To coordinate its ENM health and safety research efforts with its new Strategic Plan (Birnbaum 2012
), the NIEHS has established a Nano Workgroup spanning the institute’s extramural division, intramural division, Office of the Director, and division of the National Toxicology Program (NTP). The Nano Workgroup has been instrumental in selecting ENMs for intramural and NTP investigations, guiding the design of extramural grant programs, and maximizing the combined impact of the NIEHS’s nanotechnology research activities through an overarching research strategy. Collectively called “ONE Nano,” this integrated, strategic research program has four primary goals: a
) to gain a fundamental understanding of ENM interactions as dictated by their physicochemical properties; b
) to develop predictive models for ENM health effects assessment; c
) to develop methods to quantify exposure to ENMs; and d
) to guide the development of second generation ENMs with minimal adverse health effects. Throughout its ONE Nano research investments, the NIEHS has made it a priority to work closely with other institutes and federal agencies to advance these goals. Specific research activities of the ONE Nano program are described in the following sections.
Extramural research activities. Supporting the nation’s top environmental health researchers through extramural grants is a critical part of the NIEHS’s nanotechnology research strategy. The institute has invested heavily in innovative research focused on assessing ENM exposure and health impacts. To augment its support of grantees, the NIEHS also provides shared resources and collaborative structures that enhance the overall value of these extramural grant programs.
Nanotechnology Health Implications Research (NCNHIR) consortium. The NIEHS’s current flagship extramural program in ENM health impacts is the NCNHIR consortium. Launched in 2010 with an overarching goal of enhancing our fundamental understanding of how nanomaterials interact with biological systems, the consortium brings together > 20 NIEHS extramural grantees to facilitate meaningful interchange and speed progress in the field.
At the core of the NCNHIR program are eight centers for nanotechnology health implications research [see Supplemental Material, Table S1 (http://dx.doi.org/10.1289/ehp.1206091)]. With funding provided over a 5-year period, each center is conducting in vitro and in vivo studies on the health effects of ENMs and using the results to develop and validate new ENM risk assessment frameworks. Along with their independent research projects, five of the centers will collect and share data about a common set of ENMs—four different silver nanoparticles, and multiwalled carbon nanotubes with several different aspect ratios. Each center will then use the shared data on these ENMs to apply a different risk assessment model, including functional exposure, pharmacokinetic, pharmacodynamic, and structure activity relationship systems. By integrating results on three common ENMS using different risk assessment modeling systems, these centers will be able to provide detailed, comprehensive hazard-ranking characterization and risk assessment information to regulators and the public. Consortium activities have been structured to facilitate direct communication between researchers and regulatory agency representatives to ensure the results of the consortium studies are disseminated to the NIEHS’s partner agencies. Results are also expected to be published in the peer-reviewed literature.
NCNHIR consortium members have already contributed significant advances to the field. For example, researchers at the University of California, Los Angeles have demonstrated that high throughput in vitro
toxicological procedures can accurately predict nanomaterial physicochemical characteristics that lead to acute pulmonary inflammation and pulmonary fibrosis for metal oxide nanoparticles and carbon nanotubes (Nel et al. 2012
; Wang et al. 2012
; Zhang et al. 2012
). These predictive toxicological paradigms could speed up in vivo
assessments, allow hazard ranking of large categories of ENMs, and inform the design of ENMs. At the Center for Nanotoxicology at Pacific Northwest National Laboratory, researchers combined two models to enhance the ability to extrapolate between in vitro
and in vivo
results to help improve the design of future studies and derive credible human occupational exposure limits for ENMs. These two approaches included an in vitro
sedimentation, diffusion, and dosimetry model for ENMs that simulates delivery, and in some cases uptake, of nanoparticles to cells in culture for deriving target cell doses; and an extension of the multipath particle deposition model that derives in vivo
cell dosimetry in commonly used mouse models (Hinderliter et al. 2010
The NIEHS created the NCNHIR consortium to guide and enhance the work of the NCNHIR centers, as well as to facilitate collaboration among researchers across the ENM extramural research program. In addition to the centers, the NCNHIR consortium includes grantees supported by the Nanotechnology Grand Opportunities program (NIEHS 2010
), Outstanding New Environmental Scientist grants, and investigator-initiated Research Project Grants [see Supplemental Material, Table S2 (http://dx.doi.org/10.1289/ehp.1206091)]. The consortium structure gives this diverse group of scientists frequent opportunities to share results, discuss challenges, and exchange ideas to maximize the impact of their investigations.
The NIEHS has also invested in several cross-cutting efforts to better support grantees and disseminate research findings. First, the institute has partnered with the National Institute of Biomedical Imaging and Bioengineering (NIBIB) and the National Cancer Institute (NCI) to develop the Nanomaterial Registry (https://www.nanomaterialregistry.org
), which provides a central, curated repository for published findings related to specific nanomaterials. As the number and diversity of ENMs continues to grow, the Nanomaterial Registry is expected to become a valuable central reference point for nanotechnology researchers and engineers. Second, the NIEHS provides support for all grantees to use the Nanotechnology Characterization Laboratory (NCL), a laboratory overseen by the NCI, to centrally characterize the physical and chemical properties of ENMs used in NIEHS-funded research. Taking advantage of the NCL to provide standardized characterization of ENMs will allow grantees to more effectively link ENM properties with biological effects and produce results that are more easily comparable across studies. Finally, the NIEHS has developed the Chemical Effects in Biological Systems (CEBS) database (http://www.niehs.nih.gov/research/resources/databases/cebs/index.cfm
) as a repository for researchers to share data and findings beyond what is typically included in the published literature. This repository displays data in the context of biology and study design and is designed to allow researchers to integrate data across studies for novel meta-analysis (Fostel 2008
Nano GO. The Engineered Nanomaterials Grand Opportunity grant program (NIEHS 2010
)—known as “Nano GO”—was one of the NIEHS’s signature programs from 2009 through 2012. The program supported 10 Grand Opportunity grants and three Challenge grants with funds from the American Recovery and Reinvestment Act. Through a combination of independent and collaborative research projects, the program aimed to improve the reliability and reproducibility of toxicity testing for nanomaterials.
Exposure assessment. Our ability to evaluate the potential health risks of ENMs relies not only on understanding how ENMs interact with biological systems, but also on assessing how and to what extent people are exposed to them. However, the scientific literature currently offers scant human exposure data for ENMs. To address this gap and inform the development of nanotechnology health and safety guidelines, the NIEHS is investing in efforts to enhance methods and data sharing for ENM exposure assessment.
As a first step, the NIEHS is planning a nanomaterials exposure workshop to be held in early 2013 in Research Triangle Park, North Carolina. The workshop will build upon and expand the discussions held during a 2009 NNI workshop, Human and Environmental Exposure Assessment, which focused on developing a strategy for ENM exposure assessment research among stakeholders from industry and governmental agencies (Murashov 2011
). The follow-on workshop will include a broader array of participants—including academic and extramural researchers in addition to industry and government stakeholders—to provide a forum for these research communities to exchange ideas, highlight new findings, and guide future investments in ENM exposure assessment research and development. The workshop will include four main focal points: a
) ENM exposure assessment approaches that can inform the design of epidemiological studies; b
) measures of ENM exposure developed by the Consumer Product Safety Commission; c
) new tools and devices to evaluate nanoparticle exposure; and d
) in vitro
and in vivo
studies of ENM exposure.
Worker training. As the market for nanotechnology-enabled products grows, so too does the workforce needed to develop and manufacture these materials. These workers face unknown risks from exposure to ENMs in occupational settings. Through its Worker Education and Training Program (WETP) (NIEHS 2013a
), the NIEHS supports efforts to explore how workers who create and handle nanomaterials should be trained about the hazards they face. In 2011, the institute published Training Workers on Risks of Nanotechnology
(Kulinowski and Lippy 2011
), based on the 2009 workshop, “Global Safety and Health Issues and their Impact on Worker Training.” The report provides an overview of key issues, outlines what is currently known about worker protection practices for nanotechnology, reviews applicable U.S. regulations, suggests an outline for an awareness course for workers handling nanomaterials, and provides a framework for training workers to handle nanomaterials safely. The paper represents a first step toward the in-depth worker education and training initiatives that are needed to prepare the nanotechnology workforce as the field continues to develop.
In addition, the WETP maintains a national clearinghouse that organizes and disseminates training curricula, technical reports, and weekly news updates about issues in nanotechnology worker training and safety (NIEHS 2012
Nanotechnology applications. Much of the NIEHS’s extramural nanotechnology effort is focused on the potential toxicity of ENMs. However, nanomaterials also hold tremendous promise for developing applications that benefit the environment and public health. The NIEHS is supporting research initiatives focused on developing four such ENM applications identified by Balshaw et al. (2005)
) the sensing of environmental chemicals, b
) the development of probes for understanding the biological response to environmental factors, c
) the development of interventions to treat environmentally mediated diseases, and d
) the development of technologies for remediation of toxicants in the environment. The institute’s largest investment to date in this area has been through the Superfund Research Program (NIEHS 2013b
), which has awarded grants to scientists seeking to use ENMs for environmental remediation. Outcomes of these efforts include a “nano-towel” designed to capture mercury vapor (Johnson et al. 2008
), nanoscaled iron particles to enhance water cleanup (Lee and Sedlak 2008
), and nanoparticles that can help degrade chemicals such as polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), and polybrominated diphenyl ethers (PBDEs) (Lewis et al. 2009
; Xu et al. 2009
In addition, the NIEHS has invested in efforts to apply nanotechnology for developing devices that can characterize exposures to a wide range of substances with high sensitivity and temporal resolution. Examples include the use of carbon nanotubes to detect molecular gases in the environment (Lim et al. 2012
), molecular imprinted fibers to detect hydrocarbon exposures (Chen et al. 2012
), and the development of nanoporous pigments to detect multiple volatile toxic compounds (Lin et al. 2011
). The NIEHS also supports the development of nano-enabled tools for measuring the biological response to exposures, such as assembly of vertically aligned carbon nanotubes to measure protein expression changes in biological samples (Venkatanarayanan et al. 2012
. Nanoscale materials were first nominated to the NTP for toxicity testing by the Rice University Center for Biological and Environmental Nanotechnology in 2003. In response, the NTP established the Nanotechnology Safety Initiative (NIH 2013c) to coordinate toxicological investigations of ENMs. Drawing on expertise from partners at the U.S. Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention, the NTP oversees initiatives to conduct toxicological testing for a variety of nanomaterials and evaluate workplace exposures to ENMs. These efforts are summarized in Supplemental Material, Table S3 (http://dx.doi.org/10.1289/ehp.1206091
Evaluating ENM toxicity. In support of its Nanotechnology Safety Initiative, the NTP identified ENMs that can be used as model systems for addressing fundamental questions about how ENMs interact with biological systems. Scientists at the three core agencies that constitute the NTP—the NIEHS, the FDA’s National Center for Toxicological Research, and the National Institute for Occupational Safety and Health (NIOSH)—are evaluating the toxicological properties of a representative cross-section of several classes of ENMs. These classes include metal oxides, quantum dots, fullerene-C60, multiwalled carbon nanotubes, nanoscale silver, and nanoscale gold. An investigation of dermal penetration of nanoscale titanium dioxide and cadmium selenide/zinc sulfide quantum dots in in vivo
and in vitro
models revealed no evidence of the migration of the quantum dots into and through intact skin to the regional lymph nodes or liver, based on the measurement of cadmium in tissues and fluorescent quantum dots by confocal microscopy (Gopee et al. 2007
). In vivo
subchronic inhalation toxicity, immunotoxicity, and pulmonary clearance studies of multiple particle sizes of fullerene C60 were conducted in rats and mice [final reports are expected in 2013; pathology results can be accessed online (NTP 2012)]. Other studies have included physical and chemical characterization and inhalation feasibility evaluation of a broad array of commercially available multiwalled carbon nanotubes; in vivo
subchronic inhalation toxicity and pulmonary clearance studies of multiwalled carbon nanotubes in rats and mice; and toxicity investigations of nanoscale silver in rats, including a 13-week toxicity study and an evaluation of the effect of particle size on the pharmacokinetics and toxicity profile of nanoscale silver in vivo
. Data from NTP rodent toxicology studies can be accessed through the CEBS database (http://www.niehs.nih.gov/research/resources/databases/cebs/index.cfm
Occupational exposure research. Under an interagency agreement between the NIEHS and NIOSH, NIOSH staff are coordinating studies to evaluate exposures to ENMs or incidentally generated nanoscale particles by people involved in the manufacturing and handling of carbonaceous nanomaterials. Initial results from studies of the characteristics and amounts of nanomaterials being produced, the sizes of worker populations by facility, and the overall workforce size show that the overall workforce in the manufacture of carbonaceous nanomaterials is small but growing rapidly (15–17%/year) (Schubauer-Berigan et al. 2011
). Researchers are also evaluating the feasibility of epidemiological studies of these workers and investigating the use of protective equipment and other exposure control strategies (Dahm et al. 2011
; Methner et al. 2010a
Intramural research activities. In 2010, the NIEHS’s Clinical Research Unit initiated the Nano Health intramural research program, which aims to provide a translational research model to investigate the health effects of environmentally relevant ENMs to support the NIEHS’s ONE Nano program. In collaboration with the NTP, the intramural program focuses on evaluating ENM health effects in susceptible populations. Research initiatives include an investigation of nano-sized ceria (cerium oxide nanoparticles or CeO2) and several proposed follow-on research projects and collaborations.
Nano-sized ceria. Nano-sized particles of the chemical element cerium are added to diesel fuel to improve fuel efficiency and decrease soot emissions. As a result, cerium is expelled in vehicle exhaust, potentially exposing people to nano-sized ceria through inhalation. Researchers at the NIEHS’s Clinical Research Unit evaluated the effects of CeO2
on healthy human immune and epithelial cells ex vivo
and compared these effects on asthmatic versus healthy bronchial epithelial cells and alveolar macrophages ex vivo
. The results indicate CeO2
is cytotoxic in physiologically relevant concentrations to circulating immune cells, alveolar macrophages, and bronchial epithelia (Hussain et al. 2012a
). Researchers identified the mechanism as mediated through mitochondrial toxicity and autophagy activation. In addition, preliminary evidence shows CeO2
affects cell activation and maturation of immune cells (Hussain and Garantziotis 2012
; Hussain et al. 2012a
;). Further studies are addressing effects on nano-ceria on asthmatic cell populations.
Future directions. The coming years will likely see a modest expansion of the NIEHS’s nanotechnology-focused intramural research activities. First, the NIEHS is partnering with the U.S. Environmental Protection Agency (EPA) to use the human chamber equipment at the U.S. EPA’s Human Research Facility (Chapel Hill, NC) in a pilot study to compare the effects of CeO2 inhalation in healthy versus asthmatic volunteers. This study will build upon the NIEHS’s previous work on the effects of exposure to nano-sized ceria and help to translate previous findings into valuable public health insights. In addition, the NIEHS’s intramural researchers are planning new clinical studies in collaboration with the NTP and NIOSH to elucidate the potential effects of ENM exposure in occupational settings.