Role of research in public health.

Environmental health research is at a promising stage for more precisely identifying gene-environment components of disease. Simplistic models and reductionist approaches that have been the norm both in toxicology and in clinical medicine are beginning to be replaced with a more holistic or systems biology approach. We are slowly moving to an understanding that the time between an exposure and its consequence as a diagnosed disease is a time during which many different biochemical changes are occurring and a time during which many biomarkers of disease progression could be identified and used. With such information in hand, clinicians would be able to intervene early in disease progression. With such information, environmental health researchers and policy makers could more reliably identify which elements in our environment need to be controlled or reduced and which populations need the most protection. With such information, the incidence of many human diseases could be dramatically reduced.

Assessing the national capacity for disaster research response (DR2) within the NIEHS Environmental Health Sciences Core Centers.

INTRODUCTION: Disaster research response (DR2) is necessary to answer scientific questions about the environmental health impacts of disasters and the effectiveness of response and recovery strategies. This research explores the preparedness and capacity of National Institute of Environmental Health Sciences (NIEHS) P30 Core Centers (CCs) to conduct DR2 and engage with communities in the context of disasters. METHODS: In early 2018, we conducted an online survey of CC Directors (n = 16, 69.5% response rate) to identify their DR2 relevant scientific assets, capabilities, and activities. Summary statistics were calculated. We also conducted in-depth, semi-structured interviews with 16 (69.5%) CC Community Engagement Core directors to identify facilitators and barriers of DR2 community engagement. Interview notes were coded and thematically analyzed. RESULTS: Survey: While 56% of responding CCs reported prior participation in DR2 and preparedness to repurpose funding to support DR2, less than one third reported development of a disaster-specific data collection protocol, deployment plan, or concept of operations plan, participation in an exercise to test DR2 capacity, development of academic partnerships to conduct DR2, development of a process for fast-tracking institutional review board approvals for DR2, or maintenance of formal agreements with state, local, or community-based partner(s). A number of CCs reported developing or considering developing capacity in these areas. Barriers to, and tools and resources to enhance, CC engagement in DR2 were identified. Interviews: Four key components for community engaged DR2 were identified: pre-existing community relationships, responsive research that benefits communities, coordination among researchers, and coordination with community response partners. Several roles for, benefits of, and barriers to Community Engagement Rapid Response Teams (CERRT) were described. CONCLUSIONS: CCs have significant scientific assets and community partnerships that can be leveraged for DR2; however, additional planning is necessary to ensure that these scientific assets and community partnerships are leveraged when disasters strike.

NTP/NIEHS Global Contributions to Toxicologic Pathology.

National Toxicology Program (NTP) pathologists are engaged in important initiatives that have significant global impact. These initiatives build on its leadership in pathology peer review and publications in the areas of toxicologic pathology, clinical pathology, and laboratory animal medicine. Over the past decade, NTP/National Institute of Environmental Health Sciences research initiatives have focused on cancer and noncancer hazard identification, with the goal of understanding cellular and molecular mechanisms of disease. New initiatives of significant global impact include the web-based nonneoplastic lesion atlas and an NTP partnership with international scientists to investigate molecular mechanisms at the whole genome level, which will be used to inform potential mechanisms of environmental exposures in human cancers. Also, we are dedicated to contributing to pathology and toxicology organizations through service on executive committees and editorial boards, participating in international projects and symposiums, and providing training for future leaders in toxicologic pathology. Herein, we provide highlights of our global contributions.

Elucidating environmental dimensions of neurological disorders and disease: Understanding new tools from federal chemical testing programs.

BACKGROUND: Federal agencies are making significant investments to advance predictive approaches to evaluate chemical hazards and risks. Environmental Defense Fund (EDF) believes that engagement with the broader scientific community is critical to building and maintaining a strong biological foundation for these approaches. OBJECTIVES: On June 18-19, 2015, EDF organized a meeting to 1) foster a conversation between federal scientists advancing predictive approaches and environmental health researchers investigating environmental exposures and neurological outcomes, and 2) explore opportunities and challenges for the use of federal chemical high-throughput in vitro screening (HTS) data in hypothesis-driven research toward, ultimately, improved data for public health decision-making. DISCUSSION: The meeting achieved its objectives. Government scientists showcased their chemical testing programs and vision for how emerging data may be used to meet agency missions. Environmental health researchers shared their experiences using federal HTS data, offered recommendations for strengthening federal HTS platforms, and expressed great interest in continued engagement with evolving federal chemical testing initiatives. CONCLUSIONS: The meeting provided an invaluable exchange between two scientific communities with a shared interest in protecting public health from harmful environmental exposures, but who have not sufficiently engaged with each other. Discussions identified opportunities and work ahead for the use of HTS data in hypothesis-driven research. Though the meeting focused on neurological outcomes, the purpose, objectives and experience of the meeting are broadly applicable. EDF strongly encourages more discourse and collaboration between federal and non-government scientists working to understand environmental influences on health outcomes.

Then and now: lessons learned from community- academic partnerships in environmental health research.

On the occasion of the 50th anniversary of the National Institutes of Environmental Health Sciences we reflect on how environmental research incorporating community members as active partners has evolved, benefited communities and advanced environmental health research. We highlight the commitment to community partnerships in the aftermath of the 2010 Deep Water Horizon Oil Spill, and how that commitment helped improve science. We provide examples of community-academic partnerships across the engagement spectrum. Finally, we offer suggestions to improve the community engagement in order to cultivate more long partnerships and better scientific research.

NIEHS/FDA CLARITY-BPA research program update.

Bisphenol A (BPA) is a chemical used in the production of numerous consumer products resulting in potential daily human exposure to this chemical. The FDA previously evaluated the body of BPA toxicology data and determined that BPA is safe at current exposure levels. Although consistent with the assessment of some other regulatory agencies around the world, this determination of BPA safety continues to be debated in scientific and popular publications, resulting in conflicting messages to the public. Thus, the National Toxicology Program (NTP), National Institute of Environmental Health Sciences (NIEHS), and U.S. Food and Drug Administration (FDA) developed a consortium-based research program to link more effectively a variety of hypothesis-based research investigations and guideline-compliant safety testing with BPA. This collaboration is known as the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA). This paper provides a detailed description of the conduct of the study and a midterm update on progress of the CLARITY-BPA research program.

Follow-up to genome-wide linkage and admixture mapping studies implicates components of the extracellular matrix in susceptibility to and size of uterine fibroids.

OBJECTIVE: To conduct a follow-up association mapping to independent genome-wide linkage and admixture mapping studies of uterine leiomyoma. DESIGN: Case-control, cross-sectional study. SETTING: Not applicable. PATIENT(S): A total of 1,045 premenopausal North American participants in the National Institute of Environmental Health Sciences Uterine Fibroid Study. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): We genotyped 2,772 single-nucleotide polymorphisms from candidate genes located in peaks of linkage (2q37, 3p21, 5p13, 10p11, 11p15, 12q14, and 17q25) or admixture linkage disequilibrium (2q37, 4p16.1, and 10q26) mapping and reported to have regulated expression in uterine fibroids. RESULT(S): We report significant associations of variant members of the collagen gene family with risk and tumor size, including missense variants in COL6A3 and COL13A, with replications in African American and European American study groups. Furthermore, the cell-matrix Rho GTPase-encoding ARHGAP26 gene, and MAN1C1, a gene encoding a Golgi mannosidase involved in the maturation of procollagens, emerged as new candidate uterine leiomyoma genes affecting both risk and tumor size. CONCLUSION(S): Our data converge onto a possible model of uterine leiomyoma pathogenesis resulting from altered regulation, maintenance, and/or renewal of the extracellular matrix.

Approaches and considerations for the assessment of immunotoxicity for environmental chemicals: a workshop summary.

As experience is gained with toxicology testing and as new assays and technologies are developed, it is critical for stakeholders to discuss opportunities to advance our overall testing strategies. To facilitate these discussions, a workshop on practices for assessing immunotoxicity for environmental chemicals was held with the goal of sharing perspectives on immunotoxicity testing strategies and experiences, developmental immunotoxicity (DIT), and integrated and alternative approaches to immunotoxicity testing. Experiences across the chemical and pharmaceutical industries suggested that standard toxicity studies, combined with triggered-based testing approaches, represent an effective and efficient approach to evaluate immunotoxic potential. Additionally, discussions on study design, critical windows, and new guideline approaches and experiences identified important factors to consider before initiating DIT evaluations including assay choice and timing and the impact of existing adult data. Participants agreed that integrating endpoints into standard repeat-dose studies should be considered for fulfilling any immunotoxicity testing requirements, while also maximizing information and reducing animal use. Participants also acknowledged that in vitro evaluation of immunosuppression is complex and may require the use of multiple assays that are still being developed. These workshop discussions should contribute to developing an effective but more resource and animal efficient approach for evaluating chemical immunotoxicity.

Pesticide exposure and self-reported incident depression among wives in the Agricultural Health Study.

BACKGROUND: Depression in women is a public health problem. Studies have reported positive associations between pesticides and depression, but few studies were prospective or presented results for women separately. OBJECTIVES: We evaluated associations between pesticide exposure and incident depression among farmers' wives in the Agricultural Health Study, a prospective cohort study in Iowa and North Carolina. METHODS: We used data on 16,893 wives who did not report physician-diagnosed depression at enrollment (1993-1997) and who completed a follow-up telephone interview (2005-2010). Among these wives, 1054 reported physician diagnoses of depression at follow-up. We collected information on potential confounders and on ever use of any pesticide, 11 functional and chemical classes of pesticides, and 50 specific pesticides by wives and their husbands via self-administered questionnaires at enrollment. We used inverse probability weighting to adjust for potential confounders and to account for possible selection bias induced by the death or loss of 10,639 wives during follow-up. We used log-binomial regression models to estimate risk ratios and 95% confidence intervals. RESULTS: After weighting for age at enrollment, state of residence, education level, diabetes diagnosis, and drop out, wives' incident depression was positively associated with diagnosed pesticide poisoning, but was not associated with ever using any pesticide. Use of individual pesticides or functional or chemical classes of pesticides was generally not associated with wives' depression. Among wives who never used pesticides, husbands' ever use of individual pesticides or functional or chemical classes of pesticides was generally not associated with wives' incident depression. CONCLUSIONS: Our study adds further evidence that high level pesticide exposure, such as pesticide poisoning, is associated with increased risk of depression and sets a lower bound on the level of exposure related to depression, thereby providing reassurance that the moderate levels of pesticide exposure experienced by farmers' wives likely do not increase risk.

Low dose effects and non-monotonic dose responses for endocrine active chemicals: science to practice workshop: workshop summary.

A workshop was held in Berlin September 12-14th 2012 to assess the state of the science of the data supporting low dose effects and non-monotonic dose responses ("low dose hypothesis") for chemicals with endocrine activity (endocrine disrupting chemicals or EDCs). This workshop consisted of lectures to present the current state of the science of EDC action and also the risk assessment process. These lectures were followed by breakout sessions to integrate scientists from various backgrounds to discuss in an open and unbiased manner the data supporting the "low dose hypothesis". While no consensus was reached the robust discussions were helpful to inform both basic scientists and risk assessors on all the issues. There were a number of important ideas developed to help continue the discussion and improve communication over the next few years.

A new approach to synergize academic and guideline-compliant research: the CLARITY-BPA research program.

Recently, medical research has seen a strong push toward translational research, or "bench to bedside" collaborations, that strive to enhance the utility of laboratory science for improving medical treatment. The success of that paradigm supports the potential application of the process to other fields, such as risk assessment. Close collaboration among academic, government, and industry scientists may enhance the translation of scientific findings to regulatory decision making. The National Toxicology Program (NTP), National Institute of Environmental Health Sciences (NIEHS), and U.S. Food and Drug Administration (FDA) developed a consortium-based research program to link more effectively academic and guideline-compliant research. An initial proof-of-concept collaboration, the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA), uses bisphenol A (BPA) as a test chemical. The CLARITY-BPA program combines a core perinatal guideline-compliant 2-year chronic toxicity study with mechanistic studies/endpoints conducted by academic investigators. Twelve extramural grantees were selected by NIEHS through an RFA-based initiative to participate in the overall study design and conduct disease-relevant investigations using tissues and animals from the core study. While the study is expected to contribute to our understanding of potential effects of BPA, it also has ramifications beyond this specific focus. Through CLARITY-BPA, NIEHS has established an unprecedented level of collaboration among extramural grantees and regulatory researchers. By drawing upon the strengths of academic and regulatory expertise and research approaches, CLARITY-BPA represents a potential new model for filling knowledge gaps, enhancing quality control, informing chemical risk assessment, and identifying new methods or endpoints for regulatory hazard assessments.

An approach for integrating toxicogenomic data in risk assessment: the dibutyl phthalate case study.

An approach for evaluating and integrating genomic data in chemical risk assessment was developed based on the lessons learned from performing a case study for the chemical dibutyl phthalate. A case study prototype approach was first developed in accordance with EPA guidance and recommendations of the scientific community. Dibutyl phthalate (DBP) was selected for the case study exercise. The scoping phase of the dibutyl phthalate case study was conducted by considering the available DBP genomic data, taken together with the entire data set, for whether they could inform various risk assessment aspects, such as toxicodynamics, toxicokinetics, and dose-response. A description of weighing the available dibutyl phthalate data set for utility in risk assessment provides an example for considering genomic data for future chemical assessments. As a result of conducting the scoping process, two questions--Do the DBP toxicogenomic data inform 1) the mechanisms or modes of action?, and 2) the interspecies differences in toxicodynamics?--were selected to focus the case study exercise. Principles of the general approach include considering the genomics data in conjunction with all other data to determine their ability to inform the various qualitative and/or quantitative aspects of risk assessment, and evaluating the relationship between the available genomic and toxicity outcome data with respect to study comparability and phenotypic anchoring. Based on experience from the DBP case study, recommendations and a general approach for integrating genomic data in chemical assessment were developed to advance the broader effort to utilize 21st century data in risk assessment.

Integrating mechanistic and polymorphism data to characterize human genetic susceptibility for environmental chemical risk assessment in the 21st century.

Response to environmental chemicals can vary widely among individuals and between population groups. In human health risk assessment, data on susceptibility can be utilized by deriving risk levels based on a study of a susceptible population and/or an uncertainty factor may be applied to account for the lack of information about susceptibility. Defining genetic susceptibility in response to environmental chemicals across human populations is an area of interest in the NAS' new paradigm of toxicity pathway-based risk assessment. Data from high-throughput/high content (HT/HC), including -omics (e.g., genomics, transcriptomics, proteomics, metabolomics) technologies, have been integral to the identification and characterization of drug target and disease loci, and have been successfully utilized to inform the mechanism of action for numerous environmental chemicals. Large-scale population genotyping studies may help to characterize levels of variability across human populations at identified target loci implicated in response to environmental chemicals. By combining mechanistic data for a given environmental chemical with next generation sequencing data that provides human population variation information, one can begin to characterize differential susceptibility due to genetic variability to environmental chemicals within and across genetically heterogeneous human populations. The integration of such data sources will be informative to human health risk assessment.

Use of genomic data in risk assessment case study: II. Evaluation of the dibutyl phthalate toxicogenomic data set.

An evaluation of the toxicogenomic data set for dibutyl phthalate (DBP) and male reproductive developmental effects was performed as part of a larger case study to test an approach for incorporating genomic data in risk assessment. The DBP toxicogenomic data set is composed of nine in vivo studies from the published literature that exposed rats to DBP during gestation and evaluated gene expression changes in testes or Wolffian ducts of male fetuses. The exercise focused on qualitative evaluation, based on a lack of available dose-response data, of the DBP toxicogenomic data set to postulate modes and mechanisms of action for the male reproductive developmental outcomes, which occur in the lower dose range. A weight-of-evidence evaluation was performed on the eight DBP toxicogenomic studies of the rat testis at the gene and pathway levels. The results showed relatively strong evidence of DBP-induced downregulation of genes in the steroidogenesis pathway and lipid/sterol/cholesterol transport pathway as well as effects on immediate early gene/growth/differentiation, transcription, peroxisome proliferator-activated receptor signaling and apoptosis pathways in the testis. Since two established modes of action (MOAs), reduced fetal testicular testosterone production and Insl3 gene expression, explain some but not all of the testis effects observed in rats after in utero DBP exposure, other MOAs are likely to be operative. A reanalysis of one DBP microarray study identified additional pathways within cell signaling, metabolism, hormone, disease, and cell adhesion biological processes. These putative new pathways may be associated with DBP effects on the testes that are currently unexplained. This case study on DBP identified data gaps and research needs for the use of toxicogenomic data in risk assessment. Furthermore, this study demonstrated an approach for evaluating toxicogenomic data in human health risk assessment that could be applied to future chemicals.

Public talks and science listens: a community-based participatory approach to characterizing environmental health risk perceptions and assessing recovery needs in the wake of hurricanes katrina and rita.

In response to the human health threats stemming from Hurricanes Katrina and Rita, inter-disciplinary working groups representing P30-funded Centers of the National Institute Environmental Health Sciences were created to assess threats posed by mold, harmful alga blooms, chemical toxicants, and various infectious agents at selected sites throughout the hurricane impact zone. Because of proximity to impacted areas, UTMB NIEHS Center in Environmental Toxicology was charged with coordinating direct community outreach efforts, primarily in south Louisiana. In early October 2005, UTMB/NIEHS Center Community Outreach and Education Core, in collaboration with outreach counterparts at The University of Texas MD Anderson Cancer Center @ Smithville TX/Center for Research in Environmental Disease sent two groups into southern Louisiana. One group used Lafourche Parish as a base to deliver humanitarian aid and assess local needs for additional supplies during local recovery/reclamation. A second group, ranging through New Iberia, New Orleans, Chalmette, rural Terrebonne, Lafourche and Jefferson Parishes and Baton Rouge met with community environmental leaders, emergency personnel and local citizens to 1) sample public risk perceptions, 2) evaluate the scope and reach of ongoing risk communication efforts, and 3) determine how the NIEHS could best collaborate with local groups in environmental health research and local capacity building efforts. This scoping survey identified specific information gaps limiting efficacy of risk communication, produced a community "wish list" of potential collaborative research projects. The project provided useful heuristics for disaster response and management planning and a platform for future collaborative efforts in environmental health assessment and risk communication with local advocacy groups in south Terrebonne-Lafourche parishes.