National Academies Press: OpenBook

A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials (2012)

Chapter: 3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials

« Previous: 2 A Conceptual Framework for Considering Environmental, Health, and Safety Risks of Nanomaterials
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 70
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 71
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 72
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 73
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 74
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 75
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 76
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 77
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 78
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 79
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 80
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 81
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 82
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 83
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 84
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 85
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 86
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 87
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 88
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 89
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 90
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 91
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 92
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 93
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 94
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 95
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 96
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 97
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 98
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 99
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 100
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 101
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 102
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 103
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 104
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 105
Suggested Citation:"3 Critical Questions for Understanding Human and Environmental Effects of Engineered Nanomaterials." National Research Council. 2012. A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials. Washington, DC: The National Academies Press. doi: 10.17226/13347.
×
Page 106

Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

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

Environmental, Health, and Safety Aspects of Engineered Nanomaterials 71 Nanomaterial Quantified Dose, Organism and Nanomaterial Modifications Biodistribution, Ecosystem Sources and Exposures and Bioavailability Response Workplace setting Exposure assessment Biokinetics Acute effects Workplace controls Mobility and partitioning Bioaccumulation Synergistic effects Consumer products Chemical reactivity Dosimetry Chronic effects Discharge to ecosystem Transformations Biologic modifications Repair and adaptation Byproducts and waste Persistence Retention, clearance Ecosystem interactions 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.

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.

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 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.

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.

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-

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.

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

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.

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.

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,

Environmental, Health, and Safety Aspects of Engineered Nanomaterials 81 respectively. Sedimentation of ENMs out of the water column will decrease water column ENM concentrations and increase sediment ENM concentrations (Wiesner et al. 2009; Hotze et al. 2010). These processes will affect the organ- isms that are likely to be exposed, the exposure routes, and the effects of expo- sure. There is also evidence that nanoparticle aggregates may remain stable in suspension and maintain toxicity potential despite being present in an aggre- gated state. For example, Salonen et al. (2008) found that C70 fullerenes formed “stable, homogeneous suspensions” in water through interaction with phenolic acids that are present in and released from plant matter, and Fortner et al. (2005) identified the formation of stable suspensions of “nanocrystals” (25-500 nm diameter) of C60 fullerene aggregates in water. Fortner et al. (2005) also found that these aggregated fullerene nanocrystals exhibited antimicrobial activity, suppressing bacterial growth and respiration. Lyon and Alvarez (2008) also cited a number of studies demonstrating that these nanoscale aggregates in water can yield a material with toxicity to aquatic invertebrates, fish, and the cells of higher organisms, and that the aggregates can enter and accumulate in cells. Fi- nally, Salonen et al. (2008) showed that phenolic acid-coated C70 aggregates could translocate across the membranes of human cells in culture. In addition, they induced the contraction and death of those cells through agglomeration and aggregation into micro-sized particles that interacted with the cell membranes. A detailed understanding of ENM aggregation is needed to create models of fate and transport of ENMs in the environment. A complicating factor for aggregation and heteroaggregation is the pres- ence of polymer or surfactant coatings used to stabilize ENMs against aggrega- tion sterically or electrosterically in the absence of sufficient charge stabiliza- tion. Macromolecules attached to ENM surfaces greatly affect their attachment behavior, including attachment to NOM (Saleh al. 2008; Petosa et al. 2010). Nearly all ENMs in the environment are expected to have an engineered mac- romolecular coating or will become coated with NOM. Research findings on the effects of coatings or of adsorbed NOM on the transport of ENMs in the environment are limited and contradictory. In some cases, the coatings have been shown to prevent aggregation; in others, they have been shown to increase aggregation (Jarvie et al. 2009). Even though the dual role of NOM on the aggregation (flocculation) and dispersion of colloids has been studied by many different scientific disciplines, the complexity of NOM, and the very small size of ENMs compared with the size of the adsorbed mac- romolecules, complicates predictions of the effects of NOM on polymer-coated ENMs. The fate of the engineered coatings in the environment is not well estab- lished. Once discharged into environmental waters, the engineered coatings may be removed, and this change can cause nanomaterials to aggregate. However, some covalently bound polymeric coatings may be resistant to removal or bio- degradation and remain on the ENMs. Similarly, NOM can coat ENM surfaces and act as a natural surfactant, preventing aggregation or promoting disaggrega- tion. The ability of a coating to promote or prevent aggregation will probably

82 Understanding Human & Environmental Effects of Engineered Nanomaterials depend on the ENM surface, the coating properties, and the environmental mi- lieu. There is a notable gap in information about the coatings on ENMs and how their presence and stability are related to ENM aggregation and ultimate fate in the environment. Another important issue in assessing exposure to ENMs is nanomaterial transformation and persistence in the environment. ENM transformations in the environment may lead to materials that have different partitioning, transport, and toxicity characteristics from the native ENM. Chemical transformations in the environment can include dissolution, sulfidation, oxidation-reduction, photode- gradation, biodegradation, adsorption of organic matter and biomacromolecules, and biodegradation of macromolecular coatings. Biologic oxidation or reduction and biodegradation of macromolecular coatings will alter the surface properties of ENMs and therefore their transport and distribution in the environment. The oxidation of zero valent iron nanoparticles or the adsorption of NOM has been shown to increase their mobility in porous media (Phenrat et al. 2009a) and de- crease their toxicity to bacteria (Auffan et al. 2008; Li et al. 2010) and mammal- ian cells (Phenrat et al. 2009b). The dissolution of silver nanoparticles correlates with their toxicity to bacteria (Bae et al. 2010). Sulfidation of silver nanoparti- cles in the environment may decrease the release of silver ions and therefore their toxicity (Liu et al. 2010; Levard et al. 2011). How those chemical transformations (such as dissolution) affect the per- sistence of ENMs in the environment remains unknown. Zinc oxide and silver nanoparticles are two examples in which dissolution affects persistence, but this phenomenon occurs with many types of ENMs. The persistence of organic and fullerene systems is a function of their redox reactivity; for example, fullerenes in water can be oxidized easily in the presence of light (Hou et al. 2010). It is important to note that the transformations do not necessarily operate singly or in series. It is unclear how sulfidation or aggregation of silver nanoparticles affects their rate of dissolution and persistence in the environment. Although the simple reaction chemistry of many of the most common ENMs is established, the quantitation of the dissolution rate and dependence on environmental condi- tions remains a critical research gap. Only with this information can the persis- tence of ENMs be clearly defined. The transport and fate of ENMs are coupled; that is, modifications will af- fect their transport and ultimately affect their fate. Once ENM modifications are understood, their transport in the environment can be considered. The transport of ENMs in the environment will determine their probable accumulation points, potential exposure routes, and where dilution occurs. The latter information is needed to predict ENM concentrations in environmental media. There is little knowledge about the transport and distribution of ENMs in the environment after release. Transport in porous media is an important mechanism to consider. Whereas aggregation is attachment of ENMs to other ENMs or to suspended particles, deposition involves attachment of ENMs to fixed porous media, such as soil, sediment, or filter media used in water treatment. Strong attachment to

Environmental, Health, and Safety Aspects of Engineered Nanomaterials 83 porous media suggests minimal transport in the aquatic environment and re- moval in drinking-water treatment systems. However, attachment of ENMs to wastewater solids presents additional pathways for environmental exposures. Understanding deposition is an important precursor to accurate exposure assessment, in that studies of deposition can provide information on environ- mental sinks for ENMs. For example, exposure modeling for nanoscale titania that relied on bulk attachment behavior suggested that sludge is the likely sink for these ENMs (Gottschalk et al. 2009); this information can be used to deter- mine the distribution of ENMs in the environment and the likelihood that exist- ing control strategies (such as the use of activated carbon or sand filters in water treatment) can mitigate ENM exposure. A continuing research theme is the systematic linkage between ENM properties and their deposition and transport behavior in model and real porous media. As for aggregation, an improved understanding of the properties of ENMs that affect attachment to porous media will allow better prediction of deposition in environmental media. Factors that influence aggregation of ENMs and their attachment to porous media will be useful in assessing the distribution of ENMs in the environment. However, tools and methods are needed to measure the occurrence of ENMs at low concentrations in environmental media. In contrast with human health expo- sure assessment, monitoring for environmental exposure to ENMs is in its in- fancy. Several studies have used microscopy to examine sludge and sediment to locate ENMs (Kim et al. 2010). However, it is unlikely that such an approach would be scalable or routine. Other potential tools for environmental monitoring are difficult to use because of interference from naturally occurring nanomateri- als, the low concentration of ENMs in environmental samples, and the inability to detect individual and transformed ENMs. As discussed above, tools for con- ducting real-time monitoring of ENMs are needed. Ultimately an environmental exposure-assessment model that contains important ENM transformations as subcomponents is needed. However, a 2010 state-of-the-science report (J.M. Johnston et al. 2010) concluded that there are many data gaps in environmental-exposure models; for example, “problem for- mulation” is inadequate for assessing environmental and ecologic exposures to ENMs, and there is a need to validate and assign values to parameters for the models (screening or otherwise). Those gaps arise from the particulate nature of ENMs and the absence of data that are needed to properly assess appropriate parameters for the models. For example, needed parameters include assimilation efficiency; rates of emission of ENMs to the environment; ENM properties that affect transport in air, porous media, and water columns; interphase mass trans- fer, such as runoff from land to water; degradation rates; dilution rates; sedimen- tation rates; and distribution coefficients between phases. One exception to the need for parameters, may be the ability of these models to track particulate mat- ter from an airborne source (such as a smokestack) to receptors on the basis of

84 Understanding Human & Environmental Effects of Engineered Nanomaterials data on rates of dry and wet deposition of airborne particulate matter.6 How can the fate and transport of ENMs be fully described and modeled? There are two approaches to model the fate of ENMs in the environment. One approach uses measured bulk parameters (such as distribution coefficients) in applied empiri- cal, deterministic, or probabilistic models for heterogeneous and large-scale sys- tems. A second approach builds mechanistic models based on fundamental processes affecting the behavior of ENMs in natural systems. Identifying the relevant processes should be possible in accordance with principles of colloidal science and an understanding, albeit limited, of the behavior of ENMs in envi- ronmental media. It is critical to identify those conditions (for example, size or other properties) under which ENMs can be modeled like colloids, and those conditions that allow them to be modeled like chemicals. It remains unclear if mechanistic models can be scaled up to the ecosystem level. Models capable of estimating ENM distribution in the environment, combined with an understand- ing of the sources of environmental ENMs (discussed below), will allow re- search to address questions that provide the greatest potential to reduce uncer- tainty in environmental exposure-assessment models. Source information may include descriptions of runoff from agriculture due to ENMs in biosolids applied to the fields; processes of ENM dry and wet deposition from air, sedimentation, and later sediment transport; and groundwater infiltration from agriculture ac- tivities. Quantifiable Dose, Biodistribution, and Bioaccumulation When a material interacts with a biologic receptor, hazard assessment re- quires the definition of the quantifiable dose of the material. In the case of ENMs, the connection between the amount of material at the interface of an or- ganism and its relevant bioavailability, which can be different from the dose, is largely unknown. For example, it is not clear whether the material mass, surface area, or number concentration is the most appropriate metric for assessing the dose of nanomaterials, since the relationship among the dose metrics may change as the nanomaterials interact with biologic receptors. Physical and chemical modifications of ENMs can have a substantial effect on their bioavail- ability and biodistribution. The dose of an ENM depends on its distribution in the compartments of an organism; distribution data can be essential for defining hazards to specific organs and tissues. Thus, the fundamental metric of concen- tration in an organism is not necessarily the best measure of dose. 6 However, the particulate nature of ENMs may contribute to behaviors that will differ from that of chemicals. This is true of the parameter describing the distribution of ENMs between phases. The distribution of a molecule (for example, a dioxin) is based on the equilibrium partitioning of that molecule between two phases and can be determined from thermodynamic constants. Conversely, the distribution of ENMs will likely result from the kinetics of attachment to other particles or environmental surfaces.

Environmental, Health, and Safety Aspects of Engineered Nanomaterials 85 Human Health—Biodistribution and Dosimetry Information about the biodistribution of ENMs after exposure by inhala- tion or oral or dermal uptake is essential for the determination of relevant doses, particularly for designing in vitro studies and interpreting their findings. Simi- larly, doses used in biokinetic animal studies need to be informed by relevant data on human exposure, whether in a workplace, in a laboratory, or in con- sumer use of nano-enabled products. Those data are critical to guide the do- simetry of in vitro studies. If only a tiny fraction of inhaled nanoparticles can be expected to reach the brain (say, much less than 0.1%) (Semmler-Behnke et al. 2008; Kreyling et al. 2009), what concentration of nanoparticles would be ap- propriate to use in an in vitro study involving exposure of neuronal cells? An outstanding ENM-dosimetry question is, What is the most appropriate metric for assessing ENM dose? This is a complex issue that is peculiar to the study of nanoparticles. ENMs are chemical objects whose molecular weights are hundreds or thousands of times greater than those of most molecules; moreover, particle mass is size-dependent. For example, a parts-per-billion suspension of metal nanoparticles that are 5 nm in diameter has 25 times the surface area of a batch of 25-nm nanoparticles of the same metal and 125 times the number con- centration. Whether the dose should be expressed as particle mass, particle sur- face area, or number depends on the objective of the study. For example, data from inhalation and instillation studies suggest that at least for some toxicologic end points surface area is the appropriate metric for gauging effects. For well- characterized ENMs, it is straightforward to express dose in various ways, and dose issues can be explored with appropriate study designs. The characteristics of the ENM sample may influence the metric used. For example, measuring airborne nanoparticles at very low mass concentration would most reliably use number concentration, whereas concentrations in tissue samples may be based on a chemical analysis of mass or possibly transmission electron microscopy of number concentration. Mechanistic studies that explore what is an appropriate metric for expressing ENM dose in organisms, tissues, or cells (microdosimetry) are needed. Specifically, there is a need to define and determine biologically or toxicologically based metrics for dose, such as bio- logically available surface area or surface reactivity, recognizing that the appro- priate metric will depend on its intended purpose and underlying mechanisms. When designing animal studies, researchers are challenged in extrapolat- ing findings to real-world human exposure to ENMs. For inhalation studies, this includes not only ensuring that the physical form of the aerosol (for example, agglomeration state and particle size distribution) is similar to the form in the environment, but consideration also is needed of the differences between hu- mans and experimental animals in deposition efficiency throughout the respira- tory tract to adjust for breathing mode, airway geometry, and associated inhal- ability and respirability of the particles in question. For example, aerodyne- mically larger particles (that is agglomerated or aggregated ENMs) may be res- pirable by humans but not respirable by mice or rats.

86 Understanding Human & Environmental Effects of Engineered Nanomaterials Several models have been developed to predict deposition efficiencies of inhaled isometric particles in the human respiratory tract, most notably the In- ternational Commission on Radiological Protection model (ICRP 1994) and the Multiple Pass Particle Dosimetry (MPPD) model (Asgharian et al. 1999). The MPPD model has been expanded to estimate the deposited fraction of airborne isometric particles in rats, which is useful for dosimetric extrapolation of results from rat inhalation studies to humans. However, although those models simulate different breathing scenarios (resting, exercising, and working strenuously), in- halability, and diverse particle (including nanomaterial) characteristics (size distribution, density, and concentration), they are not useful for modeling the effects of different particle shapes. Thus, given the multitude of nanoparticle shapes—for example, fibers, tubes, aggregates, and agglomerates—there is a need to develop deposition models for human and rodent respiratory tracts that can be validated experimentally. In addition, although the MPPD model allows one to model pulmonary retention and accumulation, an expansion is needed to include particle shape and translocation from the deposition site in the respira- tory tract to other organs. Two critical research needs are to refine inhalation exposure and deposition models and to develop similar models for ingestion and dermal exposure. Virtually all analyses of research gaps in this regard have highlighted the importance of validating and linking in vitro and in vivo studies of ENMs. The models mentioned above provide one way to address an issue that is related to the scaled dose in different organisms. The ICRP model is restricted to the hu- man respiratory tract, but the MPPD model is applicable to both the rat and the human respiratory tracts. Once sufficient data have been collected on exposure and hazards associated with a specific ENM, these predictive deposition models will permit the dosimetric extrapolation of toxicologic information obtained from acute or longer-term rodent studies to establish exposure limits and risk estimates for humans. Figure 3-5 outlines this concept of dosimetric extrapola- tion as it may be applied to defining the human-equivalent concentration (HEC)7 for inhalation exposure. The deposited doses can be considered for short-term effects (short-term HEC) and for chronic effects (long-term HEC); with infor- mation on both rodent and human retention data, accumulated doses can be con- sidered. Moreover, if available databases on cell types and their numbers in a specific lung region are used, the deposited dose per cell (microdosimetry) can be estimated. Research that validates dosimetric extrapolations of exposure between different kinds of organisms is critical and will ultimately place high- throughput in vitro studies in the appropriate context. Following uptake, ENMs may distribute throughout an organism and re- side in locations distal to the initial exposure site. Nanomedicine publications offer insights into ENM biodistribution in mammals, particularly on the basis of rodent models and several routes of entry. Typically, particles larger than 10 nm 7 The HEC is the quantity of an agent that, when administered to humans, produces an effect equal to that produced in test animals with a specified smaller dose.

Environmental, Health, and Safety Aspects of Engineered Nanomaterials 87 in diameter that are administered intravenously or intraperitoneally are found in the liver; however, circulation times in the blood depend heavily on the surface properties of the materials. Subdermal injection led to appearance of ENMs in the lymph system (Ohl et al. 2004; Gopee et al. 2007; Moghimi and Moghimi 2008). After clearance into the bloodstream, one elimination pathway is proba- bly in feces via hepato-biliary elimination (Kolosnjaj-Tabi et al. 2010). Clear- ance through urine of isometric ENMs up to 9 nm in diameter has been ob- served, and urinary clearance of materials of high aspect ratio and even greater length has been reported (Choi et al. 2007). Those and other studies have pro- vided qualitative guidance on the likely target organs for ENM exposure, but they also have highlighted the role of surface modifications and routes of entry for distribution to the final organ. Knowledge of the biodistribution of nanoparticles after inhalation, oral, or dermal uptake is essential for identifying specific organs that may be targeted, including injury mechanisms, and designing the toxicity assays that best repre- sent the exposures and mechanisms of toxicity. That aspect of nanotechnology- related EHS research has not been extensively explored, in part because labels for tracking ENMs require additional development to ensure their stability in vivo. Rat Human Exposure [mg(m3)-1] Exposure (HEC) [mg(m3)-1] Breathing Minute Volume Inhaled Dose [mg(kg)-1] Inhaled Dose [mg(kg)-1] Tidal Volume, Resp. Rate Resp. Pause Particle characteristics Anatomy Deposited Dose µg(cm2)-1; Deposited Dose µg(cm2)-1; µg(g)-1 µg(g)-1 Clearance Retention Regional Uptake (Metabolism, T½) Retained (Accumulated) Dose [µg(g)-1;µg(cm2)-1] Effects FIGURE 3-5 Extrapolation of dosimetry of inhaled particles from rats to humans. The assumption is made that if retained dose is the same in rats and humans, then the effects will be the same. Source: Adapted from Oberdörster 1989.

88 Understanding Human & Environmental Effects of Engineered Nanomaterials Elimination is another process for which data and valid models are needed. Nanomaterials may display long retention half-times in some organs, but few studies (Schluep et al. 2009; Pauluhn 2010; Maldiney et al. 2011) have quantified or even determined elimination routes (Bazile et al. 1992; Alexis et al. 2008). Although fecal excretion (hepatobiliary pathway) and urinary excre- tion (of particles smaller than 5-9 nm) have been described (Choi et al. 2007; Lacerda et al. 2008a,b; Kolosnjaj-Tabi et al. 2010), quantitative elimination models need to be developed. For example, what is the elimination pathway of nanomaterials that accumulate in the central nervous system by bypassing the blood-brain barrier through neuronal translocation of inhaled nanoparticles from nasal deposits to the olfactory bulb (Oberdörster et al. 2004)? What are the most valid quantitative biokinetic models that relate ENM properties to their distribution in organisms, organs, and tissues? A crucial component of this research will be the development of tools that enable the de- tection of ENMs or their constituents in tissues for understanding the biokinetics of ENMs. Studies of biokinetics should be integrated with evaluations of ENM modifications. Establishing a comprehensive biodistribution model—including uptake, translocation, and elimination pathways and mechanisms—will be an important input for bioinformatics. Biodistribution and Bioaccumulation in the Environment ENMs will persist or accumulate mainly in the solid and aqueous phases of the environment, unless they are suspended in the atmosphere. Such envi- ronmental media may act as diluting agents only if the ENMs do not preferen- tially distribute into specific environmental (for example, sediment or air-water interface) or biologic (for example, gills) compartments. Lessons from other low-concentration molecular contaminants (for example, methyl mercury) reveal that processes can concentrate materials in specific compartments and thereby increase their relative dose and possible effects. Many aspects of distribution are physicochemically based, but in environmental systems biologic compartments are important sinks. Although many issues in this discussion are relevant to both ENM sources and ENM transformations, they are discussed here because of their relevance to biologic settings. There is a need to understand the potential for ENMs to accumulate in particular environmental compartments and to determine the area over which ENMs are distributed. An understanding of this distribution is needed to ad- dress dilution potential of ENMs released from a point source (for example, wastewater-treatment plant effluent discharge or exhausts to air) and will help to focus risk assessment of ENMs on the relevant environmental compartments. ENM distribution in the environment will be controlled largely by attachment to other ENMs or to environmental surfaces, such as minerals, plant leaves, and fish gills. Strong attachment to surfaces affects aggregation and sedimentation in aqueous environments and possibly bioavailability, bioconcentration, and persis- tence in the environment.

Environmental, Health, and Safety Aspects of Engineered Nanomaterials 89 Attachment to biosolids, which will also affect the sources of environ- mental ENMs, is a critical issue to address. For example, recent evidence sug- gests that certain ENMs are leaving wastewater-treatment plants in biosolids and effluent water (Kiser et al. 2009; Kim et al. 2010). A screening-level exposure model for ENMs will require estimates of the distribution of ENMs between biosolids in a wastewater-treatment plant and the effluent water going from the plant to a receiving body of water. Strong attachment of ENMs to biosolids may suggest that terrestrial exposure from biosolids that are spread on croplands is a greater source of ENMs than aquatic exposure to ENMs from wastewater- treatment plant effluent. Such distribution data can also be used to allocate ENM sources to their appropriate environmental compartments better, but this requires an ability to measure and characterize ENMs in complex environmental matri- ces—a research issue highlighted in Chapter 4. That information can be en- hanced by developing an understanding of the ENM properties that most affect attachment of ENMs to environmentally relevant surfaces (for example, biosol- ids, clays, and cell walls). Ultimately, distribution coefficients of ENMs can be estimated by using a small set of ENM characteristics. The distribution coeffi- cients can then be incorporated into screening-level exposure models on a mate- rial-by-material basis to decrease uncertainty in the exposure modeling. Valida- tion of models that predict the distribution of ENMs between phases will require measuring ENMs in complex natural media (soil, sediment, and air). Assuming that the models that are created to determine sources, transport, and transformations of ENMs can provide reasonable estimates of the concentra- tion and physicochemical form of ENMs in particular environmental compart- ments, the fractions of the transformed ENMs that are bioavailable to target re- ceptors need to be determined. This includes bioconcentration of ENMs themselves, bioavailability of toxic metals released from ENMs, and uptake of toxins associated with the ENMs. Indeed, the bioavailability of ENMs to or- ganisms is poorly understood, and a better understanding of it would enhance ecotoxicologic studies. It is critical to address questions about ENM bioaccumulation. Specifi- cally, can ENMs bioaccumulate? If they can, to what extent, and what specific properties are most critical for bioaccumulation? Models for predicting bioac- cumulation of contaminants in fish and fish populations are available, but not similar models for sediment-dwelling organisms and other sensitive aquatic spe- cies in the water column, such as Daphnids or aquatic plants that may be found to be sensitive receptors on the basis of the risk assessment. The biologic and physical processes that affect bioconcentration and trophic transfer of ENMs will be very different from those of molecular contaminants. For example, nanoparticle size, aggregate size, coating properties, and aspect ratio may influ- ence bioavailability and uptake. The influence of those properties on biologic uptake is not known. The presence of soil has also been shown to affect the tox- icity of certain ENMs greatly; for example, fullerenes had little influence on soil bacteria, because of the attachment of the fullerenes in the soil organic matter, in comparison with their influence on bacteria in aqueous solutions (Tong et al.

90 Understanding Human & Environmental Effects of Engineered Nanomaterials 2007). In contrast, nanosilver in wastewater biosolids applied to soil was found to inhibit plant growth and reduce soil microbial biomass (Zeliadt 2010). There- fore, bioavailability and uptake measurements need to include environmentally relevant surfaces (for example, soil for terrestrial uptake and suspended solids and organic colloids for aquatic organisms). New models for bioavailability and uptake are probably needed for ENMs and will need to be species-specific. Organism and Ecosystem Effects of Engineered Nanomaterials The responses of humans, other organisms, and the larger ecosystem to ENMs are central to understanding potential risks. Hazard assessments involv- ing single organisms or in vitro toxicity assays have been the focus of research in this field, and there have been many in vitro and in vivo studies of various cell lines and organisms. Most studies use a single material; however, there is incomplete information on effects of the array of nanomaterials currently used in products, in part because they are not available to researchers. Many studies address effects of acute exposure, but there is a lack of information on effects of chronic exposure (involving time-course experiments). However, data from acute and subchronic studies can be very valuable in selecting doses and deter- mining end points for chronic studies. In addition, doses in acute studies are high relative to likely “real world” exposure, and there is variability in how nanomaterials are introduced into exposure suspensions and therefore uncer- tainty regarding how such study conditions may influence effects. There is also uncertainty regarding how the media or biologic fluids interact with the ENMs to alter their effects (see section on Modifications of and Exposures to Engi- neered Nanomaterials). Finally, there is little information on the effects of nanomaterials on populations and communities of organisms. Human Health Effects Human-health hazard identification has been conducted for several ENMs using in vitro and in vivo methods (Cui et al. 2005; Oberdorster et al. 2007; Lewinski et al. 2008), and many studies have indicated a relationship between dose (often at extremely high doses with questionable relevance to human doses) to ENMs and a toxic response. Fewer studies have addressed dose- response issues (Wittmaack 2007; H.J. Johnston et al. 2010). Human exposure models and measurement tools are also available for assessing human exposure to ENMs in the workplace. Despite availability of those models and tools, how- ever, few exposure (largely workplace) studies are available and there is a lack of readily available measurement methods—a gap that needs to be closed in the short term. Such research is critical in that it permits stakeholders to gauge risk on the basis of actual, relevant exposures and doses. Because most hazard assessments have relied on in vitro testing with doses that tend to be higher than realistic exposures an important question is,

Environmental, Health, and Safety Aspects of Engineered Nanomaterials 91 What biologic effects occur at realistic ENM doses and dose rates, and how do ENM properties influence the magnitude of these effects? The ability of in vitro high-throughput testing to provide information on what happens in vivo has not been demonstrated, and proper in vitro tests have not been developed to examine the numerous species. A conceptual approach for toxicity testing of nanomaterials that begins to address that matter is illustrated in Figure 3-6. In addition to several in vitro and in vivo components, the figure emphasizes the need for providing exposure and hazard data that are essential for risk assessment. There is a need to characterize the relationships between in vitro and in vivo responses. Studies directed at these relationships will require standardized and validated in vitro methods (for example standardized cell types and exposure protocols) that represent specific exposure routes and validation of results from in vitro studies with responses from relevant in vivo studies. This research is vital for developing high-throughput screening strategies for ENMs. A long-term goal is to develop simple in vitro assays that predict in vivo effects at the organism level and may eventually be used for high-throughput screen- ing assays. A key requirement should be that any in vitro assay used as a predictive tool needs to have been validated with appropriate in vivo studies. Other consid- erations include the following:  Results of simple assays only identify a hazard and should be used solely for ranking, for example, to establish a hazard scale (Rushton et al. 2010).  Mechanistic pathways discovered in in vitro studies based on extraor- dinarily high unrealistic doses probably do not operate in vivo in real-world conditions, because mechanisms are dose-dependent (Slikker et al. 2004a,b), and should be interpreted with caution.  In vitro results reflect acute responses and could be highly misleading in predicting long-term effects. For example, soluble zinc oxide nanoparticles induce substantial oxidative stress responses that do not persist, because of solu- bility and induction of effective adaptive responses. Drinker et al. (1927) de- scribed this in workers exposed to zinc fumes. Another important research gap is the underlying biology of ENM interac- tions. Some nanomaterial toxicity mechanisms have been investigated, mostly under limited study conditions (for example, dose and time courses described above). Several toxicity mechanisms are described in the literature on inhala- tion-particle toxicology and related diseases, including inflammation and oxida- tive stress, immunologic effects, protein aggregation and misfolding, and DNA damage. The previous research on ENM effects has been focused largely on inflammation. However, more information on those and other mechanisms is needed. For each of the mechanisms, the characteristics of the ENM (such as size, surface properties, and composition) that are associated with a particular biologic effect should be identified along with the specific effects. How do ENM properties influence toxicologic mechanisms of action?

92 Understanding Human & Environmental Effects of Engineered Nanomaterials Physico -chemical properties In Vivo Physico -chemical properties In Vitro In Vivo Humans Target organs Animals ( Inhal/ Bolus) endpoints; Reference material Bolus Respirability hi-low dose; Relevancy Workplace Biokinetics ALI NOAELs; OELs; HECs (translocation; Mechanisms Target cells, Laboratory corona formation) Reproducibility Tissues Consumer Dose-Response Dose-Response Long -term In silico models Exposure Hazard Risk Assessment FIGURE 3-6 Concept of ENM toxicity testing for human health risk assessment. Risk assessment requires information on hazard, exposure, and exposure–response (or dose– response) relationships. Hazard identification and hazard characterization (left and mid- dle boxes) may use in vitro and in vivo methods. In vitro and in vivo studies involve many considerations, including the physical–chemical properties of the nanomaterials, the method of administering the nanomaterials, the target cells or tissues, and the dose– response relationship. Comparison of the correlations between in vitro and in vivo re- sponses—with in vivo data as the standard—is needed. The lower, bidirectional arrows refer to the dosimetric correlations between in vitro/in vivo animals and in vivo ani- mals/in vivo humans with the goal of informing the design of in vivo animal studies by using available human exposure data and dose–response information from animal studies to compare with human data. The upper, unidirectional arrow refers to extrapolating ef- fects and mechanisms from relevant animal studies to humans with the goal of deriving recommended exposure limits (OELs). In the long term, in silico models may be devel- oped to assess hazard. Abbreviations: ALI, air–liquid interface; NOAEL, no-observable- adverse-effect level; OEL, occupational exposure limit; HEC, human-equivalent concen- tration. Source: Adapted from Oberdörster 2011. Ecologic Effects Although there are many gaps in our understanding of potential human health risks from ENMs, the gaps in our understanding of potential ecologic risks are considerably greater (Bernhardt et al. 2010). One reason is that envi- ronmental hazards and exposures are more complicated owing to the greater number of potential exposure routes and receptors and the complex relationships among organism effects, population effects, and ecosystem responses. The com- plexity makes it difficult to define the problem that is being addressed in an eco- logic risk assessment—the potential organisms affected and the ecologic effects.

Environmental, Health, and Safety Aspects of Engineered Nanomaterials 93 Proper problem formulation (as discussed in Chapter 2) is a critical first step in risk assessment (EPA 1998; NRC 2009) and has yet to be adequately considered for ENMs, because potentially affected organisms and effects on ecosystem function depend on the release points, fate, and transport of ENMs in the envi- ronment; these factors are unknown at present. The process of problem formula- tion for ecosystem response to ENMs will require a tiered approach, given that the ecologic end points are not known and the relationships between organism, population, and ecosystem responses are poorly understood (Bernhardt et al. 2010). Toxicity modeling and testing will benefit from models and measure- ments on fate and transport of ENMs as this will help to determine concentra- tions that will reach ecologic targets. Like the goal of human hazard assessment, the goal of ecologic hazard as- sessment is to predict the potential for toxicity to organisms, communities of organisms, and ecosystem processes with relevant assays (Figure 3-7). Deter- mining the potential ecologic impact of nanomaterials is challenging, given the various types of organisms found in different environments, their various life- history characteristics, and their differing physiology. Research is needed to guide selection of appropriate ecologic receptors, to develop appropriate ENM assays, and to conduct model ecosystem studies that address potential effects on a larger scale, such as the population, community, or ecosystem. Gaps to be addressed include characterization of low-dose effects, assess- ment of multiple end points over a life cycle, and research on effects on multiple organisms along various pathways. Information on the actual pathways that are disrupted in whole-organism assays is critical. Duration of exposure should be considered in relation to effects, inasmuch as effects may change owing to ac- cumulation or formation of byproducts in the organism or recovery pathways. In general, all current ecologic testing strategies use single organisms, and effects are predicted from one or two model species. Data will be needed to pre- dict sensitive species and higher-order effects on communities and ecosystems, including interactions among species, species community assemblages, biodi- versity, and ecosystem function. The inability to predict such effects creates great uncertainty regarding the potential effects of ENMs on the ecosystem. Gaps in Data on Ecologic Effects of Engineered Nanomaterials Numerous standard screening-level toxicity tests for specific aquatic and terrestrial organisms have been proposed for evaluating the effects of ENMs. However, several data gaps need to be addressed to ensure that the tests can pre- dict ecosystem impacts of ENMs. The first is a poor understanding of the mechanisms of toxicity. Most ecologic effects have focused on LC50 data; only a few studies have examined specific effects or mechanisms by which nanomate- rials act on organisms. Lethality is time-dependent and chemical-dependent, and using LC50 data introduces bias into modeling through use of artificial periods

94 Understanding Human & Environmental Effects of Engineered Nanomaterials Physico -chemical properties In Physico-chemical properties In Ecologic Target organs Mechanisms damage/repair Endpoints Effects interactions Vivo Vitro hi-low dose; Relevancy among organisms Species toxicity Model organisms Target cells, Interspecies Bioaccumulation Other mechanisms Tissues Population Effects extrapolation Biokinetics Reproducibility Dose-Response Ecosystem Impacts Dose-Response Effects on energetics Effects on growth reproduction, feeding, behavior, key pathways Exposure Hazard Risk Assessment FIGURE 3-7 Ecologic hazard end points for making predictions of the environmental effects of nanomaterials. As set out in Figure 3-6, to assess the environmental risks from nanomaterials, information on hazard, exposure, and exposure-response is needed. In vitro and in vivo assays are used for assessing hazard. Conducting in vitro and in vivo studies involves considerations of the physical-chemical properties of the nanomaterials, dose-response relationships, mechanisms of toxicity, and relevancy of the tests for pro- viding useful measures, including understanding of effects on larger organisms and popu- lations. Extrapolating from in vivo effects to ecologic end points will benefit from expo- sure measurements and models to understand concentrations that will reach ecologic end points. Source: Adapted from Oberdörster 2011. that do not take intermediate end points into account (Heckmann et al. 2010; Jager et al. 2010). The ability to predict toxicity on the basis of the properties of ENMs will require some knowledge of toxicity mechanisms, in addition to data on acute and gross end points, such as death. As mentioned in the case of human toxicology models, oxidative stress is a toxicity end point that is being explored (Nel et al. 2006; Xia et al. 2006), but there have been few studies of it in ecolo- gic models (Klaper et al. 2009). Leveraging research advances to include key ecologic receptors may help to correlate ENM properties with their potential for ecologic damage. However, questions regarding the oxidative-stress response should be addressed: How much oxidative stress is “dangerous,” and when? How should response changes over time be interpreted; for example, is there a short-term reaction to the ENMs that has no long-term effects? Is oxidative stress the best end point to monitor for nanomaterial effects? Thus, future ecotoxicologic research should focus on improving understanding of toxicity mechanisms of ENMs. More information is needed on the pathways of biochemical responses to ENMs and their various properties and on the linking of the responses to adverse outcomes. In particular, pathways of adverse outcomes of exposure to nanoma-

Environmental, Health, and Safety Aspects of Engineered Nanomaterials 95 terials need to be defined beyond those of oxidative stress. Pathways of adverse outcomes (for example, effects on survival and reproduction) need to be deter- mined; that is, changes in the biologic mechanisms need to be linked to larger organism or population outcomes to yield useful measures. Researchers must evaluate how a biologic property (such as oxidative stress) translates to effects on organism survival and reproduction. Adaptation may occur after repeated exposures and make organisms tolerant to higher or longer exposures. Many other toxicity pathways might provide better and more sensitive information on ENM effects on multiple receptors. Another consideration is the dose of the nanomaterial used in molecular assays. Specifically, what dose is appropriate for investigating what pathways? A research issue related to organism testing is the effects of ENMs on other end points (aside from death) and after low-dose chronic exposure. Be- cause ENMs will probably exist at very low concentrations in the environment and will persist, low-level chronic exposure is the most likely scenario. Thus, tests with chronic exposure should be developed and validated for ENMs and other end points, including effects on growth, reproduction, metabolism, and behavior; and these effects need to be considered in testing strategies. Low-level chronic exposure studies pose challenges for nanomaterial dosing. For example, should ENMs be reintroduced as they settle out of an assay? What methods should be used for dispersing particles into the media? How can exposure and changes in ENMs be monitored in the assay? ENMs may have a variety of effects at the population level, such as effects on population dynamics, reproduction, genetic structure, demography, and ulti- mately the sustainability of a population. Therefore, it is important to determine how ENMs and their properties affect populations. For key members of systems, some effects may be measured by using chronic-assay end points mentioned above (such as effects on reproduction or growth), and measurements of age, class structure, and population genetics may provide population-level information. Examining changes in the population ge- netics or age structure of a population is not a standard approach, but such basic studies will be necessary to determine how a population of organisms will be- have when in contact with ENMs—often the most important indicator from the perspective of ecologic risk assessment and sustainability. The death or injury of an individual fish or small group of fish (organism-level response) may not be cause for alarm, but the crash of an entire population may create great problems not only for that species but for the larger community or ecosystem. ENMs may have more than overt acute toxic effects on specific species. Depending on their properties, ENMs may alter interactions among organisms in a community, for example, by changing predation, commensalism, or domi- nance. Such effects are important to understand on a large scale. The few data that exist suggest that, at a minimum, nanomaterial exposure may affect bacte- rial community structure (Lyon et al. 2008). In addition, ENMs may influence such ecosystem functions as nutrient cycling, energy, productivity, and biomass by affecting communities or organisms that are critical for these functions, for

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.

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

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?

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,

100 Understanding Human & Environmental Effects of Engineered Nanomaterials J.B. Sass, E.K. Silbergeld, and W.A Wong. 2007. Meeting report: Hazard assess- ment for nanoparticles--report from an interdisciplinary workshop. Environ. Health Perspect. 115(11):1654-1659. Bazile, D.V., C. Ropert, P. Huve, T. Verrecchia, M. Marlard, A. Frydman, M. Veillard, and G. Spenlehauer. 1992. Body distribution of fully biodegradable [c-14] poly(lactic acid) nanoparticles coated with albumin after parenteral administration to rats. Biomaterials 13(15):1093-1102. Bello, D., A.J. Hart, K. Ahn, M. Hallock, N. Yamamoto, E.J. Garcia, M.J. Ellenbecker, and B.L. Wardle. 2008. Particle exposure levels during CVD growth and subse- quent handling of vertically-aligned carbon nanotube films. Carbon 46(6):974-981. Bello, D., B.L. Wardle, N. Yamamoto, R.G. deVilloria, E.J. Garcia, A.J. Hart, K. Ahn, M.J. Ellenbecker, and M. Hallock. 2009. Exposure to nanoscale particles and fi- bers during machining of hybrid advanced composites containing carbon nano- tubes. J. Nanopart. Res. 11(1):231-249. Bernhardt, E.S., B.P. Colman, M.F. Hochella, Jr., B.J. Cardinale, R.M. Nisbet, C.J. Richardson, and L. Yin. 2010. An ecological perspective on nanomaterial impacts in the environment. J. Environ. Qual. 39(6):1954-1965. Blaser, S.A., M. Scheringer, M. Macleod, and K. Hungerbühler. 2008. Estimation of cumulative aquatic exposure and risk due to silver: Contribution of nano- functionalized plastics and textiles. Sci. Total Environ. 390(2-3):369-409. Choi, H.S., W. Liu, P. Misra, E. Tanaka, J.P. Zimmer, B.I. Ipe, M.G. Bawendi, and J.V. Frangioni. 2007. Renal clearance of quantum dots. Nat. Biotechnol. 25(10):1165- 1170. Cui, D., F. Tian, C.S. Ozkan, M. Wang, and H. Gao. 2005. Effect of single wall carbon nanotubes on human HEK293 cells. Toxicol. Lett. 155(1):73-85. Denison, R. 2005. Statement of Richard D. Denison, Senior Scientist, Environmental Defense, before the House of Representatives Committee on Science Concerning Environmental and Safety Impacts of Nanotechnology: What Research is Needed? November 17, 2005 [online]. Available: http://www.edf.org/documents/5136_Deni sonHousetestimonyOnNano.pdf [accessed May 24, 2011]. Drinker, P, R.M. Thomson, and J.L. Finn. 1927. Metal fume fever. II. Resistance acquired by inhalation of zinc oxide on two successive days. J. Ind. Hyg. 9(3):98- 105. EFSA (European Food Safety Authority). 2009. Scientific Opinion: The Potential Risks Arising from Nanoscience and Nanotechnologies on Food and Feed Safety. EFSA J. 958:1-39 [online]. Available: http://www.efsa.europa.eu/fr/scdocs/doc/sc_op_ ej958_nano_en,0.pdf [accessed Apr. 14, 2011]. EPA (U.S. Environmental Protection Agency). 1998. Guidelines for Ecological Risk Assessment. EPA/630/R-95/002F. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC. April 1998 [online]. Available: http://www. epa.gov/raf/publications/pdfs/ECOTXTBX.PDF [accessed Apr. 20, 2011]. EPA (U.S. Environmental Protection Agency). 2002. Proceedings EPA Nanotechnology and the Environment: Applications and Implications STAR Progress Review Workshop, August 28-29, 2002, Arlington, VA. Office of Research and Develop- ment, National Center for Environmental Research, U.S. Environmental Protection Agency [online]. Available: http://www.epa.gov/ncer/publications/workshop/nano_ proceed.pdf [accessed May 2, 2011]. FAO/WHO (Food and Agriculture Organization of the United Nation and World Health Organization). 2009. FAO/WHO Expert Meeting on the Application of Nanotech- nologies in the Food and Agriculture Sectors: Potential Food Safety Implications.

Environmental, Health, and Safety Aspects of Engineered Nanomaterials 101 Meeting Report. Food and Agriculture Organization of the United Nation, Rome, Italy, and World Health Organization, Geneva, Switzerland [online]. Available: http://www.fao.org/ag/agn/agns/files/FAO_WHO_Nano_Expert_Meeting_Report_ Final.pdf [accessed Oct. 12, 2011]. Fortner, J.D., D.Y. Lyon, C.M. Sayes, A.M. Boyd, J.C. Falkner, E.M. Hotze, L.B. Ale- many, Y.J. Tao, W. Guo, K.D. Ausman, V.L. Colvin, and J.B. Hughes. 2005. C60 in water: Nanocrystal formation and microbial response. Environ Sci. Technol. 39(11):4307-4316. Gopee, N.V., D.W. Roberts, P. Webb, C.R. Cozart, P.H. Siitonen, A.R. Warbritton, W.W. Yu, V.L. Colvin, N.J. Walker, and P.C. Howard. 2007. Migration of in- tradermally injected quantum dots to sentinel organs in mice. Toxicol. Sci. 98(1):249-257. Gottschalk, F., T. Sonderer, R.W. Scholz, and B. Nowack. 2009. Modeled environmental concentrations of engineered nanomaterials (TiO2, ZnO, Ag, CNT, fullerenes) for different regions. Environ. Sci. Technol. 43(24):9216-9222. Gottschalk, F., R.W. Scholz, and B. Nowack. 2010. Probabilistic material flow modeling for assessing the environmental exposure to compounds: Methodology and an ap- plication to engineered nano-TiO2 particles. Environ. Modell. Softw. 25(3):320- 332. Guo, J., X. Zhang, Q. Li, and W. Li. 2007. Biodistribution of functionalized multiwall carbon nanotubes in mice. Nucl. Med. Biol. 34(5):579-583. Han, J.H., E.J. Lee, J.H. Lee, K.P. So, Y.H. Lee, G.N. Bae, S.B. Lee, J.H. Ji, M.H. Cho, and I.J. Yu. 2008. Monitoring multiwalled carbon nanotube exposure in carbon nanotube research facility. Inhal. Toxicol. 20(8):741-749. Heckmann, L.H., J. Baas, and T. Jager. 2010. Time is of the essence. Environ. Toxicol. Chem. 29(6):1396-1398. Hirose, A., T. Nishimura, and J. Kanno. 2009. Research strategy for evaluation methods of the manufactured nanomaterials in NIHS and importance of the chronic health effects studies [in Japanese]. Kokuritsu Iyakuhin Shokuhin Eisei Kenkyusho Hokoku 127:15-27. Hotze, E.M., T. Phenrat, and G.V. Lowry. 2010. Nanoparticle aggregation: Challenges to understanding transport and reactivity in the environment. J. Environ. Qual. 39(6):1909-1924. Hou, W.C., L. Kong, K. Wepasnick, R.G. Zepp, D.H. Fairbrother, and C.T. Jafvert. 2010. Photochemistry of aqueous C60 clusters: Wavelength dependency and product characterization. Environ. Sci. Technol. 44(21):8121-8127. ICON (International Council on Nanotechnology). 2011. Nano-EHS Database Analysis Tool [online]. Available: http://cohesion.rice.edu/centersandinst/icon/report.cfm [ac- cessed May 27, 2011]. ICRP (International Commission on Radiological Protection). 1994. Human Respiratory Tract Model for Radiological Protection. ICRP Publication 66. Ann. ICRP 24(1-3). ISO (International Organization for Standardization). 2008. Nanotechnologies. Terminol- ogy and Definitions for Nano-Objects. Nanoparticle, Nanofibre and Nanoplate. ISO/TS 27687:2008. Geneva: ISO. Jager, T., T. Vandenbrouck, J. Baas, W.M. De Coen, and S.A. Kooijman. 2010. A biol- ogy-based approach for mixture toxicity of multiple endpoints over the life cycle. Ecotoxicology 19(2):351-361. Jarvie, H.P., H. Al-Obaidi, S.M. King, M.J. Bowes, M.J. Lawrence, A.F. Drake, M.A. Green, and P.J. Dobson. 2009. Fate of silica nanoparticles in simulated primary wastewater treatment. Environ. Sci. Technol. 43(22):8622-8628.

102 Understanding Human & Environmental Effects of Engineered Nanomaterials Jeong, C.H., and G.J. Evans. 2009. Inter-comparison of a Fast Mobility Particle Sizer and a Scanning Mobility Particle Sizer incorporating an ultrafine water-based conden- sation particle counter. Aerosol Sci. Technol. 43(4):364-373. Johnston, H.J., G. Hutchison, F.M. Christensen, S. Peters, S. Hankin, and V. Stone. 2010. A review of the in vivo and in vitro toxicity of silver and gold particulates: Particle attributes and biological mechanisms responsible for the observed toxicity. Crit. Rev. Toxicol. 40(4):328-346. Johnston, J.M., M. Lowry, S. Beaulieu, and E. Bowles. 2010. State-of-the-Science Report on Predictive Models and Modeling Approaches for Characterizing and Evaluating Exposure to Nanomaterials. EPA/600/R-10/129. U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/athens/publica tions/reports/Johnston_EPA600R10129_State_of_Science_Predictive_Models.pdf [accessed Nov. 23, 2011]. Kim, B., C.S. Park, M. Murayama, and M.F. Hochella. 2010. Discovery and characteriza- tion of silver sulfide nanoparticles in final sewage sludge products. Environ. Sci. Technol. 44(19):7509-7514. Kiser, M.A., P. Westerhoff, T. Benn, Y. Wang, J. Perez-Rivera, and K. Hristovski. 2009. Titanium removal and release from wastewater treatment plants. Environ. Sci. Technol. 43(17):6757-6763. Klaper, R., J. Crago, J. Barr, D. Arndt, K. Setyowati, and J. Chen. 2009. Toxicity bio- marker expression in daphnids exposed to manufactured nanoparticles: Changes in toxicity with functionalization. Environ. Pollut. 157(4):1152-1156. Kolosnjaj-Tabi, J., K.B. Hartman, S. Boudjemaa, J.S. Ananta, G. Morgant, H. Szwarc, L.J. Wilson, and F. Moussa. 2010. In vivo behavior of large doses of ultrashort and full-length single-walled carbon nanotubes after oral and intraperitoneal admini- stration to Swiss mice. ACS Nano 4(3):1481-1492. Kreyling, W.G., M. Semmler, F. Erbe, P. Mayer, S. Takenaka, H. Schulz, G. Oberdörster, and A. Ziesenis. 2002. Translocation of ultrafine insoluble iridium particles from lung epithelium to extrapulmonary organs is size dependent but very low. J. Toxi- col. Environ. Health A. 65(20):1513-1530. Kreyling, W.G., M. Semmler-Behnke, J. Seitz, W. Scymczak, A. Wenk, P. Mayer, S. Takenaka, and G. Oberdörster. 2009. Size dependence of the translocation of in- haled iridium and carbon nanoparticle aggregates from the lung of rats to the blood and secondary target organs. Inhal Toxicol. 21(suppl. 1):55-60. Kuhlbusch, T.A., S. Neumann, and H. Fissan. 2004. Number size distribution, mass con- centration, and particle composition of PM1, PM2.5, and PM10 in bag filling areas of carbon black production. J. Occup. Environ. Hyg. 1(10):660-671. Lacerda, L., M. A. Herrero, K. Venner, A. Bianco, M. Prato, and K. Kostarelos. 2008a. Carbon-nanotube shape and individualization critical for renal excretion. Small 4(8):1130-1132. Lacerda, L., A. Soundararajan, R. Singh, G. Pastorin, K.T. Al-Jamal, J. Turton, P. Frederik, M.A. Hererro, S. Li, A. Bao, D. Emfietzoglou, S. Mather, W.T. Phillips, M. Prato, A. Bianco, B. Goins, and K. Kostarelos. 2008b. Dynamic imaging of functionalized multi-walled carbon nanotube systemic circulation and urinary ex- cretion. Adv. Mater. 20(2):225-230. Lee, J.H., S.B. Lee, G.N. Bae, K.S. Jeon, J.U. Yoon, J.H. Ji, J.H. Sung, B.G. Lee, J.H. Lee, J.S. Yang, H.Y. Kim, C.S. Kang, and I.J. Yu. 2010. Exposure assessment of carbon nanotube manufacturing workplaces. Inhal. Toxicol. 22(5):369-381.

Environmental, Health, and Safety Aspects of Engineered Nanomaterials 103 Levard, C., B.C. Reinsch, F.M. Michel, C. Oumahi, G.V. Lowry, and G.E. Brown. 2011. Sulfidation processes of PVP-coated silver nanoparticles in aqueous solution: Im- pact on dissolution rate. Environ. Sci. Technol. 45(12):5260-5266. Lewinski, N., V. Colvin, and R. Drezek. 2008. Cytotoxicity of nanoparticles. Small 4(1):26-49. Li, Z., K. Greden, P.J. Alvarez, K.B. Gregory, and G.V. Lowry. 2010. Adsorbed polymer and NOM limits adhesion and toxicity of nano scale zerovalent iron to E. coli. En- viron. Sci. Technol. 44(9):3462-3467. Liu, J., D.A. Sonshine, S. Shervani, and R.H. Hurt. 2010. Controlled release of biologi- cally active silver from nanosilver surfaces. ACS Nano 4(11):6903-6913. Lux Research. 2009. The Recession’s Ripple Effect on Nanotech. Lux Research, June 9, 2009 [online]. Available: https://portal.luxresearchinc.com/reporting/research/docu ment_excerpt/4995 [accessed Dec. 5, 2011]. Lynch, I., T. Cedervall, M. Lundqvist, C. Cabaleiro-Lago, S. Linse, and K.A. Dawson. 2007. The nanoparticle-protein complex as a biological entity: A complex fluids and surface science challenge for the 21st century. Adv. Colloid Interface Sci. (134-135):167-174. Lyon, D.Y., and P.J. Alvarez. 2008. Fullerene water suspension (nC60) exerts antibacte- rial effects via ROS-independent protein oxidation. Environ. Sci. Technol. 42(21):8127-8132. Lyon, D.Y., D.A. Brown, and P.J. Alvarez. 2008. Implications and potential applications of bactericidal fullerene water suspensions: Effect of nC60 concentration, exposure conditions and shelf life. Water Sci. Technol. 57(10):1533-1538. Maldiney, T., C. Richard, J. Seguin, N. Wattier, M. Bessodes, and D. Scherman. 2011. Effect of core diameter, surface coating, and PEG chain length on the biodistribu- tion of persistent luminescence nanoparticles in mice. ACS Nano. 5(2):854-862. Mahendra, S. H. Zhu, V.L. Colvin, and P.J. Alvarez. 2008. Quantum dot weathering re- sults in microbial toxicity. Environ. Sci. Technol. 42(24):9424-9430. Marambio-Jones, C., and E.M.V. Hoek . 2010. A review of the antibacterial effects of silver nanomaterials and potential implications for human health and the environ- ment. J. Nanopart. Res. 12(5):1531-1551. Maynard, A.D., P.A. Baron, M. Foley, A.A. Shvedova, E.R. Kisin, and V. Castranova. 2004. Exposure to carbon nanotube material: Aerosol release during the handling of unrefined single-walled carbon nanotube material. J. Toxicol. Environ. Health A 67(1):87-107. McMurry, P.H. 2000. A review of atmospheric aerosol measurements. Atmos Environ. 34(12-14):1959-1999. Methner, M., L. Hodson, A. Dames, and C. Geraci. 2010. Nanoparticle Emission As- sessment Technique (NEAT) for the identification and measurement of potential inhalation exposure to engineered nanomaterials, Part B: Results from 12 field studies. J. Occup. Environ. Hyg. 7(3):163-176. Moghimi, S.M., and M. Moghimi. 2008. Enhanced lymph node retention of subcutane- ously injected IgG1-PEG2000-liposomes through pentameric IgM antibody- mediated vesicular aggregation. Biochim. Biophys. Acta 1778(1):51-55. Monopoli, M.P., D. Walczyk, A. Campbell, G. Elia, I. Lynch, F.B. Bombelli, and K.A. Dawson. 2011. Physical-chemical aspects of protein corona: Relevance to in vitro and in vivo biological impacts of nanoparticles. J. Am. Chem. Soc. 133(8):2525- 2534.

104 Understanding Human & Environmental Effects of Engineered Nanomaterials Mortensen, L.J., G. Oberdörster, A.P. Pentland, L.A. DeLouise. 2008. In vivo skin pene- tration of quantum dot nanoparticles in the murine model: The effect of UVR. Nano Lett. 8(9):2779-2787. Mueller, N.C., and B. Nowack. 2008. Exposure modeling of engineered nanoparticles in the environment. Environ. Sci. Technol. 42(12):4447-4453. Müller, R.H. and C.M. Keck. 2004. Drug delivery to the brain-realization by novel drug carriers. J. Nanosci. & Nanotechnol. 4(5):471-483. Mylon, S.E., K.L. Chen, and M. Elimelech. 2004. Influence of natural organic matter and ionic composition on the kinetics and structure of hematite colloid aggregation: Implications to iron depletion in estuaries. Langmuir 20(21):9000-9006. Nel, A., T. Xia, L. Madler, and N. Li. 2006. Toxic potential of materials at the nanolevel. Science 311(5761):622-627. NNI (National Nanotechnology Initiative). 2011a. NNI Meetings and Workshops [online]. Available: http://www.nano.gov/events/meetings-workshops [accessed May 4, 2011]. NNI (National Nanotechnology Initiative). 2011b. NNI Centers and Networks [online]. Available: http://www.nano.gov/initiatives/government/research-centers [accessed May 4, 2011]. NRC (National Research Council). 2009. Science and Decisions: Advancing Risk As- sessment. Washington DC: The National Academies Press. Oberdörster, G. 1989. Dosimetric principles for extrapolating results of rat inhalation studies to humans, using an inhaled Ni compound as an example. Health Physics 57(suppl 1):213-220. Oberdörster, G., Z. Sharp, V. Atudorei, A. Elder, R. Gelein, W. Kreyling, and C. Cox. 2004. Translocation of inhaled ultrafine particles to the brain. Inhal. Toxicol.. 16(6-7):437-445. Oberdörster, G., V. Stone, and K. Donaldson. 2007. Toxicology of nanoparticles: A his- torical perspective. Nanotoxicology 1(1):2-25. Oberdörster, G. 2011. Correlating in vitro and in vivo nanotoxicity: limitations and chal- lenges for risk assessment. Presented at the Society of Toxicology meeting. March 6-10, 2011. Washington, DC. Ohl, L., M. Mohaupt, N. Czeloth, G. Hintzen, Z. Kiafard, J. Zwirner, T. Blankenstein, G. Henning, and R. Förster. 2004. CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity 21(2):279-288. Pauluhn, J. 2010. Multi-walled carbon nanotubes (Baytubes): Approach for derivation of occupational exposure limit. Regul. Toxicol. Pharmacol. 57(1):78-89. PEN (Project on Emerging Nanotechnologies). 2011. Consumer Products: An Inventory of Consumer Products Currently on the Market. Project on Emerging Nanotechnologies [online]. Available: http://www.nanotechproject.org/inventories/consumer/ [accessed May 3, 2011]. Petosa, A.R., D.P. Jaisi, I.R. Quevedo, M. Elimelech, and N. Tufenkji. 2010. Aggregation and deposition of engineered nanomaterials in aquatic environments: Role of phys- icochemical interactions. Environ. Sci. Technol. 44(17):6532-6549. Phenrat, T., H.J. Kim, F. Fagerlund, T. Illangasekare, R.D. Tilton, and G.V. Lowry. 2009a. Particle size distribution, concentration, and magnetic attraction affect transport of polymer-modified Fe0 nanoparticles in sand columns. Environ. Sci. Technol. 43(13):5079-5085. Phenrat, T., T.C. Long, G.V. Lowry, and B. Veronesi. 2009b. Partial oxidation (“aging”) and surface modification decrease the toxicity of nanosized zerovalent iron. Envi- ron. Sci. Technol. 43(1):195-200.

Environmental, Health, and Safety Aspects of Engineered Nanomaterials 105 Phenrat, T., J.E. Song, C.M. Cisneros, D.P. Schoenfelder, R.D. Tilton, and G.V. Lowry. 2010. Estimating attachment of nano- and submicrometer-particles coated with or- ganic macromolecules in porous media: Development of an empirical model. En- viron. Sci. Technol. 44(12):4531-4538. Prow, T.W., J.E. Grice, L.L. Lin, R. Faye, M. Butler, W. Becker, E.M.T. Wurm, C. Yoong, T.A. Robertson, H.P. Soyer, and M.S. Roberts. 2011. Nanoparticles and microparticles for skin drug delivery. Advan. Drug Deliv. Rev. 63(6):470-491. Robichaud, C.O., A.E. Uyar, M.R. Darby, L.G. Zucker, and M.R. Wiesner. 2009. Esti- mates of upper bounds and trends in nano-TiO2 production as a basis for exposure assessment. Environ. Sci. Technol. 43(12):4227-4233. Rushton, E.K., J. Jiang, S.S. Leonard, S. Eberly, V. Castranova, P. Biswas, A. Elder, X. Han, R. Gelein, J. Finkelstein, and G. Oberdörster. 2010. Concept of assessing nanoparticle hazards considering nanoparticle dosimetric and chemical/biological response metrics. J. Toxicol. Environ. Health A 73(5):445-461. Sahu, M., and P. Biswas. 2010. Size distributions of aerosols in an indoor environment with engineered nanoparticle synthesis reactors operating under different scenar- ios. J. Nano. Res. 12(3):1055-1964. Saleh, N.B., L.D. Pfefferle, and M. Elimelech. 2008. Aggregation kinetics of multiwalled carbon nanotubes in aquatic systems: Measurements and environmental implica- tions. Environ. Sci. Technol. 42(21):7963-7969. Saleh, N.B., L.D. Pfefferle, and M. Elimelech. 2010. Influence of biomacromolecules and humic acid on the aggregation kinetics of single-walled carbon nanotubes. Envi- ron. Sci. Technol. 44(7):2412-2418. Salonen, E., S. Lin, M.L. Reid, M. Allegood, X. Wang, A.M. Rao, I. Vattulainen, and P.C. Ke. 2008. Real-time translocation of fullerene reveals cell contraction. Small 4(11):1986-1992. Schluep, T., J. Hwang, I.J. Hildebrandt, J. Czernin, C.H. Choi, C.A. Alabi, B.C. Mack, and M.E. Davis. 2009. Pharmacokinetics and tumor dynamics of the nanoparticle IT-101 from PET imaging and tumor histological measurements. Proc. Natl. Acad. Sci. USA. 106(27):11394-11399. Schneider, M., F. Stracke, S. Hansen, and U.F. Schaefer. 2009. Nanoparticles and their interactions with the dermal barrier. Dermato-Endocrinology 1(4):197-206. Semmler-Behnke, M., S. Takenaka, S. Fertsch, A. Wenk, J. Seitz, P. Mayer, G. Oberdör- ster, and W.G. Kreyling. 2007. Efficient elimination of inhaled nanoparticles from the alveolar region: Evidence for interstitial uptake and subsequent reentrainment onto airways epithelium. Environ. Health Perspect. 115(5):728-733. Semmler-Behnke, M., W.G. Kreyling, J. Lipka, S. Fertsch, A. Wenk, S. Takenaka, G. Schmid, and W. Brandau. 2008. Biodistribution of 1,4-and 18-nm gold particles in rats. Small 4(12):2108-2111. Slikker, W., Jr., M.E. Andersen, M.S. Bogdanffy, J.S. Bus, S.D. Cohen, R.B. Conolly, R.M. David, N.G. Doerrer, D.C. Dorman, D.W. Gaylor, D. Hattis, J.M. Rogers, W. Setzer, J.A. Swenberg, and K. Wallace. 2004a. Dose-dependent transitions in mechanisms of toxicity: Case studies. Toxicol. Appl. Pharmacol. 201(3):226-294. Slikker, W., Jr., M.E. Andersen, M.S. Bogdanffy, J.S. Bus, S.D. Cohen, R.B. Conolly, R.M. David, N.G. Doerrer, D.C. Dorman, D.W. Gaylor, D. Hattis, J.M. Rogers, R. Woodrow Setzer, J.A. Swenberg, and K. Wallace. 2004b. Dose-dependent transi- tions in mechanisms of toxicity. Toxicol. Appl. Pharmacol. 201(3):203-225. Smijs, T.G., and J.A. Bouwstra. 2010. Focus on skin as a possible port of entry for solid nanoparticles and the toxicological impact. J. Biomed. Nanotechnol. 6(5):469-484.

106 Understanding Human & Environmental Effects of Engineered Nanomaterials Tang, J., L. Xiong, S. Wang, J. Wang, L. Liu, J. Li, F. Yuan, and T. Xi. 2009. Distribu- tion, translocation and accumulation of silver nanoparticles in rats. J. Nanosci. Nanotechnol. 9(8):4924-4932. Tong, Z., M. Bischoff, L. Nies, B. Applegate, and R.F. Turco. 2007. Impact of fullerene C60 on a soil microbial community. Environ. Sci. Technol. 41(8):2985-2991. Tsai, S.J., M. Hofmann, M. Hallock, E. Ada, J. Kong, and M. Ellenbecker. 2009. Charac- terization and evaluation of nanoparticle release during the synthesis of single- walled and multi-walled carbon nanotubes by chemical vapor deposition. Environ. Sci. Technol. 43(15):6017-6023. Walczyk, D., F.B. Bombelli, M.P. Monopoli, I. Lynch, and K.A. Dawson. 2010. What the cell “sees” in bionanoscience. J. Am. Chem. Soc. 132(16):5761-5768. Wang, C.Y., W.E. Fu, H.L. Lin, and G.S. Peng. 2007. Preliminary study on nanoparticle sizes under the APEC technology cooperative framework. Meas. Sci. Technol. 18(2):487-495. Wiesner, M.R., G.V. Lowry, K.L. Jones, M.F. Hochella, R.T. Di Giulio, E. Casman, and E.S. Bernhardt. 2009. Decreasing uncertainties in assessing environmental expo- sure, risk, and ecological implications of nanomaterials. Environ. Sci. Technol. 43(17):6458-6462. Wittmaack, K. 2007. In search of the most relevant parameter for quantifying lung in- flammatory response to nanoparticle exposure: Particle number, surface area, or what? Environ. Health Perspect. 115(2):187-194. Xia, T., M. Kovochich, J. Brant, M. Hotze, J. Sempf, T. Oberley, C. Sioutas, J.I. Yeh, M.R. Wiesner, and A.E. Nel. 2006. Comparison of the abilities of ambient and manufactured nanoparticles to induce cellular toxicity according to an oxidative stress paradigm. Nano Lett. 6(8):1794-1807. Zeliadt, N. 2010. Silver beware: Antimicrobial nanoparticles in soil may harm plant life. Scientific American, August 9, 2010 [online]. Available: http://www.scientifica merican.com/article.cfm?id=silver-beware-antimicrobial-nanoparticles-in-soil-ma y-harm-plant-life [accessed July 26, 2011].

Next: 4 New Tools and Approaches for Identifying Properties of Engineered Nanomaterials That Indicate Risks »
A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials Get This Book
×
Buy Paperback | $57.00 Buy Ebook | $45.99
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

The nanotechnology sector, which generated about $225 billion in product sales in 2009, is predicted to expand rapidly over the next decade with the development of new technologies that have new capabilities. The increasing production and use of engineered nanomaterials (ENMs) may lead to greater exposures of workers, consumers, and the environment, and the unique scale-specific and novel properties of the materials raise questions about their potential effects on human health and the environment. Over the last decade, government agencies, academic institutions, industry, and others have conducted many assessments of the environmental, health, and safety (EHS) aspects of nanotechnology. The results of those efforts have helped to direct research on the EHS aspects of ENMs. However, despite the progress in assessing research needs and despite the research that has been funded and conducted, developers, regulators, and consumers of nanotechnology-enabled products remain uncertain about the types and quantities of nanomaterials in commerce or in development, their possible applications, and their associated risks.

A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials presents a strategic approach for developing the science and research infrastructure needed to address uncertainties regarding the potential EHS risks of ENMs. The report summarizes the current state of the science and high-priority data gaps on the potential EHS risks posed by ENMs and describes the fundamental tools and approaches needed to pursue an EHS risk research strategy. The report also presents a proposed research agenda, short-term and long-term research priorities, and estimates of needed resources and concludes by focusing on implementation of the research strategy and evaluation of its progress, elements that the committee considered integral to its charge.

  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  6. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  7. ×

    View our suggested citation for this chapter.

    « Back Next »
  8. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!