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.

Children's Environmental Health in South and Southeast Asia: Networking for Better Child Health Outcomes.

Children are particularly vulnerable to environmental hazards because they receive higher doses of pollutants in any given environment and often do not have equitable access to social protection mechanisms such as environmental and health care services. The World Health Organization established a global network of collaborating centres that address children's environmental health (CEH). The network developed a focus on low- and middle-income countries (LMICs) and is broadening its reach by conducting regional workshops for CEH.Objective: This paper reports on the outcomes of a workshop held in conjunction with the 17th International Conference (November 2017) of the Pacific Basin Consortium for Environment and Health, focused on the state of CEH in South and Southeast Asia as presented by seven countries from the region (India, Bangladesh, Nepal, Bhutan, Vietnam, Thailand, Sri Lanka).Workshop outcomes: Country reports presented at the meeting show a high degree of similarity with respect to the issues threatening the health of children. The most common problems are outdoor and household air pollution in addition to exposure to heavy metals, industrial chemicals, and pesticides. Many children still do not have adequate access to clean water and improved sanitation while infectious diseases remain a problem, especially for children living in poverty. Child labour is widely prevalent, generally without adequate training or personal protective equipment. The children now face the dual burden of undernutrition and stunting on the one hand and overnutrition and obesity on the other.Conclusion: It is evident that some countries in these regions are doing better than others in varying areas of CEH. By establishing and participating in regional networks, countries can learn from each other and harmonise their efforts to protect CEH so that all can benefit from closer interactions.

Expanding the Concept of Translational Research: Making a Place for Environmental Health Sciences.

SUMMARY: The National Institute of Environmental Health Sciences (NIEHS) introduces a new translational research framework that builds upon previous biomedical models to create a more comprehensive and integrated environmental health paradigm. The framework was developed as a graphical construct that illustrates the complexity of designing, implementing, and tracking translational research in environmental health. We conceptualize translational research as a series of concentric rings and nodes, defining "translation" as movement either from one ring to another or between nodes on a ring. A "Fundamental Questions" ring expands upon the research described in other frameworks as "basic" to include three interrelated concepts critical to basic science research: research questions, experimental settings, and organisms. This feature enables us to capture more granularity and thus facilitates an approach for categorizing translational research and its growth over time. We anticipate that the framework will help researchers develop compelling long-term translational research stories and accelerate public health impacts by clearly mapping out opportunities for collaborations. By using this paradigm, researchers everywhere will be better positioned to design research programs, identify research partners based on cross-disciplinary research needs, identify stakeholders who are likely to use the research for environmental decision-making and intervention, and track progress toward common goals. https://doi.org/10.1289/EHP3657.

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.

Prevention-intervention strategies to reduce exposure to e-waste.

As one of the largest waste streams, electronic waste (e-waste) production continues to grow in response to global demand for consumer electronics. This waste is often shipped to developing countries where it is disassembled and recycled. In many cases, e-waste recycling activities are conducted in informal settings with very few controls or protections in place for workers. These activities involve exposure to hazardous substances such as cadmium, lead, and brominated flame retardants and are frequently performed by women and children. Although recycling practices and exposures vary by scale and geographic region, we present case studies of e-waste recycling scenarios and intervention approaches to reduce or prevent exposures to the hazardous substances in e-waste that may be broadly applicable to diverse situations. Drawing on parallels identified in these cases, we discuss the future prevention and intervention strategies that recognize the difficult economic realities of informal e-waste recycling.

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.

E-waste: the growing global problem and next steps.

In many low- and middle-income countries, handling and disposal of discarded electrical or electronic equipment (EEE) is frequently unregulated. e-Waste contains hazardous constituents such as lead, mercury, and chromium, certain chemicals in plastics, and flame retardants. There is increasing concern about health effects related to contamination in air, soil, and water for people working and living at or near informal e-waste processing sites, especially to the most vulnerable populations, pregnant women and children. The observed adverse health effects and increasing number of e-waste sites make protecting human health and the environment from e-waste contamination an expanding challenge. Through international cooperation, awareness can be elevated about the harm that e-waste processing poses to human health. Here we discuss how international researchers, public health practitioners, and policymakers can employ solutions to reduce e-waste exposures.

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.

E-Waste and Harm to Vulnerable Populations: A Growing Global Problem.

BACKGROUND: Electronic waste (e-waste) is produced in staggering quantities, estimated globally to be 41.8 million tonnes in 2014. Informal e-waste recycling is a source of much-needed income in many low- to middle-income countries. However, its handling and disposal in underdeveloped countries is often unsafe and leads to contaminated environments. Rudimentary and uncontrolled processing methods often result in substantial harmful chemical exposures among vulnerable populations, including women and children. E-waste hazards have not yet received the attention they deserve in research and public health agendas. OBJECTIVES: We provide an overview of the scale and health risks. We review international efforts concerned with environmental hazards, especially affecting children, as a preface to presenting next steps in addressing health issues stemming from the global e-waste problem. DISCUSSION: The e-waste problem has been building for decades. Increased observation of adverse health effects from e-waste sites calls for protecting human health and the environment from e-waste contamination. Even if e-waste exposure intervention and prevention efforts are implemented, legacy contamination will remain, necessitating increased awareness of e-waste as a major environmental health threat. CONCLUSION: Global, national, and local levels efforts must aim to create safe recycling operations that consider broad security issues for people who rely on e-waste processing for survival. Paramount to these efforts is reducing pregnant women and children's e-waste exposures to mitigate harmful health effects. With human environmental health in mind, novel dismantling methods and remediation technologies and intervention practices are needed to protect communities. CITATION: Heacock M, Kelly CB, Asante KA, Birnbaum LS, Bergman AL, Bruné MN, Buka I, Carpenter DO, Chen A, Huo X, Kamel M, Landrigan PJ, Magalini F, Diaz-Barriga F, Neira M, Omar M, Pascale A, Ruchirawat M, Sly L, Sly PD, Van den Berg M, Suk WA. 2016. E-waste and harm to vulnerable populations: a growing global problem. Environ Health Perspect 124:550-555; http://dx.doi.org/10.1289/ehp.1509699.

Evidence for abasic site sugar phosphate-mediated cytotoxicity in alkylating agent treated Saccharomyces cerevisiae.

To better understand alkylating agent-induced cytotoxicity and the base lesion DNA repair process in Saccharomyces cerevisiae, we replaced the RAD27(FEN1) open reading frame (ORF) with the ORF of the bifunctional human repair enzyme DNA polymerase (Pol) ß. The aim was to probe the effect of removal of the incised abasic site 5'-sugar phosphate group (i.e., 5'-deoxyribose phosphate or 5'-dRP) in protection against methyl methanesulfonate (MMS)-induced cytotoxicity. In S. cerevisiae, Rad27(Fen1) was suggested to protect against MMS-induced cytotoxicity by excising multinucleotide flaps generated during repair. However, we proposed that the repair intermediate with a blocked 5'-end, i.e., 5'-dRP group, is the actual cytotoxic lesion. In providing a 5'-dRP group removal function mediated by dRP lyase activity of Pol ß, the effects of the 5'-dRP group were separated from those of the multinucleotide flap itself. Human Pol ß was expressed in S. cerevisiae, and this partially rescued the MMS hypersensitivity observed with rad27(fen1)-null cells. To explore this rescue effect, altered forms of Pol ß with site-directed eliminations of either the 5'-dRP lyase or polymerase activity were expressed in rad27(fen1)-null cells. The 5'-dRP lyase, but not the polymerase activity, conferred the resistance to MMS. These results suggest that after MMS exposure, the 5'-dRP group in the repair intermediate is cytotoxic and that Rad27(Fen1) protection against MMS in wild-type cells is due to elimination of the 5'-dRP group.

Mutagenesis dependent upon the combination of activation-induced deaminase expression and a double-strand break.

We explored DNA metabolic events potentially relevant to somatic hypermutation (SHM) of immunoglobulin genes using a yeast model system. Double-strand break (DSB) formation has been discussed as a possible component of the SHM process during immunoglobulin gene maturation. Yet, possible mechanisms linking DSB formation with mutagenesis have not been well understood. In the present study, a linkage between mutagenesis in a reporter gene and a double-strand break at a distal site was examined as a function of activation-induced deaminase (AID) expression. Induction of the DSB was found to be associated with mutagenesis in a genomic marker gene located 7 kb upstream of the break site: mutagenesis was strongest with the combination of AID expression and DSB induction. The mutation spectrum of this DSB and AID-mediated mutagenesis was characteristic of replicative bypass of uracil in one strand and was dependent on expression of DNA polymerase delta (Polδ). These results in a yeast model system illustrate that the combination of DSB induction and AID expression could be associated with mutagenesis observed in SHM. Implications of these findings for SHM of immunoglobulin genes in human B cells are discussed.

Base excision repair and design of small molecule inhibitors of human DNA polymerase ß.

Base excision repair (BER) can protect a cell after endogenous or exogenous genotoxic stress, and a deficiency in BER can render a cell hypersensitive to stress-induced apoptotic and necrotic cell death, mutagenesis, and chromosomal rearrangements. However, understanding of the mammalian BER system is not yet complete as it is extraordinarily complex and has many back-up processes that complement a deficiency in any one step. Due of this lack of information, we are unable to make accurate predictions on therapeutic approaches targeting BER. A deeper understanding of BER will eventually allow us to conduct more meaningful clinical interventions. In this review, we will cover historical and recent information on mammalian BER and DNA polymerase ß and discuss approaches toward development and use of small molecule inhibitors to manipulate BER. With apologies to others, we will emphasize results obtained in our laboratory and those of our collaborators.

Alkylation DNA damage in combination with PARP inhibition results in formation of S-phase-dependent double-strand breaks.

The combination of poly(ADP-ribose)polymerase (PARP) inhibitors and alkylating agents is currently being investigated in cancer therapy clinical trials. However, the DNA lesions producing the synergistic cell killing effect in tumors are not fully understood. Treatment of human and mouse fibroblasts with the monofunctional DNA methylating agent methyl methanesulfonate (MMS) in the presence of a PARP inhibitor has been shown to trigger a cell cycle checkpoint response. Among other changes, this DNA damage response to combination treatment includes activation of ATM/Chk2 and phosphorylation of histone H2A.X. These changes are consistent with DNA double-strand break (DSB) formation during the response, but the measurement of DSBs has not been addressed. Such DSB evaluation is important in understanding this DNA damage response because events other than DSB formation are known to lead to ATM/Chk2 activation and H2A.X phosphorylation. Here, we examined the structural integrity of genomic DNA after the combined treatment of cells with MMS and a PARP inhibitor, i.e., exposure to a sub-lethal dose of MMS in the presence of the PARP inhibitor 4-amino-1,8-napthalimide (4-AN). We used pulsed field gel electrophoresis (PFGE) for measurement of DSBs in both human and mouse embryonic fibroblasts, and flow cytometry to follow the phosphorylated form of H2A.X (gamma-H2A.X). The results indicate that DSBs are formed with the combination treatment, but not following treatment with either agent alone. Our data also show that formation of gamma-H2A.X correlates with PARP-1-expressing cells in S-phase of the cell cycle. The observations support the model that persistence of PARP-1 at base excision repair intermediates, as cells move into S-phase, leads to DSBs and the attendant checkpoint responses.