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4 Review of High-Priority Research Topics, Research Needs, and Gap Analysis In this chapter, the committee examines the analysis and conclusions pre- sented in Section II (pp. 9-44), âSummary of NNI EHS Research: Portfolio Re- view and Gap Analysis,â of the National Nanotechnology Initiative document Strategy for Nanotechnology-Related Environmental, Health, and Safety Re- search (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 nanotech- nology. Although the committee perceived the NNI document as falling short of its aim of defining a research strategy, elements of Section II would be impor- tant for future development of a federal research strategy. The committee approached the evaluation of Section II of the NNI docu- ment 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 as- pects 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 re- search strategy, and the committeeâs own collective assessment of federally funded research in FY2006, which allowed the committee to identify and evalu- ate 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 focusâin effect, the rationale for project selec- tion. Resources are limited, and they must be deployed to create relevant infor- mation as efficiently as possible. Embedded in any strategy document are under- lying 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 âappropriateâ or âcorrect.â The committee believes that the value-of-information (VOI) paradigm 53
54 Review of the Federal Strategy for Nanotechnology BOX 4-1 Questions that Structured the Committeeâs Analysis â¢ Is the list of research needs appropriate? â¢ Is the gap analysis complete and accurate? â¢ Was the priority-setting of needs correct? â¢ Does the research support environmental, health, and safety risk as- sessment and risk management? might have been an excellent approach to informing the development of a re- search strategy from the outset. The committee recognizes that the 2006 NNI report identified VOI as one of the principles for identifying and setting priori- ties for EHS research. A VOI approach would help assess what information would be most valu- able in improving understanding of the EHS risks of engineered nanomaterials. Its application relies on assessment of both the quality and the relevance of in- formation, and it necessarily weights efforts in favor of the most pressing re- search needs. One fundamental rule of thumb emerging from this approach is that in- formation that cannot change oneâs (or oneâs agencyâs) decision has no addi- tional 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 quanti- tative 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 committeeâs 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 substan- tially from the NNIâs 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
Review of Priority Research Topics, Research Needs and Gap Analysis 55 BOX 4-2 Environmental, Health, and Safety Research Categories Identified by the National Nanotechnology Initiative â¢ Instrumentation, metrology, and analytic methods. â¢ Nanomaterials and human health. â¢ Nanomaterials and the environment. â¢ Human and environmental exposure assessment. â¢ 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 pro- grams established within and across the regulatory and research agencies that participate in the NEHI Working Group. They provide an excellent organiza- tional framework for describing research activities. Some committee members questioned the position of risk assessment in the documentâwhether it should be elevated into a separate category or left as an integrating research themeâ 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 im- plications 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 envi- ronment; 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 be- tween 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.
56 Review of the Federal Strategy for Nanotechnology 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 âgap analysisâ 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 em- bodies perhaps the most important flaw that the committee identified in the document. Issues arising from the ineffective gap analysis led to serious defi- ciencies 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, equat- ing the focus of research projects with research results that address a specific risk-research need is misleading. The document consistentlyâin every partâ assumed that funded projects with only distant links to a research question were indeed meeting that research need. For example, in the measurement and charac- terization discussion, the development of a subangstrom-resolution microscope was said to fulfill the need âto detect nanomaterials in biological matrices.â In another category, human health, it was the committeeâs 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 poten- tial 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 com- mittee 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 re- ducing the uncertainty faced by stakeholders making decisions about nanotech- nology and its EHS risk-management practices. Thus, NNI (NEHI 2008) signifi- cantly 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 lim- its 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 nationâs 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 presidentâs 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 âprimarily aimed at understanding risks posed by nanomaterialsâ but also include research on medical-application-oriented research (NEHI 2008; Teague, unpublished material, 2008).
Review of Priority Research Topics, Research Needs and Gap Analysis 57 The criteria for priority-setting of research is not clearly stated. Infor- mation 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. Fur- thermore, 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 (âUnderstand how chemical and physical modifications affect the properties of nanomaterials,â p. 14), it is unclear why âUnderstanding the effect of surface function on mobility and transformations in waterâ is consid- ered 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 evalu- ated nor a mechanism for differentiating between high-cost low-value research and lower-cost higher-value research. Both types of research need to be consid- ered 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 instru- mentation, 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
58 Review of the Federal Strategy for Nanotechnology 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 Pre- vention 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 in- forms 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 re- search category. In the NNI assessment of relevant FY 2006 research projects, a large portion of the research targets human health through therapeutics. Its pri- mary focus is to develop novel strategies for treating cancer and other ailments that deserve the attention of scientists and clinicians. That may accelerate pro- gress in cancer research and will undoubtedly advance knowledge of nanomate- rial-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 re- search portfolio does not address the most rudimentary problems in environ- mental, 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 committeeâs approach, the evalua- tion 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 charac- teristics and biologic effects of nanomaterials challenges conventional ap- proaches to risk. In the past, risk decision-making was typically driven by the chemical constituents of a material, not by physical structureâalthough there are a few notable exceptions, such as asbestos and the distinctions between in-
Review of Priority Research Topics, Research Needs and Gap Analysis 59 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 previ- ously 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 char- acteristics, 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 num- ber of material classes. Developing methods to assess and to monitor the poten- tial 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 toler- ance 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 im- portant degree.2 Understanding appropriate tolerances will be an iterative proc- ess that emerges from a well thought-out and integrated research strategy. If resources are to be assigned appropriately, some initial estimates of what is im- portant are needed. That leads to the third overarching issue: context. Risk-related nanomate- rial metrology will depend on the type of material under investigation, the con- text 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 ex- posure monitoring and material-dispersion evaluation. Likewise, analytic meth- ods 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).
60 Review of the Federal Strategy for Nanotechnology teristics that may differ between nanomaterials. For example, understanding the interactions between gold nanoparticles and DNA will require a detailed under- standing of particle shape, size, and surface chemistry; but in monitoring expo- sure 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 â¢ An assessment of the current state of the art of nanomaterial analysis. â¢ Classification and grouping of nanomaterials that convey the physical and chemical properties relevant to biologic effects. â¢ Definition and evaluation of appropriate accuracy and precision (toler- ance) for measuring those properties. â¢ Identification and clarification of the analytic needs of researchers working with nanomaterials in toxicology, exposure assessment, environmental science, and medicine. â¢ Standardization of methods and metrics used in nanotoxicology studies, including standardized approaches for route of administration and dose metrics. â¢ Cross-disciplinary translation of established methods to the needs of the nanotechnology-related EHS researchers. â¢ 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 con- tainment 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 Appen- dix A as relevant to this research categoryâalthough important for the ad- vancement of nanoscience and nanotechnologyâhave little obvious relevance to EHS issues. There is little effort to address the gap between what is needed and what has been funded.
Review of Priority Research Topics, Research Needs and Gap Analysis 61 BOX 4-3 Research Needs for Instrumentation, Metrology, and Analytical Methods 1. Develop methods to detect nanomaterials in biological matrices, the environment, and the workplace. 2. Understand how chemical and physical modifications affect the properties of nanomaterials. 3. Develop methods for standardizing assessment of particle size, size distribution, shape, structure, and surface area. 4. Develop certified reference materials for chemical and physical characterization of nanomaterials. 5. Develop methods to characterize a nanomaterialâs spatio-chemical composition, purity, and heterogeneity. Source: NEHI 2008. Research need 1, âDevelop methods to detect nanomaterials in biological matrices, the environment, and the workplace,â 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 neces- sary. Those three topics underpin much of the research and action needed to understand and address potential environmental and health implications of engi- neered 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 rele- vant 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 nanotechnol- ogy-related EHS research. Likewise, research aimed at developing nanoparticles as contrast enhancers has limited relevance to the general problem of detecting
62 Review of the Federal Strategy for Nanotechnology 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 Mem- branes 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, âUnderstand how chemical and physical modifications affect the properties of nanomaterals" sits uneasily in this section of the docu- ment, 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 âbiologicâ 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 hu- man health and the nanomaterials and the environment categories. What does belong in this high-priority group is a discussion of how to characterize the mo- lecular properties of the nanomaterial-biologic and nanomaterial-environmental interface. Information on a nanomaterialâs 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 identi- fiedââEvaluate solubility in hydrophobic and hydrophilic media as a function of modifications to further modeling of biological uptakeâ and âUnderstand the effect of surface function on mobility and transformation in waterââare by con- trast too narrowly defined to support strategically relevant progress. These two research areas on their own do not adequately address the studies needed to de- velop a clearer understanding of how physical and chemical modifications affect the properties of nanomaterials. Research need 3, âDevelop methods for standardizing assessment of parti- cle size, size distribution, shape, structure, and surface area,â is based on the fact that such methods are vital for developing a clear understanding of how engi- neered nanomaterials might affect human health and the environmentâand how
Review of Priority Research Topics, Research Needs and Gap Analysis 63 to avoid the effects. Many of the specific aims listed here are relevant to and important for addressing nanotechnology-related EHS issues. This should re- main 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 commu- nity 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, âDevelop certified reference materials for chemical and physical characterization of nanomaterials,â is important but complex. Standard materials are required to validate the characterization protocols described in re- search 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 sur- face 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. Ef- forts 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 ad- dressed. Without such understanding of the limitations of reference materials, there are no safeguards to prevent inappropriate levels of investment on irrele- vant materials. Research need 5, âDevelop methods to characterize a nanomaterialâs spa- tio-chemical composition, purity, and heterogeneity,â 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
64 Review of the Federal Strategy for Nanotechnology need 3) because it is important in connection with the molecular-level detail of the nanomaterial-biologic interface. However, to conduct this research requires specific quantitative analysis with the necessary spatial resolution and strategies for handling the challenges of such analysis in relevant biologic matrices. Some discussion of research in the text (NEHI 2008, p. 16) is not con- nected to the subtopics in Figure 3. These are important research topics, but their linkages to the identified research needs are not apparent. The descriptions of research projects in the text are generally current exploratory and application- based research projects that in some cases happen to have some relevance to risk. Although the identified research needs and topics intersect to a degree with the needs of the nanotechnology-EHS community (NEHI 2008, Figure 3), the funded programs are often disconnected. Overall, this section of the report could be improved if it presented a clear strategic route to addressing characterization-related EHS issues. The priorities presented, although reasonable in parts, do not provide such a route. A notable absence from the instrumentation, metrology, and analytic methods category is research related to the chemical properties of nanomaterials. That would involve adding a topic to research need 5 to address adsorption, compatibility, and reactivity of nanomaterials. For example, the nonspecific fouling of nanomaterial surfaces has important consequences for the absorption, fate, and distribution of the material. Methods to evaluate the corona, the mole- cules and macromolecules that interact with nanomaterial surfaces, accurately and rapidly are thus of immediate importance. In addition, acellular assays that can monitor reactivity of nanomaterials, such as their participation in the genera- tion and cycling of reactive oxygen species, are important and should be ad- dressed. Another important topic is the change in physical and chemical charac- teristics of the nanomaterials in biologic systems. For example, nanomaterials of some size may agglomerate to different degrees in a biologic fluid and have dif- ferent effects (Maynard 2002; OberdÃ¶rster et al. 2005; Jiang et al. 2008a). The 2006 funded projects described in the document do support EHS risk assessment to some extent, but the degree of support is not commensurate with the investment, and the mechanisms to apply many of these research projects to nanotechnology EHS seem to be lacking. The funded projects are important, and they represent a large research investment that broadly advances nanoscience and nanotechnology; but they do not necessarily increase our ability to identify, assess, and manage the potential EHS effects of engineered nanomaterials. Largely missing are projects that directly advance both immediate applied research and long-range fundamental knowledge specifically directed towards addressing nanotechnology-related risk research. More effective identification, assessment, and management of nanotech- nology-related risk is a challenging goal that will require many resources and focused effort; the current documentâs description of 2006 research suggests that this investment is not being made.
Review of Priority Research Topics, Research Needs and Gap Analysis 65 Conclusions A strength of this section is that the importance of metrology and analy- sis is highlighted and recognized. The identification of standard reference mate- rials and methods is notable, and represents some of the research topics (for ex- ample, production of commercial samples for workplace monitoring) that need to be present in a federal research strategy. The âSummary of Balance- Assessment for Instrumentation, Metrology, and Analytical Methods Categoryâ (p. 17) is critical for seeing how all the programs fit together; its expansion and a clearer analysis would go a long way toward conveying the big picture. There is no analysis of the state of the art to justify existing and future research investments. No consideration is given to the relevance of current abilities and methods and the extent to which they negate the need for future research in some fields. For instance, methods already exist to characterize air- borne particles by size, mass, surface area, and number concentration that extend down to a few nanometers. Analytic techniques exist that are capable of measur- ing trace quantities of specific chemicals; and electron and atomic-force micros- copy with a resolution of tenths of a nanometer are mature technologies. To what extent are they already being used to address potential nanomaterial ef- fects? There is no attempt to translate established methods to nanotechnology- related EHS research needs. No consideration is given to how existing and emerging analytic methods might be applied to EHS effects. There is little evi- dence that characterization techniques in fields outside risk research can be ap- plied to potential effects without substantial investment in translating the tech- nology to a new kind of application or developing risk-specific technologies. Justifying general metrology research as relevant to risk research without appro- priate âbridgingâ is deceptive. Funded projects are disconnected from research needs. The list of pro- jects funded in FY 2006 and identified as relevant to these research needs seems to be a list of convenience in that it represents current exploratory and applica- tion-based research that may have some relevance to addressing risk. Assessing the projects does not provide a strategic route to addressing characterization- related EHS issues. The text is littered with subjective qualifiers: research âcan be applied,â âcould be useful,â âwill likely benefit.â It is the language of wishful thinking, not critical analysis. Research is not relevant to immediate nanotechnology-related EHS needs. No consideration is given to the accuracy and precision required for risk- relevant nanomaterial characterization. As a result, the research is open-ended and apt to consume considerable resources in addressing questions that are not relevant to protecting public health and the environment. No consideration is
66 Review of the Federal Strategy for Nanotechnology given to the different contexts within which risk-related measurements are needed; consequently, there is a danger of substantial research investment in projects and programs that do not address critical issues. Finally, it is important to keep research on instrumentation, metrology, and analytic methods a primary focus in the federal strategy. Progress in nanotechnology-related EHS research requires advances not just in hazard iden- tification, exposure assessment, standard development, and risk management but in the measurement and characterization of the materials. The current strategy falls short of supporting the necessary research. More effort is needed to ensure that existing and future research efforts address nanotechnology-related EHS needs in a way that provides stakeholders with the knowledge and tools they need to identify, assess, and manage potential risks associated with nanomateri- als across their life cycle. Nanomaterials and Human Health Introduction The rapidly expanding development, marketing, and application of nano- materials with little information on their ability to interact with or disrupt bio- logic systems raise concerns about their safety in occupational and environ- mental settings. The safety of nanomaterials is of concern to multiple stake- holders, including government bodies with human or environmental health mis- sions (for example, the Food and Drug Administration, the Environmental Pro- tection Agency [EPA], and the National Institute for Occupational Safety and Health), commercial producers, and nongovernment organizations (for example, the Natural Resources Defense Council, the Environmental Defense Fund, and the American Federation of Labor and Congress of Industrial Organizations). Each of those stakeholder organizations focuses on EHS-related concerns re- garding nanomaterials, including medical and therapeutic applications and safety, occupational exposure and worker health, and environmental and con- sumer exposure and health. The committee reviewed the adequacy of the nano- materials and human health research section in the context of its completeness, accuracy, and ability to address important EHS issues for each of the stake- holders by addressing the questions posed in Box 4-1. Evaluation and Assessment The NNI document identifies five broad, inclusive high-priority research needs related to nanomaterials and human health (NEHI 2008, see Figure 5, p. 24) and specifies a total of 29 focused research topics in connection with them. Each topic is essential for addressing EHS risk assessment and management needs. The emphasis on biologic responses and on exposure routes and meas- urements is logical and noteworthy. Overall, the list of research needs on nano-
Review of Priority Research Topics, Research Needs and Gap Analysis 67 materials and human health is reasonably complete (see Box 4-4). However, some important clarifications and additions need to be incorporated. The combined list of research in the two needs âUnderstand the absorption and transport of nanomaterials throughout the human bodyâ and âUnderstand the relationship between the properties of nanomaterials and uptake via the res- piratory or digestive tracts or through the eyes or skin, and assess body burdenâ is complete except for the absence of an emphasis on quantitative kinetics and application of kinetic models. It should include, where appropriate, quantitative models, such as physiologically based pharmacokinetic models, that account for the influence of physiologic, biologic, and other processes that influence nano- material kinetics. Such models would facilitate assessment of interindividual, interspecies, and life-stage-dependent differences in kinetics and dosimetry and other susceptibility factors. The models would constitute a first step in develop- ing more inclusive, integrative computational models for predicting biologic effects. Moreover, those two research needs describe a single research topic that comprises the human bodyâs absorption, distribution, metabolism and transfor- mation, and elimination (ADME) of nanomaterials. Therefore, they should be integrated into a single research activity focused on understanding the absorp- tion and transport of nanomaterials through the human body and the influence of their physicochemical properties on ADME and toxicity. An important element in understanding the ADME aspects of nanomaterials is to determine whether biologic processes modify the physico-chemical characteristics of the nanomate- rial, including changes in surface properties, size, and oxidation state of the components. The research need âIdentify or develop appropriate in vitro and in vivo as- says/models to predict in vivo human responses to nanomaterials exposureâ em- phasizes in vivo and in vitro hazard-screening tools and offers prediction of bio- logic response (for example, toxicity) as a goal. The committee notes that prediction of biologic response requires the development of quantitative dose- response data and in some cases mechanistic or mode-of-action data from highly coordinated studies, the articulation of a quantitative representation of the bio- logic and physical processes, and ultimately the development and use of integra- tive, quantitative computational (in silico) models (ICON 2008). The NNI document should articulate the research required to address each of those steps. For example, both quantitative structure-property-activity relationships and de- velopment of biologically based dose-response models should be specifically included as research needs to assist in the integration of data and prediction of toxicity. The topics identified in the two remaining research needs, âDevelop methods to quantify and characterize exposure to nanomaterials and characterize nanomaterials in biological matricesâ and âDetermine the mechanisms of inter- action between nanomaterials and the body at the molecular, cellular, and tissue levels,â were deemed complete. However, the committee did consider that,
68 Review of the Federal Strategy for Nanotechnology BOX 4-4 Research Needs for Nanomaterials and Human Health Understand the absorption and transport of nanomaterials throughout the human body. Develop methods to quantify and characterize exposure to nanomaterials and characterize nanomaterials in biological matrices. Identify or develop appropriate in vitro and in vivo assays/models to predict in vivo human responses to nanomaterials exposure. Understand the relationship between the properties of nanomaterials and uptake via the respiratory or digestive tracts or though the eyes or skin, and assess body burden. Determine the mechanisms of interaction between nanomaterials and the body at the molecular, cellular, and tissular levels. Source: NEHI 2008. where feasible, it would be prudent to identify activities in each category that complement and influence those in other categories in an effort to promote re- search coordination. For example, studies addressing research needs in nanoma- terials and human health would benefit from a focus on occupationally or envi- ronmentally relevant materials, exposure levels, and exposure routes on the basis of well-characterized nanomaterials (research that is addressed in the instrumen- tation, metrology, and analytic methods category and the human and environ- mental exposure assessment category). The more integrated approach would increase the value and relevance of the research. Although the rationale for selecting priorities of the research topics (NEHI 2008, Figure 5) was not clear to the committee, it considered that the sequence of implementation was for the most part logical. An initial focus on develop- ment of methods to quantify nanomaterials in situ is reasonable because these methods are required for the success of the other research, all of which involves exposure, dose measures, or tracking of nanomaterials in biologic matrices. Ini- tial efforts to identify which portals of entry have high rates of absorption and which organ systems preferentially accumulate nanomaterials were also viewed as appropriate. However, consideration of the diversity of nanomaterials and their applications is critical. Such knowledge should guide selection of appropri- ate in vitro and in vivo systems for hazard screening and mechanistic work. The NNI implied, in Figure 5, that all mechanistic work was of value and should be conducted in the near term. The committee considers that some clari- fication is needed. Targeted mechanistic research on the interaction of nanoma- terials with known biologic or toxicologic pathways and mechanisms (for exam-
Review of Priority Research Topics, Research Needs and Gap Analysis 69 ple, oxidative stress, mutagenesis, or inflammation) addresses important ques- tions about hazard and classification of materials by response in the near term. Although hypothesis-driven, exploratory mechanistic research could address important questions in the near term, purely exploratory mechanistic work might be most valuable if guided by knowledge about relevant exposures routes, end points, and tissues and cell types and may be more useful once some initial re- search questions are addressed. The NNI conducted its gap analysis without substantive consideration of the relevance of the research to the two distinct communities that use the infor- mation (research focused on clinical uses and patient populations and research focused on occupational and environmental health risks). More than 50% of the projects listed for human health target research directly relevant to therapeutics rather than assessing the potential EHS risks posed by nanomaterials. The com- mittee felt that the relevance of the therapeutic studies was overstated. Three examples of the imbalance in the funded research projects are presented below. The NNI identified 30 grants as addressing the research need âUnderstand the absorption and transport of nanomaterials throughout the human bodyâ (which contained seven specific objectives). The sole conclusion regarding gaps identified was that âfurther research on gastrointestinal and intraocular uptake is needed.â However, on closer examination of the 30 grants identified as relevant, only two were focused on issues that directly addressed ADME data that might be useful for environmental and occupational risk evaluation: âEffect of nano- scale materials on biological systems: Relationship between physicochemical properties and toxicological propertiesâ and âImpact of physicochemical proper- ties on skin absorption of manufactured nanomaterials.â The remaining 28 funded projects were focused on medical applications of nanotechnology, such as the design of drug-delivery systems or other aspects of therapeutics. Those research projects will undoubtedly generate information that is conceptually useful in understanding the behavior of specific types of nanomaterials, but it is unlikely that they will generate data that would be directly applicable to risk assessment of environmental and occupational health hazards. The NNI docu- ment states, with little justification or documentation, that 17 projects directly addressed that research need; this implies that 13 projects have no particular relevance, so it is not clear why the entire budgets of those projects would be included in the tally of funding in this topic. Thus, if one were to carefully ex- amine the FY 2006 funding committed to understanding each of the seven sub- topics identified in the research need âUnderstand the absorption and transport of nanomaterials throughout the human body,â there would be at most two grants that might provide useful information in them. It is hard to imagine that the only âgapsâ identified by the NNI are in gastrointestinal and ocular uptake, inasmuch as no exposure assessments have been conducted to understand the extent to which gastrointestinal uptake and intraocular uptake are important routes of exposure . Another example of the flawed gap analysis is in the research need âIden- tify or develop appropriate in vitro and in vivo assays/models to predict in vivo
70 Review of the Federal Strategy for Nanotechnology human responses to nanomaterials exposure.â Eight appropriate subcategories were identified (Figure 5). In connection with this research need, only six FY 2006 projects were identified. Although the NNI states that all six directly ad- dress the need, examination of their content suggests that only three directly address one or more of the subtopics (B3-1, B3-5, and B3-6 in Appendix A). The other three projects (B3-2, B3-3, and B3-4) may generate relevant informa- tion but do not explicitly address any of the subtopics in a way that would be useful for environmental or occupational risk assessment. The NNI acknowl- edges that the gap analysis is flawed, but it offers no recommendations on how to address this critical limitation. âWhile there is a low number of projects in this priority research need, this assessment does not capture applicable research in other areas nor many additional research efforts on testing schemes that were not captured by the gap analysis, so a determination of future priorities based on this analysis may be misleadingâ (p. 22). Indeed, the âSummary of Balance- Assessmentâ for the section does not mention the paucity of research addressing predictive toxicology for nanomaterials (development and validation of in vitro assays that predict in vivo toxicity). It is difficult to fathom how two federally funded projects in FY 2006 (B3-1 and B3-5) that directly address the develop- ment of in vitro and in vivo assays and models to predict human response to nanomaterials would be considered a sufficient research effort. The focus of the research on therapeutics means that the data needs for risk assessment are not being supported. The gap analysis does not accurately or adequately represent research gaps related to nanomaterials that might pose health and safety risks to consumers, researchers, and workers. The committee considers the apparent lack of a sizable number of research projects that directly address the immediate research needs related to potential occupational and con- sumer risks posed by nanomaterials to be a substantial data gap. Revision of the table (NEHI 2008, p. 20) to separate studies focused on therapeutics from stud- ies that emphasize materials important to these other communities (workers, consumers, and the public) would facilitate a transparent and unbiased assess- ment of data gaps that will help to spur the needed research. The small number of projects addressing the research needs in the nano- materials and human health section and their bias toward therapeutic applica- tions rather than materials relevant to the environmental, occupational, and con- sumer exposure settings constituted sufficient evidence that the funded research will not support risk-assessment and risk-management needs for these classes of nanomaterials, generate the information needed to support EHS risk assessment and risk management, or provide critical data for regulatory agencies. Conclusions There is a need for broad coordination in the parallel pursuit of re- search needs in the nanomaterial and human health category and across re- search categories. Research projects in nanomaterials and human health would
Review of Priority Research Topics, Research Needs and Gap Analysis 71 benefit from research on occupationally or environmentally relevant materials, exposure levels, and exposure routesâwork that is carried out in other research categories. A more integrated approach would increase the value and relevance of the research. The list of high-priority research on nanomaterials and human health is, with few notable exceptions, complete. Additional emphasis of research on the analysis and evaluation of ADME and toxicity of engineered and other nano- scale materials that are related to likely exposures is needed. In particular, there is a need for the collection of quantitative kinetic data and the development of quantitative kinetic models, including, where appropriate, physiologically based models and structure-property-activity models. The gap analysis was neither accurate nor complete. The gap analysis re- sulted in the NNIâs overstating the relevance of therapeutic studies to the identi- fied research needs and not fairly representing the paucity of projects that truly address the potential EHS risks posed by nanomaterials. Although most of the therapeutic studies are focused on developing novel strategies for treating cancer and other ailments that deserve the attention of scientists and clinicians, they will not directly contribute to the body of knowledge needed to ensure protec- tion of public health and the environment from potential risks posed by nano- technology and its products. Nanomaterials and the Environment Introduction Nanomaterial exposures and their effects on organisms and ecosystems are influenced by the nature of the material and its applications and will probably depend on the physical and chemical characteristics of the particles, including size, shape, surface chemistry; the frequency, magnitude, and duration of re- leases or exposures; and countless modifications in material structure and prop- erties mediated by environmental processes. A research strategy that addresses environmental end points must address the breadth of possible variables that may define nanomaterial transport, transformation, bioavailability, bioaccumula- tion, and trophic transfer and mechanisms that may control toxicity on cellular and organismal scales. Classically, environmental research has focused on the relationship be- tween chemical composition of contaminants and their environmental behavior and effects. The recognition that nanoscale structure may be more predictive of environmental parameters has forced researchers to rethink concentration- response approaches and place more emphasis on more robust particle charac- terization in environmental matrices. Broadening exposure characterization will inevitably lead to better predictions of effects.
72 Review of the Federal Strategy for Nanotechnology Several challenges face environmental scientists who are conducting re- search on nanomaterials: developing reproducible testing methods that provide insight into environmental characteristics, quantifying appropriate effect end points that reflect both physical and chemical stress, developing quantitative structure-activity relationships, and incorporating this information into ecologic risk assessment. Addressing those challenges will require multidisciplinary ap- proaches that include material scientists and physicists in the more traditional environmental collaborations of engineers, chemists, biologists, and toxicolo- gists. Test methods designed to characterize environmental soluble contami- nants may not be appropriate for use with nanoparticles. Quantifying the behav- ior of a solute in environmental matrices is already challenging; understanding the behavior of nanoparticles may require restructuring assay systems that facili- tate particle detection and characterization. That is critical because research has suggested that nanoparticle behavior depends heavily on the characteristics of the environmental matrix. Therefore, it is not sufficient to characterize the test material only before conducting the assay. Particles must also be characterized during the assay, and how their characteristics change must be evaluated (May- nard 2002; OberdÃ¶rster et al. 2005; Jiang et al. 2008a). For example, nanoparti- cle suspensions in freshwater may have aggregation rates that result in substan- tial changes in aquatic organismsâ exposure to them. The response of aquatic organisms may therefore depend on aggregation rate and on exposure duration (for example, continuous vs episodic). Most ecotoxicologists are not accustomed to quantifying responses of or- ganisms to particles. Although some approaches and insights can be garnered from existing mammal-particle toxicologic research, they will not be useful or predictive for all trophic levels. Research has suggested that aquatic organisms discriminate among colloids of different sizes, but there are no data that support extrapolation of these relationships to nanoparticles (Christaki et al. 1998). Quantitative structure-activity relationships (QSARs) have been developed for myriad contaminants and used successfully in ecologic risk assessment. Quantifying the influence of nanoscale structure and suspension characteristics (for example, particle size, shape, surface chemistry, and aggregation rate) on environmental characteristics might lead to development of QSAR-like predic- tive tools. However before such tools can be developed, the appropriate meas- ures of the nanomaterial properties that may affect end points must first be iden- tified, through extensive testing of many different well-characterized nano- materials for these endpoints. Current ecologic risk-assessment methods may be a useful starting point, but methods for quantifying nanoparticle-related risk may need to evolve as re- search on behavior and effects unfolds. It is not apparent that classic metrics for predicting exposure and effects are applicable to nanoparticles. For example, nanoparticle suspensions may have both physical effects associated with their size and shape and chemical effects associated with their surface chemistry and
Review of Priority Research Topics, Research Needs and Gap Analysis 73 particle composition. The applicability of such measures as volatility or octanol- water partitioning is doubtful. Elements of an effective research strategy to address the environmental behavior, fate, bioavailability, and effects of nanomaterials and their associated ecologic risk should include â¢ The development of reproducible testing methods that provide insight into environmental characteristics. â¢ An assessment of the most important nanostructural characteristics that influence environmental characteristics. â¢ Determining the appropriate ranges of environmental concentrations to inform effects research. â¢ Development of mathematical tools that link environmental characteris- tics to appropriate environmental effects or end points. â¢ Identification of the appropriate end points. â¢ Incorporation of nanomaterial research results into ecologic risk as- sessment and modification of risk-assessment methods to accommodate effects and exposure phenomena peculiar to nanoparticles. Evaluation and Assessment The committee reviewed the adequacy of the nanomaterials and the envi- ronment section of the 2008 NNI document to assess its ability to encourage research and facilitate quantitative ecologic risk assessment. The strategy was reviewed for its completeness, research priority-setting, and ability to support risk-assessment and risk-management needs. The NNI document identified five research needs in the category of Nanomaterials and the Environment (NEHI 2008, Figure 7, p. 31). Each of the needs is critical for advancing knowledge and supporting ecologic risk assess- ment and management (see Box 4-5). The research needs appear to have been derived by extrapolating from the inventory of current research activities rather than as a high-level assessment of near-term to long-term needs. Some discus- sion of research needs that moves beyond such extrapolation is found in the background paragraphs that describe the need for improved measurement of toxicity, determination of mechanisms of toxicity, development of structure- activity relationships, and consideration of environmental modifications of nanomaterials. Strategic planning for research is also reflected in Figure 7 (NEHI 2008, p. 31). Trophic transfer, including bioaccumulation and bioconcen- tration, is one possible ecologic end point that, although meriting research, ap- pears to be absent from the proposed strategy. Similarly, it is not clear how weak links in ecosystem-level responsesâfor example, those related to such ecosys- tem services as nutrient cyclingâwill be identified.
74 Review of the Federal Strategy for Nanotechnology BOX 4-5 Research Needs for Nanomaterials and the Environment 1. Understand the effects of engineered nanomaterials in individuals of a species, and applicability of testing schemes to measure effects. 2. Understand environmental exposures through identification of prin- cipal sources of exposure and exposure routes. 3. Determine factors affecting the environmental transport of nano- materials. 4. Understand the transformation of nanomaterials under different en- vironmental conditions. 5. Evaluate abiotic, and ecosystem-wide, effects. Source: NEHI 2008. The report sorts 38 projects into the five research needs. The research needs are important for accomplishing the goals laid out for this section. While the goals are presented and described as a priority list, most of the current pro- jects (22 of 38) address research need 3, âDetermine factors affecting the envi- ronmental transport of nanomaterials.â One concern is NNIâs priority-setting of research needs. Exposure scenarios should precede toxicity testing for ecosys- tem risk assessments. Similarly, understanding of environmental fate and trans- port would be necessary before assessment of organisms at risk. For example, if the behavior of a particular nanomaterial results in sediment deposition, testing effects on sediment-dwelling rather than pelagic organisms might be a priority. While some bioavailability and mechanistic toxicity testing should be a high priority, the committee cautions against extensive toxicity testing without fully understanding environmental fate and transport processes necessary to quantify exposure. Effects characterization without an adequate understanding of envi- ronmental exposure may result in resources being expended on research that does not contribute to ecologic risk assessment or facilitate extension to higher- level ecosystem effects. The committee agrees that toxicity bioassay method development must be a high priority. The first research need concerns the effects of engineered nanomaterials on organisms and the development of methods for measuring the effects at the genomic, molecular, cellular, organismal, and population levels. Determining whether nanomaterials have an effect as defined by a widely accepted, measur- able end point is critical for determining whether they should be considered fur- ther for the purposes of risk assessment. However, these end points have been developed and refined largely in response to soluble contaminants, not particles. Therefore, the committee supports the priority of research investigations that focus on nontraditional ecotoxicologic end points that are more appropriate for particles, such as nanoparticle effects on protein configuration or phagocytotic responses. Information about testable hypotheses can be gleaned from the scien-
Review of Priority Research Topics, Research Needs and Gap Analysis 75 tific literature on the human health effects of exposure to particulate contami- nants such as silica, asbestos, and carbon black which have been extensively studied. In addition to different end points, toxicity assessments must include exposure characterizations. The committee supports the priority of understand- ing the influence of particle characteristics on ecotoxicologic bioassays. Cur- rently these bioassays are always accompanied by quantitative assessments of contaminant exposure (concentration); bioassays of nanoparticles need to in- clude contaminant characterization beyond a mass exposure number. Particle size, shape, surface area, and surface chemistry are all potential determinants in the outcome of biota-nanoparticle interactions. The most important part of this research is the development of sensitive, reproducible ecotoxicologic bioassays for the assessment of the effects of particles. The second-ranked priority research need is to understand exposure by identifying principal sources and exposure routes. Only one project was identi- fied as addressing that topic during FY 2006. This work should have high prior- ity and should be done quickly because it will inform the array of relevant con- centrations to be studied and because it is impossible to predict which organisms will be exposed without adequate exposure characterization. However, the re- search void introduces considerable uncertainty into the range of concentrations that should be used and even the systems that should be studied. The research void is substantiated by the fact that a search of the EPA Web site yields only one research project focusing on nanoparticle exposure funded in FY 2007 and only three focusing on fate and transport (EPA 2008). Similarly, in the 2006 inventory, one project was identified as addressing ecosystemwide effects, that is, effects that go beyond those of individual species (âNanoscale Size Effects on the Biogeochemical Reactivity of Iron Oxides in Active Environmental Nanosystemsâ). That is not surprising inasmuch as the entire ecotoxicologic literature is slanted to individuals, and few studies focus on higher orders of organization (for example, populations, communities, and eco- systems). The need to cover a wider array of nanomaterials than those of natural origin identified for study in the inventoried 2006 projects is cited in NNI (NEHI 2008). This is a critical need. To apply current knowledge on materials of natural origin to an understanding of risks posed by engineered nanomateri- als, more research is needed to understand how the physicochemical properties and toxicity of natural and engineered nanomaterials differ (see discussion of research gaps below). The largest fraction of research projects on nanomaterials and the envi- ronment identified in the FY 2006 inventory investigates factors that affect envi- ronmental transport of nanomaterials. The NNI document identifies a lack of emphasis on âmore appliedâ research and little evaluation of existing transport models (NEHI 2008, p. 28). One research need identified here is the determina- tion of physicochemical processes that control the fate and transport of different nanomaterials. Surface modification of nanoparticles in the environment is im- portant because of its potential influence on particle behavior, including ag- glomeration, aggregation, and sedimentation which may affect bioavailability
76 Review of the Federal Strategy for Nanotechnology and possibly nanoparticle reactivity. A more mechanistic approach might pro- vide the foundation of the development of predictive models, provide insights into exposure pathways, and identify organisms at risk. Results of this research may provide insights into exposure pathways and organisms at particular risk, so substantial effort is warranted. Research need 4 is âUnderstand the transformation of nanomaterials under different environmental conditions.â Physical, chemical, and biologic transfor- mations are all identified as meriting research. There were 10 projects that were not sorted into the five research needs. Their importance was noted in that they could also lead to nanotechnology ap- plications that contribute to lessening current environmental contamination. In summary, all the research needs identified as having priority in the NNI document are appropriate and even critical for providing information needed for informed risk assessment. The committee reinforces the need for characterization methods to identify nanomaterials in biologic and environmental matrices and the products of nanomaterial-environment interactions. As stated by the NNI, this must be an overarching consideration. The call to focus on âas-manufacturedâ nanomaterials may misdirect interim risk assessments by creating large gaps in the understanding of how âmanufacturedâ nanomaterials and those found in natural systems may differ. With the caveats described above, the priorities in this category are appro- priate in that a consideration of hazard below the level of ecosystems often pre- cedes ecosystem-level evaluation. However, estimates of transport and trans- formation are required to assess environmental exposure and should therefore have higher priority than evaluation of ecosystemwide effects because the latter cannot be usefully studied without knowing what the likely environmental con- centrations will be and what organisms might be exposed. Therefore, the com- mittee recommends that the research needs be rearranged as (2), (4), (1), (3), (5). Exposure and transport processes would be characterized before effects. That would provide a rationale for the selection of bioassay species. Transformation processes would be characterized before higher-level ecosystem effects. At pre- sent, the distribution of projects among the research needs does not appear to be consistent with the proposed priorities or with our recommended sequence. At- tention should be given to making resource allocation consistent with the priori- tized research needs. Although the research strategy appears to reflect an important collection of existing federally funded research, there are several gaps in the identified re- search needs: â¢ The strategy document does not specifically identify the need for study- ing naturally occurring or incidental nanoparticles that have similar structures or that may be identical with manufactured nanomaterials. â¢ The document does not identify development of protocols to evaluate nanomaterial loss from products as a research need despite an apparent trend
Review of Priority Research Topics, Research Needs and Gap Analysis 77 toward using nanomaterials predominantly as composites in more complex ma- trices of resins, fabrics, and coatings. â¢ The document does not consider characterization of bioavailability and toxicity of nanoparticles in complex media, such as effluents. It is important because many nanoparticles will enter the environment in effluents and dis- charges. â¢ The document does not mention the need to characterize interactions among nanoparticles and other environmental contaminants. Such interactions could alter environmental behavior, bioavailability, and toxicity of nanomateri- als. â¢ Characterization of nanoparticle transport through food webs is critical for ecosystem health, including potential human exposure. â¢ Methods for identifying nanomaterial sources, such as isotopic âfinger- printingâ techniques, and modeling techniques to track movement of nanoparti- cles in the environment are needed. â¢ Research to assess the potential environmental âcollateral damageâ as- sociated with nanomaterial fabrication needs to be clearly linked to life-cycle analysis mentioned in the NNI document. The latter topic goes far beyond using off-the-shelf technologies for risk management in material production. It requires an assessment of the quantities and qualities of wastes generated in manufacturing specific nanomaterials and of the risks associated with handling and disposing of the wastes and of the feed- stocks used in the manufacture of nanomaterials. Although the document notes the need to develop methods for characteriz- ing nanomaterials in complex matrices, it does not describe a mechanism for ensuring translation of method developments that may occur in the biomedical sciences, fundamental nanochemistry, or elsewhere in the EHS community. The disconnect between ecologic risk-assessment and risk-management methods for particles vs solutes has not been addressed, and environmental scientists are left to borrow from the human health literature on particles. Although much can be learned from the extensive literature on the impact of particles on human health, caution is needed when making extrapolations to ecologic endpoints, because of the potential differences in exposure scenarios and in physiology and biochemis- try among organisms. Development of ecologic risk-assessment and risk- management tools should progress in tandem with the research on fate, behav- ior, and toxicity already identified. Conclusions A strength of this section is that the major topics identified for research are appropriate. Each is critical for meeting the ultimate goal of risk assessment and material management.
78 Review of the Federal Strategy for Nanotechnology Several important research topics have been overlooked. It is important that the research strategy be comprehensive so that high-priority research can be accomplished in a logical manner. Research needs must be comprehensive to ensure that ecologic risks can be assessed and nanomaterials managed objec- tively and with minimal uncertainties. There was no justification for the setting of priorities of the research needs, nor were they set in relation to resource allocation. The priorities of research needs were not well justified, and even a cursory examination suggests that a different prioritization might be more logical. Projects funded in FY 2006 and identified as relevant to the research needs do not support the proposed pri- oritization. Priority of research on factors that control transport, fate, and exposure should be expressed in a fashion that clarifies the need for this work to inform ecotoxicity studies. This is a critical inaccuracy in the document. The document suggests that ecotoxicity research should proceed immediately without attention to identifying species at risk on the basis of an understanding of nanoparticle behavior, fate, and transport. That could result in a substantial waste of re- sources. Human and Environmental Exposure Assessment Introduction For nanomaterials to present a risk to human health or ecosystems, both exposure and hazard must exist. Without knowledge about exposure potential at some point in the life cycle of nanomaterials, it is not possible to assess risk ap- propriately or to implement well-founded risk-management practices. Research conducted with the goal of assessing potential exposure to nanomaterials must take into account the physicochemical properties of the nanomaterials because they affect partitioning from portal of entry to secondary compartments in the human body and the environment. The risk-assessment paradigm (NRC 1983) connects exposure to dose to response. This section focuses primarily on expo- sure and dose. Dose-response relationships are addressed in other sections of the report. One of the strengths of the 2008 NNI strategy document is that it clearly identifies exposure research as a high-priority need and articulates its relevance to risk assessment. It also highlights the paucity of research in this regard and reflects on the nascent nature of nanotechnology (NEHI 2008, p. 34) and lack of exposure information. Because exposure is a critical determinant of dose, exposure-assessment information will be necessary for informing the design of toxicologic and ecotoxicologic studies with respect to exposure in animal and in vitro studies.
Review of Priority Research Topics, Research Needs and Gap Analysis 79 But the exposure-dose relationship needs to be considered critically in assessing nanomaterial interactions with organisms and the environment. For example, most of the studies on the assessment of toxicity of nanomaterials have used extremely high exposure concentrations (doses), which are usually irrelevant in realistic exposure scenarios (OberdÃ¶rster et al. 2005) except possibly industrial exposures and accidents. Although such high-dose studies can identify a hazard, they also lead to identification of mechanisms that may not be relevant at lower exposures and thus may contribute to an unrealistic perception of risk. In addi- tion, most of the studies have focused on acute exposures and neglected chronic and environmentally relevant exposures. Evaluation and Assessment The NNI document identified five research needs in the category of Hu- man and Environmental Exposure Assessment (NEHI 2008, Figure 9, p. 36). The five research needs (see Box 4-6) are all important, but they are not well elaborated. As an organizing principle, the NNI document (p. 33) adopts the approach of identifying and characterizing exposed populations by categories and relating their exposures. The committee believes that the broader concept of human and ecologic exposure potential throughout the life cycle of nanomateri- als (from manufacture to packaging, distribution, consumer use, and disposal) needs to be considered as an overarching research theme. In addition, with re- spect to human exposures, the document focuses mainly on occupational issues. Environmental exposures receive little attention in this section except as concep- tualized in Figure 10 and wording in section III (p. 46) that calls out the need to characterize the health of and presumably identify exposures to environments. Issues related to environmental exposure are also addressed briefly in the cate- gory âNanomaterials in the Environment.â BOX 4-6 Research Needs for Human and Environmental Exposure Assessment 1. Characterize exposure among workers. 2. Identify population groups and environments exposed to engi- neered Nanoscale materials. 3. Characterize exposure to the general population from industrial processes and industrial and consumer products containing nanomaterials. 4. Characterize health of exposed populations and environments. 5. Understand workplace processes and factors that determine expo- sure to nanomaterials. Source: NEHI 2008.
80 Review of the Federal Strategy for Nanotechnology The gap analysis presented in the document lacks substantive discussion of exposure except for a cursory treatment of occupational exposure. The com- mittee noted that the NNI did not identify the lack of research on exposure throughout the life cycle of nanomaterials as an important gap. That omission appears to be due to the lack of research projects on this subject in the portfolio of FY2006 projects. Understanding metrology and developing tools to characterize and meas- ure attributes of nanomaterialsâincluding particle size, number, and surface areaârelevant to exposure is not identified as a research need, and it is implied that it is adequately addressed by a few projects in the instrumentation and me- trology section (p. 33). Of particular concern is the challenge of assessing âdoseâ in toxicologically relevant terms. Although this is not a new challenge in the field of toxicology (appropriate dose metrics for particulate matter exposure have been studied for decades), whether nanomaterial âdoseâ is best assessed by particle mass concentration, surface area, concentration of reactive functional groups, or other means, will be an especially important area for standardization in nanotoxicology research. Types of research that should be considered include the following: â¢ Developing instrumentation for personal monitoring. â¢ Monitoring air and water discharges in the workplace. â¢ Research on exposure associated with product use throughout the life cycle from manufacture to distribution and consumer use to disassembly and disposal (Thomas and Sayre 2005; Borm et al. 2006). â¢ Research on source apportionment, for example, exposure to materials of manufactured origin relative to exposure from naturally occurring or non- manufactured anthropogenic materials, such as combustion products. â¢ Research on contributions of specific nanoparticles to total exposure, including personal exposure (personal samplers) vs area exposure. â¢ Research on personal susceptibility because lessons learned from expo- sure to particulate matter (including ultrafines) suggest that such factors as age, sex, windows of exposure, genetic makeup, and pre-existing diseases can play a critical role in susceptibility. â¢ Research on routes of environmental exposure, including commercial trends and the potential for nanomaterial penetration into conventional material markets, with an assessment of the unintended and associated environmental losses. â¢ Development of methods of identifying environmental âhot spots,â in- cluding fundamental studies of nanoparticle movement through the environment and interactions with known environmental pollutants. â¢ Research on trend forecasting, using tools from social sciences to allow gross exposure assessment and more targeted studies. Some nanomaterials have been produced and used for decades in large quantities, such as TiO2 and carbon
Review of Priority Research Topics, Research Needs and Gap Analysis 81 black (although these are not âengineeredâ); in the case of carbon black in par- ticular, several epidemiologic studies have begun to capture workplace expo- sures (Morfeld and McCunney 2007). The ordering of research needs in exposure research appears incongruous. For example, although characterizing workplace exposure appears to have the highest priority for research in this category, it seems misplaced with respect to research need 2, which aims to identify population groups and environments that may be exposed to engineered nanoscale materials. Similarly, research need 5 seems to be required to arrive at the conclusion that characterization of work- place exposure should be important for research. Indeed, understanding which population groups and environments may be exposed appears to be a prerequi- site for selecting the type of workplace settings that should be the focus of re- search to characterize exposures among workers. Both research needs 1 and 5 appear to have been eliminated in the final list in Section III (p. 46). In general, research priorities seem to have been simply an articulation of the collection of existing research in FY 2006, not priorities for research required to address knowledge gaps. Appropriate priority-setting of research would enable proper allocation of resources. That does not necessarily imply a chronology of re- search; many types of important research can and should be addressed in paral- lel. As presented, there will be large gaps in exposure-assessment information needed for EHS risk assessment and management. There appears to be a lack of clarity as to how and where exposure issues need to be addressed. They are scat- tered among several sections of the document with no apparent linkage. And the critical linkage between environmental and human exposure is overlooked. Be- cause ecologic exposures may be more difficult to assess than occupational ex- posures because there are more uncontrolled variables, it is important that envi- ronmental exposure research be a priority, and greater recognition of the commonalities of this research need to both the Human and Environmental Ex- posure Assessment and the Nanomaterials in the Environment categories is needed. The research priorities described in the NNI document will potentially support environmental health and safety research needs, but they are largely insufficient to allow for rigorous exposure assessment. Information on exposure to engineered, incidental, and natural nanoparticles is critical for development and implementation of effective risk-management plans. Conclusions The NNI acknowledges the importance of exposure research (primarily in occupational settings), but the research portfolio, gap analysis, and priority order do not adequately reflect attention to it.
82 Review of the Federal Strategy for Nanotechnology The 2008 NNI document does not address human and environmental exposure potential throughout the life cycle of nanomaterials. It focuses pri- marily on occupational exposure. The exposure-assessment section is imbalanced and does not adequately connect with research on environmental processes that determine environ- mental exposures. Understanding metrology and developing tools to characterize and measure attributes of nanomaterialsâincluding particle size, number, and surface areaârelevant 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 or- ganism 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 stud- ies 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 catego- ries, 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 uncertain- ties 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 com- bining 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
Review of Priority Research Topics, Research Needs and Gap Analysis 83 subsumed under the five research needs in NEHI (2008) are only evident in the reportâs 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 prac- tices 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; devel- opment 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: âissues 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.â 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 Im- plications Working Group (NEHI) would constitute a useful structure for bring- ing the needs of risk managers in the regulatory agencies to the attention of sci- entists in the primary research agencies. The NNI strategy states that âinput about the needs of regulatory decision makers expedites the development of information to support both risk assessment and risk management of nanomate- rialsâ (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 NNIâs own data collection methods, as NNI acknowledges on p. 38, âthe apparent lack of fund- 3 âControl banding is a qualitative risk-assessment and risk-management approach to promoting occupational health and safety.â For additional information, see NIOSH (2005).
84 Review of the Federal Strategy for Nanotechnology BOX 4-7 Research Needs for Risk Management Methods 1. Understand and develop best workplace practices, processes, and environmental exposure controls. 2. Examine product or material life cycle to inform risk reduction deci- sions. 3. Develop risk characterization information to determine and classify nanomaterials based on physical or chemical properties. 4. Develop nanomaterial-use and safety incident trend information to help focus risk management efforts. 5. 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.â 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 emerg- ing technology, but it is not informative, especially given the poor description of what is involved in the research needs. Moreover, in a research field character- ized by uncertain risks and poor-quality information about risks, it is not appro- priate 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 descrip- tion 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 priori- ties was based on the descriptions in the 2008 document. Because the content is explicitly related to risk management, the question of relevance to risk manage- ment was not considered separately. Analysis of Individual Risk-Management Research Subjects The strategy briefly describes 14 projects in the risk-management methods
Review of Priority Research Topics, Research Needs and Gap Analysis 85 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, âDevelop risk characterization information to determine and classify nanomaterials based on physical or chemical properties,â implies devel- opment 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, âDe- velop nanomaterial-use and safety-incident trend information to help focus risk management efforts,â apparently because one 2006 project was believed to ad- dress 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 âresearch needâ instead of as an infrastructure or surveillance activity, espe- cially when it is only a voluntary activity and therefore unlikely to be compre- hensive or representative in its characterization. Moreover, the information col- lected is stated to be ânanomaterial-characterizationâ rather than ârisk- characterizationâ information identified as a research need. That is another ex- ample of how the document is compromised by its efforts to make existing pro- jects 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 re- search, and little in this document indicates strategies or priorities for filling them. Research need 2 deals with life-cycle analysis and comprehensively con- siders, âmanufacturing, incorporation into an integrated product, consumer use,
86 Review of the Federal Strategy for Nanotechnology and recycling or disposalâ (p. 4). It is essential that not only the finished product but the materials, byproducts, and waste in producing the materials be consid- ered 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 mate- rials (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 life- cycle analysis for product classes not considered in the two current research pro- jects. The document suggests that the research gap is so large, âa systematic evaluation . . . is needed to evaluate where the most critical of such gaps would existâ (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 ap- proaches). 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 com- munication 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 reac- tivity 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: âdevelop risk characterization information to determine and classify nanomaterials based on physical or chemical properties,â âdevelop nanomaterial-use and safety- incident trend information,â and âexpand exposure route-specific risk manage- ment methods research and life cycle analysis research on the basis of nanoma- terial use scenarios expected to present greatest exposure and potential for health or environmental effects.â The committee agrees that these seven research pri- orities, 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 in- clude identifying nanotechnology-enabled products that can assist in managing risks posed by conventional hazards, and permitting the replacement of hazard- ous chemicals with less hazardous materials. For example, the document indi-
Review of Priority Research Topics, Research Needs and Gap Analysis 87 cates that the properties of nanomaterials can be used to âclean contaminated soil and groundwaterâ (p. 3). That suggests an important risk-management activ- ity for EPA. Although this kind of research was mentioned in the 2006 NNI re- port 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 prob- lems 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 time- lines, 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 inade- quate 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 graphi- cal timeline gives high priority to nearly all research needs, providing little stra- tegic 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, includ- ing management of environmental and consumer risks with emphasis on po- tential 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 distin- guish 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 con- stitutes another considerable gap. It pertains to consideration of risk- management approaches to both general population exposures and specific po- tential exposure settings, such as accidents and spills, environmental discharges, and exposure through consumer products with the likelihood of exposure of in- fants 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 reason- able 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-
88 Review of the Federal Strategy for Nanotechnology 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 tech- nologies like nanotechnology, but the narrow focus on 2006 studies and failure to describe adequately what is meant by the research categories and how pro- jects are to be given priority constitute a failure to develop a strategic plan to meet the need. COMMITTEEâS 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 re- search 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 âit 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 se- quentially are initiatedâ (p. 44). On the basis of the breakdown in funding, the NNI concludes that, âin 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 areasâ (p. 2). However, the analysis does not ad- dress 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 committeeâs 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 fo- cuses on finding new applications of nanotechnology-related therapeutics. That does not lead to the general understanding of factors governing absorption, dis- tribution, 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 exam- ple, cosmetics).
Review of Priority Research Topics, Research Needs and Gap Analysis 89 TABLE 4-1 NNI Evaluation of Federal Grant Awards in FY 2006 That Are Directly Relevant to EHS Issues Number of $ Invested Category Projects (Millions), FY 2006 Instrumentation, Metrology, and 78 26.6 Analytical Methods Human Health 100 24.1 Environment 49 12.7 Human and Environmental Exposure 5 1.1 Assessment 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 ob- tained 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 in- cluded in the presidentâs 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 profes- sional 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 pre- sented 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 under- standing the potential risks posed by engineered nanomaterials or would other- wise be reasonably expected to provide data that are directly relevant to EHS evaluation. The ranges in Table 4-2 reflect the variability in professional judg- ment among committee members; such an evaluation has elements of subjectiv- ity. Nevertheless, what is critical is that fewer than half the projects listed in Appendix A are relevant to understanding of EHS issues related to nanomateri- als. Therefore, the amount of money being spent by the federal government spe- cifically to address EHS needs in nanotechnology is certainly far less than the
90 Review of the Federal Strategy for Nanotechnology TABLE 4-2 NRC Committeeâs Estimate of Percentage of FY 2006 Projects That Are Aimed Primarily at Understanding Potential Risks Posed by Engineered Nanomaterials Category Committeeâs Professional Judgment Instrumentation, Metrology, and 18-40% Analytical Methods 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 rele- vant 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 con- sider specific biologic settings. Additional examples are discussed in Section II. Inventories of the research needs are sufficient for some topical catego- ries, but they are poorly defined and incomplete in risk management and ex- posure assessment. For example, the discussion of exposure assessment does not address exposures throughout the life cycle of nanomaterials and the discus- sion 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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