Exposure range matters: considering non-linear associations in the meta-analysis of environmental pollutant exposure using examples of per- and polyfluoroalkyl substances and birth outcomes.

Meta-analysis is a powerful analytic method for summarizing effect estimates across studies. However, conventional meta-analysis often assumes a linear exposure-outcome relationship and does not account for variability over the exposure ranges. In this work, we first used simulation techniques to illustrate that the linear-based meta-analytical approach may result in oversimplistic effect estimation based on three plausible non-linear exposure-outcome curves (S-shape, inverted U-shape, and M-shape). We showed that subgroup meta-analysis that stratifies on exposure levels can investigate non-linearity and identify the consistency of effect magnitudes in these simulated examples. Next, we examined the heterogeneity of effect estimates across exposure ranges in two published linear-based meta-analyses of prenatal exposure to per- and polyfluoroalkyl substances (PFAS) on changes in mean birth weight or risk of preterm birth. The re-analysis found some varying effect sizes and potential heterogeneity when restricting to different PFAS exposure ranges, but findings were sensitive to the cut-off choices used to rank the exposure levels. Finally, we discussed methodological challenges and recommendations for detecting and interpreting potential non-linear associations in meta-analysis. Using meta-analysis without accounting for exposure range could contribute to literature inconsistency for exposure-induced health effects and impede evidence-based policymaking. Therefore, investigating result heterogeneity by exposure range is recommended.

Residential Proximity to Oil and Gas Development and Mental Health in a North American Preconception Cohort Study: 2013-2023.

Objectives. To evaluate associations between oil and gas development (OGD) and mental health using cross-sectional data from a preconception cohort study, Pregnancy Study Online. Methods. We analyzed baseline data from a prospective cohort of US and Canadian women aged 21 to 45 years who were attempting conception without fertility treatment (2013-2023). We developed residential proximity measures for active OGD during preconception, including distance from nearest site. At baseline, participants completed validated scales for perceived stress (10-item Perceived Stress Scale, PSS) and depressive symptoms (Major Depression Inventory, MDI) and reported psychotropic medication use. We used log-binomial regression and restricted cubic splines to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs). Results. Among 5725 participants across 37 states and provinces, residence at 2 km versus 20 to 50 km of active OGD was associated with moderate to high perceived stress (PSS ≥ 20 vs < 20: PR = 1.08; 95% CI = 0.98, 1.18), moderate to severe depressive symptoms (MDI ≥ 20 vs < 20: PR = 1.27; 95% CI = 1.11, 1.45), and psychotropic medication use (PR = 1.11; 95% CI = 0.97, 1.28). Conclusions. Among North American pregnancy planners, closer proximity to OGD was associated with adverse preconception mental health symptomatology. (Am J Public Health. 2024;114(9):923-934. https://doi.org/10.2105/AJPH.2024.307730).

Delineating Urbanicity and Rurality: Impact on Environmental Exposure Assessment.

Environmental exposures and their health impacts can vary substantially between urban and rural areas. However, different methods for classifying these areas could lead to inconsistencies in environmental exposure and health studies, which are often overlooked. We constructed different urban/rural classification systems based on multiple population-based (e.g., total population, population density, and commuting) and built-environment-based (e.g., nighttime light intensity, building density, road density, distance to urban centers, point of interest density, and urban area coverage) indicators and various classification schemes. These classification systems were applied to Virginia and West Virginia, United States. We compared differences in urban/rural spatial patterns, demographic compositions, and exposures of particulate matter (PM2.5), greenspace, and land surface temperature using these urban/rural classification systems to understand their impacts on environmental exposure and health research. Our findings reveal clear differences in spatial patterns and demographic compositions across various systems. We also observed that different systems can lead to changes in the magnitude and direction of urban/rural disparities in environmental exposure assessment. Addressing the complexities in delineating urbanicity and rurality may include careful consideration of classification systems to reflect those aspects of urbanicity and rurality that are relevant to the research question or the use of multiple, complementary systems.

Urinary phenol concentrations and fecundability and early pregnancy loss.

STUDY QUESTION: Are urinary phenol concentrations of methylparaben, propylparaben, butylparaben, triclosan, benzophenone-3, 2,4-dichlorophenol or 2,5-dichlorophenol associated with fecundability and early pregnancy loss? SUMMARY ANSWER: 2,5-dichlorophenol concentrations were associated with an increased odds of early pregnancy loss, and higher concentrations of butylparaben and triclosan were associated with an increase in fecundability. WHAT IS KNOWN ALREADY: Phenols are chemicals with endocrine-disrupting potential found in everyday products. Despite plausible mechanisms of phenol reproductive toxicity, there are inconsistent results across few epidemiologic studies examining phenol exposure and reproductive function in non-fertility treatment populations. STUDY DESIGN, SIZE, DURATION: Specimens and data were from the North Carolina Early Pregnancy Study prospective cohort of 221 women attempting to conceive naturally from 1982 to 1986. This analysis includes data from 221 participants across 706 menstrual cycles, with 135 live births, 15 clinical miscarriages and 48 early pregnancy losses (before 42 days after the last menstrual period). PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants collected daily first-morning urine specimens. For each menstrual cycle, aliquots from three daily specimens across the cycle were pooled within individuals and analyzed for phenol concentrations. To assess sample repeatability, we calculated intraclass correlation coefficients (ICCs) for each phenol. We evaluated associations between phenol concentrations from pooled samples and time to pregnancy using discrete-time logistic regression and generalized estimating equations (GEE), and early pregnancy loss using multivariable logistic regression and GEE. MAIN RESULTS AND THE ROLE OF CHANCE: ICCs for within-person variability across menstrual cycles in pooled phenol concentrations ranged from 0.42 to 0.75. There was an increased odds of early pregnancy loss with 2,5-dichlorophenol concentrations although the CIs were wide (5th vs 1st quintile odds ratio (OR): 4.79; 95% CI: 1.06, 21.59). There was an increased per-cycle odds of conception at higher concentrations of butylparaben (OR: 1.62; 95% CI: 1.08, 2.44) and triclosan (OR: 1.49; 95% CI: 0.99, 2.26) compared to non-detectable concentrations. No associations were observed between these endpoints and concentrations of other phenols examined. LIMITATIONS, REASONS FOR CAUTION: Limitations include the absence of phenol measurements for male partners and a limited sample size, especially for the outcome of early pregnancy loss, which reduced our power to detect associations. WIDER IMPLICATIONS OF THE FINDINGS: This study is the first to use repeated pooled measures to summarize phenol exposure and the first to investigate associations with fecundability and early pregnancy loss. Within-person phenol concentration variability underscores the importance of collecting repeated samples for future studies. Exposure misclassification could contribute to differences between the findings of this study and those of other studies, all of which used one urine sample to assess phenol exposure. This study also contributes to the limited literature probing potential associations between environmental exposures and early pregnancy loss, which is a challenging outcome to study as it typically occurs before a pregnancy is clinically recognized. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health (award number F31ES030594), the Intramural Research Program of the National Institutes of Health, the National Institute of Environmental Health Sciences (project numbers ES103333 and ES103086) and a doctoral fellowship at the Yale School of Public Health. The authors declare they have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Investigation of Sources of Fluorinated Compounds in Private Water Supplies in an Oil and Gas-Producing Region of Northern West Virginia.

Per- and polyfluoroalkyl substances (PFASs) are a class of toxic organic compounds that have been widely used in consumer applications and industrial activities, including oil and gas production. We measured PFAS concentrations in 45 private wells and 8 surface water sources in the oil and gas-producing Doddridge, Marshall, Ritchie, Tyler, and Wetzel Counties of northern West Virginia and investigated relationships between potential PFAS sources and drinking water receptors. All surface water samples and 60% of the water wells sampled contained quantifiable levels of at least one targeted PFAS compound, and four wells (8%) had concentrations above the proposed maximum contaminant level (MCL) for perfluorooctanoic acid (PFOA). Individual concentrations of PFOA and perfluorobutanesulfonic acid exceeded those measured in finished public water supplies. Total targeted PFAS concentrations ranged from nondetect to 36.8 ng/L, with surface water concentrations averaging 4-fold greater than groundwater. Semiquantitative, nontargeted analysis showed concentrations of emergent PFAS that were potentially higher than targeted PFAS. Results from a multivariate latent variable hierarchical Bayesian model were combined with insights from analyses of groundwater chemistry, topographic characteristics, and proximity to potential PFAS point sources to elucidate predictors of PFAS concentrations in private wells. Model results reveal (i) an increased vulnerability to contamination in upland recharge zones, (ii) geochemical controls on PFAS transport likely driven by adsorption, and (iii) possible influence from nearby point sources.

Conventional Fossil Fuel Extraction, Associated Biogeochemical Processes, and Topography Influence Methane Groundwater Concentrations in Appalachia.

The production of fossil fuels, including oil, gas, and coal, retains a dominant share in US energy production and serves as a major anthropogenic source of methane, a greenhouse gas with a high warming potential. In addition to directly emitting methane into the air, fossil fuel production can release methane into groundwater, and that methane may eventually reach the atmosphere. In this study, we collected 311 water samples from an unconventional oil and gas (UOG) production region in Pennsylvania and an oil and gas (O&G) and coal production region across Ohio and West Virginia. Methane concentration was negatively correlated to distance to the nearest O&G well in the second region, but such a correlation was shown to be driven by topography as a confounding variable. Furthermore, sulfate concentration was negatively correlated with methane concentration and with distance to coal mining in the second region, and these correlations were robust even when considering topography. We hypothesized that coal mining enriched sulfate in groundwater, which in turn inhibited methanogenesis and enhanced microbial methane oxidation. Thus, this study highlights the complex interplay of multiple factors in shaping groundwater methane concentrations, including biogeochemical conversion, topography, and conventional fossil extraction.

Per- and polyfluoroalkyl substances and sleep health in U.S. adults, NHANES 2005-2014.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals that induce oxidative inflammatory responses and disrupt the endocrine and central nervous systems, all of which can influence sleep. OBJECTIVE: To investigate the association between PFAS exposure and sleep health measures in U.S. adults. METHODS: We analyzed serum concentration data of four PFAS [perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA)] reported for 8913 adults in NHANES 2005-2014. Sleep outcomes, including trouble sleeping, having a diagnosis of sleep disorder, and recent daily sleep duration classified as insufficient or excessive sleep (<6 or >9 h/day) were examined. Weighted logistic regression was used to estimate the association between the sleep outcomes and each PFAS modeled continuously (log2) or in exposure tertiles. We applied quantile g-computation to estimate the effect of the four PFAS as a mixture on the sleep outcomes. We conducted a quantitative bias analysis to assess the potential influence of self-selection and uncontrolled confounding. RESULTS: We observed some inverse associations between serum PFAS and trouble sleeping or sleep disorder, which were more consistent for PFOS (e.g., per log2-PFOS (ng/ml) and trouble sleeping OR = 0.93, 95%CI: 0.89, 0.98; sleep disorder OR = 0.89, 95%CI: 0.83, 0.95). Per quartile increase of the PFAS mixture was inversely associated with trouble sleeping and sleep disorder. No consistent associations were found for sleep duration across analyses. Our bias analysis suggests that the finding on sleep disorder could be explained by a moderate level of self-selection and negative confounding effects. CONCLUSIONS: We found no evidence to suggest exposure to four legacy PFAS worsened self-reported sleep health among U.S. adults. While some inverse associations between specific PFAS and sleep disorder were observed, self-selection and uncontrolled confounding biases may play a role in these findings.

Residential proximity to unconventional oil and gas development and birth defects in Ohio.

BACKGROUND: Chemicals used or emitted by unconventional oil and gas development (UOGD) include reproductive/developmental toxicants. Associations between UOGD and certain birth defects were reported in a few studies, with none conducted in Ohio, which experienced a thirty-fold increase in natural gas production between 2010 and 2020. METHODS: We conducted a registry-based cohort study of 965,236 live births in Ohio from 2010 to 2017. Birth defects were identified in 4653 individuals using state birth records and a state surveillance system. We assigned UOGD exposure based on maternal residential proximity at birth to active UOG wells and a metric specific to the drinking-water exposure pathway that identified UOG wells hydrologically connected to a residence ("upgradient UOG wells"). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for all structural birth defects combined and specific birth defect types using binary exposure metrics (presence/absence of any UOG well and presence/absence of an upgradient UOG well within 10 km), adjusting for confounders. Additionally, we conducted analyses stratified by urbanicity, infant sex, and social vulnerability. RESULTS: The odds of any structural defect were 1.13 times higher in children born to mothers living within 10 km of UOGD than those born to unexposed mothers (95%CI: 0.98-1.30). Odds were elevated for neural tube defects (OR: 1.57, 95%CI: 1.12-2.19), limb reduction defects (OR: 1.99, 95%CI: 1.18-3.35), and spina bifida (OR 1.93; 95%CI 1.25-2.98). Hypospadias (males only) was inversely related to UOGD exposure (OR: 0.62, 95%CI: 0.43-0.91). Odds of any structural defect were greater in magnitude but less precise in analyses using the hydrological-specific metric (OR: 1.30; 95%CI: 0.85-1.90), in areas with high social vulnerability (OR: 1.27, 95%CI: 0.99-1.60), and among female offspring (OR: 1.28, 95%CI: 1.06-1.53). CONCLUSIONS: Our results suggest a positive association between UOGD and certain birth defects, and findings for neural tube defects corroborate results from prior studies.

Where Is Air Quality Improving, and Who Benefits? A Study of PM2.5 and Ozone Over 15 Years.

In the United States, concentrations of criteria air pollutants have declined in recent decades. Questions remain regarding whether improvements in air quality are equitably distributed across subpopulations. We assessed spatial variability and temporal trends in concentrations of particulate matter with an aerodynamic diameter ≤2.5 µm (PM2.5) and ozone (O3) across North Carolina from 2002-2016, and associations with community characteristics. Estimated daily PM2.5 and O3 concentrations at 2010 Census tracts were obtained from the Fused Air Quality Surface Using Downscaling archive and averaged to create tract-level annual PM2.5 and O3 estimates. We calculated tract-level measures of: racial isolation of non-Hispanic Black individuals, educational isolation of non-college educated individuals, the neighborhood deprivation index (NDI), and percentage of the population in urban areas. We fitted hierarchical Bayesian space-time models to estimate baseline concentrations of and time trends in PM2.5 and O3 for each tract, accounting for spatial between-tract correlation. Concentrations of PM2.5 and O3 declined by 6.4 µg/m3 and 13.5 ppb, respectively. Tracts with lower educational isolation and higher urbanicity had higher PM2.5 and more pronounced declines in PM2.5. Racial isolation was associated with higher PM2.5 but not with the rate of decline in PM2.5. Despite declines in pollutant concentrations, over time, disparities in exposure increased for racially and educationally isolated communities.

Regional Scale Assessment of Shallow Groundwater Vulnerability to Contamination from Unconventional Hydrocarbon Extraction.

Concerns over unconventional oil and gas (UOG) development persist, especially in rural communities that rely on shallow groundwater for drinking and other domestic purposes. Given the continued expansion of the industry, regional (vs local scale) models are needed to characterize groundwater contamination risks faced by the increasing proportion of the population residing in areas that accommodate UOG extraction. In this paper, we evaluate groundwater vulnerability to contamination from surface spills and shallow subsurface leakage of UOG wells within a 104,000 km2 region in the Appalachian Basin, northeastern USA. We test a computationally efficient ensemble approach for simulating groundwater flow and contaminant transport processes to quantify vulnerability with high resolution. We also examine metamodels, or machine learning models trained to emulate physically based models, and investigate their spatial transferability. We identify predictors describing proximity to UOG, hydrology, and topography that are important for metamodels to make accurate vulnerability predictions outside their training regions. Using our approach, we estimate that 21,000-30,000 individuals in our study area are dependent on domestic water wells that are vulnerable to contamination from UOG activities. Our novel modeling framework could be used to guide groundwater monitoring, provide information for public health studies, and assess environmental justice issues.

Assessing Unconventional Oil and Gas Exposure in the Appalachian Basin: Comparison of Exposure Surrogates and Residential Drinking Water Measurements.

Health studies report associations between metrics of residential proximity to unconventional oil and gas (UOG) development and adverse health endpoints. We investigated whether exposure through household groundwater is captured by existing metrics and a newly developed metric incorporating groundwater flow paths. We compared metrics with detection frequencies/concentrations of 64 organic and inorganic UOG-related chemicals/groups in residential groundwater from 255 homes (Pennsylvania n = 94 and Ohio n = 161). Twenty-seven chemicals were detected in ≥20% of water samples at concentrations generally below U.S. Environmental Protection Agency standards. In Pennsylvania, two organic chemicals/groups had reduced odds of detection with increasing distance to the nearest well: 1,2-dichloroethene and benzene (Odds Ratio [OR]: 0.46, 95% confidence interval [CI]: 0.23-0.93) and m- and p-xylene (OR: 0.28, 95% CI: 0.10-0.80); results were consistent across metrics. In Ohio, the odds of detecting toluene increased with increasing distance to the nearest well (OR: 1.48, 95% CI: 1.12-1.95), also consistent across metrics. Correlations between inorganic chemicals and metrics were limited (all |ρ| ≤ 0.28). Limited associations between metrics and chemicals may indicate that UOG-related water contamination occurs rarely/episodically, more complex metrics may be needed to capture drinking water exposure, and/or spatial metrics in health studies may better reflect exposure to other stressors.

Observed vs. self-reported agricultural activities: Evaluating 24-hr recall in a pilot study.

Few studies have evaluated the validity of self-report of work activities because of challenges in obtaining objective measures. In this study, farmers' recall of the previous day's agricultural activities was compared to activities observed by field staff during air monitoring. Recall was assessed in 32 farmers from the Biomarkers of Exposure and Effect in Agriculture Study, a subset of a prospective cohort study. The farmers participated in 56 visits that comprised air monitoring the day before an interview. The answers for 14 agricultural activities were compared to activities observed by field staff during air monitoring (median duration 380 min, range 129-486). For each task, evaluated as yes/no, overall agreement, sensitivity, specificity, and kappa were calculated. Median prevalence of the 14 activities was 8% from observation and 13% from participants (range: 2-54%). Agreement was generally good to perfect, with a median overall agreement of 95% (range: 89-100%), median sensitivity of 84% (50-100%), median specificity of 95% (88-100%), and median kappa of 0.65 (0.31-1.0). Reasons for disagreement included activities occurring when the field staff was not present (i.e., milking cows), unclear timing notes that made it difficult to determine whether the activity occurred the day of and/or day before the interview, definition issues (i.e., participant included hauling in the definition of harvesting), and difficulty in observing details of an activity (i.e., whether hay was moldy). This study provides support for accurate participant recall the day after activities.

Groundwater Methane in Northeastern Pennsylvania Attributable to Thermogenic Sources and Hydrogeomorphologic Migration Pathways.

Conflicting evidence exists as to whether or not unconventional oil and gas (UOG) development has enhanced methane transport into groundwater aquifers over the past 15 years. In this study, recent groundwater samples were collected from 90 domestic wells and 4 springs in Northeastern Pennsylvania located above the Marcellus Shale after more than a decade of UOG development. No statistically significant correlations were observed between the groundwater methane level and various UOG geospatial metrics, including proximity to UOG wells and well violations, as well as the number of UOG wells and violations within particular radii. The δ13C and methane-to-higher chain hydrocarbon signatures suggested that the elevated methane levels were not attributable to UOG development nor could they be explained by using simple biogenic-thermogenic end-member mixing models. Instead, groundwater methane levels were significantly correlated with geochemical water type and topographical location. Comparing a subset of contemporary methane measurements to their co-located pre-drilling records (n = 64 at 49 distinct locations) did not indicate systematic increases in methane concentration but did reveal several cases of elevated concentration (n = 12) across a spectrum of topographies. Multiple lines of evidence suggested that the high-concentration groundwater methane could have originated from shallow thermogenic methane that migrated upward into groundwater aquifers with Appalachian Basin brine.

Exposure to polychlorinated biphenyls and organochlorine pesticides and thyroid cancer in connecticut women.

BACKGROUND: Thyroid cancer incidence has increased substantially over the past decades, and environmental risk factors have been suggested to play a role. Polychlorinated biphenyls (PCB) and organochlorine pesticides (OCP) are established thyroid hormone disruptors, but their relationship to thyroid cancer is not known. METHODS: We investigated the relationship between serum PCB and OCP concentrations and papillary thyroid cancer (PTC) in 250 incident female PTC cases and 250 female controls frequency-matched on age, all residing in Connecticut. Interviews and serum samples were collected from 2010 to 2013. Samples were analyzed for 32 different chemicals using gas chromatography with isotope dilution high resolution mass spectrometry. We calculated odds ratios (OR) and 95% confidence intervals (CI) using single pollutant logistic regression models for concentrations (per interquartile range) of individual PCB/OCP and summed groups of structurally or biologically similar PCB/OCP, adjusted for education, family history of cancer, alcohol consumption, age, and body mass index. Sub-analyses included stratification by tumor size (≤ and >1 cm) and birth before or during peak PCB production (born in 1960 or earlier and born after 1960), as exposures during early life may be important. We also applied three multi-pollutant approaches (standard multi-pollutant regression, hierarchical Bayesian modeling, principal components regression analysis) to investigate associations with co-exposures to multiple PCB/OCPs. RESULTS: No PCB/OCPs were positively associated with PTC in primary analyses. Statistically significant associations were observed for 9 of the 32 chemicals and 3 summed groups of similar chemicals in the those born during peak production based on single-pollutant models. Multi-pollutant analyses suggested null associations overall. CONCLUSIONS: Our results using single and multi-pollutant modeling do not generally support an association between PCB or OCP exposure and PTC, but some associations in those born during peak production suggest that additional investigation into early-life exposures and subsequent thyroid cancer risk may be warranted.

A Multiregion Analysis of Shale Drilling Activity and Rates of Sexually Transmitted Infections in the United States.

BACKGROUND: Fossil fuel extraction from deep shale rock formations using new drilling technologies such as hydraulic fracturing has rapidly increased in the Unites States over the past decade. Increases in nonlocal, specialized workers to meet the demands of this complex industry have been suggested to influence the rates of sexually transmitted infections (STIs) in counties with shale drilling activity; these associations may vary geographically. In this multiregion analysis, we examine the associations between shale drilling activity and rates of 3 reportable STIs in Colorado, North Dakota, and Texas, states with active shale drilling. METHODS: We obtained annual reported rates of chlamydia, gonorrhea, and syphilis from the Centers for Disease Control and Prevention, number of active shale wells from Enverus (formerly known as DrillingInfo), and sociodemographic covariates from the US Census Bureau. We used multivariable mixed-effects Poisson regression modeling to estimate rate ratios (RR) with 95% confidence intervals (CIs) adjusted for potential confounders and secular trends. RESULTS: In Texas, county-years with high drilling activity had 10% increased rates of chlamydia (RR, 1.10; 95% CI, 1.04-1.17) and 15% increased rates of gonorrhea (RR, 1.15; 95% CI, 1.04-1.28), compared with county-years with no drilling. No statistically significant associations were reported for syphilis or for any STIs in Colorado or North Dakota. CONCLUSIONS: Associations between shale drilling and chlamydia and gonorrhea in Texas may reflect increased risk in areas with higher drilling activity and a greater number of major metropolitan areas. Interstate differences highlight the need for local epidemiology to prioritize community health policies.

Unconventional oil and gas development and health outcomes: A scoping review of the epidemiological research.

BACKGROUND: Hydraulic fracturing together with directional and horizontal well drilling (unconventional oil and gas (UOG) development) has increased substantially over the last decade. UOG development is a complex process presenting many potential environmental health hazards, raising serious public concern. AIM: To conduct a scoping review to assess what is known about the human health outcomes associated with exposure to UOG development. METHODS: We performed a literature search in MEDLINE and SCOPUS for epidemiological studies of exposure to UOG development and verified human health outcomes published through August 15, 2019. For each eligible study we extracted data on the study design, study population, health outcomes, exposure assessment approach, statistical methodology, and potential confounders. We reviewed the articles based on categories of health outcomes. RESULTS: We identified 806 published articles, most of which were published during the last three years. After screening, 40 peer-reviewed articles were selected for full text evaluation and of these, 29 articles met our inclusion criteria. Studies evaluated pregnancy outcomes, cancer incidence, hospitalizations, asthma exacerbations, sexually transmitted diseases, and injuries or mortality from traffic accidents. Our review found that 25 of the 29 studies reported at least one statistically significant association between the UOG exposure metric and an adverse health outcome. The most commonly studied endpoint was adverse birth outcomes, particularly preterm deliveries and low birth weight. Few studies evaluated the mediating pathways that may underpin these associations, highlighting a clear need for research on the potential exposure pathways and mechanisms underlying observed relationships. CONCLUSIONS: This review highlights the heterogeneity among studies with respect to study design, outcome of interest, and exposure assessment methodology. Though replication in other populations is important, current research points to a growing body of evidence of health problems in communities living near UOG sites.

Genetic susceptibility may modify the association between cell phone use and thyroid cancer: A population-based case-control study in Connecticut.

Emerging studies have provided evidence on the carcinogenicity of radiofrequency radiation (RFR) from cell phones. This study aims to test the genetic susceptibility on the association between cell phone use and thyroid cancer. Population-based case-control study was conducted in Connecticut between 2010 and 2011 including 440 thyroid cancer cases and 465 population-based controls with genotyping information for 823 single nucleotide polymorphisms (SNPs) in 176 DNA genes. We used multivariate unconditional logistic regression models to estimate the genotype-environment interaction between each SNP and cell phone use and to estimate the association with cell phone use in populations according to SNP variants. Ten SNPs had P < 0.01 for interaction in all thyroid cancers. In the common homozygote groups, no association with cell phone use was observed. In the variant group (heterozygotes and rare homozygotes), cell phone use was associated with an increased risk for rs11070256 (odds ratio (OR): 2.36, 95% confidence interval (CI): 1.30-4.30), rs1695147 (OR: 2.52, 95% CI: 1.30-4.90), rs6732673 (OR: 1.59, 95% CI: 1.01-2.49), rs396746 (OR: 2.53, 95% CI: 1.13-5.65), rs12204529 (OR: 2.62, 95% CI: 1.33-5.17), and rs3800537 (OR: 2.64, 95% CI: 1.30-5.36) with thyroid cancers. In small tumors, increased risk was observed for 5 SNPs (rs1063639, rs1695147, rs11070256, rs12204529 and rs3800537), In large tumors, increased risk was observed for 3 SNPs (rs11070256, rs1695147, and rs396746). Our result suggests that genetic susceptibilities modify the associations between cell phone use and risk of thyroid cancer. The findings provide more evidence for RFR carcinogenic group classification.

Prenatal exposure to perfluoroalkyl substances and behavioral difficulties in childhood at 7 and 11 years.

BACKGROUND: Perfluoroalkyl substances (PFAS) are suggested to interfere with thyroid hormone during pregnancy and influence fetal neurodevelopment. Epidemiological evidence regarding behavioral difficulties in childhood associated with prenatal PFAS exposure has been inconclusive. OBJECTIVE: We evaluated the association between prenatal PFAS exposure and behavioral difficulties at 7 and 11 years, and investigated the potential mediating role of maternal thyroid hormones. METHODS: Using pooled samples in the Danish National Birth Cohort established between 1996 and 2002, we estimated the associations between concentrations of six types of PFAS in maternal plasma (median, 8 gestational weeks) and child behavioral assessments from the Strength and Difficulties Questionnaire (SDQ), reported by parents at 7 years (n = 2421), and by parents (n = 2070) and children at 11 years (n = 2071). Behavioral difficulties were defined as having a composite SDQ score above the 90th percentile for total difficulties and externalizing or internalizing behaviors. We used logistic regression to estimate the adjusted Odds Ratio (OR) by doubling increase of prenatal PFAS (ng/ml). The possible mediating effect of maternal thyroid function classified based on thyroid stimulating hormone (TSH) and free thyroxine (fT4) levels were evaluated. RESULTS: Prenatal perfluorononanoic acid (PFNA) was consistently associated with total and externalizing behavioral difficulties in all three SDQ measures reported by parents (OR = 1.40, 95% CI: 1.14-1.73 for age 7; OR = 1.27, 95% CI: 1.05-1.53 for age 11) or children (OR = 1.32, 95% CI: 1.11-1.58) while no consistent associations were observed for other types of PFAS. A small magnitude of natural indirect effects via maternal thyroid dysfunction (ORs ranged from 1.01 to 1.03) of several PFAS were observed for parent-reported total and externalizing behaviors at 7 years only. DISCUSSION: Prenatal PFNA exposure was associated with externalizing behavioral difficulties in childhood in repeated SDQ measures at 7 and 11 years. The slight mediating effects of maternal thyroid hormones in early gestation warrant further evaluation.

Dioxin exposure and breast cancer risk in a prospective cohort study.

BACKGROUND: Dioxins are persistent organic pollutants generated from industrial combustion processes such as waste incineration. To date, results from epidemiologic studies of dioxin exposure and breast cancer risk have been mixed. OBJECTIVES: To prospectively examine the association between ambient dioxin exposure using a nationwide spatial database of industrial dioxin-emitting facilities and invasive breast cancer risk in the Nurses' Health Study II (NHSII). METHODS: NHSII includes female registered nurses in the US who have completed self-administered biennial questionnaires since 1989. Incident invasive breast cancer diagnoses were self-reported and confirmed by medical record review. Dioxin exposure was estimated based on residential proximity, duration of residence, and emissions from facilities located within 3, 5, and 10 km around geocoded residential addresses updated throughout follow-up. Cox regression models adjusted for breast cancer risk factors were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: From 1989 to 2013, 3840 invasive breast cancer cases occurred among 112,397 participants. There was no association between residential proximity to any dioxin facilities (all facilities combined) and breast cancer risk overall. However, women who resided within 10 km of any municipal solid waste incinerator (MSWI) compared to none had increased breast cancer risk (adjusted HR = 1.15, 95% CI: 1.03, 1.28), with stronger associations noted for women who lived within 5 km (adjusted HR = 1.25, 95% CI: 1.04, 1.52). Positive associations were also observed for longer duration of residence and higher dioxin emissions from MSWIs within 3, 5, and 10 km. There were no clear differences in patterns of association for ER + vs. ER-breast cancer or by menopausal status. DISCUSSION: Results from this study support positive associations between dioxin exposure from MSWIs and invasive breast cancer risk.

Beyond genomics: understanding exposotypes through metabolomics.

BACKGROUND: Over the past 20 years, advances in genomic technology have enabled unparalleled access to the information contained within the human genome. However, the multiple genetic variants associated with various diseases typically account for only a small fraction of the disease risk. This may be due to the multifactorial nature of disease mechanisms, the strong impact of the environment, and the complexity of gene-environment interactions. Metabolomics is the quantification of small molecules produced by metabolic processes within a biological sample. Metabolomics datasets contain a wealth of information that reflect the disease state and are consequent to both genetic variation and environment. Thus, metabolomics is being widely adopted for epidemiologic research to identify disease risk traits. In this review, we discuss the evolution and challenges of metabolomics in epidemiologic research, particularly for assessing environmental exposures and providing insights into gene-environment interactions, and mechanism of biological impact. MAIN TEXT: Metabolomics can be used to measure the complex global modulating effect that an exposure event has on an individual phenotype. Combining information derived from all levels of protein synthesis and subsequent enzymatic action on metabolite production can reveal the individual exposotype. We discuss some of the methodological and statistical challenges in dealing with this type of high-dimensional data, such as the impact of study design, analytical biases, and biological variance. We show examples of disease risk inference from metabolic traits using metabolome-wide association studies. We also evaluate how these studies may drive precision medicine approaches, and pharmacogenomics, which have up to now been inefficient. Finally, we discuss how to promote transparency and open science to improve reproducibility and credibility in metabolomics. CONCLUSIONS: Comparison of exposotypes at the human population level may help understanding how environmental exposures affect biology at the systems level to determine cause, effect, and susceptibilities. Juxtaposition and integration of genomics and metabolomics information may offer additional insights. Clinical utility of this information for single individuals and populations has yet to be routinely demonstrated, but hopefully, recent advances to improve the robustness of large-scale metabolomics will facilitate clinical translation.