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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? The objective is to discuss emerging issues in arsenic research and identify data gaps across disciplines. 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. 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. 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. 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.

In 2008, the National Institute of Environmental Health Sciences/National Toxicology Program, the U.S. Environmental Protection Agency's National Center for Computational Toxicology, and the National Human Genome Research Institute/National Institutes of Health Chemical Genomics Center entered into an agreement on \"high throughput screening, toxicity pathway profiling, and biological interpretation of findings.\" In 2010, the U.S. Food and Drug Administration (FDA) joined the collaboration, known informally as Tox21. The Tox21 partners agreed to develop a vision and devise an implementation strategy to shift the assessment of chemical hazards away from traditional experimental animal toxicology studies to one based on target-specific, mechanism-based, biological observations largely obtained using in vitro assays. Here we outline the efforts of the Tox21 partners up to the time the FDA joined the collaboration, describe the approaches taken to develop the science and technologies that are currently being used, assess the current status, and identify problems that could impede further progress as well as suggest approaches to address those problems. Tox21 faces some very difficult issues. However, we are making progress in integrating data from diverse technologies and end points into what is effectively a systems-biology approach to toxicology. This can be accomplished only when comprehensive knowledge is obtained with broad coverage of chemical and biological/toxicological space. The efforts thus far reflect the initial stage of an exceedingly complicated program, one that will likely take decades to fully achieve its goals. However, even at this stage, the information obtained has attracted the attention of the international scientific community, and we believe these efforts foretell the future of toxicology.

Humans are exposed to a diverse mixture of chemical and non-chemical exposures across their lifetimes. Well-designed epidemiology studies as well as sophisticated exposure science and related technologies enable the investigation of the health impacts of mixtures. While existing statistical methods can address the most basic questions related to the association between environmental mixtures and health endpoints, there were gaps in our ability to learn from mixtures data in several common epidemiologic scenarios, including high correlation among health and exposure measures in space and/or time, the presence of missing observations, the violation of important modeling assumptions, and the presence of computational challenges incurred by current implementations. To address these and other challenges, NIEHS initiated the Powering Research through Innovative methods for Mixtures in Epidemiology (PRIME) program, to support work on the development and expansion of statistical methods for mixtures. Six independent projects supported by PRIME have been highly productive but their methods have not yet been described collectively in a way that would inform application. We review 37 new methods from PRIME projects and summarize the work across previously published research questions, to inform methods selection and increase awareness of these new methods. We highlight important statistical advancements considering data science strategies, exposure-response estimation, timing of exposures, epidemiological methods, the incorporation of toxicity/chemical information, spatiotemporal data, risk assessment, and model performance, efficiency, and interpretation. Importantly, we link to software to encourage application and testing on other datasets. This review can enable more informed analyses of environmental mixtures. We stress training for early career scientists as well as innovation in statistical methodology as an ongoing need. Ultimately, we direct efforts to the common goal of reducing harmful exposures to improve public health.

[...]unbiased approaches (i.e., approaches that provide comprehensive characterization of exposure without an a priori hypothesis) such as the exposome are needed to move beyond \"looking under the lamppost\" (i.e., only measuring exposure for chemicals with available toxicology data). [...]participants in the NIEHS Mixtures Workshop discussed the importance of developing mixtures-related databases. Because it is challenging to search the literature for interactions among chemicals, there was a great deal of interest in the development of databases that would accommodate different levels of mixture study results (i.e., in vitro studies to human studies).

Due to the physical, metabolic, and hormonal changes before, during, and after pregnancy, women-defined here as people assigned female at birth-are particularly susceptible to environmental insults. Racism, a driving force of social determinants of health, exacerbates this susceptibility by affecting exposure to both chemical and nonchemical stressors to create women's health disparities. To better understand and address social and structural determinants of women's health disparities, the National Institute of Environmental Health Sciences (NIEHS) hosted a workshop focused on the environmental impacts on women's health disparities and reproductive health in April 2022. This commentary summarizes foundational research and unique insights shared by workshop participants, who emphasized the need to broaden the definition of the environment to include upstream social and structural determinants of health. We also summarize current challenges and recommendations, as discussed by workshop participants, to address women's environmental and reproductive health disparities. The challenges related to women's health equity, as identified by workshop attendees, included developing research approaches to better capture the social and structural environment in both human and animal studies, integrating environmental health principles into clinical care, and implementing more inclusive publishing and funding approaches. Workshop participants discussed recommendations in each of these areas that encourage interdisciplinary collaboration among researchers, clinicians, funders, publishers, and community members. https://doi.org/10.1289/EHP12996.

The National Institute of Environmental Health Sciences (NIEHS) continues to prioritize research to better understand the health effects resulting from exposure to mixtures of chemical and nonchemical stressors. Mixtures research activities over the last decade were informed by expert input during the development and deliberations of the 2011 NIEHS Workshop \"Advancing Research on Mixtures: New Perspectives and Approaches for Predicting Adverse Human Health Effects.\" NIEHS mixtures research efforts since then have focused on key themes including ) prioritizing mixtures for study, ) translating mixtures data from and studies, ) developing cross-disciplinary collaborations, ) informing component-based and whole-mixture assessment approaches, ) developing sufficient similarity methods to compare across complex mixtures, ) using systems-based approaches to evaluate mixtures, and ) focusing on management and integration of mixtures-related data. We aimed to describe NIEHS driven research on mixtures and combined exposures over the last decade and present areas for future attention. Intramural and extramural mixtures research projects have incorporated a diverse array of chemicals (e.g., polycyclic aromatic hydrocarbons, botanicals, personal care products, wildfire emissions) and nonchemical stressors (e.g., socioeconomic factors, social adversity) and have focused on many diseases (e.g., breast cancer, atherosclerosis, immune disruption). We have made significant progress in certain areas, such as developing statistical methods for evaluating multiple chemical associations in epidemiology and building translational mixtures projects that include both and models. Moving forward, additional work is needed to improve mixtures data integration, elucidate interactions between chemical and nonchemical stressors, and resolve the geospatial and temporal nature of mixture exposures. Continued mixtures research will be critical to informing cumulative impact assessments and addressing complex challenges, such as environmental justice and climate change. https://doi.org/10.1289/EHP14340.

Differences in interlaboratory research protocols contribute to the conflicting data in the literature regarding engineered nanomaterial (ENM) bioactivity. Grantees of a National Institute of Health Sciences (NIEHS)-funded consortium program performed two phases of in vitro testing with selected ENMs in an effort to identify and minimize sources of variability. Consortium program participants (CPPs) conducted ENM bioactivity evaluations on zinc oxide (ZnO), three forms of titanium dioxide (TiO2), and three forms of multiwalled carbon nanotubes (MWCNTs). In addition, CPPs performed bioassays using three mammalian cell lines (BEAS-2B, RLE-6TN, and THP-1) selected in order to cover two different species (rat and human), two different lung epithelial cells (alveolar type II and bronchial epithelial cells), and two different cell types (epithelial cells and macrophages). CPPs also measured cytotoxicity in all cell types while measuring inflammasome activation [interleukin-1β (IL-1β) release] using only THP-1 cells. The overall in vitro toxicity profiles of ENM were as follows: ZnO was cytotoxic to all cell types at ≥ 50 μg/mL, but did not induce IL-1β. TiO2 was not cytotoxic except for the nanobelt form, which was cytotoxic and induced significant IL-1β production in THP-1 cells. MWCNTs did not produce cytotoxicity, but stimulated lower levels of IL-1β production in THP-1 cells, with the original MWCNT producing the most IL-1β. The results provide justification for the inclusion of mechanism-linked bioactivity assays along with traditional cytotoxicity assays for in vitro screening. In addition, the results suggest that conducting studies with multiple relevant cell types to avoid false-negative outcomes is critical for accurate evaluation of ENM bioactivity.

Disaster events adversely affect the health of millions of individuals each year. They create exposure to physical, chemical, biological, and psychosocial hazards while simultaneously exploiting community and individual-level vulnerabilities that allow such exposures to exert harm. Since 2013, the National Institute of Environmental Health Sciences (NIEHS) has led the development of the Disaster Research Response (DR2) program and infrastructure; however, research exploring the nature and effects of disasters on human health is lacking. One reason for this research gap is the challenge of developing and deploying cost-effective sensors for exposure assessment during disaster events. The objective of this commentary is to synergize the consensus findings and recommendations from a panel of experts on sensor science in support of DR2. The NIEHS convened the workshop, \"Getting Smart about Sensors for Disaster Response Research\" on 28 and 29 July 2021 to discuss current gaps and recommendations for moving the field forward. The workshop invited full discussion from multiple viewpoints, with the goal of identifying recommendations and opportunities for further development of this area of research. The panel of experts included leaders in engineering, epidemiology, social and physical sciences, and community engagement, many of whom had firsthand experience with DR2. The primary finding of this workshop is that exposure science in support of DR2 is severely lacking. We highlight unique barriers to DR2, such as the need for time-sensitive exposure data, the chaos and logistical challenges that ensue from a disaster event, and the lack of a robust market for sensor technologies in support of environmental health science. We highlight a need for sensor technologies that are more scalable, reliable, and versatile than those currently available to the research community. We also recommend that the environmental health community renew efforts in support of DR2 facilitation, collaboration, and preparedness. https://doi.org/10.1289/EHP12270.