparent, this problem was particularly severe with respect to the instrumentation, metrology, and analytic methods category and the human-health category. The extent of the problem is so great that the committee is concerned that the current funding or allocation of funding for EHS research needs related to nanomaterials may not be adequate to address current uncertainties in the manner needed to understand the risks posed by nanomaterials. REFERENCES Borm, P.J., D. Robbins, S. Haubold, T. Kuhlbusch, H. Fissan, K. Donaldson, R. Schins, V. Stone, W. Kreyling, J. Lademann, J. Krutmann, D. Warheit, and E. Oberdorster. 2006. The potential risks of nanomaterials: A review carried out for ECETOC. Part Fibre Toxicol. 3(1):11. Christaki, U., J.R. Dolan, S.P. Pelegrí, and F. Rassoulzadegan. 1998. Consumption of picoplankton-size particles by marine ciliates: Effects of physiological state of the ciliate and particle quality. Limnol. Oceanogr. 43(3):458-464. EPA (U.S. Environmental Protection Agency). 2008. Nanotechnology: Research Projects. National Center for Environmental Research. February 26, 2008. Available: http://es.epa.gov/ncer/nano/research/index.html [accessed October 16, 2008]. GAO (U.S. General Accountability Office). 2008. Report to Congressional Requesters Nanotechnology: Better Guidance is Needed to Ensure Accurate Reporting of Fed-eral Research Focused on Environmental, Health, and Safety Risks. GAO-08-402. Washington, DC: U.S. General Accountability Office. March 2008 [online]. Available: http://www.gao.gov/new.items/d08402.pdf [accessed Aug. 26, 2008]. ICON (International Council on Nanotechnology). 2008. Towards Predicting Nano-Biointeractions: An International Assessment of Nanotechnology Environment, Health, and Safety Research Needs. International Council on Nanotechnology No. 4. May 1, 2008 [online]. Available: http://cohesion.rice.edu/CentersAndInst/ICON/emplibrary/ICON_RNA_Report_Full2.pdf [accessed Aug. 26, 2008]. Jiang, J., G. Oberdörster, and P. Biswas. 2008a. Characterization of size, surface charge, and agglomeration state of nanoparticle dispersions for toxicological studies. J. Nanopart. Res. DOI 10.1007/s11051-008-9446-4. Jiang, J., G. Oberdörster, A. Elder, R. Gelein, P. Mercer, and P. Biswas. 2008b. Does nanoparticle toxicity depend on size and crystal phase? Nanotoxicology 2(1):33-42. Maynard, A. 2002. Experimental determination of ultrafine TiO2 deagglomeration in a surrogate pulmonary surfactant: Preliminary results. Ann. Occup. Hyg. 46(Suppl. 1):197-202. Maynard, A. 2008. Testimony to Committee on Science and Technology, U.S. House of Representatives: The National Nanotechnology Initiative Amendments Act of 2008, Annex A. Assessment of U.S. Government Nanotechnology Environmental Safety and Health Research for 2006. April 16, 2008 [online]. Available: http://democrats.science.house.gov/Media/File/Commdocs/hearings/2008/Full/16apr/Maynard_Testimony.pdf [accessed Aug. 27, 2008].
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