Broadening the Environmental Lens to Include Social and Structural Determinants of Women's Health Disparities.

BACKGROUND: 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. OBJECTIVES: 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. DISCUSSION: 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.

Looking for Proof in the Wrong Generation?

The article in this issue "Grandmaternal Perinatal Serum DDT in Relation to Granddaughter Early Menarche and Adult Obesity: Three Generations in the Child Health and Development Studies Cohort," by Cirillo and colleagues, is the first to report multigenerational health effects in granddaughters stemming from early life exposures to the pesticide o,p'-DDT in grandmothers. Health effects associated with F0 environmental chemical exposures in multiple generations have been reported in rodent studies, but not in humans. The striking finding in this body of work by Cohn and her colleagues is that the granddaughters were never directly exposed to o,p'-DDT-only their grandmothers were, potentially when they were adolescents. The increased rise of obesity and early menarche due to o,p'-DDT exposures generations earlier may help explain why it has been so difficult to describe environmental contributors of disease. Have we been looking for exposures in the wrong generation?See related article by Cirillo et al., p. 1480.

Environmental Factors Involved in Maternal Morbidity and Mortality.

Nongenetic, environmental factors contribute to maternal morbidity and mortality through chemical exposures via air, water, soil, food, and consumer products. Pregnancy represents a particularly sensitive window of susceptibility during which physiological changes to every major organ system increase sensitivity to chemicals that can impact a woman's long-term health. Nonchemical stressors, such as low socioeconomic status, may exacerbate the effects of chemical exposures on maternal health. Racial/ethnic minorities are exposed disproportionately to both chemicals and nonchemical stressors, which likely contribute to the observed health disparities for maternal morbidities and mortality. Epidemiological studies linking exposures to adverse maternal health outcomes underscore the importance of environmental health impacts, and mechanistic studies in model systems reveal how chemicals perturb biological pathways and processes. Environmental stressors are associated with a variety of immediate maternal health impacts, including hypertensive disorders of pregnancy, fibroids, and infertility, as well as long-term maternal health impacts, such as higher risk of breast cancer and metabolic disorders. Identifying and reducing a pregnant woman's environmental exposures is not only beneficial to her offspring but also important to preserve her short- and long-term health.

Human and animal evidence of potential transgenerational inheritance of health effects: An evidence map and state-of-the-science evaluation.

BACKGROUND: An increasing number of reports suggest early life exposures result in adverse effects in offspring who were never directly exposed; this phenomenon is termed "transgenerational inheritance." Given concern for public health implications for potential effects of exposures transmitted to subsequent generations, it is critical to determine how widespread and robust this phenomenon is and to identify the range of exposures and possible outcomes. OBJECTIVES: This scoping report examines the evidence for transgenerational inheritance associated with exposure to a wide range of stressors in humans and animals to identify areas of consistency, uncertainty, data gaps, and to evaluate general risk of bias issues for the transgenerational study design. METHODS: A protocol was developed to collect and categorize the literature into a systematic evidence map for transgenerational inheritance by health effects, exposures, and evidence streams following the Office of Health Assessment and Translation (OHAT) approach for conducting literature-based health assessments. RESULTS: A PubMed search yielded 63,758 unique records from which 257 relevant studies were identified and categorized into a systematic evidence map by evidence streams (46 human and 211 animal), broad health effect categories, and exposures. Data extracted from the individual studies are available in the Health Assessment Workspace Collaborative (HAWC) program. There are relatively few bodies of evidence where multiple studies evaluated the same exposure and the same or similar outcomes. Studies evaluated for risk of bias generally had multiple issues in design or conduct. CONCLUSIONS: The evidence mapping illustrated that risk of bias, few studies, and heterogeneity in exposures and endpoints examined present serious limitations to available bodies of evidence for assessing transgenerational effects. Targeted research is suggested to addressed inconsistencies and risk of bias issues identified, and thereby establish more robust bodies of evidence to critically assess transgenerational effects - particularly by adding data on exposure-outcome pairs where there is some evidence (i.e., reproductive, metabolic, and neurological effects).

Systematic review of community health impacts of mountaintop removal mining.

BACKGROUND: The objective of this evaluation is to understand the human health impacts of mountaintop removal (MTR) mining, the major method of coal mining in and around Central Appalachia. MTR mining impacts the air, water, and soil and raises concerns about potential adverse health effects in neighboring communities; exposures associated with MTR mining include particulate matter (PM), polycyclic aromatic hydrocarbons (PAHs), metals, hydrogen sulfide, and other recognized harmful substances. METHODS: A systematic review was conducted of published studies of MTR mining and community health, occupational studies of MTR mining, and any available animal and in vitro experimental studies investigating the effects of exposures to MTR-mining-related chemical mixtures. Six databases (Embase, PsycINFO, PubMed, Scopus, Toxline, and Web of Science) were searched with customized terms, and no restrictions on publication year or language, through October 27, 2016. The eligibility criteria included all human population studies and animal models of human health, direct and indirect measures of MTR-mining exposure, any health-related effect or change in physiological response, and any study design type. Risk of bias was assessed for observational and experimental studies using an approach developed by the National Toxicology Program (NTP) Office of Health Assessment and Translation (OHAT). To provide context for these health effects, a summary of the exposure literature is included that focuses on describing findings for outdoor air, indoor air, and drinking water. RESULTS: From a literature search capturing 3088 studies, 33 human studies (29 community, four occupational), four experimental studies (two in rat, one in vitro and in mice, one in C. elegans), and 58 MTR mining exposure studies were identified. A number of health findings were reported in observational human studies, including cardiopulmonary effects, mortality, and birth defects. However, concerns for risk of bias were identified, especially with respect to exposure characterization, accounting for confounding variables (such as socioeconomic status), and methods used to assess health outcomes. Typically, exposure was assessed by proximity of residence or hospital to coal mining or production level at the county level. In addition, assessing the consistency of findings was challenging because separate publications likely included overlapping case and comparison groups. For example, 11 studies of mortality were conducted with most reporting higher rates associated with coal mining, but many of these relied on the same national datasets and were unable to consider individual-level contributors to mortality such as poor socioeconomic status or smoking. Two studies of adult rats reported impaired microvascular and cardiac mitochondrial function after intratracheal exposure to PM from MTR-mining sites. Exposures associated with MTR mining included reports of PM levels that sometimes exceeded Environmental Protection Agency (EPA) standards; higher levels of dust, trace metals, hydrogen sulfide gas; and a report of increased public drinking water violations. DISCUSSION: This systematic review could not reach conclusions on community health effects of MTR mining because of the strong potential for bias in the current body of human literature. Improved characterization of exposures by future community health studies and further study of the effects of MTR mining chemical mixtures in experimental models will be critical to determining health risks of MTR mining to communities. Without such work, uncertainty will remain regarding the impact of these practices on the health of the people who breathe the air and drink the water affected by MTR mining.

Effects of Neonicotinoid Pesticide Exposure on Human Health: A Systematic Review.

BACKGROUND: Numerous studies have identified detectable levels of neonicotinoids (neonics) in the environment, adverse effects of neonics in many species, including mammals, and pathways through which human exposure to neonics could occur, yet little is known about the human health effects of neonic exposure. OBJECTIVE: In this systematic review, we sought to identify human population studies on the health effects of neonics. METHODS: Studies published in English between 2005 and 2015 were searched using PubMed, Scopus, and Web of Science databases. No restrictions were placed on the type of health outcome assessed. Risk of bias was assessed using guidance developed by the National Toxicology Program's Office of Health Assessment and Translation. RESULTS: Eight studies investigating the human health effects of exposure to neonics were identified. Four examined acute exposure: Three neonic poisoning studies reported two fatalities (n = 1,280 cases) and an occupational exposure study of 19 forestry workers reported no adverse effects. Four general population studies reported associations between chronic neonic exposure and adverse developmental or neurological outcomes, including tetralogy of Fallot (AOR 2.4, 95% CI: 1.1, 5.4), anencephaly (AOR 2.9, 95% CI: 1.0, 8.2), autism spectrum disorder [AOR 1.3, 95% credible interval (CrI): 0.78, 2.2], and a symptom cluster including memory loss and finger tremor (OR 14, 95% CI: 3.5, 57). Reported odds ratios were based on exposed compared to unexposed groups. CONCLUSIONS: The studies conducted to date were limited in number with suggestive but methodologically weak findings related to chronic exposure. Given the wide-scale use of neonics, more studies are needed to fully understand their effects on human health. Citation: Cimino AM, Boyles AL, Thayer KA, Perry MJ. 2017. Effects of neonicotinoid pesticide exposure on human health: a systematic review. Environ Health Perspect 125:155-162; http://dx.doi.org/10.1289/EHP515.

Safe use of high intakes of folic acid: research challenges and paths forward.

Adequate folic acid intake is an effective dietary-based prevention tool for reducing the risk of neural tube defects. Achieving adequate intake for the prevention of neural tube defects frequently requires the consumption of foods fortified with folic acid and/or the use of folic acid-containing dietary supplements. To date, research on the potential for adverse effects of high intakes of folic acid has been limited. Without such research, it is difficult to define a value for high intake. In May 2015, an expert panel was tasked with examining the available scientific literature and making research recommendations within 4 general categories of potential folate-related adverse health effects: cancer, cognition in conjunction with vitamin B12 deficiency, hypersensitivity-related outcomes, and thyroid and diabetes-related disorders. This article summarizes the expert panel's conclusions, outlines the challenges faced when reviewing the literature, and examines some of the panel's recommendations for research.

How credible are the study results? Evaluating and applying internal validity tools to literature-based assessments of environmental health hazards.

Environmental health hazard assessments are routinely relied upon for public health decision-making. The evidence base used in these assessments is typically developed from a collection of diverse sources of information of varying quality. It is critical that literature-based evaluations consider the credibility of individual studies used to reach conclusions through consistent, transparent and accepted methods. Systematic review procedures address study credibility by assessing internal validity or "risk of bias" - the assessment of whether the design and conduct of a study compromised the credibility of the link between exposure/intervention and outcome. This paper describes the commonalities and differences in risk-of-bias methods developed or used by five groups that conduct or provide methodological input for performing environmental health hazard assessments: the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group, the Navigation Guide, the National Toxicology Program's (NTP) Office of Health Assessment and Translation (OHAT) and Office of the Report on Carcinogens (ORoC), and the Integrated Risk Information System of the U.S. Environmental Protection Agency (EPA-IRIS). Each of these groups have been developing and applying rigorous assessment methods for integrating across a heterogeneous collection of human and animal studies to inform conclusions on potential environmental health hazards. There is substantial consistency across the groups in the consideration of risk-of-bias issues or "domains" for assessing observational human studies. There is a similar overlap in terms of domains addressed for animal studies; however, the groups differ in the relative emphasis placed on different aspects of risk of bias. Future directions for the continued harmonization and improvement of these methods are also discussed.

Systematic review and evidence integration for literature-based environmental health science assessments.

BACKGROUND: Systematic-review methodologies provide objectivity and transparency to the process of collecting and synthesizing scientific evidence in reaching conclusions on specific research questions. There is increasing interest in applying these procedures to address environmental health questions. OBJECTIVES: The goal was to develop a systematic-review framework to address environmental health questions by extending approaches developed for clinical medicine to handle the breadth of data relevant to environmental health sciences (e.g., human, animal, and mechanistic studies). METHODS: The Office of Health Assessment and Translation (OHAT) adapted guidance from authorities on systematic-review and sought advice during development of the OHAT Approach through consultation with technical experts in systematic review and human health assessments, as well as scientific advisory groups and the public. The method was refined by considering expert and public comments and through application to case studies. RESULTS AND DISCUSSION: Here we present a seven-step framework for systematic review and evidence integration for reaching hazard identification conclusions: 1) problem formulation and protocol development, 2) search for and select studies for inclusion, 3) extract data from studies, 4) assess the quality or risk of bias of individual studies, 5) rate the confidence in the body of evidence, 6) translate the confidence ratings into levels of evidence, and 7) integrate the information from different evidence streams (human, animal, and "other relevant data" including mechanistic or in vitro studies) to develop hazard identification conclusions. CONCLUSION: The principles of systematic review can be successfully applied to environmental health questions to provide greater objectivity and transparency to the process of developing conclusions.

Evaluation of the association between persistent organic pollutants (POPs) and diabetes in epidemiological studies: a national toxicology program workshop review.

BACKGROUND: Diabetes is a major threat to public health in the United States and worldwide. Understanding the role of environmental chemicals in the development or progression of diabetes is an emerging issue in environmental health. OBJECTIVE: We assessed the epidemiologic literature for evidence of associations between persistent organic pollutants (POPs) and type 2 diabetes. METHODS: Using a PubMed search and reference lists from relevant studies or review articles, we identified 72 epidemiological studies that investigated associations of persistent organic pollutants (POPs) with diabetes. We evaluated these studies for consistency, strengths and weaknesses of study design (including power and statistical methods), clinical diagnosis, exposure assessment, study population characteristics, and identification of data gaps and areas for future research. CONCLUSIONS: Heterogeneity of the studies precluded conducting a meta-analysis, but the overall evidence is sufficient for a positive association of some organochlorine POPs with type 2 diabetes. Collectively, these data are not sufficient to establish causality. Initial data mining revealed that the strongest positive correlation of diabetes with POPs occurred with organochlorine compounds, such as trans-nonachlor, dichlorodiphenyldichloroethylene (DDE), polychlorinated biphenyls (PCBs), and dioxins and dioxin-like chemicals. There is less indication of an association between other nonorganochlorine POPs, such as perfluoroalkyl acids and brominated compounds, and type 2 diabetes. Experimental data are needed to confirm the causality of these POPs, which will shed new light on the pathogenesis of diabetes. This new information should be considered by governmental bodies involved in the regulation of environmental contaminants.

Maternal alcohol consumption, alcohol metabolism genes, and the risk of oral clefts: a population-based case-control study in Norway, 1996-2001.

Heavy maternal alcohol consumption during early pregnancy increases the risk of oral clefts, but little is known about how genetic variation in alcohol metabolism affects this association. Variants in the alcohol dehydrogenase 1C (ADH1C) gene may modify the association between alcohol and clefts. In a population-based case-control study carried out in Norway (1996-2001), the authors examined the association between maternal alcohol consumption and risk of oral clefts according to mother and infant ADH1C haplotypes encoding fast or slow alcohol-metabolizing phenotypes. Subjects were 483 infants with oral cleft malformations and 503 control infants and their mothers, randomly selected from all other livebirths taking place during the same period. Mothers who consumed 5 or more alcoholic drinks per sitting during the first trimester of pregnancy had an elevated risk of oral cleft in their offspring (odds ratio (OR) = 2.6, 95% confidence interval (CI): 1.4, 4.7). This increased risk was evident only in mothers or children who carried the ADH1C haplotype associated with reduced alcohol metabolism (OR= 3.0, 95% CI: 1.4, 6.8). There was no evidence of alcohol-related risk when both mother and infant carried only the rapid-metabolism ADH1C variant (OR = 0.9, 95% CI: 0.2, 4.1). The teratogenic effect of alcohol may depend on the genetic capacity of the mother and fetus to metabolize alcohol.

Maternal genes and facial clefts in offspring: a comprehensive search for genetic associations in two population-based cleft studies from Scandinavia.

BACKGROUND: Fetal conditions can in principle be affected by the mother's genotype working through the prenatal environment. METHODOLOGY/PRINCIPAL FINDINGS: Genotypes for 1536 SNPs in 357 cleft candidate genes were available from a previous analysis in which we focused on fetal gene effects. After data-cleaning, genotypes for 1315 SNPs in 334 autosomal genes were available for the current analysis of maternal gene effects. Two complementary statistical methods, TRIMM and HAPLIN, were used to detect multi-marker effects in population-based samples from Norway (562 case-parent and 592 control-parent triads) and Denmark (235 case-parent triads). We analyzed isolated cleft lip with or without cleft palate (iCL/P) and isolated cleft palate only (iCP) separately and assessed replication by looking for genes detected in both populations by both methods. In iCL/P, neither TRIMM nor HAPLIN detected more genes than expected by chance alone; furthermore, the selected genes were not replicated across the two methods. In iCP, however, FLNB was identified by both methods in both populations. Although HIC1 and ZNF189 did not fully satisfy our stringency criterion for replication, they were strongly associated with iCP in TRIMM analyses of the Norwegian triads. CONCLUSION/SIGNIFICANCE: Except for FLNB, HIC1 and ZNF189, maternal genes did not appear to influence the risk of clefting in our data. This is consistent with recent epidemiological findings showing no apparent difference between mother-to-offspring and father-to-offspring recurrence of clefts in these two populations. It is likely that fetal genes make the major genetic contribution to clefting risk in these populations, but we cannot rule out the possibility that maternal genes can affect risk through interactions with specific teratogens or fetal genes.

The quest for the elusive causative SNP.

El Kares et al. present evidence that fetal genetic variation in the 3' end of ALDH1A2 may influence nephrogenesis and blood retinoic acid levels. This may be correct, but only replication of this association, ideally accounting for both the fetal and the maternal genotypes, will provide a better understanding of the biology that underlies the association.

Genetic determinants of facial clefting: analysis of 357 candidate genes using two national cleft studies from Scandinavia.

BACKGROUND: Facial clefts are common birth defects with a strong genetic component. To identify fetal genetic risk factors for clefting, 1536 SNPs in 357 candidate genes were genotyped in two population-based samples from Scandinavia (Norway: 562 case-parent and 592 control-parent triads; Denmark: 235 case-parent triads). METHODOLOGY/PRINCIPAL FINDINGS: We used two complementary statistical methods, TRIMM and HAPLIN, to look for associations across these two national samples. TRIMM tests for association in each gene by using multi-SNP genotypes from case-parent triads directly without the need to infer haplotypes. HAPLIN on the other hand estimates the full haplotype distribution over a set of SNPs and estimates relative risks associated with each haplotype. For isolated cleft lip with or without cleft palate (I-CL/P), TRIMM and HAPLIN both identified significant associations with IRF6 and ADH1C in both populations, but only HAPLIN found an association with FGF12. For isolated cleft palate (I-CP), TRIMM found associations with ALX3, MKX, and PDGFC in both populations, but only the association with PDGFC was identified by HAPLIN. In addition, HAPLIN identified an association with ETV5 that was not detected by TRIMM. CONCLUSION/SIGNIFICANCE: Strong associations with seven genes were replicated in the Scandinavian samples and our approach effectively replicated the strongest previously known association in clefting--with IRF6. Based on two national cleft cohorts of similar ancestry, two robust statistical methods and a large panel of SNPs in the most promising cleft candidate genes to date, this study identified a previously unknown association with clefting for ADH1C and provides additional candidates and analytic approaches to advance the field.

Oral facial clefts and gene polymorphisms in metabolism of folate/one-carbon and vitamin A: a pathway-wide association study.

An increased risk of facial clefts has been observed among mothers with lower intake of folic acid or vitamin A around conception. We hypothesized that the risk of clefts may be further moderated by genes involved in metabolizing folate or vitamin A. We included 425 case-parent triads in which the child had either cleft lip with or without cleft palate (CL/P) or cleft palate only (CPO), and no other major defects. We analyzed 108 SNPs and one insertion in 29 genes involved in folate/one-carbon metabolism and 68 SNPs from 16 genes involved in vitamin A metabolism. Using the Triad Multi-Marker (TRIMM) approach we performed SNP, gene, chromosomal region, and pathway-wide association tests of child or maternal genetic effects for both CL/P and CPO. We stratified these analyses on maternal intake of folic acid or vitamin A during the periconceptional period. As expected with this high number of statistical tests, there were many associations with P-values<0.05; although there were fewer than predicted by chance alone. The strongest association in our data (between fetal FOLH1 and CPO, P=0.0008) is not in agreement with epidemiologic evidence that folic acid reduces the risk of CL/P in these data, not CPO. Despite strong evidence for genetic causes of oral facial clefts and the protective effects of maternal vitamins, we found no convincing indication that polymorphisms in these vitamin metabolism genes play an etiologic role.

Folate and one-carbon metabolism gene polymorphisms and their associations with oral facial clefts.

Folate metabolism plays a critical role in embryonic development. Prenatal folate supplementation reduces the risk of neural tube defects and probably oral facial clefts. Previous studies of related metabolic genes have associated polymorphisms in cystathionine-beta-synthase (CBS) and 5,10-methylenetetrahydrofolate reductase (MTHFR) with cleft risk. We explored associations between genes related to one-carbon metabolism and clefts in a Norwegian population-based study that included 362 families with cleft lip with or without cleft palate (CL/P) and 191 families with cleft palate only (CPO). We previously showed a 39% reduction in risk of CL/P with folic acid supplementation in this population. In the present study we genotyped 12 polymorphisms in nine genes related to one-carbon metabolism and looked for associations of clefting risk with fetal polymorphisms, maternal polymorphisms, as well as parent-of-origin effects, using combined likelihood-ratio tests (LRT). We also stratified by maternal periconceptional intake of folic acid (>400 microg) to explore gene-exposure interactions. We found a reduced risk of CL/P with mothers who carried the CBS C699T variant (rs234706); relative risk was 0.94 with one copy of the T allele (95% CI 0.63-1.4) and 0.50 (95% CI 0.26-0.96) with two copies (P = 0.008). We found no evidence of interaction of this variant with folate status. We saw no evidence of risk from the MTHFR C677T variant (rs1801133) either overall or after stratifying by maternal folate intake. No associations were found between any of the polymorphisms and CPO. Genetic variations in the nine metabolic genes examined here do not confer a substantial degree of risk for clefts.

Apolipoprotein E alleles and sensorineural hearing loss.

The purpose of this paper is to determine if a relationship exists between APOE alleles and nonsyndromic, sensorineural hearing loss (SNHL) in adults. APOE genotype was determined on DNA obtained from a sample of 89 subjects with nonsyndromic, adult onset SNHL. Median age was 64 years old, and 51 (57%) were males. Allele frequencies in the study population were compared to those in the general population. Subjects were divided into two groups, one by severity of hearing loss and another by severity of impairment of word recognition. Each group was stratified by severity, and allele frequencies were compared to the general population. The study found that the APOE allele epsilon 4 was less prevalent in the study population with SNHL than in the general population. No relationship was found between the epsilon 4 allele and severity of hearing loss or severity of impairment of word recognition. The study revealed that the APOE epsilon 4 allele was under-represented in the study sample as compared to the general population. Future studies associating the epsilon 4 allele with SNHL need to be population-based, longitudinal, or done in younger subjects.