Adapting to Climate Change: Leveraging Systems-Focused Multidisciplinary Research to Promote Resilience.

Approximately 2000 official and potential Superfund sites are located within 25 miles of the East or Gulf coasts, many of which will be at risk of flooding as sea levels rise. More than 60 million people across the United States live within 3 miles of a Superfund site. Disentangling multifaceted environmental health problems compounded by climate change requires a multidisciplinary systems approach to inform better strategies to prevent or reduce exposures and protect human health. The purpose of this minireview is to present the National Institute of Environmental Health Sciences Superfund Research Program (SRP) as a useful model of how this systems approach can help overcome the challenges of climate change while providing flexibility to pivot to additional needs as they arise. It also highlights broad-ranging SRP-funded research and tools that can be used to promote health and resilience to climate change in diverse contexts.

Enhancing Data Integration, Interoperability, and Reuse to Address Complex and Emerging Environmental Health Problems.

Environmental health sciences (EHS) span many diverse disciplines. Within the EHS community, the National Institute of Environmental Health Sciences Superfund Research Program (SRP) funds multidisciplinary research aimed to address pressing and complex issues on how people are exposed to hazardous substances and their related health consequences with the goal of identifying strategies to reduce exposures and protect human health. While disentangling the interrelationships that contribute to environmental exposures and their effects on human health over the course of life remains difficult, advances in data science and data sharing offer a path forward to explore data across disciplines to reveal new insights. Multidisciplinary SRP-funded teams are well-positioned to examine how to best integrate EHS data across diverse research domains to address multifaceted environmental health problems. As such, SRP supported collaborative research projects designed to foster and enhance the interoperability and reuse of diverse and complex data streams. This perspective synthesizes those experiences as a landscape view of the challenges identified while working to increase the FAIR-ness (Findable, Accessible, Interoperable, and Reusable) of EHS data and opportunities to address them.

Understanding exposures and latent disease risk within the National Institute of Environmental Health Sciences Superfund Research Program.

Understanding the health effects of exposures when there is a lag between exposure and the onset of disease is an important and challenging topic in environmental health research. The National Institute of Environmental Health Sciences (NIEHS) Superfund Basic Research and Training Program (SRP) is a National Institutes of Health (NIH) grant program that uses a multidisciplinary approach to support biomedical and environmental science and engineering research. Because of the multidisciplinary nature of the program, SRP grantees are well-positioned to study exposure and latent disease risk across humans, animal models, and various life stages. SRP-funded scientists are working to address the challenge of connecting exposures that occur early in life and prior to conception with diseases that manifest much later, including developing new tools and approaches to predict how chemicals may affect long-term health. Here, we highlight research from the SRP focused on understanding the health effects of exposures with a lag between exposure and the onset of the disease as well as provide future directions for addressing knowledge gaps for this highly complex and challenging topic. Advancing the knowledge of latency to disease will require a multidisciplinary approach to research, the need for data sharing and integration, and new tools and computation approaches to make better predications about the timing of disease onset. A better understanding of exposures that may contribute to later-life diseases is essential to supporting the implementation of prevention and intervention strategies to reduce or modulate exposures to reduce disease burden.

Greater than the sum of its parts: focusing SRP research through a systems approach lens.

The National Institute of Environmental Health Sciences Superfund Research Program (SRP) funds diverse transdisciplinary research to understand how hazardous substances contribute to disease. SRP research focuses on how to prevent these exposures by promoting problem-based, solution-oriented research. SRP's mandate areas encompasses broad biomedical and environmental science and engineering research efforts and, when combined with research translation, community engagement, training, and data science, offers broad expertise and unique perspectives directed at a specific big picture question. The purpose of this commentary is to adapt a systems approach concept to SRP research to accommodate the complexity of a scientific problem. The SRP believes a systems approach offers a framework to understand how scientists can work together to integrate diverse fields of research to prevent or understand environmentally-influenced human disease by addressing specific questions that are part of a larger perspective. Specifically, within the context of the SRP, a systems approach can elucidate the complex interactions between factors that contribute to or protect against environmental insults. Leveraging a systems approach can continue to advance SRP science while building the foundation for researchers to address difficult emerging environmental health problems.

Benefits of basic research from the Superfund Research Program.

The National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) Hazardous Substances Basic Research and Training Program [Superfund Research Program (SRP)] funds transdisciplinary research projects spanning the biomedical and environmental sciences to address issues related to potentially hazardous substances. We used a case study approach to identify how SRP-funded basic biomedical research has had an impact on society. We examined how transdisciplinary research projects from the SRP have advanced knowledge and led to additional clinical, public health, policy, and economic benefits. SRP basic biomedical research findings have contributed to the body of knowledge and influenced a broad range of scientific disciplines. It has informed the development of policies and interventions to reduce exposure to environmental contaminants to improve public health. Research investments by the SRP have had a significant impact on science, health, and society. Documenting the benefits of these investments provides insight into how basic research is translated to real-world applications.

Sharing SRP data to reduce environmentally associated disease and promote transdisciplinary research.

The National Institute of Environmental Health Sciences (NIEHS) Superfund Basic Research and Training Program (SRP) funds a wide range of projects that span biomedical, environmental sciences, and engineering research and generate a wealth of data resulting from hypothesis-driven research projects. Combining or integrating these diverse data offers an opportunity to uncover new scientific connections that can be used to gain a more comprehensive understanding of the interplay between exposures and health. Integrating and reusing data generated from individual research projects within the program requires harmonization of data workflows, ensuring consistent and robust practices in data stewardship, and embracing data sharing from the onset of data collection and analysis. We describe opportunities to leverage data within the SRP and current SRP efforts to advance data sharing and reuse, including by developing an SRP dataset library and fostering data integration through Data Management and Analysis Cores. We also discuss opportunities to improve public health by identifying parallels in the data captured from health and engineering research, layering data streams for a more comprehensive picture of exposures and disease, and using existing SRP research infrastructure to facilitate and foster data sharing. Importantly, we point out that while the SRP is in a unique position to exploit these opportunities, they can be employed across environmental health research. SRP research teams, which comprise cross-disciplinary scientists focused on similar research questions, are well positioned to use data to leverage previous findings and accelerate the pace of research. Incorporating data streams from different disciplines addressing similar questions can provide a broader understanding and uncover the answers to complex and discrete research questions.

The Importance of Community Engagement and Research Translation within the NIEHS Superfund Research Program.

The National Institute of Environmental Health Sciences Superfund Research Program (SRP) funds university-based, solution-oriented research to understand how hazardous substances contribute to disease and how to prevent exposures to these hazardous substances. A unique aspect of the SRP is that, beyond the biomedical, environmental sciences, and engineering research projects, SRP-funded centers are required to include community engagement to build partnerships with affected communities and research translation to communicate and facilitate the use of research findings. The SRP views both as effective ways to inform and advance science for protection of public health. The purpose of community engagement within the centers is to ensure bidirectional communication between the researchers and the community, identify best practices and activities in community engagement for prevention and intervention activities, enhance knowledge, and support the needs of the communities impacted by hazardous waste sites. The SRP views research translation as communicating and facilitating the use of research findings emanating from the center in a manner most appropriate for their application and for the advancement of a center's research objectives. The SRP has a strong history of seeking opportunities to work with communities and stakeholders, by translating and sharing research findings in an impactful and informative manner with long-lasting benefits to improve public health.

Assessing the Economic and Societal Benefits of SRP-Funded Research.

BACKGROUND: The National Institute of Environmental Health Sciences (NIEHS) Superfund Basic Research and Training Program (SRP) funds a wide range of transdisciplinary research projects spanning the biomedical and environmental sciences and engineering, supporting and promoting the application of that research to solving real-world problems. OBJECTIVES: We used a case study approach to identify the economic and societal benefits of SRP-funded research, focusing on the use of potentially hazardous substance remediation and site monitoring tools. We also identified successes and challenges involved in translating SRP grantees' research findings and advances into application. DISCUSSION: We identified remediation and detection research projects supported by the SRP with the most potential for economic and societal benefits and selected 36 for analysis. To examine the benefits of these applied technologies, we interviewed 28 SRP-supported researchers and 41 partners. Five case studies emerged with the most complete information on cost savings-total savings estimated at >$100 million. Our analysis identified added societal benefits such as creation of small businesses, land and water reuse, sustainable technologies, exposure reduction, and university-industry partnerships. CONCLUSIONS: Research funded by the SRP has yielded significant cost savings while providing additional societal benefits. https://doi.org/10.1289/EHP3534.

The National Institute of Environmental Health Sciences Superfund Research Program: a model for multidisciplinary training of the next generation of environmental health scientists.

The National Institute of Environmental Health Sciences (NIEHS) Superfund Research Program (SRP) funds university-based, multidisciplinary research on human health and environmental science and engineering with the central goals to understand how hazardous substances contribute to disease and how to prevent exposures to these environmental chemicals. This multi-disciplinary approach allows early career scientists (e.g. graduate students and postdoctoral researchers) to gain experience in problem-based, solution-oriented research and to conduct research in a highly collaborative environment. Training the next generation of environmental health scientists has been an important part of the SRP since its inception. In addition to basic research, the SRP has grown to include support of broader training experiences such as those in research translation and community engagement activities that provide opportunities to give new scientists many of the skills they will need to be successful in their field of research. Looking to the future, the SRP will continue to evolve its training component by tracking and analyzing outcomes from its trainees by using tools such as the NIEHS CareerTrac database system, by increasing opportunities for trainees interested in research that goes beyond US boundaries, and in the areas of bioinformatics and data integration. These opportunities will give them the skills needed to be competitive and successful no matter which employment sector they choose to enter after they have completed their training experience.

Pharmacokinetics of Ethionamide Delivered in Spray-Dried Microparticles to the Lungs of Guinea Pigs.

The use of ethionamide (ETH) in treating multidrug-resistant tuberculosis is limited by severe side effects. ETH disposition after pulmonary administration in spray-dried particles might minimize systemic exposure and side effects. To explore this hypothesis, spray-dried ETH particles were optimized for performance in a dry powder aerosol generator and exposure chamber. ETH particles were administered by the intravenous (IV), oral, or pulmonary routes to guinea pigs. ETH appearance in plasma, bronchoalveolar lavage, and lung tissues was measured and subjected to noncompartmental pharmacokinetic analysis. Dry powder aerosol generator dispersion of 20% ETH particles gave the highest dose at the exposure chamber ports and fine particle fraction of 72.3%. Pulmonary ETH was absorbed more rapidly and to a greater extent than orally administered drug. At Tmax, ETH concentrations were significantly higher in plasma than lungs from IV dosing, whereas insufflation lung concentrations were 5-fold higher than in plasma. AUC(0-t) (area under the curve) and apparent total body clearance (CL) were similar after IV administration and insufflation. AUC(0-t) after oral administration was 6- to 7-fold smaller and CL was 6-fold faster. Notably, ETH bioavailability after pulmonary administration was significantly higher (85%) than after oral administration (17%). These results suggest that pulmonary ETH delivery would potentially enhance efficacy for tuberculosis treatment given the high lung concentrations and bioavailability.

14th congress of combustion by-products and their health effects-origin, fate, and health effects of combustion-related air pollutants in the coming era of bio-based energy sources.

The 14th International Congress on Combustion By-Products and Their Health Effects was held in Umeå, Sweden from June 14th to 17th, 2015. The Congress, mainly sponsored by the National Institute of Environmental Health Sciences Superfund Research Program and the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning, focused on the "Origin, fate and health effects of combustion-related air pollutants in the coming era of bio-based energy sources". The international delegates included academic and government researchers, engineers, scientists, policymakers and representatives of industrial partners. The Congress provided a unique forum for the discussion of scientific advances in this research area since it addressed in combination the health-related issues and the environmental implications of combustion by-products. The scientific outcomes of the Congress included the consensus opinions that: (a) there is a correlation between human exposure to particulate matter and increased cardiac and respiratory morbidity and mortality; (b) because currently available data does not support the assessment of differences in health outcomes between biomass smoke and other particulates in outdoor air, the potential human health and environmental impacts of emerging air-pollution sources must be addressed. Assessment will require the development of new approaches to characterize combustion emissions through advanced sampling and analytical methods. The Congress also concluded the need for better and more sustainable e-waste management and improved policies, usage and disposal methods for materials containing flame retardants.

Arsenic and Environmental Health: State of the Science and Future Research Opportunities.

BACKGROUND: Exposure to inorganic and organic arsenic compounds is a major public health problem that affects hundreds of millions of people worldwide. Exposure to arsenic is associated with cancer and noncancer effects in nearly every organ in the body, and evidence is mounting for health effects at lower levels of arsenic exposure than previously thought. Building from a tremendous knowledge base with > 1,000 scientific papers published annually with "arsenic" in the title, the question becomes, what questions would best drive future research directions? OBJECTIVES: The objective is to discuss emerging issues in arsenic research and identify data gaps across disciplines. METHODS: The National Institutes of Health's National Institute of Environmental Health Sciences Superfund Research Program convened a workshop to identify emerging issues and research needs to address the multi-faceted challenges related to arsenic and environmental health. This review summarizes information captured during the workshop. DISCUSSION: More information about aggregate exposure to arsenic is needed, including the amount and forms of arsenic found in foods. New strategies for mitigating arsenic exposures and related health effects range from engineered filtering systems to phytogenetics and nutritional interventions. Furthermore, integration of omics data with mechanistic and epidemiological data is a key step toward the goal of linking biomarkers of exposure and susceptibility to disease mechanisms and outcomes. CONCLUSIONS: Promising research strategies and technologies for arsenic exposure and adverse health effect mitigation are being pursued, and future research is moving toward deeper collaborations and integration of information across disciplines to address data gaps. CITATION: Carlin DJ, Naujokas MF, Bradham KD, Cowden J, Heacock M, Henry HF, Lee JS, Thomas DJ, Thompson C, Tokar EJ, Waalkes MP, Birnbaum LS, Suk WA. 2016. Arsenic and environmental health: state of the science and future research opportunities. Environ Health Perspect 124:890-899; http://dx.doi.org/10.1289/ehp.1510209.

Current Research and Opportunities to Address Environmental Asbestos Exposures.

Asbestos-related diseases continue to result in approximately 120,000 deaths every year in the United States and worldwide. Although extensive research has been conducted on health effects of occupational exposures to asbestos, many issues related to environmental asbestos exposures remain unresolved. For example, environmental asbestos exposures associated with a former mine in Libby, Montana, have resulted in high rates of nonoccupational asbestos-related disease. Additionally, other areas with naturally occurring asbestos deposits near communities in the United States and overseas are undergoing investigations to assess exposures and potential health risks. Some of the latest public health, epidemiological, and basic research findings were presented at a workshop on asbestos at the 2014 annual meeting of the Society of Toxicology in Phoenix, Arizona. The following focus areas were discussed: a) mechanisms resulting in fibrosis and/or tumor development; b) relative toxicity of different forms of asbestos and other hazardous elongated mineral particles (EMPs); c) proper dose metrics (e.g., mass, fiber number, or surface area of fibers) when interpreting asbestos toxicity; d) asbestos exposure to susceptible populations; and e) using toxicological findings for risk assessment and remediation efforts. The workshop also featured asbestos research supported by the National Institute of Environmental Health Sciences, the Agency for Toxic Substances and Disease Registry, and the U.S. Environmental Protection Agency. Better protection of individuals from asbestos-related health effects will require stimulation of new multidisciplinary research to further our understanding of what constitutes hazardous exposures and risk factors associated with toxicity of asbestos and other hazardous EMPs (e.g., nanomaterials).

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

Polycyclic aromatic hydrocarbons: from metabolism to lung cancer.

Excessive exposure to polycyclic aromatic hydrocarbons (PAHs) often results in lung cancer, a disease with the highest cancer mortality in the United States. After entry into the lung, PAHs induce phase I metabolic enzymes such as cytochrome P450 (CYP) monooxygenases, i.e. CYP1A1/2 and 1B1, and phase II enzymes such as glutathione S-transferases, UDP glucuronyl transferases, NADPH quinone oxidoreductases (NQOs), aldo-keto reductases (AKRs), and epoxide hydrolases (EHs), via the aryl hydrocarbon receptor (AhR)-dependent and independent pathways. Humans can also be exposed to PAHs through diet, via consumption of charcoal broiled foods. Metabolism of PAHs through the CYP1A1/1B1/EH pathway, CYP peroxidase pathway, and AKR pathway leads to the formation of the active carcinogens diol-epoxides, radical cations, and o-quinones. These reactive metabolites produce DNA adducts, resulting in DNA mutations, alteration of gene expression profiles, and tumorigenesis. Mutations in xenobiotic metabolic enzymes, as well as polymorphisms of tumor suppressor genes (e.g. p53) and/or genes involved in gene expression (e.g. X-ray repair cross-complementing proteins), are associated with lung cancer susceptibility in human populations from different ethnicities, gender, and age groups. Although various metabolic activation/inactivation pathways, AhR signaling, and genetic susceptibilities contribute to lung cancer, the precise points at which PAHs induce tumor initiation remain unknown. The goal of this review is to provide a current state-of-the-science of the mechanisms of human lung carcinogenesis mediated by PAHs, the experimental approaches used to study this complex class of compounds, and future directions for research of these compounds.

Comparative long-term toxicity of Libby amphibole and amosite asbestos in rats after single or multiple intratracheal exposures.

In former mine workers of Libby, MT, exposure to amphibole-containing vermiculite was linked to increased rates of asbestosis, lung cancer, and mesothelioma. Although many studies showed adverse effects following exposure to Libby amphibole (LA; a mixture of winchite, richterite, and tremolite), little is known regarding the relative toxicity of LA compared to regulated asbestos, or regarding the risks associated with acute high-dose exposures relative to repeated low-dose exposures. In this study, pulmonary function, inflammation, and pathology were assessed after single or multiple intratracheal (IT) exposures of LA or a well-characterized amosite (AM) control fiber with equivalent fiber characteristics. Male F344 rats were exposed to an equivalent total mass dose (0.15, 0.5, 1.5, or 5 mg/rat) of LA or AM administered either as a single IT instillation, or as multiple IT instillations given every other week over a 13-wk period, and necropsied up to 20 mo after the initial IT. When comparing the two fiber types, in both studies LA resulted in greater acute neutrophilic inflammation and cellular toxicity than equal doses of AM, but long-term histopathological changes were approximately equivalent between fibers, suggesting that LA is at least as toxic as AM. In addition, although no dose-response relationship was discerned, mesothelioma or lung carcinomas were found after exposure to low and high dose levels of LA or AM in both studies. Conversely, when comparing studies, an equal mass dose given over multiple exposures instead of a single bolus resulted in greater chronic pathological changes in lung at lower doses, despite the initially weaker acute inflammatory response. Overall, these results suggest that there is a possibility of greater long-term pathological changes with repeated lower LA dose exposures, which more accurately simulates chronic environmental exposures.

Nanotoxicology and nanotechnology: new findings from the NIEHS and Superfund Research Program scientific community.

Nanomaterials are characterized by their small size (i.e., nanometer scale) and can be engineered from nearly any chemical substance, creating materials that differ in composition, particle size, shape, and surface coatings. These materials are often seen as a "double-edged sword" by having properties that make them potentially beneficial in product development, drug delivery, and remediation of hazardous substances, but these same properties may result in interaction with biological systems and potential effects in the environment. The National Institute of Environmental Health Sciences (NIEHS) is interested in both the potential risks associated with exposure to these materials, while harnessing the power of engineered nanomaterials to improve public health. This presentation will consist of discussion of nanoparticle studies by NIEHS researchers and the extramural community and its efforts to develop cross-agency initiatives to solve the many vexing issues associated with nanomaterials. For example, researchers from the NIEHS National Toxicology Program (NTP) are evaluating a number of nanomaterial classes in comprehensive toxicology studies. NIEHS also has an extensive extramural research grant portfolio consisting of the Nano Grand Opportunities (Nano GO) Program and NIEHS Centers for Nanotechnology Health Implications Research (NCNHIR) Consortium consisting of U19 and U01 Cooperative Centers. Furthermore, the NIEHS Superfund Research Program (SRP), which supports a network of university (P42, R01), small business (SBIR/STTR), and training grants (R25), provides funding to grantees evaluating the toxicology of nanomaterials, developing new or improved nanotechnologies to monitor and remediate hazardous substances, and training professionals in the use of these of materials. The NIEHS's Worker Education Branch also offers educational materials for training workers on risks of nanotechnology in laboratories, manufacturing facilities, at hazardous waste cleanup sites, and during emergency responses. In conclusion, this presentation will stimulate dialogue regarding the need for more research on these complex materials and serve as a resource about the wide variety of ongoing studies on nanomaterials at NIEHS that will contribute to the determination of risk associated with this class of compounds.

Combustion By-Products and their Health Effects--combustion engineering and global health in the 21st century: issues and challenges.

The 13th International Congress on Combustion By-Products and their Health Effects was held in New Orleans, Louisiana from May 15 to 18, 2013. The congress, sponsored by the Superfund Research Program, National Institute of Environmental Health Sciences, and National Science Foundation, brought together international academic and government researchers, engineers, scientists, and policymakers. With industrial growth, increased power needs and generation and coal consumption and their concomitant emissions, pernicious health effects associated with exposures to these emissions are on the rise. This congress provides a unique platform for interdisciplinary exchange and discussion of these topics. The formation, conversion, control, and health effects of combustion by-products, including particulate matter and associated heavy metals, persistent organic pollutants, and environmentally persistent free radicals, were discussed during the congress. This review will summarize and discuss the implications of the data presented.