Environmental Health Perspectives

BackgroundEnvironment-wide association studies (ExWAS) offer a systematic approach to identifying chemical biomarker-health outcome associations, yet few have applied rigorous multi-stage validation. MethodsWe screened 92 chemical biomarkers against 48 health outcomes in NHANES 2017-2018 (2,796 tests across four screening rounds; not all chemicals were crossed with all outcomes). Associations passing an initial FDR screen were subjected to cross-cycle validation in NHANES 2015-2016--the primary inferential safeguard given the adaptive screening design--followed by dose-response analysis and multiple sensitivity specifications. Survey-weighted regression models adjusted for age, sex, race/ethnicity, poverty-income ratio, BMI, and smoking. ResultsOf 26 associations passing FDR correction, 21 were testable in cross-cycle validation; of these, 15 (71%) replicated with concordant direction and p < 0.05 in a temporally independent NHANES 2015-2016 sample. Of these 15, 14 remained robust after analyte-specific sensitivity checks; urinary creatinine adjustment identified one association (iodine-BMI) as a dilution artifact. Two novel findings emerged: dimethylarsonic acid with uric acid ({beta} = 0.20 mg/dL per log-unit DMA, 95% CI: 0.15-0.26) and urinary perchlorate with BUN ({beta} = 1.21 mg/dL per log-unit perchlorate, 95% CI: 0.97-1.45); a third high-novelty association (methylmercury-waist circumference) is likely explained by fish consumption patterns. ConclusionsMulti-stage ExWAS with cross-cycle validation identified 14 robust chemical-health associations. Two novel findings--DMA-uric acid and perchlorate-BUN--survived all sensitivity checks and warrant prospective investigation.

This protocol is reported in accordance with the SPIRIT 2025 guidelines for clinical trial protocols. IntroductionYoung children, from birth to age 5 y are particularly vulnerable to indoor air pollutants and respiratory pathogens. Portable air purifiers (or filtration) and upper-room ultraviolet germicidal irradiation (UVGI) are two widely used interventions with the potential to improve indoor air quality (IAQ) and reduce sick-related absences. However, a review of the literature revealed no real-world randomised studies evaluating their effectiveness in reducing young childrens sick-related absences in early care and education (ECE) classrooms. Methods and AnalysisThe OK-AIR study is a longitudinal, cluster-randomised 2x2 factorial trial conducted in Head Start centers using two implementation cohorts: Cohort 1 (five Head Start centers and 20 classrooms from 2023 to 2024) and Cohort 2 (11 centers and 59 classrooms from 2025 to 2026), with expanded inclusion of rural areas. Cohort 1 enrolled 204 children, 48 teachers and 5 site directors, and Cohort 2 enrolled 462 children, 97 teachers and 11 site directors. Within each center, four classrooms are randomised to: (1) control; (2) portable filtration; (3) upper-room ultraviolet germicidal irradiation (UVGI); or (4) both interventions. Cohort 2 was initially planned as a second factorial trial but was amended to a purifier-only design due to funding changes; details are provided in the protocol amendments section. We collect continuous IAQ data, including particulate matter (PM) with aerodynamic diameters [&le;]1 {micro}m (PM1), [&le;]2.5 {micro}m (PM2.5), [&le;]4 {micro}m (PM4), and [&le;]10 {micro}m (PM10); total volatile organic compounds (TVOCs) index; nitrogen oxides (NOx) index; carbon monoxide (CO), noise; temperature; and relative humidity, alongside daily child absences. Seasonal environmental surface swabs (dining tables and toilet flooring) are tested by Reverse-Transcriptase quantitative Polymerase Chain Reaction (RT-qPCR) for Influenza A/B, Respiratory Syncytial Virus (RSV), Human Parainfluenza Virus Type 3 (HPIV3), Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and Norovirus. IAQ monitoring is structured across Winter, Spring, Summer, and Fall, including designated baseline/off-period weeks to characterize temporal and seasonal variability in environmental measures across classrooms and centers. Multi-informant surveys (Director, Teacher, Parent) capture contextual factors, and childrens social-emotional development is assessed using teacher ratings on the Devereux Early Childhood Assessment (DECA). The primary outcome is the sick-related absence rate, analyzed as cumulative absences over the attendance year while accounting for clustering by school and classroom using generalized mixed-effects models. Secondary outcomes include childrens social-emotional ratings, IAQ metrics and pathogen detection rates; analyses of IAQ incorporate time/seasonal structure, and season-stratified absenteeism analyses will be treated as secondary/exploratory refinements. An economic evaluation will estimate incremental intervention costs and cost-effectiveness/cost-benefit (such as cost per sick-related absence day averted). Ethics and DisseminationThis study was approved by the Institutional Review Board (IRB) at the University of Oklahoma. Findings will be shared through peer-reviewed publications; presentations at local, state, and national conferences; research briefs developed for lay and policy audiences; and community briefings prioritizing the participating early childhood programs and communities. DisclaimerThe views expressed are those of the authors and do not reflect the official views of the Uniformed Services University or the United States Department of War. Strengths and Limitations of This StudyO_LIReal-world longitudinal cluster RCT: The study uses a rigorous longitudinal cluster-randomised 2x2 factorial design in real-world ECE settings. C_LIO_LICombined interventions: Interventions target both air filtration and disinfection, allowing for combined and comparative evaluation. C_LIO_LIObjective air-quality monitoring: Continuous monitoring of IAQ metrics provides objective and reliable data on environmental change. C_LIO_LIEnvironmental pathogen surveillance: qPCR on surface swabs yields an objective biological outcome to triangulate with IAQ and absences. C_LIO_LIComprehensive context and child measures: Multi-method and multi-reporter data collection includes Head Start attendance records, continuous air monitoring, pathogen detection, contextual surveys completed by center directors, teachers, and parents, and standardized social-emotional assessments (DECA) completed by classroom teachers. Head Start program records providing childrens longer-term health data available through Health Insurance Portability and Accountability Act (HIPAA) authorization. C_LIO_LIClustered/temporal complexity: Seasonal design accounts for variation over time but may introduce complexity in modeling temporal effects. C_LIO_LIPractical Implications: Study findings will have practical implications for Head Start and other ECE programs striving to maximize child attendance with cost effective strategies. C_LI

BackgroundOutdoor workers are particularly vulnerable to the adverse impacts of heat, but many studies focus on heat exposure in residential settings only. This leads to a limited understanding of the full mortality burden due to occupational heat exposures. Here, we aimed to improve estimates of the total, short-term mortality burden attributable to outdoor occupational heat exposure in the United States (US). MethodsWe developed a panel data set for 3,108 US counties during 2010-2019 by linking all-cause mortality among the working age population, derived from CDC WONDER, with the prevalence of workers exposed to outdoor occupational heat, which integrates data on wet bulb globe temperature, workplace activities, and employment counts. We developed a quasi-Poisson regression model adjusted for ambient temperature, total precipitation, and county and state-year fixed effects to estimate short-term excess deaths attributable to outdoor occupational heat exposure. FindingsNationwide, approximately 3.8% (95% CI: 2.5-5.8%) of all workers were annually exposed to dangerous wet-bulb globe temperatures. This outdoor occupational heat exposure resulted in approximately 9,800 (3,100-17,000) annual excess deaths in the working age population. An estimated 62% of excess deaths occurred in the most socially vulnerable counties despite accounting for 25% of workers. InterpretationThe mortality burden of occupational heat exposure is likely far larger than 39 officially reported annual deaths that the Bureau of Labor Statistics reports for this time period. The workplace should be an explicit focus of heat policies, advocacy, and adaptation measures. FundingUS Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health.

Millions of outdoor workers cannot avoid wildfire smoke, likely leading to inequalities in exposure and health risk. We characterized work-related exposure to wildfire PM2.5 for 3,108 contiguous US counties during 2006-2019. Despite experiencing less ambient exposure to wildfire PM2.5, counties with higher portions of non-Hispanic Black and Hispanic Americans experienced higher work-related exposure. We also find suggestive evidence that the effect of ambient smoke fine particulate matter (PM2.5) concentrations on all-cause mortality may differ by workplace exposure. These findings suggest that workplace exposures should be considered in wildfire smoke adaptation measures.

PFAS are ubiquitous endocrine-disrupting pollutants that cross the placenta and impact offspring health, but the extent and timing of their transfer to both placental and fetal compartments remain poorly understood. We aimed to characterize the relationship between trimester-specific maternal serum levels of prenatal PFAS and paired placental and cord levels at term. Data came from Glowing, a prospective birth cohort (n=151). Seventeen PFAS were measured in maternal serum, cord serum, and pulverized flash-frozen villous placenta with liquid chromatography-tandem mass spectrometry. Mixed effects models tested transplacental transfer efficiency (TTE) over pregnancy. Regularization models, stochastic intervention, and quantile g-computation models tested the association between maternal and placental or cord PFAS levels. TTE increased linearly across trimesters for all PFAS (p<0.001). Quartile increases in maternal PFAS were strongly associated with placental levels (0.018-0.24 ng/g, p<0.001). Stochastic intervention identified T1 PFNA and PFDA; T2 PFOS, PFOA, PFHxS, and PFNA; and T3 PFHxS as robust predictors (p<0.001) of placental levels, consistent with quantile-based contributions. Quartile increases in maternal and placental PFAS concentrations were associated with cord levels (0.08 ng/g-0.55 ng/g, p<0.001). Stochastic intervention identified T1 PFOS and PFHxS; T2 PFOS and PFNA; T3 PFOA; and placental PFOA as important predictors (p<0.05) of cord levels, consistent with quantile-based contributions. Early-to-mid gestation, especially 2nd trimester PFAS measures, were the strongest sentinels of placental and cord serum levels, apart from PFOA which was best reflected by 3rd trimester or placental levels. Placental PFOS and PFOA strongly influenced cord levels. Our findings underscore the heterogeneity in PFAS transfer or metabolism across pregnancy and the placenta.

Wildfires have become more frequent and intense worldwide. Wildfire emitted particulate matter (WFPM) can be more toxic than urban background PM due to its greater content of nanoscale size (WFPM0.1) and presence of more polar organic compounds, including polycyclic aromatic hydrocarbons (PAHs). While exposure to WFPM has been linked to cardiovascular and respiratory diseases, its impact on female reproduction remains elusive. Here, we used an in vivo mouse intratracheal exposure model and a 3D ovarian follicle culture system, together with molecular, transcriptomic, and computational approaches, to examine the female reproductive effects of lab-synthesized (LS-WFPM0.1) and real-world Canadian WFPM0.1 (C-WFPM0.1), collected from the New York City and New Jersey metropolitan area during the June 2023 wildfire events. Intratracheal exposure to environmentally relevant dose of LS-WFPM0.1 disrupted mouse estrous cycles and elevated serum concentrations of estradiol and testosterone. RT-qPCR and single-follicle RNA-sequencing (RNA-seq) analysis revealed altered steroidogenic genes, transcriptomic changes, and activation of aryl hydrocarbon receptor (AhR) in antral follicles from mice treated with LS-WFPM0.1. LS-WFPM0.1 consistently increased testosterone secretion and stimulated genes related to androgen synthesis and AhR in vitro. Single-follicle and single-oocyte RNA-seq analysis identified differentially expressed genes related to inflammation in somatic cells and mitochondrial respiratory chain in oocytes. Both C-WFPM0.1 and benzo[a]pyrene, a high-molecular-weight PAH, reproduced these ovarian defects. Mechanistically, AhR inhibition reversed hyperandrogenism induced by WFPM0.1. Together, our findings suggest that WFPM0.1, an increasingly pervasive environmental exposure, adversely impacts female reproductive functions by disrupting ovarian steroidogenesis and inducing hyperandrogenism through AhR activation, highlighting an urgent unmet need for further mechanistic studies and epidemiological investigations to define the reproductive risks of wildfire smoke exposure in human populations.

Young children (from birth to 5 years old) are uniquely vulnerable to environmental hazards due to their higher exposure relative to body weight, rapid physiological and neurological development, and strong reliance on caregivers for protection and care. Such risks are often amplified in marginalized communities with socioeconomic disadvantage and limited access to resources. However, widely used indices, such as the Social Vulnerability Index (SVI), the Climate Vulnerability Index (CVI) and the Child Opportunity Index (COI), were not specifically developed for young children and may not capture the combined environmental and socioeconomic risks faced by this age group. To address this critical gap, we developed a county-level Early Childhood Environmental Health Vulnerability Index (EC-EHVI) for the contiguous U.S. using multidimensional indicators within an Exposure-Sensitivity-Adaptive Capacity framework and informed by Bronfenbrenners bioecological model. We identified the underlying drivers and the spatial patterns of the EC-EHVI. Our results showed that the EC-EHVI exhibited the strongest association with county-level young child mortality and explained a larger proportion of spatial heterogeneity compared with the SVI, CVI, and COI. Elevated vulnerability clustered in the Great Plains and Southeastern U.S., where over half of high-risk counties were exposure-driven, and 411 high-high hotspots were identified. The EC-EHVI offers a valuable spatial decision-support tool for designing targeted, place-based interventions and advancing environmental health equity for young children. Plain Language SummaryYoung children (birth to age five) are uniquely vulnerable to environmental hazards. Because their bodies are developing and they consume more air, food, and water relative to their weight, environmental exposures can have severe, lifelong impacts. These risks are often magnified in under-resourced communities. Yet, most existing vulnerability tools were not built with young children in mind, potentially obscuring the combined environmental and social threats they face. To address this gap, we developed a new county-level index to pinpoint where young children are most at risk across the contiguous United States. Our tool integrates data on environmental exposure, community sensitivity, and the resources available to help families cope. When tested, our new index was more strongly linked to young child mortality than several widely used existing measures. We identified major high-risk clusters, particularly in the Great Plains and the Southeastern U.S. This tool can help policymakers and public health officials better target resources and interventions to protect young children and promote environmental health equity. Key PointsO_LIWe developed a county-level Early Childhood Environmental Health Vulnerability Index across the contiguous U.S. C_LIO_LIElevated vulnerability clustered in the Southeast, Great Plains, and Appalachia, with additional hotspots in Michigan and Maine. C_LIO_LIMore than half of high-vulnerability counties were exposure-driven, emphasizing the key role of environmental hazards in child health. C_LI

Ambient air pollution has been associated with increased incidence of chronic disease and is estimated to contribute towards 4.2 million early deaths annually. Whilst the health impacts are well described, less is understood about the underlying biological mechanisms, particularly when considering the co-occurrence of multiple pollutants. Using an atmospheric chemistry transportation model (EMEP4UK), we generate pre-baseline sampling pollution exposure estimates for eight pollutants in Generation Scotland (N = 22,071, recruited between 2006 - 2011). Cox-proportional hazard models reveal associations between pollution exposure and all-cause dementia (PM2.5) and myocardial infarction (NO3_Coarse) over 18 years of follow-up. We perform Bayesian multivariate epigenome-wide (N = 18,512, Illumina EPIC v.1) and proteomic (N = 15,314, 133 mass-spectrometry proteins) association studies, revealing 11 pollutant-methylation associations and 140 pollutant-protein associations. We identify positive associations between exposure (PM2.5 and NO3_Fine) and epigenetic age-acceleration (PhenoAge epigenetic clock). Furthermore, we explore the development of pollutant EpiScores, assessing these in holdout and independent test sets. Our results enhance knowledge of molecular correlates of air pollution exposure, whilst providing further evidence of contributions of air pollutants to chronic disease.

Computational toxicology increasingly relies on evidence, high-throughput screening, predictive (Q)SAR, adverse outcome pathways (AOPs), physiologically based kinetic (PBK/PBPK) models, and exposure databases to support integrated approaches to testing and assessment (IATA). Yet the practical workflow remains fragmented across heterogeneous tools, data formats, and licensing regimes. Large language models (LLMs) can lower the interface barrier, but free-text interaction alone is insufficient for regulatory-grade science: it is difficult to audit, difficult to reproduce, and prone to overconfident errors. Here we introduce ToxMCP, a collection of Model Context Protocol (MCP) servers designed as a guardrailed, federated integration layer for reproducible computational toxicology. ToxMCP wraps toxicology-relevant capabilities, including chemical identity and regulatory context (EPA CompTox), rapid ADMET profiling (ADMETlab 3.0), mechanistic pathway retrieval and structuring (AOP knowledge services), quantitative read-across workflows (OECD QSAR Toolbox), and mechanistic PBPK simulation (Open Systems Pharmacology Suite), as typed tools with explicit inputs/outputs, provenance bundles, and policy hooks (e.g., applicability domain checks, critical-action confirmation, and role-based access control). We demonstrate how natural-language risk questions can be compiled into auditable tool invocations, returning mechanistic metrics such as tissue AUC/Cmax, sensitivity curves, and conservative points of departure. We further outline an evaluation protocol for measuring computational reproducibility, task throughput, and scientific utility across multi-tool toxicology tasks. ToxMCP reframes LLMs for toxicology from conversational summarizers into accountable orchestrators of established scientific kernels, enabling faster iteration while preserving the evidentiary structure expected in regulatory and academic settings. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/703989v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1b8ccceorg.highwire.dtl.DTLVardef@18e0703org.highwire.dtl.DTLVardef@16e87feorg.highwire.dtl.DTLVardef@1a24f13_HPS_FORMAT_FIGEXP M_FIG C_FIG

Exposure to high ambient temperature is responsible for more than 11,000 deaths and over 230,000 disability-adjusted life-years in the United States each year. However, which individuals and populations are most at risk, and why, is still not well understood. In 2015, a subset of "Z" diagnosis codes (or "Z-codes") were introduced as a standardized option for healthcare providers to document the social needs and conditions of their patients. To assess heat-related risk across social determinants of health (SDoH), we leverage these codes using a dataset of patient-level emergency department (ED) visits from seven US states. Using a bi-directional, time-stratified, case-crossover design and conditional logistic regression, we compared hospital encounters for seven different health outcomes with SDoH Z-codes at discharge to a reference group matched on age, sex, race, ethnicity, year and hospital. We investigated the following Z-code domains: inadequate housing (Z59.0, Z59.1), poverty-related (Z56.0, Z59.5-Z59.7), living alone (Z60.2), institutional living (Z65.1, Z59.3), and other problems with the social environment (other Z60 sub-codes). We calculated cumulative odds ratios (ORs) for a 3-day lag change in temperature from the 95th to 50th percentile, using ZIP code-specific temperature percentiles. Among 60,557,958 ED visits with available demographic and meteorological data, 461,468 (0.8%) included a SDoH Z-code. Across temperature metrics and outcomes, patients with SDoH Z-codes consistently showed higher associations with heat than the matched reference group without SDoH Z-codes. The largest difference was for acute kidney injury, with a ratio of ORs of 1.21 (1.10,1.33) for daily mean temperature. Notable subgroup findings included elevated kidney-related risks in patients with inadequate housing or poverty-related SDoH, increased mental health risks among those living alone, and elevated cardiovascular risks in people with other problems related to the social environment.

BackgroundRising global temperatures and eutrophication are increasing the intensity and frequency of cyanobacterial harmful algal blooms that release toxins including microcystin-LR (MC-LR). MC-LR inhibits protein phosphatases in the human liver and brain, but its accumulation in the placenta is unclear. Placental transporter expression varies across pregnancy and is influenced by physiological cues, such as low oxygen concentrations which activate HIF1A, and trophoblast cell fusion forming syncytiotrophoblasts that engage CREB-driven transcription. This study examined whether MC-LR accumulates in placental cells, which transporters mediate uptake, and how these transporters are regulated by HIF1A and CREB. MethodsIntracellular accumulation of MC-LR (0.1-10 {micro}M, 3 hour) was measured in human cytotrophoblasts (JAR, BeWo) and extravillous trophoblasts (HTR-8/SVneo) by western blotting for MC-LR-adducted proteins. Organic anion transporting polypeptide (OATP) involvement was tested using cyclosporin A (10 {micro}M), an OATP inhibitor, before exposure to the OATP substrate or MC-LR. Cells were also cultured under 3%, 8%, or 20% O2 to induce hypoxic responses or treated with forskolin (a potent intracellular cAMP inducer) to stimulate cell fusion before MC-LR exposure. ResultsMC-LR accumulated in all three placenta cell lines in a concentration-dependent manner. Cyclosporin A reduced MC-LR uptake by 57% in JAR cells, confirming OATP-mediated transport. Low O2 increased OATP4A1 expression and function but reduced protein phosphatase expression, decreasing MC-LR-bound proteins by 52-72%. Forskolin increased OATP4A1 expression and enhanced MC-LR uptake >2.5-fold. ConclusionMC-LR enters placental trophoblasts via active OATP transport, likely OATP4A1, and uptake increases under hypoxia and trophoblast fusion.

IntroductionDrowning risk begins with water exposure, yet population-water relationships have rarely been quantified at scale using environmental measures. This study explored whether satellite-derived data was associated with subnational drowning mortality and whether associations differed by country income level. MethodsWe linked Global Burden of Disease (GBD 2021) age-standardised drowning mortality rates to satellite-derived exposures for 212 subnational regions across 12 countries (2006-2021; 3,392 region-years). Exposures were extracted via Google Earth Engine and standardised. Gamma-log generalised linear mixed models included region random intercepts and year fixed effects. Income-stratified models were estimated separately. Supplementary models assessed maritime vessel activity. ResultsNear-water population percentage was the strongest correlate of drowning (IRR 1.40; 95% CI 1.33-1.47). Permanent water coverage was protective (IRR 0.80; 0.73-0.88), as were nighttime lights (IRR 0.96; 0.95-0.97) and hot days [&ge;]30{degrees}C (IRR 0.95; 0.92-0.99). Mean temperature (IRR 1.17; 1.11-1.23) and precipitation (IRR 1.03; 1.01-1.04) were positively associated. Near-water effects were consistent across income strata (LIC 1.25; MIC 1.31; HIC 1.24), while other predictors showed weak or inconsistent within-strata associations. Vessel activity was modestly associated with drowning in Global Fishing Watch models (IRR 1.05; 1.01-1.09) but not in Synthetic Aperture Radar models. DiscussionSatellite-derived indicators can characterise drowning risk at scale, with population proximity to water emerging as a robust cross-context correlate. Protective associations for permanent water suggest landscape configuration may shape risk beyond proximity alone, highlighting geospatial datas value for targeting prevention where surveillance is limited.

Background Ambient air pollution is a leading global health risk and disproportionately affects populations of Low- and Middle-Income Countries (LMICs). In 2021, WHO revised its Air Quality Guidelines (AQG), lowering recommended annual limits for Particulate Matter 2.5 (PM2.5) and Nitrogen Dioxide (NO2). We estimated the potential health and economic impacts of achieving WHO Interim Target 3 (IT3) and AQG concentrations across LMICs. Methods We conducted a health impact assessment across 136 LMICs to quantify one-year changes in all-cause and cause-specific mortality (chronic obstructive pulmonary disease [COPD], ischaemic heart disease [IHD], and stroke) and disease incidence (COPD, dementia, IHD, and stroke) under WHO IT3 and AQG counterfactual scenarios for PM2.5 and NO2. Concentration-response functions were applied at 1km x 1km resolution. Economic welfare impacts of mortality risk reductions were estimated using country-adjusted values of a statistical life (VSL, Int$ PPP-adjusted 2021). Direct medical and productivity-related costs associated with incident cases were estimated using a cost-of-illness (COI) framework. Uncertainty intervals (UI) reflect uncertainty in concentration-response functions. Results Attainment of WHO IT3 and AQG concentrations for PM2.5 was associated with an estimated 16.04% reduction (6.58million, UI: 6.10-7.07million) and 22.97% reduction (9.43million, UI: 8.75-10.11million) in annual deaths, respectively. Corresponding VSL-based estimates of deaths averted were Int$5.5 trillion (7.0% of aggregate LMIC GDP) and Int$8.4 trillion (10.6% of GDP), respectively. For NO2, IT3 and AQG scenarios were associated with estimated reductions of approximately 1.06% (approximately 435,000 deaths, UI: 388,000-483,000) and 2.79% (435,000 deaths; UI: 388,000-483,000), yielding gains of Int$0.6 trillion (0.7% of GDP) and Int$1.5 trillion (1.9% of GDP). Disease-specific mortality reductions were most prominent for IHD and stroke in Asia and Africa. Under the PM2.5 AQG scenario, an estimated 2.82million (1.67-2.97) COPD, 1.10million (0.83-1.37) dementia, 7.3million (6.41-8.19) IHD, and 2.3million (2.19-2.41) stroke cases could be delayed or averted in one year. Associated reductions in direct medical and productivity-related costs were greatest for IHD, COPD, and stroke. NO2-related morbidity reductions were smaller across all outcomes. All estimates represent one-year changes in risk relative to counterfactual exposure and may reflect delayed rather than permanently avoided events. Discussion Achieving both WHO IT3 and AQG values in LMICs could yield substantial reductions in premature mortality and disease incidence, particularly for cardiovascular and respiratory conditions, alongside large, monetised welfare gains from reduced mortality risk. These findings underscore the considerable societal value of air quality improvements and support accelerated action toward meeting WHO guideline levels in regions bearing the highest pollution burden.

IntroductionAmbient and indoor fine particle air pollution (PM2{middle dot}5) estimates have been associated with pregnancy complications. We aimed to link direct personal exposure measurements with placenta-mediated pregnancy complications in three sub-Saharan African countries. MethodsWe recruited a geographically and energy use stratified sub-sample of 343 rural and urban women who had recently given birth in the PREgnancy Care Integrating translational Science, Everywhere (PRECISE) prospective pregnancy cohort in The Gambia (n = 160), Kenya (n = 105), and Mozambique (n = 78). Individual-level exposure to PM2{middle dot}5 was assessed using high-resolution personal monitoring, during both wet and dry seasons. Minute-level data were summarised as mean and peak daily PM2{middle dot}5 concentrations, and correlated with maternal blood pressure (BP), gestational age at delivery, fetal growth, and stillbirth, in the index pregnancy. Results107/343 (32{middle dot}2%) women experienced pregnancy hypertension, 57/343 (16{middle dot}0%) women delivered preterm, 203/304 (66{middle dot}8%) infants with known birthweights were appropriately-grown, and 9/343 (2{middle dot}7%) infants were stillborn. Higher mean (p=0{middle dot}012) and peak (p=0{middle dot}007) exposures were associated with reduced fetal growth velocity, with greater mean exposure associated with small-for-gestational age infants (p=0{middle dot}016). Greater mean (p=0{middle dot}017) and peak (p=0{middle dot}045) PM{square}.{square} exposures were associated with lower birthweight centile. No associations were observed with pregnancy hypertension, pregnancy duration, or stillbirth. DiscussionThis study provides exploratory evidence that personal PM2{middle dot}5 exposure is associated with impaired fetal growth in sub-Saharan Africa. Prioritising access to clean fuels, reducing emissions from informal transport and waste systems, and incorporating personal exposure monitoring into maternal health frameworks could yield measurable improvements in birth outcomes and health equity.

BackgroundAir pollution is a potentially modifiable risk factor for dementia with a population attributable risk fraction of 3%. Little is known about the causal mechanisms behind the association, so we aimed to investigate this. MethodsData from the UK Biobank were used to investigate the association between six measures of air pollution (NO2, NOx, PM2{middle dot}5-10, PM2{middle dot}5, PM2{middle dot}5 absorbance and PM10) and dementia incidence. Indirect pathways through four mediators (cardiovascular conditions, mental health treatment, insufficient exercise and social isolation) were explored. Logistic regression was used to model the associations between air pollution, mediators and dementia. Casual mediation analysis implemented using the g-formula was used to investigate the joint indirect effect through the mediators. FindingsExposure to the highest quintile of PM2{middle dot}5 (Rte:1{middle dot}14, 95% CI:1{middle dot}06-1{middle dot}23), NOx (Rte:1{middle dot}11, 95% CI:1{middle dot}03-1{middle dot}20) or NO2 (Rte:1{middle dot}08, 95% CI:0{middle dot}99-1{middle dot}16), compared to the lowest quintile, was associated with higher dementia risk. Most of the observed association resulted from the direct effect of air pollution, consisting of pathways not captured through considered mediators. Amongst those in the highest PM2{middle dot}5 quintile, jointly intervening on the four mediators would result in a 1% reduction in risk of dementia (Rpnie:1{middle dot}01, 95% CI: 1{middle dot}01-1{middle dot}02). The randomised pure natural indirect effect was similar for NO2 (Rpnie:1{middle dot}01, 95% CI: 1{middle dot}00-1{middle dot}01) and NOx (Rpnie:1{middle dot}01, 95% CI: 1{middle dot}01-1{middle dot}02). InterpretationMost of the association between dementia and PM2{middle dot}5, NO2 and NOx occurs through the direct effect of air pollution, or other unmeasured mediators, and not pathways through these four mediators. FundingMedical Research Council (Grant MR/W006774/1).

IntroductionParticulate Matter (PM2.5) exposure contributes to the global disease burden, yet its monitoring remains sparse and uneven and is limited in many limited ground monitoring network settings. Road-traffic proxy indicators can provide indirect estimates of PM2.5 where measurements are limited but require context-specific validation. We evaluated three PM2.5 road-traffic related proxies:(I) population-Weighted Road Network Density (WRND), (ii) Euclidean (straight line) distance from highways (EH), and (iii) Euclidean distance from main roads (EM). MethodsWe validated proxies using high-resolution outdoor filtered PM2.5 personal exposure measurements collected over 1 year from 343 postpartum participants in The Gambia, Kenya, and Mozambique. Village-level spatial patterns for the PM2.5-proxy relationship were mapped using 5 km hexagonal aggregated tessellations. Proxy-PM2.5 associations were assessed using Spearman correlation, and predictive utility was tested using country-specific and global Random Forest (RF) models (3-fold cross-validation), reporting R2, RMSE, and feature importance ResultsSpatial mapping showed heterogeneous proxy-PM2.5 relationships across and within sites, with elevated PM2.5 occurring in both low- and high-proxy contests. WRND-PM2.5 correlations were weak overall and statistically significant only in Mozambique (r = 0.351; p = 0.005), with non-significant associations in Kenya (r = -0.041; p = 0.673) and The Gambia (r = -0.020; p = 0.909). EH-PM2.5 correlations were positive in The Gambia (r = 0.335; p = 0.053) and Mozambique (r = 0.292; p = 0.020) but negative and significant in Kenya (r = -0.224; p = 0.018).Single-variable RF models performed poorly across all countries (R2 < 0.45) and the Global model (R2=0.42). Combining proxies improved performance in Kenya (R2=0.52; RMSE=31.7{micro}g/m3) and Mozambique (R2=0.60; RMSE=8.9 {micro}g/m3), Global R2=0.46; RMSE=29.1 {micro}g/m3), although in The Gambia, the combined model (R2=0.53; RMSE=37.6 {micro}g/m3) did not exceed the best single-proxy model. ConclusionRoad-network proxies provide context-dependent signals of personal PM2.5 exposure, and predictive performance is strengthened when proxies are combined in a hybrid model.

Background: Beaches are popular summertime destinations in Canada. However, they can be affected by specific fecal pollution sources, increasing the risk of recreational water illness. Objectives: This study was conducted to determine the risks of acute gastrointestinal illness (AGI) among Canadian beachgoers and to evaluate the influence of different fecal indicator bacteria (FIB) and other water quality measures on assessing these risks. Methods: In a prospective cohort design, beachgoers were recruited at sites across Canada from 2023 to 2025. Sociodemographic characteristics and exposures were determined through an on-site survey, with a 7-day follow-up survey to determine risks of AGI. Bayesian mixed-effects logistic regression models were fitted to evaluate the effects of an ordinal water contact variable (no contact, minimal contact, body immersion, and swallowed water) on the incident risk of AGI, with an interaction included for water quality indicators. The levels of six FIB and water quality measures were assessed: Escherichia coli, enterococci DNA, three microbial source tracking DNA markers (human HF183/BacR287, human mitochondria, seagull Gull4), and turbidity. Results: A total of 4085 participants were recruited, with 67.6% completing the follow-up survey. The overall incident risk of AGI was 2.6%. Both swallowing water and body immersion increased AGI risks compared to no water contact: median of 20 excess cases (95% Credible Interval [CrI]: 4, 64) and 5 excess cases (95% CrI: 1, 19) of AGI predicted per 1000 beachgoers, respectively. Escherichia coli and seagull DNA marker levels were associated with AGI among those who had water contact, particularly among those who reported swallowing water. Discussion: While the overall burden of AGI due to beach water contact in Canada was low, increased risks are associated with E. coli levels particularly among those who swallow water. This could be related to fecal contamination from seagulls. However, there is substantial uncertainty in the predicted effect sizes.

BackgroundChronic Kidney Disease of unknown etiology is a growing health concern in low-and middle-income countries. While occupational heat stress is recognized as a potential contributor to kidney dysfunction among agricultural workers, the causal relationship between heat stress, core body temperature (Tc), and kidney function remains unclear. MethodsWe conducted an observational study over two harvest seasons in Guatemala, following 148 male sugarcane workers across six months. Heat stress was measured using heat index (HI) and Tc with ingestible telemetric temperature pills. Particulate matter (PM) exposure was measured using personal breathing zone samplers worn during the work shift. We evaluated changes in kidney function using pre-and post-shift estimated glomerular filtration rate (eGFR). We applied G-computation to estimate causal effects and modeled hypothetical policy interventions reducing HI, Tc, and PM exposure, simulating occupational heat reduction strategies. ResultsThe average daily HI was 37.4 {degrees}C (SD: 2.0) with an average Tc increase of 1.16 {degrees}C (SD: 0.48) per shift. Both HI and Tc were associated with declines in eGFR across the work shift. At an HI of 34 {degrees}C, workers experienced an average eGFR decline of about 5 mL/min/1.73 m{superscript 2}, while at 40 {degrees}C the decline exceeded 16 mL/min/1.73 m{superscript 2}. High HI early in the season and elevated Tc later in the season contributed to kidney decline. A simulated intervention reducing HI exposure by 5% improved eGFR change by 1.46 mL/min/1.73 m{superscript 2}. PM exposure did not have a significant impact on eGFR decline. ConclusionReducing workday heat exposure may mitigate acute kidney function decline. These findings support the development of policy interventions aimed at reducing external heat exposure and internal heat strain to protect kidney health. More research is needed to investigate the potential contribution of other environmental factors, including PM exposure.

Background Polycyclic aromatic hydrocarbons (PAHs) and volatile organic compounds (VOCs) are combustion-derived pollutants linked to cardiovascular disease. Prior NHANES analyses have evaluated these chemicals individually, failing to capture the correlated co-exposure structures that characterize real-world environmental burden, thereby underscoring the need for application. In this study, we applied an unsupervised machine learning pipeline to urinary biomarker data to identify multi-chemical exposure clusters and quantify their differential cardiovascular risk profiles in a nationally representative US sample. Methods We analyzed 2,979 participants from NHANES between 2017-2018, representing an estimated 36.8 million US adults after complex survey weighting. Twenty-five urinary biomarkers (6 PAH, 19 VOC metabolites) were log-transformed, imputed using Multivariate Imputation by Chained Equations (MICE), and standardized. Uniform Manifold Approximation and Projection (UMAP) was used for dimensionality reduction, followed by Gaussian Mixture Model (GMM) clustering. Survey-weighted prevalence estimates with 95% confidence intervals (CIs) were calculated for hypertension and high total cholesterol within each cluster. Weighted multivariable logistic regression was used to estimate odds ratios (OR) for hypertension, adjusting for age, sex, race/ethnicity, and income. Results Four exposure clusters were identified with a mean assignment probability of 0.948. The High combustion cluster (n=370; estimated 5.1 million US adults) exhibited the highest multi-chemical burden and a weighted hypertension prevalence of 39.3% (95% CI 37.2-41.4%), compared to 28.7% (95% CI 21.9-35.5%) in the Low exposure reference group. After demographic adjustment, High combustion cluster membership was independently associated with 38.4% higher odds of prevalent hypertension (OR 1.38). The prediction model achieved a cross-validated area under the receiver operating characteristic curve (AUC) of 0.849 (SD 0.017). Non-Hispanic Black participants constituted approximately 40% of the High combustion cluster, exceeding their representation in lower-risk clusters. Conclusions Multi-chemical exposome profiling identifies four cardiovascularly distinct subpopulations in the US adult population. Membership in the High combustion exposure cluster was associated with higher odds of prevalent hypertension and disproportionately affected Non-Hispanic Black participants. These findings support the use of multichemical approaches over single-pollutant analyses and highlight the relevance of environmental exposure patterns for making policy and targeted cardiovascular risk stratification.

Colorectal cancer (CRC) is the second leading cause of cancer death globally and the number one cause of cancer death in people under 50 years old. The reasons for the rise of early-onset CRC are unknown, and while anatomically distinct subtypes of CRC have substantial clinical and molecular associations, the etiology of region-specific disease, such as early-onset CRC's enrichment in the distal colon, remains unclear. Understanding regional mutagenesis may identify risk factors for this public health concern and CRC more broadly. To evaluate mutational dynamics across the premalignant colon, we performed whole-genome sequencing of 125 individual colon crypts taken from six standardized regions biopsied during colonoscopy, collected from 11 donors without polyps and 10 with polyps. We observed mutation spectra and accumulation rates consistent with previous whole-organ studies, with greater subclonal mutation capture enabled by experimental design. T>[A,C,G] mutations, which are associated with colibactin genotoxicity from pks+ Escherichia coli, were significantly enriched in the rectum of donors with and without polyps (adjusted p-values < 0.01). Moreover, when comparing findings to crypts from individuals with CRC and sequenced CRC tumors, we observed consistent enrichment of the colibactin-associated mutational signature "ID18" in the rectum in both normal colon crypts and CRC tumors, without significant difference in colibactin-specific single nucleotide variant or insertion-deletion burden in crypts across the three clinical groups (i.e., no polyp, polyp, and CRC). These findings argue against a causal or prognostic role for colibactin in CRC, instead indicating that the proposed association with early-onset disease reflects anatomic specificity rather than cancer-specific clinical relevance.