Table of Contents
Editorial
Review
Abstract
Background: Despite progress in reducing industrial air pollution, rising wildfire frequency and intensity, driven in part by climate change, pose significant health risks. Accurate estimates of wildfire-generated fine particulate matter with an aerodynamic diameter () are needed for advancing health research, policymaking, and environmental protection.
Objective: This review evaluates existing methodologies and data sources for estimating wildfire-generated , aiming to improving accuracy and accessibility for health research, policy development, and environmental management strategies.
Methods: We conducted a systematic literature search across Medline, Scopus, Web of Science, Google Scholar, and Embase (January 2018 to March 2024) using keywords such as “ exposure,” and “wildfire .” Studies were included if they were publicly available, focused on North America (primarily the US), and provided wildfire-attributable data. Of 2,757 articles identified, 418 full texts were screened, and 33 met inclusion criteria. Four studies offered wildfire-specific estimates of , and one dataset was excluded due to accessibility issues, leaving three for analysis. We processed data using R (version R 4.3.1; R Development Core Team) at the ZIP code level for consistency and examined total and wildfire-specific estimates for California in 2010 (low fire activity) and 2018 (high fire activity), focusing on Los Angeles (densely monitored) and Modoc (no monitors) counties. Analyses included Pearson correlation, cross-correlation, and Granger causality to assess temporal relationships and consistency.
Results: From the 33 studies included, three main estimation approaches emerged: chemical extraction, thresholding, and integration of satellite and fire-specific data (e.g., smoke plumes and fire perimeters). Most studies combined ground-based monitor data, satellite-derived aerosol optical depth, and explanatory data like meteorology and land use. The three public datasets indicated that in California, wildfire-specific contributed 11.2%–36.9% of total in 2010 and 13.7%–21.2% in 2018 with stronger agreement in 2018. Correlations were stronger in Modoc County (no monitors) (0.44–0.51 in 2010; 0.79–0.88 in 2018) than in Los Angeles County (densely populated area, 20 EPA monitors, where correlations ranged from 0.19–0.21 in 2010 and 0.54–0.79 in 2018). Overall, the datasets estimating total were more consistent than wildfire-specific estimates.
Conclusions: We offer a review of current data sources used for wildfire-specific estimation and compare publicly available datasets. As expected, the contribution of wildfire smoke to overall increased with wildfire activity. However, limited publicly available datasets hinder comprehensive comparisons and generalizations for health research and outcomes. https://doi.org/10.1289/EHP15672
Abstract
Background: The Michigan Polybrominated Biphenyl (PBB) Registry, followed since 1976, was created after a 1973 chemical manufacturing mistake. The flame retardant PBB was accidentally mixed into animal feed and distributed to Michigan farms for nearly a year, exposing farm residents and animal product consumers.
Objective: We synthesized knowledge to date on health effects of PBB exposure within the Michigan PBB Registry and describe research findings in the context of literature on other persistent organic pollutants (POPs) and endocrine-disrupting chemicals (EDCs).
Methods: We reviewed literature published from 1973 to 2025 on human health effects of PBB following the Michigan contamination, using PubMed and Thompson Reuters (ISI) Web of Science databases. We excluded studies not in English; studies on exposures besides PBB; animal studies; reviews, abstracts, or letters to the editor; studies without a health outcome; and studies outside of Michigan or unrelated to the 1973 contamination. For each article, two researchers performed title and abstract screening, full article review, and data extraction.
Results: We included 79 publications out of 601 identified and screened. Early studies did not find many health outcomes associated with PBB, possibly because of methodological limitations. More recent studies on long-term and multigenerational impacts found an increased breast cancer risk, accelerated pubertal development and earlier menarche for girls exposed in utero, urogenital problems and slower pubertal development in boys exposed in utero, lower estrone 3-glucuronide and follicle-stimulating hormone among women exposed in childhood, and increased miscarriage risk among daughters of exposed women. Epigenetic and metabolomic research reported altered pathways related to estrogenic effects and immune function as well as the epigenetic alterations of spermatogenic cells.
Discussion: This unique community–academic partnership has produced insights into multigenerational consequences of EDC/POP exposures across the life course. The findings from this cohort underscore the broader relevance of critical windows of vulnerability, particularly during fetal development and childhood. https://doi.org/10.1289/EHP15012
Research
Abstract
Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition with increasing prevalence worldwide. Air pollution may be a major contributor to the rise in ASD cases. This study investigated how the risk of ASD associated with prenatal and early postnatal exposure to specific air pollutants is modified by key sociodemographic factors, exploring vulnerable exposure periods.
Methods: We conducted a California population-based cohort study of 44,173 ASD cases among 2,371,379 children born between 2013 and 2018 (California birth registry), linked to California Department of Developmental Services (DDS) records to extract ASD diagnoses prior to the end of 2022. Prenatal and 1-year postnatal air pollution exposures [fine particulate matter with aerodynamic diameter (), nitrogen dioxide (), and ozone ()] were estimated using an advanced land-use regression (LUR) spatiotemporal model with machine learning. Logistic regression was used to estimate odds ratios and 95% confidence intervals for four models: single pollutant at a single period (prenatal or postnatal), multi-pollutant at a single period, single pollutant with dual periods (prenatal and postnatal), and multi-pollutant with dual time period co-adjustment, adjusting for relevant individual and regional covariates.
Results: Prenatal and postnatal exposures increased ASD odds in all models. was associated with ASD pre- and postnatally in single and multi-pollutant models but only postnatally in dual time period models. In contrast, showed the opposite pattern of with slightly negative associations in single and multi-pollutant models that turned positive for the prenatal period in dual time period models. The postnatal effect was strongest among Black and Hispanic children, suggesting higher contributions from traffic-related exposures.
Conclusions: Exposure to specific air pollutants during pregnancy and in the postnatal periods is associated with an increased risk of ASD, with sociodemographic differences potentially highlighting exposure hot spots and sources as well as subpopulation vulnerabilities. https://doi.org/10.1289/EHP15573
Abstract
Background: Per- and polyfluoroalkyl substances (PFAS) exposure is widespread and has been linked with gynecologic disease. To our knowledge, no study has measured PFAS in endometrial tissue.
Methods: Eutopic endometrial tissue specimens () were collected from Investigating Mixtures of Pollutants and Endometriosis in Tissue (IMPLANT) study participants undergoing laparoscopy or laparotomy for any indication (2007–2009). Nine PFAS were measured by high-performance liquid chromatography–tandem mass spectrometry [perfluorodecanoic acid (PFDA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorododecanoic acid (PFDoDA), perfluoroheptanoic acid (PFHpA), perfluorooctanesulfonamide (PFOSA), and perfluoroundecanoic acid (PFUnDA)]. Surgeons diagnosed endometriosis by gold-standard visualization and evaluated the endometriosis staging as moderate and severe (stages 3 and 4) compared to minimal and mild (stages 1 and 2) using American Society of Reproductive Medicine (ASRM) classification. We used modified Poisson regression models adjusted for age (continuous), race (white, all other race/ethnicities), smoking status (serum cotinine ), study site (Utah, California), and body mass index (continuous) to obtain relative risks (RR) of endometriosis diagnosis and 95% confidence intervals (CIs) for each PFAS. PFAS mixtures were evaluated using Bayesian kernel machine regression.
Results: Participants were, on average, years old, and 75% of participants were non-Hispanic white. Of the 181 participants with an incident endometriosis diagnosis, 73% had ASRM stage 1 or 2, while 27% had stage 3 or 4. Median [interquartile range (IQR)] eutopic endometrium tissue levels, in nanograms per gram, were 6.58 (6.44) for PFOS, 1.93 (1.71) for PFOA, 0.65 (0.75) for PFHxS, 0.58 (0.52) for PFNA, and 0.12 (0.18) for PFOSA. PFAS in the endometrial tissue was not associated with endometriosis. However, select PFAS in the eutopic tissue were associated with a risk of more advanced (stage 3 or 4 vs. 1 or 2) endometriosis [PFOSA (95% CI: 1.10, 1.43), PFHxS (95% CI: 1.12, 1.68), PFOS (95% CI: 1.02, 1.81)].
Conclusion: PFAS were widely detected in eutopic endometrial tissue. There was no evidence that PFAS in endometrial tissue were associated with a higher risk of endometriosis diagnosis. However, PFOS, PFOSA, and PFHxS in the endometrial tissue were associated with risk of more severe stage of endometriosis. https://doi.org/10.1289/EHP15852
Abstract
Background: Low pressure events (LPEs), defined as a water service disruption that presumably lowers system water pressure, can cause drinking water contamination, resulting in increased illness risk to consumers.
Objectives: This study sought to examine whether LPEs increase the risk for highly credible acute gastrointestinal illness (HCGI) and acute respiratory illness (ARI) and to compare water quality in exposed and unexposed areas in the United States.
Methods: A matched cohort study was conducted during the period 2015–2019. For each LPE, household survey exposed areas were matched 1:2 with unexposed areas based on water-main size and material at the point of repair, as well as the housing type and demographic characteristics of the local population from the most recent census tract data. Water samples were collected to monitor physicochemical and microbiological water quality parameters. Households (HHs) were surveyed about water use and illness during the 2 wk after the LPE. Multivariable log-binomial models clustered on utility and LPE number were used to investigate associations between LPE exposure and HCGI and ARI.
Results: Five water utilities reported 58 LPEs, including planned maintenance (76%) and emergency (24%) events. Controlling for livestock near home, private well presence, number of people in HH, and travel away from home, exposed HHs were at higher risk of HCGI in comparison with unexposed HHs (; 95% confidence interval: 1.05, 1.37). No associations between LPE and ARI were detected. Certain LPEs characteristics like pipe material, size, and depth were associated with an increased HH HCGI risk. HHs experiencing LPEs where low disinfectant residual, high adenosine triphosphate, or general Bacteroidales were detected in water following an LPE repair were also at a higher risk for HCGI.
Conclusions: LPEs were associated with 20% higher risk of HCGI in HHs. Planned improvements to water distribution system infrastructure, adherence to industry standard distribution repair practices, and water monitoring following pipe repairs could supplement community alert systems to reduce illnesses from LPEs. https://doi.org/10.1289/EHP15564
Abstract
Background: Maximum contaminant level violations occur more frequently among some public water systems (PWS) serving marginalized communities across the United States. Spatially resolved PWS service area data are now available, allowing for better understanding of relationships between sociodemographic factors and water quality.
Objectives: We examined associations between detection and concentrations of arsenic (As), chromium (Cr), manganese (Mn), and selenium (Se) and the sociodemographic characteristics of residents served by PWS at two spatial scales: PWS service areas and counties.
Methods: We leveraged data on inorganic contaminants in drinking water samples from PWS collected by state agencies and the US Environmental Protection Agency over the decade between 2005–2015 and curated in a national database developed by the Environmental Working Group. Sociodemographic data were from the 2006–2015 American Community Survey. We developed two-step hurdle models that included: a) a categorical model predicting contaminant detection and b) a continuous model predicting contaminant concentration. We developed these hurdle models using PWS service areas or counties as spatial units of analysis and compared results.
Results: PWS serving 5% higher proportions of limited English–speaking households had significantly greater detections of As, Cr, and Se, ranging from 1.25 [95% confidence interval (CI): 1.18, 1.32] times higher probability of Cr detection to 1.69 (95% CI: 1.58, 1.80) times higher probability of Se detection. Small PWS ( customers) had higher concentrations of these same three contaminants. PWS serving greater proportions of Black residents had a lower probability of detecting As, Cr, and Se, but significantly higher concentrations of Cr, Mn, and Se, particularly outside large urban areas. The direction of significant associations was consistent between spatial units of analysis, but county results tended to exhibit greater effect sizes and fewer significant associations.
Discussion: PWS service area data help to identify drinking water concerns specific to served communities and reduce issues related to statistical bias at larger spatial scales. Targeted subsidies for water infrastructure in communities served by small PWS would help reduce disparities in exposures to drinking water contaminants. https://doi.org/10.1289/EHP14793
Abstract
Background: Burning biomass fuels for cooking is a widespread environmental exposure that may adversely affect child health. We conducted an 18-month randomized field trial comparing a liquefied petroleum gas (LPG) stove, continuous fuel delivery, and behavioral messaging intervention starting in pregnancy through infancy with usual cooking practices using biomass fuels in Puno, Peru. A total of 800 pregnant women were enrolled. The intervention successfully lowered personal exposures to fine particulate matter with aerodynamic diameter () during pregnancy and infancy.
Objective: We sought to evaluate the effects of the intervention on neurodevelopment among preschool-age offspring.
Methods: We conducted a longitudinal follow-up study in a subset of Peruvian children born during the trial and assessed neurodevelopment between 24 and 36 months of age. Trained staff measured neurodevelopment using the Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III). The Bayley-III neurodevelopmental assessment test yields separate cognition, language, and motor scores. We measured personal exposures to three times during pregnancy and three times in infancy. We conducted modified intention-to-treat analyses of the intervention on Bayley-III scores and exposure–response analyses between prenatal and postnatal exposures and Bayley-III scores.
Results: A total of 301 children (mean age months, 47.8% girls, and 54.8% in intervention) were visited. Mean cognitive, language, and motor scores were , , and , respectively. On intention-to-treat, the adjusted differences between intervention and control arms were [98.3% confidence interval (CI): , 1.15], (, 0.1), and (, 2.29) for the composite cognitive, language, and motor scores, respectively. We did not identify associations between exposures during the 18-month intervention and any of the Bayley-III scores or when the personal exposures to were separated as either prenatal or postnatal.
Discussion: The LPG intervention did not improve neurodevelopment in Peruvian children. We also did not find an association between prenatal or postnatal exposures and neurodevelopment. https://doi.org/10.1289/EHP15500
- Xilin Shen,
- Maximilien Génard-Walton,
- Paige L. Williams,
- Jennifer B. Ford,
- Irene Souter,
- Yazeed Allan,
- Antonia M. Calafat,
- Dan Zhang,
- Jorge E. Chavarro,
- Russ Hauser,
- Lidia Mínguez-Alarcón, and
- the Earth Study Team
Abstract
Background: Phthalate exposures are ubiquitous and have been associated with pregnancy complications. Interaction between serum long-chain n-3 polyunsaturated fatty acids (n3PUFA) and phthalate biomarkers is biologically plausible because both can bind to human peroxisome proliferator–activated receptors (PPARs), which are involved in placenta development. However, evidence of this interaction in humans is lacking.
Objective: This study evaluated whether serum n3PUFA modifies the associations of biomarkers of phthalate exposure on pregnancy outcomes.
Methods: Among 351 women undergoing in vitro fertilization in the Environment and Reproductive Health study (2004–2017), we evaluated the effect modification of eicosapentaenoic acid (EPA) and serum docosahexaenoic acid (DHA) on the association of pregnancy outcomes with the mixture of urinary concentrations of phthalate biomarkers by quantile g-computation. All models were adjusted for age, body mass index, prior smoking, infertility diagnosis, treatment year, and urinary specific gravity.
Results: Concentrations of the phthalate biomarkers mixture were associated with higher adjusted probabilities of pregnancy loss and lower estimated probabilities of live birth among women with serum in the lowest tertile ( of total fatty acids), but not among women with middle-to-high serum ( and 0.15, respectively). Among women in the lowest tertile of serum , the adjusted probability [95% confidence interval (CI)] of pregnancy loss for women in the lowest and highest quartile of phthalates mixtures was 5% (95% CI: 2%, 16%) and 44% (95% CI: 23%, 85%), respectively (). The corresponding estimates were 14% (95% CI: 5%, 41%) and 11% (95% CI: 3%, 42%) among women with serum in the highest tertile ( of total fatty acids) (). Similar trends were observed for live birth but not for implantation and clinical pregnancy.
Conclusions: This study suggests adverse effects of phthalate exposure on pregnancy loss and live birth may be attenuated by intakes of n3PUFA. These results, if replicated, could inform clinical practice reducing the burden of infertility by phthalate exposure among the general population and improving pregnancy outcomes among subfertile couples. https://doi.org/10.1289/EHP15942
Abstract
Background: Neurotoxicity of exposure to volatile organic compounds (VOCs) has been documented in animal studies, but related epidemiological investigations are very limited; particularly, those based on biomonitoring data are not available yet.
Objectives: This study aimed to evaluate the trimester-specific association between maternal urinary concentrations of multiple VOC metabolites and child neurodevelopment.
Methods: Twenty VOC metabolites were measured in urine samples repeatedly collected at the first, second, and third trimesters from 1,023 pregnant women in Wuhan, China. The Bayley Scales of Infant and Toddler Development (Chinese Revision) was used to assess children’s neurocognitive development at 2 years old. General linear models and generalized estimating equations were used to analyze the associations of individual urinary VOC metabolite concentrations with children’s neurodevelopment. Weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) were used to evaluate the effect of the VOC metabolite mixture on children’s neurodevelopment.
Results: Risk assessment showed that the average hazard quotients of cyanide, 1,3-butadiene, and acrolein during pregnancy exceeded the recommended safety thresholds in more than 90% of the women. Higher urinary concentration of 2-aminothiazoline-4-carboxylic acid (ATCA) (a metabolite of cyanide) was associated with lower child mental development index (MDI) score, and the association was significant at the first trimester among males. Each interquartile ratio-fold increase in the urinary concentration of ATCA at the first trimester was associated with a decrease of 4.25 points (95% confidence interval: , ) in males’ MDI scores. Additionally, WQS regression and BKMR analyses suggested that the VOC metabolite mixture was significantly associated with lower MDI in males, and the association was mainly driven by ATCA.
Conclusions: Exposure to cyanide at environmentally relevant doses may impact neurodevelopment, particularly among males. Early pregnancy appeared to be the sensitive window of the exposure. Further studies are needed to confirm these findings. Corresponding measures need to be taken to reduce gestational exposure to cyanide. https://doi.org/10.1289/EHP15539
Abstract
Background: Many studies have reported associations of fine particulate matter with aerodynamic diameter ()with mortality but fewer at low concentrations and even fewer using causal modeling or correcting for exposure error bias. None have corrected for the nonrepresentativeness of monitoring locations.
Objectives: We examined the association of with all-cause mortality in the Medicare cohort using a combination of causal modeling, flexible concentration–response modeling, and bias correction for exposure error, while controlling for and as well as standard confounders.
Methods: Using monitors not used to fit our model, we fitted 72 regression calibration models stratified by season, region, and elevation in the US. We fitted a B-spline with 4 degrees of freedom to the calibrated and fitted separate generalized propensity score models for each spline component using gradient boosting. We also used inverse probability weights to account for the nonrepresentativeness of monitoring locations. Using the generalized propensity scores and the B-splines, we fitted quasi-Poisson models to counts of deaths in each ZIP code-year stratified by race, Medicaid status, and gender. Separate models were fit for participants identifying as black and as white and for ZIP codes with higher and lower poverty rates. We fit a model using the original exposure to estimate the extent of exposure error bias.
Results: The propensity score analysis achieved good balance for all covariates. Controlling for the propensity scores, we found a concentration–response curve with no evidence of a threshold and whose confidence interval did not include the null from and upward. There were 223,666,531 person-years of follow-up between the current US Environmental Protection Agency (EPA) standard of and the World Health Organization (WHO) guideline of , and the rate ratio between them was 1.088 [95% confidence interval (CI): 1.064, 1.113]. Using the original exposure, the rate ratio was 1.076 (95% CI: 1.070, 1.083). Hence, effects continue below the EPA standard, and calibrated estimates of effect were 16% higher. Effects were larger from among participants identifying as black.
Discussion: The concentration–response curve between air pollution and mortality remains after adjustment for exposure error and using causal models and continues to concentrations below current US EPA and EU standards and even below WHO guidelines. Exposure error in the original exposure resulted in noticeable downward bias at low concentrations. Persons identifying as black are more susceptible. https://doi.org/10.1289/EHP15238
Abstract
Background: Emerging evidence has implicated built and natural environmental exposures in the etiology and exacerbation of anxiety symptoms.
Objectives: Our objective was to assess individual and joint associations between neighborhood socioeconomic status (nSES), walkability, greenness, fine particulate matter (), nitrogen dioxide (), and temperature and generalized anxiety disorder (GAD) symptoms.
Methods: We included 81,897 participants of the Nurses’ Health Study II. GAD symptoms were measured in 2013 and 2017 using the seven-item Generalized Anxiety Disorder scale (GAD-7). Walkability and nSES z-scores were calculated at the census tract level. Summer and annual average greenness were measured using Normalized Difference Vegetation Index (NDVI) at 270 m and 1,230 m buffer sizes. 1-, 3-, and 12-month averages of particulate matter with an aerodynamic diameter of (), nitrogen dioxide (), and temperature were predicted using spatiotemporal models. Exposures were measured at the residential level. Longitudinal logistic and generalized estimating equations (GEE) models estimated odds ratios (OR) and 95% confidence intervals (CIs) for clinically relevant GAD symptoms (GAD-7 points). We assessed effect modification by nSES, summer NDVI (), and select covariates. We employed quantile g-computation to assess the association between environmental exposure mixtures and GAD symptoms more directly.
Results: In single-exposure models, summer NDVI (e.g., for , ; 95% CI: 0.94, 0.98), (e.g., for 12-month average , ; 95% CI: 1.01, 1.04), 12-month average temperature (; 95% CI: 1.03, 1.07), and walkability (; 95% CI: 1.01, 1.03) were associated with GAD symptoms. In the joint-exposure model, nSES (; 95% CI: 0.95, 0.98) and summer NDVI were associated (; 95% CI: 0.88, 0.96); all other associations were attenuated. Associations with summer NDVI (), temperature, and were modified by nSES, with stronger associations in socioeconomically deprived areas.
Discussion: In this population, higher levels of summer greenness and nSES may be protectively associated with GAD symptoms, whereas medium- and long-term exposure, long-term temperature, and walkability are adversely associated with GAD symptoms. Socioeconomically deprived areas may bear additional risks. The results of the quantile g-computation analysis suggest that environmental exposures may act antagonistically with one another in relation to GAD symptoms. https://doi.org/10.1289/EHP14458
Abstract
Background: Research has detected associations between air pollution exposure and type 2 diabetes (T2DM), but findings from large cohort studies are needed to ascertain the most influential pollutants, susceptible subpopulations, and low-level exposure associations. Our aim was to prospectively evaluate the association between long-term exposure to fine particulate matter in aerodynamic diameter () and nitrogen dioxide () and T2DM incidence in the Nurses’ Health Study (NHS) and Nurses’ Health Study II (NHSII) cohorts of US women.
Methods: Monthly and exposures were predicted from spatiotemporal models and linked to participants’ residential addresses. We used Cox proportional hazards models to assess the association between 24-month moving average and exposure and self-reported, clinician-diagnosed T2DM from 1992–2019. We adjusted for time-varying lifestyle factors, reproductive hormonal factors, and individual and neighborhood socioeconomic status (SES). Results were meta-analyzed. We evaluated whether relationships persisted at levels below the current US EPA National Ambient Air Quality Standards (NAAQS). Lastly, we examined multiplicative and additive interactions by body mass index (BMI), smoking status, physical activity, neighborhood SES, and region.
Results: Over follow-up, there were 19,083 incident T2DM cases among the 208,733 women in NHS and NHSII. In fully adjusted single-pollutant models, the hazard ratio (HR) for an interquartile range (IQR) () higher 24-month average exposure was 1.05 [95% confidence interval (CI): 1.02, 1.08] for incident T2DM. The HR for an IQR () higher exposure was 1.05 (95% CI: 1.01, 1.09). Both associations were robust to co-adjustment. Associations remained stable when restricting to levels below the NAAQS as compared to the full dataset. Stronger associations were observed in individuals who had a BMI , were physically active, and resided in the Northeast.
Conclusions: Our results showed a positive association between T2DM and long-term exposure to and , persisting even at levels below the current EPA NAAQS. https://doi.org/10.1289/EHP15673
Abstract
Background: Physiological heat strain induced by extreme temperatures in cities has led to significant heat-related deaths. Although socioeconomic adaptation is suggested to mitigate this issue, its effectiveness is limited. Conversely, there is a lack of comprehensive evaluation on the effectiveness of landscape-level strategies for mitigating heat-related deaths.
Objectives: We developed a comprehensive modeling framework to estimate the impacts of environmental stresses and mitigating strategies on heat-related deaths in China’s cities from 2016 to 2055.
Methods: The framework assesses future heat-related deaths through five experiments considering the influences of climate change, urbanization, socioeconomic adaptation, and landscape-level strategies. We used extrapolated region-specific exposure–response functions (ERF) and recent advancement of geo-statistics for public health to generate urban patch level ERF curves. We used these curves and temperature and population data to generate future heat-related deaths with a resolution and conducted 5,000 Monte Carlo simulations for uncertainty analysis.
Results: Our analyses estimated that heat-related mortality will increase from deaths per million in 2016 to deaths per million in 2055 under SSP2-RCP4.5 (shared socioeconomic pathways–representative concentration pathways) scenario and from deaths per million to deaths per million under SSP5-RCP8.5 scenario, despite socioeconomic adaptation and landscape-level strategies. Socioeconomic adaptation (reducing deaths by ) and landscape-level strategies (reducing deaths by ) significantly mitigate heat-related deaths with varying effectiveness across different income levels. Specifically, in high-income cities with dense populations, landscape-level strategies are 2.2–4.3 times more effective than socioeconomic adaptation. Within these cities, implementing the same landscape-level strategies in the high-density urban centers led to an additional reduction up to in comparison with surrounding areas.
Discussion: Our framework helps to systematically understand the effectiveness of landscape-level strategies in reducing heat-related mortality. Future sustainable city management should prioritize landscape-level strategies along with socioeconomic adaptation to support healthy and comfortable communities. https://doi.org/10.1289/EHP15010
- Tomomi Nishie,
- Tomoki Taya,
- Shunichi Omori,
- Kenya Ueno,
- Yoshinori Okamoto,
- Shogo Higaki,
- Marina Oka,
- Yachiyo Mitsuishi,
- Taiga Tanaka,
- Mana Nakamoto,
- Hideaki Kawahara,
- Natsuki Teraguchi,
- Tomoyuki Kotaka,
- Misaki Sawabe,
- Miu Takahashi,
- Shoko Kitaike,
- Minori Wada,
- Keiko Iida,
- Akihiro Yamashita,
- Hideto Jinno,
- Atsuhiko Ichimura,
- Ikuo Tooyama,
- Noriyoshi Sakai,
- Masahiko Hibi,
- Akira Hirasawa, and
- Tatsuyuki Takada
Abstract
Background: Developing human fetuses may be exposed to the chemical compound bisphenol A (BPA), and retinoic acid (RA) has been detected at low levels in water sources. RA signaling regulates key developmental genes and is essential for organ development, including the brain. We previously reported that RA/BPA coexposure of mouse embryonic stem cells potentiates RA signaling, which warrants further investigation.
Objective: This study was undertaken in human induced pluripotent stem cells (iPSCs) and zebrafish embryos to investigate whether coexposure to BPA and exogenous RA could potentiate HOX gene expression and exert pleiotropic effects on RA signaling.
Methods: Human iPSCs and zebrafish embryos were exposed to exogenous RA (0, 7.5, 10, 12.5, 100, 200 or ) or BPA () alone or coexposed to BPA () and exogenous RA (). Postexposure changes in HOX genes were assessed by quantitative polymerase chain reaction and/or transcriptome analyses. RA receptor antagonists were used to identify the receptor responsible for signaling. In zebrafish, spatial expression of fgf8a and hoxb1a was evaluated by whole-mount in situ hybridization. Mauthner cell and craniofacial cartilage anomalies were studied by immunostaining and Alcian blue staining, respectively. Transcriptome was compared between iPSCs and zebrafish to identify alterations of common biological processes. Gradient curves of RA signal were calculated to simulate the effects of exogenous RA and BPA in zebrafish.
Results: In both iPSCs and zebrafish, RA/BPA coexposure had higher expression of 3′ HOX genes in comparison with RA alone; BPA alone had no effect. Addition of RA receptor antagonists abolished these changes. In zebrafish, RA/BPA coexposure, in comparison with RA alone, resulted in a significant rostral shift in hoxb1a expression and increased rate of anomalies in Mauthner cells and craniofacial cartilage. Transcriptome comparison and correlations between the experimental results and gradient curve simulations strengthened these observations.
Conclusion: Our findings suggest a mechanistic link between chemical exposure and neurodevelopmental impairments and demonstrate involvement of exogenous RA signaling in endocrine disruption. Further investigation is needed to explore why BPA alone did not affect endogenous RA signaling, whereas exogenous RA signaling was potentiated with RA/BPA coexposure. https://doi.org/10.1289/EHP15574
Abstract
Background: With thousands of chemicals in commerce and the environment, rapid identification of potential hazards is a critical need. Combining broad molecular profiling with targeted in vitro assays, such as high-throughput transcriptomics (HTTr) and receptor screening assays, could improve identification of chemicals that perturb key molecular targets associated with adverse outcomes.
Objectives: We aimed to link transcriptomic readouts to individual molecular targets and integrate transcriptomic predictions with orthogonal receptor-level assays in a proof-of-concept framework for chemical hazard prioritization.
Methods: Transcriptomic profiles generated via TempO-Seq in U-2 OS and HepaRG cell lines were used to develop signatures composed of genes uniquely responsive to reference chemicals for distinct molecular targets. These signatures were applied to 75 reference and 1,126 nonreference chemicals screened via HTTr in both cell lines. Selective bioactivity toward each signature was determined by comparing potency estimates against the bulk of transcriptomic bioactivity for each chemical. Chemicals predicted by transcriptomics were confirmed for target bioactivity and selectivity using available orthogonal assay data from the US Environmental Protection Agency ToxCast program. A subset of 37 selectively acting chemicals from HTTr that did not have sufficient orthogonal data were prospectively tested using one of five receptor-level assays.
Results: Of the 1,126 nonreference chemicals screened, 201 demonstrated selective bioactivity in at least one transcriptomic signature and 57 were confirmed as selective nuclear receptor agonists. Chemicals bioactive for each signature were significantly associated with orthogonal assay bioactivity, and signature-based points-of-departure were equally or more sensitive than biological pathway altering concentrations in 95.4% of signature-prioritized chemicals. Prospective profiling found that 18 of 37 (49%) chemicals without prior orthogonal assay data were bioactive against the predicted receptor.
Discussion: Our work demonstrates that integrating transcriptomics with targeted orthogonal assays in a tiered framework can support Next Generation Risk Assessment by informing putative molecular targets and prioritizing chemicals for further testing. https://doi.org/10.1289/EHP16024
Abstract
Background: Global and site-specific changes in DNA methylation and gene expression are associated with cardiovascular development, aging, and disease, but how the transcriptome and epigenome of the heart change across the life course in males vs. females and how chemical exposures early in life influence this programming have not yet been investigated.
Objectives: We used an established mouse model of developmental exposures to investigate the effects of perinatal exposure to either lead (Pb) or diethylhexyl phthalate (DEHP), two ubiquitous environmental contaminants that are both strongly associated with cardiovascular diseases (CVDs), on DNA methylation and gene expression across the life course in whole hearts.
Methods: Dams were randomly assigned to receive human physiologically relevant levels of Pb ( in water), DEHP ( chow), or control water and chow. Exposures started 2 weeks prior to mating and continued until weaning at postnatal day 21 (3 wk of age). Approximately 1 male and 1 female offspring per litter were followed to 3 wk, 5 months, or 10 months of age, at which time whole hearts were collected ( per sex per exposure). Enhanced reduced representation bisulfite sequencing (ERRBS) was used to assess the cardiac DNA methylome at 3 wk and 10 months, and RNA-Seq was conducted at all three time points. MethylSig and edgeR were used to identify age-related differentially methylated regions (DMRs) and differentially expressed genes (DEGs), respectively, within each sex and exposure group. Cell type deconvolution of bulk RNA-Seq data was conducted using the MuSiC algorithm and publicly available single-cell RNA-Seq data.
Results: Thousands of DMRs and hundreds of DEGs were identified in control, DEHP, and Pb-exposed hearts across time between 3 wk and 10 months of age. A closer look at the genes and pathways showing differential DNA methylation revealed that the majority were unique to each sex and exposure group. Overall, pathways governing development and differentiation changed across time in all conditions. A small number of genes in each group showed significant differences in DNA methylation and gene expression with life stage, including several that were different in toxicant-exposed but not control mice. We also observed subtle but significant differences in the proportion of several cell types that were associated with life stage, sex, or developmental exposure.
Discussion: Together these data suggest that gene expression and DNA methylation programs, as well as cellular composition, may differ across the life course long after cessation of exposure in perinatal Pb- or DEHP-exposed mice compared to controls and highlight potential biomarkers of developmental toxicant exposures; however, additional studies are required for confirmation. Further studies are also needed to investigate how epigenetic and transcriptional differences impact cardiovascular health across the life course, particularly in old age when the risk of cardiovascular diseases is markedly increased. https://doi.org/10.1289/EHP15503
- Jieun Min,
- Whanhee Lee,
- Jieun Oh,
- Cinoo Kang, and
- Eunhee Ha
Abstract
Background: Epidemiology studies have reported inconsistent associations of humidity with heat-related health outcomes, despite strong plausibility of such physiological associations. In this regard, there has been a heated debate on which humidity metric to use in epidemiological research.
Objectives: This study aimed to compare the role of two common humidity metrics, relative and absolute humidity, in heat-related mortality in summer using a nationwide mortality dataset.
Methods: We applied a case time-series design for summer (June–September) mortality across the entire 229 districts of South Korea from 2011 to 2019. The temperature was fitted using a distributed lag nonlinear model (DLNM) with 10 lag days. A linear interaction between the cross-basis of temperature and humidity was included in each model to examine the different patterns of association between heat and mortality by humidity level (low and high humidity defined by fifth and 95th percentile of each humidity distribution).
Results: A total of 780,102 deaths were recorded in the summer from 2011 to 2019 in South Korea. The association between extreme heat (temperature approximately above the 99th percentile of the temperature distribution) and mortality was modified more by absolute humidity than by relative humidity, although the effect modification of both humidity indicators was not statistically significant. The relative risks at the 99.Ninth percentile temperature in comparison with the minimum mortality temperature were 1.21 [95% confidence interval (CI): 1.11, 1.31] and 1.22 (95% CI: 1.03, 1.44) for low and high relative humidity, respectively, and 1.11 (95% CI: 0.89, 1.37) and 1.25 (95% CI: 1.15, 1.34) for low and high absolute humidity, respectively.
Discussion: Our findings provide epidemiological evidence on the role of relative and absolute humidity in heat-related mortality and suggest that absolute humidity may be a more appropriate metric than relative humidity when assessing health impact. https://doi.org/10.1289/EHP15827
Abstract
Background: Plastic-containing medical devices are commonly used in critical care units and other patient care settings. Patients are often exposed to xenobiotic agents that are leached out from plastic-containing medical devices, including bisphenol A (BPA) and phthalates. Given the potential health implications, there is an urgent need for a comprehensive understanding of this exposure.
Objectives: This multi-institutional study aimed to determine the time-dependent concentrations and analyze the exposure patterns of bisphenol A (BPA) and phthalate metabolites in urine obtained from infants with congenital heart defects (CHD) undergoing cardiac surgery during the perioperative period.
Methods: We collected daily urine samples from infants with CHD undergoing cardiac surgery during the perioperative period (from birth to 21 d) and measured BPA, di(2-ethylhexyl)phthalate (DEHP) metabolites (MEHP, MEHHP, MEOHP, MECPP), and non-DEHP phthalate metabolites (MBP, MBzP, MMP, MEP, MCPP) using ultra-high-performance liquid chromatography–tandem mass spectrometry. Machine learning–based cluster analysis was utilized to analyze these time-dependent data.
Results: Utilizing a machine learning–based clustering approach, six distinct clustering groups were identified among infants exhibiting similar time-series toxicokinetic exposure patterns. These distinct clustering groups correlated with the utilization of extracorporeal membrane oxygenation (ECMO) and cardiopulmonary bypass (CPB), as well as the intensity of medical care. Notably, clustering groups associated with ECMO use demonstrated elevated levels of urinary BPA and DEHP metabolites compared to those without ECMO use, a trend not observed with non-DEHP metabolites. Moreover, peak concentrations in toxicokinetic profiles were associated with intensity of medical care.
Discussion: Our findings suggest that dynamic changes of urinary BPA and DEHP metabolites corresponded to the type and number of medical devices used in infants. Further studies are needed to investigate the potential toxicological risks of infants with CHD undergoing cardiac surgery exposed to these chemicals in medical devices. https://doi.org/10.1289/EHP15034
Abstract
Background: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) have been shown to disrupt normal follicular development and ovulation. However, it is unknown which specific PFAS in follicular fluid negatively impact oocyte development and embryo quality or whether any of the metabolites present in the follicular fluid contribute to these adverse effects.
Objectives: We conducted a cross-sectional and cohort study to identify specific PFAS with significant adverse effects on embryo quality and their associated modes of action.
Methods: We enrolled 378 women undergoing assisted reproductive technology (ART) and collected follicular fluid samples during oocyte retrieval. We performed PFAS detection and untargeted metabolomics on the follicular fluid. The associations of individual PFAS with high-quality embryo rates and clinical pregnancy outcomes were assessed using beta regression and logistic regression, respectively, and the potential joint effect of mixtures of PFAS was assessed using Bayesian kernel machine regression (BKMR) and quantile g-computation models. A causal mediation effect model was performed to estimate the average indirect impact of PFAS, mediated by high-quality embryo rates, on clinical pregnancy outcomes, as well as its direct impact representing all other causal effects. Spearman’s rank correlation coefficient was used to identify the associations between the differentially expressed metabolites and the high-quality embryo rates.
Results: The detection frequencies of 15 PFAS exceeded 85%, and perfluorooctanoic acid (PFOA) had the highest median concentration (). The PFAS mixture was negatively associated with the high-quality embryo rate, and PFOA was the major contributor (conditional posterior inclusion ). PFAS was also negatively associated with clinical pregnancy outcome, and the causal mediation analysis revealed that the embryo quality potentially mediated the relationship between the clinical pregnancy outcome with PFOA [proportion mediated: 0.181; 95% confidence interval (CI): 0.024, 0.755], perfluoro-n-nonanoic acid (PFNA) (proportion mediated: 0.148; 95% CI: 0.022, 0.656), or perfluoro-n-tridecanoic acid (PFTrDA) (proportion mediated: 0.130; 95% CI: 0.005, 0.693). The decreased organonitrogens (Pro-Trp and lauryldimethylamine oxide) and sphingolipids metabolites (phytosphingosine, N-myristoylsphinganine, and N-lauroyl-d-erythro-sphinganine) in the follicular fluid were associated with PFOA-related poor embryo quality.
Conclusions: High exposure to follicular fluid PFAS was negatively correlated with embryo quality during ART, with PFOA likely to be the major contributor. PFOA-related poor embryo quality was associated with the reduction of organonitrogens and sphingolipids metabolites that are crucial for the maintenance of normal cell growth and metabolism. https://doi.org/10.1289/EHP15422
Abstract
Background: The increase in the frequency and scale of climate-related disasters is closely linked to greenhouse gas emissions (GHGEs) from food systems. Due to a lack of a comprehensive emission database that covers entire food systems, data on per capita dietary GHGEs are limited.
Objective: We created the Food Systems–related GHGE Factor Database (FS-GHGEF-D) to cover an entire food system and estimate per capita GHGEs for Korea.
Methods: We include GHGE factors for 3,894 food items derived from 24-h recall data of the seventh Korea National Health and Nutrition Examination Survey (2016–2018). We extracted these factors from 920 articles, excluding studies that focused only on specific GHG types or single-system boundaries and used a Monte Carlo Markov chain simulation to assess uncertainty of estimates.
Results: The FS-GHGEF-D covered 96.6% of food items. A total of 265 food items, primarily alcoholic and nonalcoholic beverages, were characterized by high degrees of uncertainty. However, removing these foods did not significantly alter the average GHGE factor across all food groups or affect coverage significantly, with the exception of the beverage category (both alcoholic and nonalcoholic). The average daily diet–related GHGEs per capita in Korea, as calculated using FS-GHGEF-D, were . Among food groups, meats contributed the most to the total variation in dietary GHGEs in the Korea population (75.7%). Men generally emitted more GHGEs than did women, with men in their 30s being the highest emitters.
Discussion: This study highlights the utility of a full-system GHGE database that addresses prior limitations in global estimates. Korean dietary patterns exceed climate-compatible thresholds, with substantial variation by demographic groups. These findings support the need for equity-focused strategies and integration of environmental considerations into national dietary guidelines for sustainable and climate-resilient food systems. https://doi.org/10.1289/EHP15534
Abstract
Background: Quantitative characterization of the health impacts associated with exposure to chemical mixtures has received considerable attention in current environmental and epidemiological studies. With many existing statistical methods and emerging approaches, it is important for practitioners to understand which method is best suited for their inferential goals.
Objective: The goal of this paper is to provide empirical simulation-based evidence regarding performance of mixture methods to help guide researchers on selecting the best available methods to address three scientific questions in mixtures analysis: identifying important components of a mixture, identifying interactions among mixture components, and creating a summary score for risk stratification and prediction.
Methods: We conducted a review and comparison of 11 analytical methods available for use in mixtures research through extensive simulation studies for continuous and binary outcomes. In addition, we carried out an illustrative data analysis using the PROTECT birth cohort from Puerto Rico to examine the associations between exposure to chemical mixtures—metals, polycyclic aromatic hydrocarbons (PAHs), phthalates, and phenols—and birth outcomes.
Results: Our simulation results suggest that the choice of methods depends on the goal of analysis and that there is no clear winner across the board. For selection of important toxicants in the mixtures and for identifying interactions, Elastic net (Enet) by Zou et al., Lasso for Hierarchical Interactions (HierNet) by Bien et al., and selection of nonlinear interactions by a forward stepwise algorithm (SNIF) by Narisetty et al. have the most stable performance across simulation settings. For overall summary or a cumulative measure, we find that using the Super Learner to combine multiple environmental risk scores can lead to improved risk stratification and prediction properties.
Conclusions: We develop an integrated R package “CompMix” that provides a platform for mixtures analysis where the practitioners can implement a pipeline that includes several approaches for mixtures analysis. Our study offers guidelines for selecting appropriate statistical methods for addressing specific scientific questions related to mixtures research. We identify critical gaps where new and better methods are needed. https://doi.org/10.1289/EHP15305
Abstract
Background: An increasing number of studies have reported noteworthy health risks associated with dermal exposure to volatile organic compounds (VOCs) from feminine hygiene products (FHPs).
Objectives: This study sought to address the gap in understanding the absorption, distribution, metabolism, and excretion dynamics of dermal exposure to VOCs from FHPs and to identify chemicals and products that could cause significant body burden.
Methods: We used measured contents of eight widely present VOCs across five categories of FHPs to estimate dermal exposure, and applied a physiologically based toxicokinetic (PBTK) modeling approach to elucidate VOC toxicokinetics in human body tissues. Inhalation exposure estimates were derived from 20 air samples collected via passive sampling and analyzed using a thermal desorption system coupled with gas chromatography–mass spectrometry. Predicted urinary VOC concentrations based on dermal and inhalation exposure were validated against 99 measurements from 25 females.
Results: Via skin absorption, the estimated levels of most target VOCs in nearly all tissues, except adipose and the rest of the body, rapidly peaked within an hour of product use. Specifically, -cymene was estimated to reach in adipose tissue before decreasing over several hours due to efficient excretion pathways, including liver metabolism and exhalation. The model estimated that although the majority of absorbed VOCs (78.9%) were eliminated via liver metabolism, exhalation, and urine excretion, VOCs with higher than 3.5, such as -cymene, hexane, and -nonane, exhibited a potential cumulative trend in adipose tissue. This trend resulted in the estimated VOC concentrations in adipose tissue being 1 to 4 orders of magnitude higher than those estimated in other tissues. In certain cases, -nonane posed a potential noncancer risk (up to 0.07), and benzene presented a notable cancer risk (up to ), primarily attributed to washes and moisturizers, respectively.
Discussion: These findings reveal potential significant body burden and health risks associated with dermal exposure to VOCs from FHPs, warranting further research and regulatory measures. Comprehensive assessment of internal exposure by integrating with toxicokinetic modeling to elucidate chemical distribution in various tissues is recommended, rather than by measuring only one type of biomarker, to illustrate exposure variances and ensure accurate risk assessment. https://doi.org/10.1289/EHP15418
Abstract
Background: Billions of the world’s poorest households are faced with the lack of access to both safe drinking water and clean cooking. One solution to microbiologically contaminated water is boiling, often promoted without acknowledging the additional risks incurred from indoor air degradation from using solid fuels.
Objectives: This modeling study explores the trade-off of increased air pollution from boiling drinking water under multiple contamination and fuel use scenarios typical of low-income settings.
Methods: We calculated the total change in disability-adjusted life years (DALYs) from household air pollution (HAP) and diarrhea from fecal contamination of drinking water for scenarios of different source water quality, boiling effectiveness, and stove type. We used Uganda and Vietnam, two countries with a high prevalence of water boiling and solid fuel use, as case studies.
Results: Boiling drinking water reduced the diarrhea disease burden by a mean of 1,100 DALYs and 367 DALYs per 10,000 people for those under and over 5 y of age in Uganda, respectively, for high-risk water quality and the most efficient (lab-level) boiling scenario, with smaller reductions for less-contaminated water and ineffective boiling. Similar results were found in Vietnam, though with fewer avoided DALYs in children under 5 y of age due to different demographics. In both countries, for households with high baseline HAP from existing solid fuel use, adding water boiling to cooking on a given stove was associated with a limited increase in HAP DALYs due to the log-linear exposure–response curves. Boiling, even at low effectiveness, was associated with net DALY reductions for medium- and high-risk water, even with unclean stoves/fuels. Use of clean stoves coupled with effective boiling significantly reduced total DALYs.
Discussion: Boiling water generally resulted in net decreases in DALYs. Future efforts should empirically measure health outcomes from HAP vs. diarrhea associated with boiling drinking water using field studies with different boiling methods and stove types. https://doi.org/10.1289/EHP15059
Research Letter
Erratum
- Tomomi Nishie,
- Tomoki Taya,
- Shunichi Omori,
- Kenya Ueno,
- Yoshinori Okamoto,
- Shogo Higaki,
- Marina Oka,
- Yachiyo Mitsuishi,
- Taiga Tanaka,
- Mana Nakamoto,
- Hideaki Kawahara,
- Natsuki Teraguchi,
- Tomoyuki Kotaka,
- Misaki Sawabe,
- Miu Takahashi,
- Shoko Kitaike,
- Minori Wada,
- Keiko Iida,
- Akihiro Yamashita,
- Hideto Jinno,
- Atsuhiko Ichimura,
- Ikuo Tooyama,
- Noriyoshi Sakai,
- Masahiko Hibi,
- Akira Hirasawa, and
- Tatsuyuki Takada
