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Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials

INTRODUCTION

This chapter articulates the most pressing research gaps to be addressed for advancing understanding of the environmental and human health effects of nanotechnology with the overall goal of mitigating any risk. The gaps, which are articulated as questions, are organized according to the source-response paradigm that runs through this report and are evaluated by the principles established in Chapter 2. These questions relate to engineered nanomaterial (ENM) sources and manufacturing; modifications, fate, and transport; bioavailability and dose; and effects on organisms and ecosystems. Figure 3-1 presents a source-to-response paradigm that the committee used to organize and to identify the gaps and corresponding critical research questions. The boxes above the arrow generally track the life cycle of an ENM. The topics below the arrows are specific issues that help to define the research landscape.

The source-response paradigm is familiar, but in extending it to nanotechnology several specific elements need to be included. Most notable is the challenge of identifying ENM sources (far left box). Because uses of nanomaterials are relatively new, changing, and expanding rapidly, definitive information about most exposure scenarios is not available.

Figure 3-1 also highlights the central role of modifications and fate and transport of ENMs in determining exposure (second box). As ENMs move from a source to a biologic receptor, myriad modifications can occur, which are challenging to anticipate and characterize. As a result, the measurement and definition of dose and bioavailability can be difficult, and these are listed as a separate research subject (third box).



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3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials INTRODUCTION This chapter articulates the most pressing research gaps to be addressed for advancing understanding of the environmental and human health effects of nanotechnology with the overall goal of mitigating any risk. The gaps, which are articulated as questions, are organized according to the source-response para- digm that runs through this report and are evaluated by the principles established in Chapter 2. These questions relate to engineered nanomaterial (ENM) sources and manufacturing; modifications, fate, and transport; bioavailability and dose; and effects on organisms and ecosystems. Figure 3-1 presents a source-to- response paradigm that the committee used to organize and to identify the gaps and corresponding critical research questions. The boxes above the arrow gener- ally track the life cycle of an ENM. The topics below the arrows are specific issues that help to define the research landscape. The source-response paradigm is familiar, but in extending it to nanotech- nology several specific elements need to be included. Most notable is the chal- lenge of identifying ENM sources (far left box). Because uses of nanomaterials are relatively new, changing, and expanding rapidly, definitive information about most exposure scenarios is not available. Figure 3-1 also highlights the central role of modifications and fate and transport of ENMs in determining exposure (second box). As ENMs move from a source to a biologic receptor, myriad modifications can occur, which are chal- lenging to anticipate and characterize. As a result, the measurement and defini- tion of dose and bioavailability can be difficult, and these are listed as a separate research subject (third box). 70

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Environmental, Health, and Safety Aspects of Engineered Nanomaterials 71 Organism and Nanomaterial Quantified Quantified Dose, Nanomaterial Ecosystem Modifications Biodistribution, Sources Response and Exposures and Bioavailability Acute effects Workplace setting Exposure assessment Biokinetics Synergistic effects Workplace controls Mobility and partitioning Bioaccumulation Chronic effects Consumer products Chemical reactivity Dosimetry Repair and adaptation Discharge to ecosystem Transformations Biologic modifications Ecosystem interactions Byproducts and waste Persistence Retention, clearance FIGURE 3-1 Central topics for EHS research on ENMs. Research on the EHS aspects of nanotechnology can be organized into groupings that map onto a framework that consid- ers how a source of nanomaterial (left) may result in an organism or ecosystem response (right). Although Figure 3-1 presents a paradigm for organizing information about nanotechnology and its risks, it does not address the full diversity of exposed populations. Occupational exposure to ENMs is likely, given the extensive re- search enterprise and burgeoning startup business community. Inhalation expo- sure in manufacturing may occur if processes rely on gas-phase production of materials or if materials are aerosolized. Consumer exposure to ENMs also is of immediate interest in that makers of products ranging from sunscreens to car bumpers have touted the inclusion of nanotechnology (PEN 2011). Topical and ingestion exposure from use of personal-care and other consumer products is possible. And the environment is exposed through disposal or intentional appli- cation of ENMs for remediation and through incidental or accidental release and runoff. However, those different exposure scenarios involve many common re- search issues, particularly in the early stages of the ENM life cycle. Because research on risks to human vs ecosystem health poses different challenges, par- ticularly when ENM-related hazards are considered, the discussion in some sec- tions is separated to reflect these differences. The discussion below is organized according to the source-to-response paradigm to address critical gaps, but many key questions in nanotechnology- EHS research are intrinsically systems problems that can be addressed only by integrating the interactions of various components of the paradigm (See Figures 2-1 and 3-1). The assumptions and data from the more established foundation disciplines of pulmonary toxicology, environmental impact analysis, nanomedi- cine, and risk assessment are discussed where relevant. The chapter concludes with a compilation of research questions based around Figure 3-1 (see Table 3-1); the questions capture issues that are critical to the many stakeholders re- sponsible for managing potential ENM-related risks.

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72 Understanding Human & Environmental Effects of Engineered Nanomaterials PRIOR RESEARCH-GAP ANALYSIS—AN OVERVIEW Several convergent themes can be found in past research-gap analyses of the environmental and health impacts of nanotechnology (see Chapter 1). Most notable for this analysis are  The vital need for standardized ENMs, harmonized characterization methods, and standard biologic tests.  Research gaps concerning the in vivo evaluation of ENMs, particularly for chronic exposures and their impact on physiologic or biochemical end- points.1  Gaps in understanding low-level environmental exposure to ENMs and their impact on organisms through changes in development, reproduction, and growth. While this is not a complete list, those topics represent conclusions reached in multiple synthesis reports over the last few years. The need for standardization has emerged repeatedly in research-needs discussions and reflects the communitywide sentiment that ensuring reproduci- ble and meaningful findings requires a common platform of materials, methods, and, most recently, models. In 2002, EPA held a workshop on nanotechnology and the environment that included a discussion of impacts; that event and a workshop at the University of Florida began the analysis of the grand challenges in this field (EPA 2002). Those early efforts emphasized the need for uniform and standard materials to facilitate comparison of results between different ex- posure and toxicity studies. Later workshops echoed earlier findings and empha- sized the need to harmonize protocols for toxicologic evaluations. Testimony given to the U.S. Congress on strategies for nanotechnology-EHS research also highlighted the need to standardize materials, methods, and models (for exam- ple, Denison 2005). Chapter 4 addresses these needs. Some workshops have offered priorities for research. In 2006, a meeting at the Woodrow Wilson Center considered the toxicology of ENMs by route of exposure and noted the importance of dermal and gastrointestinal exposure of humans (Balbus et al. 2007). That emphasis reflected the perception that the substantial literature on the toxicology of inhaled particles in humans could in- form understanding of that exposure route and that comparatively little was known about the potential for exposure to ENMs by the dermal and gastrointes- tinal routes. Also noted in many reports is the importance of chronic-toxicity and developmental-toxicity studies and the overemphasis on acute studies (for example, Hirose et al. 2009). This emphasis reflects the relative ease of perform- ing acute studies in vitro, providing faster, lower-cost studies that dominate pub- lications in the peer-reviewed literature. 1 Physiologic or biochemical changes resulting from exposures.

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Environmental, Health, and Safety Aspects of Engineered Nanomaterials 73 Additional insights into critical research gaps can be derived from exami- nation of the peer-reviewed literature. The International Council on Nanotech- nology (ICON) maintains a database of peer-reviewed publications on nano- technology and issues related to nanotechnology-EHS research. The database integrates the complementary journal content found in the Web of Knowledge and PubMed. For this assessment, ICON’s categorization of the publications is critical. Skilled researchers review publication abstracts that meet a broad set of criteria and then classify the publications on the basis of their content—for ex- ample, exposure and hazards, environmental vs human health outcomes, and types of materials. An analysis of ICON’s database of peer-reviewed publica- tions reveals the relative imbalance between research on exposure and research on hazards: exposure-assessment studies constitute fewer than 25% of all papers published between 2001 and 2009 (Figure 3-2). This gap is important to address, but reflects a common trend for all chemicals in that greater attention is given to toxicity research than to exposure research. Similarly, there is a dearth of infor- mation about workplace exposure. There is also an imbalance between environmental and human health stud- ies (Figure 3-3). A theme observed both in the recent NNI workshops (NNI 2011a) and in the research directions of recently funded centers (NNI 2011b) has been the im- portance of systematic modeling of the relationships between materials and ef- fects. The focus on systematic modeling has developed as investigators have grappled with the challenges of managing many types of nanomaterials, of for- mulations, of surface coatings, of delivery or packaging systems, and of expo- sure routes. The sheer number of possible variations makes conventional testing paradigms impractical. The role of modeling is addressed in detail in Chapter 4. All All EHS FIGURE 3-2 The number of peer-reviewed publications relating to exposure and hazard. Although the number of peer-reviewed publications on EHS effects of nanotechnology has grown substantially, far more publications address issues related to hazard than expo- sure. Adapted from ICON 2011.

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74 Understanding Human & Environmental Effects of Engineered Nanomaterials FIGURE 3-3 The number of peer-reviewed publications on environmental issues. Al- though the number of peer-reviewed publications on EHS effects of nanotechnology has grown substantially, only a small number of publications address environmental issues. Adapted from ICON 2011. RESEARCH-GAP ANALYSIS AND IDENTIFICATION OF CRITICAL RESEARCH QUESTIONS Figure 3-1 is used in this section to structure consideration of the central research questions with major issues highlighted in boldface and mostly formu- lated as research questions. The committee addresses the relevance of these cen- tral questions to an understanding of potential human and environmental effects of ENMs. Sources of Engineered Nanomaterials A major issue related to EHS consequences of nanotechnology is the un- certainty of potential exposure. Nanotechnology is not yet highly developed as an industry, so that there is little experience with actual exposures to workers, the population, and the environment generally. Moreover, given the expected growth of the industry, existing release scenarios may not be indicative of those in the future (Figure 3-4). This uncertainty about exposure scenarios complicates problem definition and scoping—the necessary first step in a risk assessment. Efforts are needed to obtain exposure data related to present conditions in order to characterize exposures, and in combination with hazard data, assess potential risks.

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Environmental, Health, and Safety Aspects of Engineered Nanomaterials 75 FIGURE 3-4 Projection of the size of the nanotechnology market. Source: Data from Lux 2009. Table 3-2 lists a selection of classes of ENMs that notably include many variants. These materials represent different systems for researchers to charac- terize and study, and a consistent question facing researchers is, which of these classes of materials is of immediate interest and of relevance for EHS re- search? One approach to answer that question uses projected market size and potential risk based on plausibility and emergent risk (see Chapter 2 for discus- sion of these terms.) Such an analysis has led, for example, to a research focus on nanoscale silver. Nanosilver is widely used in commerce and when released into the environment could have effects on aquatic life (J.M. Johnston et al. 2010). However, because the number of products containing nanoscale materials is expected to explode in the next several years (see Figure 3-4), selecting target materials on the basis of existing or projected market size is problematic. In ad- dition, some products may result in very small releases (for example, computer devices) and other products greater releases to particular populations (for exam- ple, cosmetics). Research could be directed toward three or four classes of mate- rials or materials in specific types of applications (for example, cosmetics) that pose a plausible and emergent risk. Research also could be focused on funda- mental processes affecting exposure potential, for example, factors affecting releases from commonly used nanomaterial-containing matrices such as plastics, or on fundamental properties influencing nanoparticle-macromolecular interac- tions. The research on specific material types should be continually revisited and informed through regular surveys of nanomaterial production and use patterns. What are the maximum anticipated amounts of exposures to ENM sources to which workers, consumers, and ecosystems could be exposed? Realistic estimates of human and environmental exposures to ENMs from well-

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76 Understanding Human & Environmental Effects of Engineered Nanomaterials characterized sources are critical inputs for setting priorities for research. Sur- veys and registries of known products and their ENM constituents could allow ENM users, industry, and academic researchers to characterize at least the maximum concentrations of ENMs of various types from sources, particularly in workplace environments. Accurate information on these ENM sources is vital, as researchers today make crude assumptions about release potential and ENM concentrations in workplaces and other environments. Characterizing the nature of point sources of ENMs (for example, wastewater-treatment plant effluent) and nonpoint sources of ENMs (for example, stormwater or agricultural runoff) is essential for determining environmental compartments and locations that will be affected and for estimating the expected concentration of ENMs in those media. How might concentrations of ENMs from different sources apportion themselves in workplace, consumer, and various environmental compart- ments? Although basic information about point sources is essential, it is clear that ENMs will not remain at their sources. They will move into different envi- ronmental compartments, and environmental-exposure models are needed to describe this behavior. Methods for estimating releases of ENMs to the envi- ronment are currently based on estimates of total material flows (Blaser et al. 2008; Mueller and Nowack 2008; Robichaud et al. 2009; Gottschalk et al. 2010) and on assumptions of distribution of products that they will be used in and the fraction of the ENMs in those materials that will be released over their life cy- cle. Current models do not incorporate information about ENM properties. As- sumptions about product uses and fractions of ENMs in materials that are re- leased are empirical at best and not readily validated as there is presently no accurate means of tracking the mass of ENMs produced, used in specific prod- ucts, or disposed of. More important, there is no information on the fraction of TABLE 3-2 Examples of Common Nanoscale Materials and Their Applicationsa Features and Types Example Products Fullerenes C60, carbon nanotubes, graphene Conductive films, fuel cells, composites, cosmetics Ceramics Iron oxides, ceria, titania Photocatalysts, magnetic data storage, window coatings, sun-screens, paint Metals Silver, gold, platinum Antimicrobial fabrics, oxidation catalysts, sensor elements Quantum Dots Cadmium chalcogenides Solar cells, diodes, biologic markers Polymers Copolymer assemblies, Coatings, rheologic control, dendrimers drug delivery a There is little information on the relative exposure to these different materials or their products.

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Environmental, Health, and Safety Aspects of Engineered Nanomaterials 77 ENMs that may be expected to be released during normal use, at the end of a material’s life, or during recycling. The models mentioned above are designed to provide an upper limit of ENM exposure, but they are representations of still largely unknown scenarios. Particularly for environmental exposure, detection schemes are needed to validate the models and to signal that there is a potential for exposure. That kind of early-warning system could also be developed for workplace exposure. Thus, an important research question is, How can ENMs be detected in air, in water, and in complex media, to allow real-time monitor- ing of sources of ENM exposure? Modification of and Exposure to Engineered Nanomaterials Identification of a source of ENMs leads to the need to assess the potential for exposure. For ENMs, the assessment of potential exposures is complicated by the many modifications of the ENMs that may occur. In addition to investi- gating how much nanomaterial may be present at a receptor, it is also critical to specify the form of the nanomaterial at the point of exposure. A nanoscale mate- rial may undergo both subtle and extreme changes as it moves through biologic and environmental systems. The changes can be in size, surface chemistry, and reactivity and these changes might lead to different hazards. That complexity is not dissimilar to exposure issues related to, for example, dissolution of metals in water; depending on the details of the water chemistry, metals may be in differ- ent oxidation states or have different degrees of bioavailability (Mahendra et al. 2008). As in the case of metals, models that can predict the form of nanoscale materials, given the environmental compartments, are vital. Once the form of the nanomaterial is established, many of the exposure questions are reduced to accu- rate measurement of the quantity of material. In addressing ENM modifications and the related implications for exposure and hazard, the distinction between human health and environmental health is relevant. Modification processes may be different if a material is first transported through the environment vs through the human body, and the tools needed for exposure assessment also differ and are treated separately below. Human Health—Needed Research on Material Modification and Exposure Assessment There are three primary routes of human exposure: inhalation, ingestion, and dermal absorption. Inhalation is the most studied pathway; research on the effects of inhaling particles in the ultrafine size range long antedated the emer- gence of nanotechnology, and commercial instruments are available for detect- ing submicrometer ambient particles. For example, when measuring airborne engineered nanoparticles, equipment such as the Scanning Mobility Particle Sizer or Fast Mobility Particle Sizer can be used (McMurry 2000; Asbach et al. 2009; Jeong and Evans 2009; Aggarwal 2010). However, the circumstances for

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78 Understanding Human & Environmental Effects of Engineered Nanomaterials inhalation exposure to ENMs have not been well characterized and one critical research gap is the identification of conditions that will cause ENMs that are in the gas phase, in liquids, or embedded in solids to become airborne. The frequency of conditions that might lead to inhalation exposures over the lifecycle of ENMs is also uncertain. While ENMs manufactured in the gas phase can produce aerosolized materials, most applications use ENMs in solu- tion or embedded in devices or composites. However, application-specific proc- esses could result in inhalation exposures. Nanocomposites could be machined so that dust is produced, or they may be used in applications (for example, as additives to fuels) that lead to their emission in exhausts or gases. Only a few studies have assessed exposure at nanomaterial manufacturing sites (Kuhlbusch et al 2004; Maynard et al 2004; Bello et al. 2008; Han et al 2008; Bello et al. 2009; Tsai et al. 2009; Lee et al. 2010; Methner et al 2010; Sahu and Biswas 2010). The potential for such exposures at other stages of the ENM lifecycle needs more study. When airborne particles are inhaled, they deposit in three regions of the res- piratory tract (upper, tracheobronchial, and alveolar) depending on their size. For example, the smaller nanoparticles (less than 5 nm), if inhaled as single particles, deposit to a high degree in the upper respiratory tract (nasopharyngeal region) whereas larger particles (about 10 nm) deposit to a greater degree in the tracheo- bronchial region, and the larger particles (about 20 nm) deposit with the highest deposition efficiency (up to 50% of inhaled particles) in the alveolar region. The primary mechanism for deposition of airborne nanomaterials is by diffusion, while larger particles, including aggregated and agglomerated nanoparticles, deposit by sedimentation (gravitational forces) and by impaction (inertia).2 During inhalation, modifications of ENMs may occur in the lung lining fluid, possibly including agglomeration and deagglomeration. The size depend- ence of particles for clearance by airway mucociliary and alveolar mechanisms and translocation from the respiratory tract into the bloodstream has been exam- ined in model systems (Guo et al. 2007; Kreyling et al. 2002, 2009; Semmler- Behnke et al. 2007, 2008; Tang et al. 2009). The agglomeration-aggregation3 state of ENMs deep in the respiratory tract is not well understood and is related to the modifications of the ENM surface induced by the lung lining fluid and along translocation pathways. 2 Other minor deposition mechanisms specific for certain materials include intercep- tion (for fibers), electrostatic image forces, and condensational growth (in the highly saturated regions of the respiratory tract). 3 Agglomeration results from “the collection of weakly bound particles or aggregates or mixtures of the two where the resulting external surface area is similar to the sum of the surface areas of the individual components” (ISO 2008). Aggregation results from “strongly bonded or fused particles where the resulting external surface area may be sig- nificantly smaller than the sum of calculated surface areas of the individual components” (ISO 2008). However, the committee recognizes that the distinction between these terms is more operational than theoretical, and different communities use these terms differ- ently.

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Environmental, Health, and Safety Aspects of Engineered Nanomaterials 79 Far less is known about dermal and ingestion exposure than about inhala- tion exposure. A number of review articles have examined the exposure to nanomaterials via the dermal route (for example, Schneider et al. 2009; Smijs and Bouwstra 2010; Prow et al. 2011). The ability of nanomaterials to penetrate skin is influenced by the condition of the skin and the physicochemical proper- ties of the nanomaterials (for example, size, charge density, photostability, and hydrophobicity). Data suggest that nanoparticles greater than 10 nm in diameter are unlikely to penetrate human skin. However, uptake may occur if skin is damaged or diseased (Mortensen et al. 2008; Prow et al. 2011), although data on penetration of nanomaterials into damaged skin is limited. The persistence4 and potential effects of ENMs, particularly photoactive materials, on skin requires additional research. Research on ingestion of ENMs as a direct exposure route is just begin- ning. The Food and Agriculture Organization and the World Health Organiza- tion (FAO/WHO 2009) summarized information on the potential food safety implications of ENMs. Direct exposure to ENMs may occur from their use in food, for example to enhance nutritional value or to improve flavor or color (EFSA 2009) or in food packaging. Assessing exposures to ENMs poses chal- lenges because of the need to characterize and quantify the material once it is released and to assess its stability and potential biotransformation during food processing or in food (FAO/WHO 2009). Critical research questions include, What is the propensity of ENMs to survive in the gastrointestinal tract, par- ticularly the acidic gastric milieu, as particles? If they survive, what is the ex- tent of absorption and assimilation into the organism? Once nanomaterials enter the human body, their surfaces may be modified by native biomolecules, and these modifications may influence their dosimetry. The process, referred to as opsonization or differential adsorption, involves ad- sorption of proteins and lipids onto the surface of ENMs (protein corona forma- tion), which potentially modifies their size, surface charge, and aggregation state (Muller and Keck 2004; Lynch et al. 2007). Research focused on biologic sur- face modification is increasing, but the topic is complex. Such fundamental nanoparticle characteristics as hydrophobicity, size, and charge probably dictate the composition of the corona5 of a nanoparticle. Moreover, the dynamics of biomolecular association are not always on the same timescale. Recent evidence indicates the formation of a “hard” corona with stable proteins and an outer, “weaker” corona that has quickly exchanging proteins (Walczyk et al. 2010; 4 It should be noted that defining “persistence” of an ENM is more challenging than for traditional molecules with defined molecular formulas. This is true for all processes that alter the form of the ENM from its pristine state to a transformed one. Chapter 4 provides additional discussion on the appropriate metrics for defining alteration or degra- dation rates. 5 The corona is the coating of proteins that bind to the surface when nanoparticles in- teract with biologic fluids.

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80 Understanding Human & Environmental Effects of Engineered Nanomaterials Monopoli et al. 2011). A critical research question is, What are the nature and implications of biomolecular modifications of ENMs? Environment—Needed Research on Modifications and Exposure Assessment As discussed earlier, modification of ENMs in the environment is a key element of their exposure potential. Publications over the last 5 years have high- lighted the diversity and complexity of nanomaterial modifications. ENMs can dissolve, aggregate, disaggregate, agglomerate, disagglomerate, or be chemi- cally transformed in environmental systems (for example, sulfidation or adsorp- tion of Natural Organic Matter (NOM)). Specifically in the atmosphere, released ENMs may become incorporated into preexisting atmospheric particles, or may be coated through adsorption or condensation of atmospheric vapors. A given ENM, if discharged to a stream, could have a physical and chemi- cal composition and a fate different from what would follow application to plants in fertilizer in an agricultural field. There is a need to understand the transformation processes and their variation with ENM structure. Adding to the research challenge is the fact that these processes (for example, ENM aggrega- tion) can affect transport and fate, exposure, and ultimately toxicity. Research approaches need to recognize the complexity of the underlying processes and use systems approaches to examine the interdependencies of the processes. The models discussed in Chapter 4 are essential tools for addressing these chal- lenges. Of all the ENM modification processes, aggregation (both homoaggrega- tion and heteroaggregation) is the most central to environmental health (Hotze et al. 2010). Aggregation is a result of the attachment of particles to themselves (homoaggregation) or to other environmental surfaces (heteroaggregation). The attachment of ENMs to surfaces depends heavily on the solution conditions (for example, pH, ionic strength, and ionic composition) and on the physics of the attachment, that is, how the ENM approaches the surfaces of particles (Mylon et al. 2004; Hotze et al. 2010). The presence of organic matter or biomacro- molecules also substantially affects an ENM’s attachment to surfaces (Wiesner et al. 2009; Phenrat et al. 2010; Saleh et al. 2010). If nanomaterials collect into larger micrometer-size aggregates, their transport and reactivity may be different from those of materials that remain as isolated nanoscale high surface-to-volume materials. Aggregation into larger particles may also affect interactions with recep- tors. ENMs may interact with other particles in the environment, such as clay particles (heteroaggregation) that can affect their transport and distribution. For example, heteroaggregation of ENMs with soil particles will alter their transport to water by runoff (for example, from croplands that are applied with biosolids). Heteroaggregation of ENMs with larger airborne or waterborne particles will increase their rate of deposition from air or their sedimentation rate in water,

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96 Understanding Human & Environmental Effects of Engineered Nanomaterials example, changing the abundance of nitrifying bacteria or the availability of nutrients. The questions remain: How do the properties of ENMs influence their impact on community structure? How do the properties of ENMs influ- ence ecosystem function? How do ENM transformations in environmental media and in vivo influence these effects? A suite of standard tests for higher- level effects (effects on the community or ecosystem) does not exist. That prob- lem, which is not peculiar to ENMs, presents a serious challenge for modeling ecologic impacts. There is a need for basic research to describe those potential ecosystem impacts with key ENMs, rather than with only high-throughput as- says. Common Issues in Human Health and Ecologic Effects Research Issues that cut across human and ecologic health include determining the potential mechanisms of toxicity of nanomaterials and how they vary with ENM composition and dose, including developing data so as to correlate in vitro and in vivo responses; understanding effects of chronic exposure to nanomaterials; and obtaining data on multiple end points that precede or do not result in death of cells or organisms. There are also some common issues regarding experimental design and methods. Access to a library of materials that have a variety of core and surface properties is needed so that a systematic evaluation of ENM properties can be conducted. Sufficient nanomaterials that have different structures and modifica- tions are not available; there is little information about what may be most appro- priate to test from an industry or commercial standpoint; and standard negative or positive control materials are not on hand to use for assays and comparisons among laboratories. There is also a need for standardized reference materials. Dosimetric studies—to understand the transformations of ENMs in vivo— and the ability to characterize ENMs in vivo or in a representative physiologic buffer are needed to correlate the properties of ENMs with their observed ef- fects. For each experiment, information is needed on the key physicochemical properties of ENMs, such as size and size distribution, shape, agglomeration and aggregation state, surface properties (area, charge, reactivity, coating and con- taminant chemistry, and defects), solubility (lipid and aqueous), and crystallin- ity, many of which can change depending on the method of production, during preparation, or storage. Moreover, surface changes will occur when materials are introduced into physiologic media or into an organism. Although data on the impact of such changes on biodistribution and effects are beginning to be gener- ated, a major gap is methods for characterizing the altered surface of nanomate- rials after transformation that results from interaction with proteins and lipids at different sites in an organism. Determination of the form of the ENMs that an organism will be exposed to will depend on the fate and transformation of ENMs in the environment (to be assessed with models) and will help to inform effects testing.

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Environmental, Health, and Safety Aspects of Engineered Nanomaterials 97 Additional challenges arise with the use of dispersants, solvents, or or- ganic carbon, generally accepted and recommended to render nanoparticles ei- ther monodispersed or stable in toxicity studies. Such techniques pose a di- lemma, in that dispersants will alter surface properties of ENMs, which in turn may alter their interactions with cells and organisms and thus affect the dose that an organism receives or that is delivered to an in vitro cellular assay. Compari- sons of results achieved with each dispersion method are needed so that the most appropriate conditions for toxicity testing can be selected. Toward an Understanding of Systems and Complexity in Nanotechnology-Related Environmental, Health, and Safety Research The research gaps presented in the prior sections were categorized into questions regarding stages in the source-to-response paradigm of an ENM, but it is critical to recognize the interplay between the questions. That interplay is at the heart of systems science that recognizes that issues in one part of a para- digm can influence outcomes in other parts. This overarching issue has been inadequately addressed in the literature and is best addressed with models (see Chapter 4). Materials originate at various points along the value chain and life cycle and direct exposures of the environment or organisms to ENMs occur, as de- scribed in Chapter 2 (Figure 2-1). The ENMs will have specific surface proper- ties and chemical characteristics (for example, size, shape, chemical composi- tion, and charge). Those properties will determine the types of processes that the materials undergo that can affect their potential for exposure or hazard (for ex- ample, attachment to surfaces or dissolution). The present chapter has presented processes that most likely will affect the exposure and hazard potential of ENMs. The impact of those processes on the potential for exposure or hazard can be measured or modeled (see Chapter 4). Models are needed because limited resources do not allow direct measurement of the exposure or toxicity potential of all new ENMs that come to market. However, measurements are needed to construct and validate exposure and toxicity models. Data on all aspects of EHS research regarding ENM properties, processes, and model validation should be collected and stored in a manner that enables data mining and integration with bioinformatic models. The deployment of bioinformatic models will require harmonization of data types and protocols that facilitate sharing. Such models will ultimately enable risk characterization and risk-based decisions to be made on the basis of the properties of ENMs released to the environment. Two exam- ples that illustrate this process follow. Consider the release of single-walled carbon nanotubes (SWCNT) to the environment. They may be released during manufacture, during use of products containing them, or at the end of their life. Their properties (for example, surface charge, surface functionality, aspect ratio, and presence of adsorbed macromole- cules) will affect the fundamental processes that control their exposure potential

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98 Understanding Human & Environmental Effects of Engineered Nanomaterials TABLE 3-1 Summary of Critical Research Questions Sources What types of ENMs are of the highest priority with regards to nano-EHS research? What are the maximum anticipated amounts of ENMs to which workers, consumers, and ecosystems could be exposed? How might concentrations of ENMs from different sources apportion themselves in workplace, consumer, and various environmental compartments? How can ENMs be detected in air, in water, and in complex media, to allow real-time monitoring of ENM sources of exposures? Modifications and Exposures Human Health What conditions will cause ENMs in the gas phase, in liquids, or embedded in solids to become airborne? What is the ability of certain ENMs (for example, photoactive materials) to persist on skin after application and what are the potential effects? What types of ENMs can survive the gastrointestinal tract? Do they assimilate intact into the organism? What are the nature and implications of biomolecular modifications of ENMs? Ecosystem Health Under what conditions will ENMs aggregate or disaggregate in relevant environmental media? How stable are the coatings of ENMs? How does this relate to ENM aggregation and fate? How rapidly do ENMs dissolve in various relevant environmental media? What properties of ENMs promote attachment to environmentally relevant surfaces? How can the fate and transport of ENMs in the environment be fully described and modeled? Dose, Biodistribution, and Bioavailability Human Health What is the most appropriate metric to describe ENM dose? How does applied dose (for example, dermal, ingestion or inhalation) translate into bioavailability? Can dosimetric extrapolations between organisms be used to validate in-vitro and in-vivo studies? What are the most valid quantitative biokinetic models that relate ENM properties to their distribution in organisms, organs, and tissues? Ecosystem Health What factors control the distribution of ENMs into biologic compartments in the environment? How can the environmental dose to an organism be related to bioavailability? Can ENMs bioaccumulate and to what extent? If so, what properties are most critical for bioaccumulation? Hazard Human Health What biologic effects occur at realistic ENM doses and dose rates? How do ENM properties influence these effects? How can in-vitro assays be developed and validated so that results are relevant to in-vivo exposures? How do ENM properties influence toxicologic mechanisms of action? Ecosystem Health How can toxicity mechanisms for ENMs be better understood? How can community and ecosystem level effects be anticipated from single organism tests? How do properties of ENMs (and their transformations) influence community structure and ecosystem function?

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Environmental, Health, and Safety Aspects of Engineered Nanomaterials 99 and toxicity. Charge, functional groups, and adsorption of organic macromole- cules all increase or decrease attachment of SWCNTs to surfaces, including other SWCNTs, environmental surfaces (such as aquifer media), and cell mem- branes. The tendency of an ENM to attach to a surface affects aggregation, mo- bility in porous media, and cellular uptake, which are described in exposure models. Those properties also affect the potential for hazard and are described in hazard models. In that way, the properties of an ENM are correlated with its potential for exposure and toxic effects. Another example is silver nanoparticles (Ag NPs). Substantial amounts of data are available on the fate, transport, and effects of Ag NPs (Marambio-Jones and Hoek 2010). Ag NPs can undergo oxidative dissolution and dissolve in wa- ter and biologic media. Dissolution affects persistence in the environment and exposure potential. Soluble Ag species also affect the toxicity pathways and modes of action of Ag NPs, and it is important to determine whether there is a toxic effect of NPs or the effect is the result of the Ag ion. Thus, dissolution is an important process that affects both exposure and hazard potential of Ag NPs, and it is important to consider factors affecting dissolution rates in different bio- logic and environmental media (for example, Levard et al. 2011; Liu et al. 2010). The properties of the NPs and media that can be used to predict the rate and extent of dissolution of Ag NPs remain to be fully determined; once they are better understood, the potential exposure to and hazard posed by Ag NPs can be related to them. REFERENCES Aggarwal, S.G. 2010. Recent developments in aerosol measurement techniques and the metrological issues. MAPAN 25(3):165-189. Alexis, F., E. Pridgen, L.K. Molnar, and O.C. Farokhzad. 2008. Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol. Pharm. 5(4):505- 515. Asbach, C., H. Kaminski, H. Fissan, C. Monz, D. Dahmann, S. Mülhopt, H.R. Paur, H.J. Kiesling, F. Herrmann, M. Voetz, and T.A.J. Kuhlbusch. 2009. Comparison of four mobility particle sizers with different time resolution for stationary exposure measurements. J. Nanopart Res. 11(7):1593-1609. Asgharian, B., F.J. Miller, and R.P. Subramaniam. 1999. Dosimetry Software to Predict Particle Deposition in Humans and Rats. CIIT Activities 19(3). Auffan, M., W. Achouak, J. Rose, M.A. Roncato, C. Chaneac, D.T. Waite, A. Masion, J.C. Woicik, M.R. Wiesner, and J.Y. Bottero. 2008. Relation between the redox state of iron-based nanoparticles and their cytotoxicity toward Escherichia coli. Environ. Sci. Technol. 42(17):6730-6735. Bae, E., H.J. Park, J. Lee, Y. Kim, J. Yoon, K. Park, K. Choi, and J. Yi. 2010. Bacterial cytotoxicity of the silver nanoparticle related to physicochemical metrics and ag- glomeration properties. Environ. Toxicol. Chem. 29(10):2154-2160. Balbus, J.M., A.D. Maynard, V.L. Colvin, V. Castranova, G.P. Daston, R.A. Denison, K.L. Dreher, P.L. Goering, A.M. Goldberg, K.M. Kulinowski, N.A. Monteiro- Riviere, G. Oberdörster, G.S. Omenn, K.E. Pinkerton, K.S. Ramos, K.M. Rest,

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