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Humans are exposed to combinations of chemicals. In cumulative risk assessment (CRA), regulatory bodies such as the European Food Safety Authority consider dose addition as a default and sufficiently conservative approach. The principle of dose addition was confirmed previously for inducing craniofacial malformations in zebrafish embryos in binary mixtures of chemicals with either similar or dissimilar modes of action (MOAs).In this study, we explored a workflow to select and experimentally test multiple compounds as a complex mixture with each of the compounds at or below its no observed adverse effect level (NOAEL), in the same zebrafish embryo model.Selection of candidate compounds that potentially induce craniofacial malformations was done usingA final selection of eight compounds was examined in the zebrafish embryo model, and craniofacial malformations were observed in embryos exposed to each of the compounds, thus confirming the developmental toxicity as predicted by theThis case study of a complex mixture inducing craniofacial malformations in zebrafish embryos shows that dose addition can adequately predicted the cumulative effect of a mixture of multiple substances at low doses, irrespective of the (expected) MOA. The applied workflow may be useful as an approach for CRA in general. https://doi.org/10.1289/EHP9888.

Background: Mounting evidence has shown that long-term exposure to fine particulate matter [PM ≤2.5μm in aerodynamic diameter (PM2.5)] and ozone (O3) can increase mortality. However, the health effects associated with long-term exposure to nitrogen dioxide (NO2) are less clear, in particular the evidence is scarce for NO2 at low levels that are below the current international guidelines. Methods: We constructed a population-based full cohort comprising all Medicare beneficiaries (aged ≥65, N=13,590,387) in the southeastern United States from 2000 to 2016, and we then further defined the below-guideline cohort that included only those who were always exposed to low-level NO2, that is, with annual means below the current World Health Organization guidelines (i.e., ≤21 ppb). We applied previously estimated spatially and temporally resolved NO2 concentrations and assigned annual means to study participants based on their ZIP code of residence. Cox proportional hazards models were used to examine the association between long-term exposure to low-level NO2 and all-cause mortality, adjusting for potential confounders. Results: About 71.1% of the Medicare beneficiaries in the southeastern United States were always exposed to low-level NO2 over the study period. We observed an association between long-term exposure to low-level NO2 and all-cause mortality, with a hazard ratio (HR)= 1.042 (95% CI: 1.040, 1.045) in single-pollutant models and a HR= 1.047 (95% CI: 1.045, 1.049) in multipollutant models (adjusting for PM2.5 and O3), per 10-ppb increase in annual NO2 concentrations. The penalized spline indicates a linear exposure–response relationship across the entire NO2 exposure range. Medicare enrollees who were White, female, and residing in urban areas were more vulnerable to long-term NO2 exposure. Conclusion: Using a large and representative cohort, we provide epidemiological evidence that long-term exposure to NO2, even below the national and global ambient air quality guidelines, was approximately linearly associated with a higher risk of mortality among older adults, independent of PM2.5 and O3 exposure. Improving air quality by reducing NO2 emissions, therefore, may yield significant health benefits. https://doi.org/10.1289/EHP9044

Background: We do not currently understand how spatiotemporal variations in the composition of fine particulate air pollution [fine particulate matter with aerodynamic diameter ≤2.5μm (PM2.5)] affects population health risks. However, recent evidence suggests that joint concentrations of transition metals and sulfate may influence the oxidative potential (OP) of PM2.5 and associated health impacts. Objectives: The purpose of the study was to evaluate how combinations of transition metals/OP and sulfur content in outdoor PM2.5 influence associations with acute cardiovascular events. Methods: We conducted a national case-crossover study of outdoor PM2.5 and acute cardiovascular events in Canada between 2016 and 2017 (93,344 adult cases). Monthly mean transition metal and sulfur (S) concentrations in PM2.5 were determined prospectively along with estimates of OP using acellular assays for glutathione (OPGSH), ascorbate (OPAA), and dithiothreitol depletion (OPDTT). Conditional logistic regression models were used to estimate odds ratios (OR) [95% confidence intervals (CI)] for PM2.5 across strata of transition metals/OP and sulfur. Results: Among men, the magnitudes of observed associations were strongest when both transition metal and sulfur content were elevated. For example, an OR of 1.078 (95% CI: 1.049, 1.108) (per 10μg/m3) was observed for cardiovascular events in men when both copper and S were above the median, whereas a weaker association was observed when both elements were below median values (OR=1.019, 95% CI: 1.007, 1.031). A similar pattern was observed for OP metrics. PM2.5 was not associated with acute cardiovascular events in women. Discussion: The combined transition metal and sulfur content of outdoor PM2.5 influences the strength of association with acute cardiovascular events in men. Regions with elevated concentrations of both sulfur and transition metals in PM2.5 should be examined as priority areas for regulatory interventions. https://doi.org/10.1289/EHP9449

Background: Epidemiological studies have shown that exposure to ambient fine particulate matter with aerodynamic diameter less than or equal to 2.5 μm (PM2.5) correlates with a decrease in sperm count, but the biological mechanism remains elusive. Objectives: This study tested whether hypothalamic inflammation, an emerging pathophysiological mediator, mediates the development of lower epididymal sperm count due to PM2.5 exposure. Methods: Inhibitor κB kinase 2 (IKK2) was conditionally knocked out either in all neurons or subtypes of hypothalamic neurons of mice. Effects of concentrated ambient PM2.5 (CAP) exposure on hypothalamic inflammation, the hypothalamic–pituitary–gonadal (HPG) axis, and epididymal sperm count of these mouse models were then assessed. Furthermore, to test whether hypothalamic inflammation is sufficient to decrease sperm production, we overexpressed constitutively active IKK2 (IKK2ca) either in all neurons or subtypes of hypothalamic neurons and assessed hypothalamic inflammation, the HPG axis, and sperm production of these overexpression mouse models. Results: CAP-exposed wild-type control mice vs. filtered air (FA)-exposed wild-type control mice had a higher expression of hypothalamic inflammatory markers, lower functional indexes of the HPG axis, and a lower epididymal sperm count. In contrast, all these measurements for CAP- vs. FA-exposed mice deficient of IKK2 in all neurons were comparable. We also found that overexpression of IKK2ca in either all neurons or pro-opiomelanocortin (POMC) neurons only, but not in Agouti-related protein (AgRP) neurons only, resulted in lower functional indexes of the HPG axis and a lower epididymal sperm count. Moreover, we showed that CAP- vs. FA-exposed mice deficient of IKK2 in POMC neurons had a comparable expression of hypothalamic inflammatory markers, comparable functional indexes of the HPG axis, and a comparable epididymal sperm count. Discussion: This mouse model study shows a causal role of IKK2 of POMC neurons in the development of lower epididymal sperm count due to PM2.5 exposure, providing a mechanistic insight into this emerging pathogenesis. https://doi.org/10.1289/EHP8868

Introduction: Cannabis regulation and use are undergoing dramatic changes. New cannabis products and new ways of using are emerging. These changes have the potential to affect exposure to cannabis smoke and other emissions from cannabis use. Cannabis smoke is known to contain fine, respirable particles (PM2.5) and other toxicants and carcinogens.Objectives: To assess the potential for exposure to PM2.5 from novel cannabis aerosols, we measured PM2.5 concentrations in a cannabis retail outlet (a dispensary) that permits on-site consumption of cannabis via non-combustion methods including vaporization and dabbing.Methods: PM2.5 concentrations in the dispensary were measured around the clock for five weeks using 2 laser photometer instruments (429,604 data points collected over 38.69 days). The instruments were calibrated gravimetrically using a controlled cigarette generation system at regular intervals during the experiment. Outdoor PM2.5 concentrations were taken from a nearby EPA monitoring station.Results: The average PM2.5 concentration in the dispensary retail space, during business hours, was 84 ± 124 µg/m3, with a median of 47 µg/m3. The average PM2.5 concentration when the business was closed was 3 ± 7 µg/m3 with a median of 2 µg/m3. The highest daily concentrations correlated with the hours with the most customers.Conclusion: Our results suggest that the use of cannabis products indoors, even by non-combustion methods, increases the concentration of PM2.5. These findings are of concern to the public health because the business studied was in compliance with local laws and because PM2.5 exposure is a known cause of cardiopulmonary and metabolic disease.

Background: Exposure to secondhand smoke (SHS) is a risk factor for developing sporadic forms of sporadic dementia. A human tau (htau) mouse model is available that exhibits age-dependent tau dysregulation, neurofibrillary tangles, neuronal loss, neuroinflammation, and oxidative stress starting at an early age (3–4 months) and in which tau dysregulation and neuronal loss correlate with synaptic dysfunction and cognitive decline. Objective: The goal of this study was to assess the effects of chronic SHS exposure (10 months’ exposure to ∼30 mg/m3) on behavioral and cognitive function, metabolism, and neuropathology in mice. Methods: Wild-type (WT) and htau female and male mice were exposed to SHS (90% side stream, 10% main stream) using the SCIREQ® inExpose™ system or air control for 168 min per day, for 312 d, 7 d per week. The exposures continued during the days of behavioral and cognitive testing. In addition to behavioral and cognitive performance and neuropathology, the lungs of mice were examined for pathology and alterations in gene expression. Results: Mice exposed to chronic SHS exposure showed the following genotype-dependent responses: a) lower body weights in WT, but not htau, mice; b) less spontaneous alternation in WT, but not htau, mice in the Y maze; c) faster swim speeds of WT, but not htau, mice in the water maze; d) lower activity levels of WT and htau mice in the open field; e) lower expression of brain PHF1, TTCM1, IGF1β, and HSP90 protein levels in WT male, but not female, mice; and f) more profound effects on hippocampal metabolic pathways in WT male than female mice and more profound effects in WT than htau mice. Discussion: The brain of WT mice, in particular WT male mice, might be especially susceptible to the effects of chronic SHS exposure. In WT males, independent pathways involving ascorbate, flavin adenine dinucleotide, or palmitoleic acid might contribute to the hippocampal injury following chronic SHS exposure. https://doi.org/10.1289/EHP8428

Background: Experimental evidence and studies of children and adolescents suggest that ambient fine particulate matter [particulate matter ≤2.5μm in aerodynamic diameter (PM2.5)] air pollution may be obesogenic, but the relationship between PM2.5 and the risk of body weight gain and obesity in adults is uncertain. Objectives: Our goal was to characterize the association between PM2.5 and the risks of weight gain and obesity. Methods: We followed 3,902,440 U.S. Veterans from 2010 to 2018 (median 8.1 y, interquartile range: 7.3–8.4) and assigned time-updated PM2.5 exposures by linking geocoded residential street addresses with satellite-based estimates of surface-level PM2.5 mass (at ∼1-km2 resolution). Associations with PM2.5 were estimated using Cox proportional hazards models for incident obesity [body mass index (BMI)≥30 kg/m2] and a 10-lb increase in weight relative to baseline and linear mixed models for associations with intra-individual changes in BMI and weight. Results: A 10-μg/m3 higher average annual PM2.5 concentration was associated with risk of incident obesity [n=2,325,769; hazard ratio (HR)=1.08 (95% CI: 1.06, 1.11)] and the risk of a 10-lb (4.54 kg) increase in weight [HR=1.07 (95% CI: 1.06, 1.08)] and with higher intra-individual changes in BMI [0.140 kg/m2 per year (95% CI: 0.139, 0.142)] and weight [0.968 lb/y (95% CI: 0.955, 0.981)]. Nonlinear exposure–response models indicated associations at PM2.5 concentrations below the national standard of 12 μg/m3. As expected, a negative exposure control (ambient air sodium) was not associated with obesity or weight gain. Associations were consistent in direction and magnitude across sensitivity analyses that included alternative outcomes and exposures assigned at different spatial resolutions. Discussion: PM2.5 air pollution was associated with the risk of obesity and weight gain in a large predominantly male cohort of U.S. Veterans. Discussions about health effects of PM2.5 should include its association with obesity, and deliberations about the epidemiology of obesity should consider its association with PM2.5. Investigation in other cohorts will deepen our understanding of the relationship between PM2.5 and weight gain and obesity. https://doi.org/10.1289/EHP7944

Background: Uranium contamination of drinking-water sources on American Indian (AI) reservations in the United States is a largely ignored and underfunded public health crisis. With an estimated 40% of the headwaters in the western U.S. watershed, home to many AI reservation communities, being contaminated with untreated mine waste, the potential health effects have largely been unexplored. With AI populations already facing continued and progressive economic and social marginalization, higher prevalence of chronic disease, and systemic discrimination, associations between various toxicant exposures, including uranium, and various chronic conditions, need further examination. Objectives: Uranium’s health effects, in addition to considerations for uranium drinking-water testing, reporting, and mitigation in reference to AI communities through the lens of water quality, is reviewed. Discussion: A series of environmental health policy recommendations are described with the intent to proactively improve responsiveness to the water quality crisis in AI reservation communities in the United States specific to uranium. There is a serious and immediate need for better coordination of uranium-related drinking-water testing and reporting on reservations in the United States that will better support and guide best practices for uranium mitigation efforts. https://doi.org/10.1289/EHP7537

Background: Risk assessment of chemical mixtures or complex substances remains a major methodological challenge due to lack of available hazard or exposure data. Therefore, risk assessors usually infer hazard or risk from data on the subset of constituents with available toxicity values. Objectives: We evaluated the validity of the widely used traditional mixtures risk assessment paradigms, Independent Action (IA) and Concentration Addition (CA), with new approach methodologies (NAMs) data from human cell-based in vitro assays. Methods: A diverse set of 42 chemicals was tested both individually and as mixtures for functional and cytotoxic effects in vitro. A panel of induced pluripotent stem cell (iPSCs)-derived models (hepatocytes, cardiomyocytes, endothelial, and neurons) and one primary cell type (HUVEC) were used. Bayesian concentration–response modeling of individual chemicals or their mixtures was performed for a total of 47 phenotypes to derive point-of-departure (POD) values. Probabilistic IA or CA was conducted to estimate the mixture effects based on the bioactivity profiles from the individual chemicals and compared with mixture bioactivity. Results: All mixtures showed significant bioactivity, even though some were constructed using individual chemical concentrations considered “low” or “safe.” Even though CA is much more accurate as a predictor of mixture effects in comparison with IA, with CA-based POD typically within an order of magnitude of the actual mixture, in some cases, the bioactivity of the mixtures appeared to be much greater than that of their components under either additivity assumption. Discussion: These results suggest that CA is a preferred first approximation for predicting mixture toxicity when data for all constituents are available. However, because the accuracy of additivity assumptions varies greatly across phenotypes, we posit that mixtures and complex substances need to be directly tested for their hazard potential. NAMs provide a practical solution that rapidly yields highly informative data for mixtures risk assessment. https://doi.org/10.1289/EHP7600

Background: The impact of nitrogen dioxide (NO2) and particulate matter with an aerodynamic diameter of less than or equal to 2.5. microns (PM2.5) exposures on lung function has been investigated mainly in children and less in adults. Furthermore, it is unclear whether short-term deviations of air pollutant concentration need to be considered in long-term exposure models. Objectives: The aims of this study were to investigate the association between short-term air pollution exposure and lung function and to assess whether short-term deviations of air pollutant concentration should be integrated into long-term exposure models. Methods: Short-term (daily averages 0–7 d prior) and long-term (1- and 4-y means) NO2 and PM2.5 concentrations were modeled using satellite, land use, and meteorological data calibrated on ground measurements. Forced expiratory volume within the first second (FEV1) of forced exhalation and forced vital capacity (FVC) were measured during a LuftiBus assessment (2003–2012) and linked to exposure information from the Swiss National Cohort for 36,085 adults (ages 18–95 y). We used multiple linear regression to estimate adjusted associations, and additionally adjusted models of long-term exposures for short-term deviations in air pollutant concentrations. Results: A 10μg/m3 increase in NO2 and PM2.5 on the day of the pulmonary function test was associated with lower FEV1 and FVC (NO2: FEV1 −8.0 ml [95% confidence interval: −13.4, −2.7], FVC −16.7 ml [−23.4, −10.0]; PM2.5: FEV1 −15.3 ml [−21.9, −8.7], FVC −18.5 ml [−26.5, −10.5]). A 10μg/m3 increase in 1-y mean NO2 was also associated with lower FEV1 (−7.7 ml; −15.9, 0.5) and FVC (−21.6 ml; −31.9, −11.4), as was a 10μg/m3 increase in 1-y mean PM2.5 (FEV1: −42.2 ml; −56.9, −27.5; FVC: −82.0 ml; −100.1, −63.9). These associations were robust to adjustment for short-term deviations in the concentration of each air pollutant. Conclusions: Short- and long-term air pollution exposures were negatively associated with lung function, in particular long-term PM2.5 exposure with FVC. Our findings contribute substantially to the evidence of adverse associations between air pollution and lung function in adults. https://doi.org/10.1289/EHP7529

Background: Despite the substantial role indoor exposure has played in heat wave–related mortality, few epidemiological studies have examined the health effects of exposure to indoor heat. As a result, knowledge gaps regarding indoor heat–health thresholds, vulnerability, and adaptive capacity persist. Objective: We evaluated the role of indoor heat exposure on mortality and morbidity among the elderly (≥65 years of age) in Houston, Texas. Methods: Mortality and emergency hospital admission data were obtained through the Texas Department of State Health Services. Summer indoor heat exposure was modeled at the U.S. Census block group (CBG) level using building energy models, outdoor weather data, and building characteristic data. Indoor heat–health associations were examined using time-stratified case-crossover models, controlling for temporal trends and meteorology, and matching on CBG of residence, year, month, and weekday of the adverse health event. Separate models were fitted for three indoor exposure metrics, for individual lag days 0–6, and for 3-d moving averages (lag 0–2). Effect measure modification was explored via stratification on individual- and area-level vulnerability factors. Results: We estimated positive associations between short-term changes in indoor heat exposure and cause-specific mortality and morbidity [e.g., circulatory deaths, odds ratio per 5°C increase=1.16 (95% CI: 1.03, 1.30)]. Associations were generally positive for earlier lag periods and weaker across later lag periods. Stratified analyses suggest stronger associations between indoor heat and emergency hospital admissions among African Americans compared with Whites. Discussion: Findings suggest excess mortality among certain elderly populations in Houston who are likely exposed to high indoor heat. We developed a novel methodology to estimate indoor heat exposure that can be adapted to other U.S. locations. In locations with high air conditioning prevalence, simplified modeling approaches may adequately account for indoor heat exposure in vulnerable neighborhoods. Accounting for indoor heat exposure may improve the estimation of the total impact of heat on health. https://doi.org/10.1289/EHP6340

Background: Environmental factors may contribute to the development of Kawasaki disease in children, but prenatal environmental exposures are understudied. Objective: We used a population-based cohort to investigate whether prenatal exposure to outdoor air pollution is associated with the incidence of Kawasaki disease in childhood. Methods: We performed a longitudinal cohort study of all children born in Quebec, Canada, between 2006 and 2012. Children were followed for Kawasaki disease from birth until 31 March 2018. We assigned prenatal air pollutant exposure according to the residential postal code at birth. The main exposure was annual average concentration of ambient fine particulate matter [PM ≤2.5μm in aerodynamic diameter (PM2.5) and nitrogen dioxide (NO2) from satellite-based estimates and land-use regression models. As secondary exposures, we considered industrial PM2.5, NO2, and sulfur dioxide (SO2) emissions estimated from dispersion models. We estimated hazard ratios (HRs) using Cox proportional hazards models, adjusted for maternal age, parity, sex, multiple birth, maternal smoking during pregnancy, socioeconomic status, birth year, and rural residence. We considered single and multipollutant models. We performed several sensitivity analyses, including assessing modifying effects of maternal comorbidities (e.g., diabetes, preeclampsia). Results: The cohort comprised 505,336 children, including 539 with Kawasaki disease. HRs for each interquartile range increase in ambient air pollution were 1.16 (95% CI: 0.96, 1.39) for PM2.5 and 1.12 (95% CI: 0.96, 1.31) for NO2. For industrial air pollution, HRs were 1.07 (95% CI: 1.01, 1.13) for SO2, 1.09 (95% CI: 0.99, 1.20) for NO2, and 1.01 (95% CI: 0.97, 1.05) for PM2.5. In multipollutant models, associations for ambient PM2.5 and NO2 (i.e., from all sources) were robust to adjustment for industrial pollution, and vice versa. Discussion: In this population-based cohort study, both prenatal exposure to ambient and industrial air pollution were associated with the incidence of Kawasaki disease in childhood. Further studies are needed to consolidate the observed associations. https://doi.org/10.1289/EHP6920

Background: Previous research has identified an association between fine particulate matter (PM2.5) air pollution and lung cancer. Most of the evidence for this association, however, is based on research using lung cancer mortality, not incidence. Research that examines potential associations between PM2.5 and incidence of non-lung cancers is limited. Objectives: The primary purpose of this study was to evaluate the association between the incidence of cancer and exposure to PM2.5 using >8.5 million cases of cancer incidences from U.S. registries. Secondary objectives include evaluating the sensitivity of the associations to model selection, spatial control, and latency period as well as estimating the exposure–response relationship for several cancer types. Methods: Surveillance, Epidemiology, and End Results (SEER) program data were used to calculate incidence rates for various cancer types in 607 U.S. counties. County-level PM2.5 concentrations were estimated using integrated empirical geographic regression models. Flexible semi-nonparametric regression models were used to estimate associations between PM2.5 and cancer incidence for selected cancers while controlling for important county-level covariates. Primary time-independent models using average incidence rates from 1992–2016 and average PM2.5 from 1988–2015 were estimated. In addition, time-varying models using annual incidence rates from 2002–2011 and lagged moving averages of annual estimates for PM2.5 were also estimated. Results: The incidences of all cancer and lung cancer were consistently associated with PM2.5. The incident rate ratios (IRRs), per 10-μg/m3 increase in PM2.5, for all and lung cancer were 1.09 (95% CI: 1.03, 1.14) and 1.19 (95% CI: 1.09, 1.30), respectively. Less robust associations were observed with oral, rectal, liver, skin, breast, and kidney cancers. Discussion: Exposure to PM2.5 air pollution contributes to lung cancer incidence and is potentially associated with non-lung cancer incidence. https://doi.org/10.1289/EHP7246

Background: Endocrine-disrupting chemicals can interfere with hormonal homeostasis and have adverse effects for both humans and the environment. Their identification is increasingly difficult due t...

Background: House dust contains many organic contaminants that can compete with the thyroid hormone (TH) thyroxine (T4) for binding to transthyretin (TTR). How these contaminants work together at levels found in humans and how displacement from TTR in vitro relates to in vivo T4-TTR binding is unknown. Objectives: Our aims were to determine the TTR-binding potency for contaminant mixtures as found in house dust, maternal serum, and infant serum; to study whether the TTR-binding potency of the mixtures follows the principle of concentration addition; and to extrapolate the in vitro TTR-binding potency to in vivo inhibition levels of T4-TTR binding in maternal and infant serum. Methods: Twenty-five contaminants were tested for their in vitro capacity to compete for TTR-binding with a fluorescent FITC-T4 probe. Three mixtures were reconstituted proportionally to median concentrations for these chemicals in house dust, maternal serum, or infant serum from Nordic countries. Measured concentration–response curves were compared with concentration–response curves predicted by concentration addition. For each reconstituted serum mixture, its inhibitor–TTR dissociation constant (Ki) was used to estimate inhibition levels of T4-TTR binding in human blood. Results: The TTR-binding potency of the mixtures was well predicted by concentration addition. The ∼20% inhibition in FITC-T4 binding observed for the mixtures reflecting median concentrations in maternal and infant serum was extrapolated to 1.3% inhibition of T4-TTR binding in maternal and 1.5% in infant blood. For nontested mixtures reflecting high-end serum concentrations, these estimates were 6.2% and 4.9%, respectively. Discussion: The relatively low estimated inhibition levels at median exposure levels may explain why no relationship between exposure to TTR-binding compounds and circulating T4 levels in humans has been reported, so far. We hypothesize, however, that 1.3% inhibition of T4-TTR binding may ultimately be decisive for reaching a status of maternal hypothyroidism or hypothyroxinemia associated with impaired neurodevelopment in children. https://doi.org/10.1289/EHP5911

Background: Exposure to fine particulate matter (PM2.5) during wildfire seasons has been associated with adverse health outcomes. Previous studies have focused on daily exposure, but PM2.5 levels in smoke events can vary considerably within 1 d. Objectives: We aimed to assess the immediate and lagged relationship between sub-daily exposure to PM2.5 and acute health outcomes during wildfire seasons in British Columbia. Methods: We used a time-stratified case-crossover study design to evaluate the association between modeled hourly PM2.5 and ambulance dispatches during wildfire seasons from 2010 to 2015. Distributed lag nonlinear models were used to estimate the lag-specific and cumulative odds ratios (ORs) at lags from 1 to 48 h. We examined the relationship for all dispatches and dispatches related to respiratory, circulatory, and diabetic conditions, identified by codes for ambulance dispatch (AD), paramedic assessment (PA) or hospital diagnosis (HD). Results: Increased respiratory health outcomes were observed within 1 h of exposure to a 10-μg/m3 increase in PM2.5. The 48-h cumulative OR [95% confidence interval (CI)] was 1.038 (1.009, 1.067) for the AD code Breathing Problems and 1.098 (1.013, 1.189) for PA code Asthma/COPD. The point estimates were elevated within 1 h for the PA code for Myocardial Infarction and HD codes for Ischemic Heart Disease, which had 24-h cumulative ORs of 1.104 (0.915, 1.331) and 1.069 (0.983, 1.162), respectively. The odds of Diabetic AD and PA codes increased over time to a cumulative 24-h OR of 1.075 (1.001, 1.153) and 1.104 (1.015, 1.202) respectively. Conclusions: We found increased PM2.5 during wildfire seasons was associated with some respiratory and cardiovascular outcomes within 1 h following exposure, and its association with diabetic outcomes increased over time. Cumulative effects were consistent with those reported elsewhere in the literature. These results warrant further investigation and may have implications for the appropriate time scale of public health actions. https://doi.org/10.1289/EHP5792

Background: Research on the relationship between long-term exposure to particulate matter with aerodynamic diameter ≤2.5μm (PM2.5) and poor cognitive function is lacking in developing countries, especially in highly polluted areas. Objectives: We evaluated associations of long-term exposure to PM2.5 with poor cognitive function in a diverse, national sample of older adults in China. Methods: This analysis included data on 13,324 older adults (5,879 who were 65–79 years of age, 3,052 who were 80–89 years of age, 2,634 who were 90–99 years of age, and 1,759 who were ≥100 years of age) with normal cognitive function at baseline from March 2002 to September 2014, with 64,648 person-years of follow-up. We used a geographic information system analysis to estimate the annual average satellite-derived PM2.5 concentration for the geocoded location of the participants’ baseline residences. Poor cognitive function was defined as a score of less than 18 on the Chinese version of the Mini-Mental State Examination (MMSE). Competing risk models were performed to explore the association of PM2.5 with poor cognitive function. Results: Each 10-μg/m3 increase in PM2.5 was associated with a 5.1% increased risk of poor cognitive function [adjusted hazard ratio (HR): 1.051; 95% confidence interval (CI): 1.023, 1.079]. Compared to the lowest quartile of PM2.5 (

Photograph of a man exhaling a large visible cloud of e-cigarette vapor

Background: In an effort to decrease the rates of smoking conventional tobacco cigarettes, electronic cigarettes (e-cigarettes) have been proposed as an effective smoking cessation tool. However, little is known about their toxicological impacts. This is concerning given that e-cigarette use is perceived as less harmful than conventional tobacco cigarettes during pregnancy for both the mother and fetus. Objective: The goal of this study was to test the neurodevelopmental consequences of maternal e-cigarette use on adult offspring behavior and neuroimmune outcomes. Methods: Pregnant female CD-1 mice were randomly assigned to one of three treatment groups (n=8–10 per group) and exposed daily to either filtered air, propylene glycol and vegetable glycerol (50:50 PG/VG vehicle), or to PG/VG with 16mg/mL nicotine (+Nic). Whole-body exposures were carried out for 3 h/d, 7 d/week, from gestational day (GD)0.5 until GD17.5. Adult male and female offspring (8 weeks old) were assessed across a battery of behavioral assessments followed by region-specific quantification of brain cytokines using multiplex immunoassays. Results: Adult offspring of both sexes exposed to +Nic exhibited elevated locomotor activity in the elevated plus maze and altered stress-coping strategies in the forced swim task. Moreover, male and female offspring exposed to PG/VG with and without nicotine had a 5.2% lower object discrimination score in the novel object recognition task. In addition to differences in offspring behavior, maternal e-cigarette exposure with nicotine led to a reduction in interleukin (IL)-4 and interferon-gamma (IFNγ) in the diencephalon, as well as lower levels of hippocampal IFNγ (females only). E-cigarette exposure without nicotine resulted in a 2-fold increase of IL-6 in the cerebellum. Discussion: These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067

Background: Fuel oil–derived volatile organic compounds (VOCs) inhalation is associated with accidental marine spills. After the Prestige petroleum tanker sank off northern Spain in 2002 and the Deepwater Horizon oil rig catastrophe in 2009, subjects involved in environmental decontamination showed signs of ongoing or residual lung disease up to 5 y after the exposure. Objectives: We aimed at investigating mechanisms driving persistent respiratory disease by developing an animal model of inhalational exposure to fuel oil–derived VOCs. Methods: Female Wistar and Brown Norway (BN) rats and C57BL mice were exposed to VOCs produced from fuel oil mimicking the Prestige spill. Exposed animals inhaled the VOCs 2 h daily, 5 d per week, for 3 wk. Airway responsiveness to methacholine (MCh) was assessed, and bronchoalveolar lavage (BAL) and lung tissues were analyzed after the exposure and following a 2-wk washout. Results: Consistent with data from human studies, both strains of rats that inhaled fuel oil–derived VOCs developed airway hyperresponsiveness that persisted after the washout period, in the absence of detectable inflammation in any lung compartment. Histopathology and quantitative morphology revealed the development of peripherally distributed pulmonary emphysema, which persisted after the washout period, associated with increased alveolar septal cell apoptosis, microvascular endothelial damage of the lung parenchyma, and inhibited expression of vascular endothelial growth factor (VEGF). Discussion: In this rat model, fuel oil VOCs inhalation elicited alveolar septal cell apoptosis, likely due to DNA damage. In turn, the development of a peculiar pulmonary emphysema pattern altered lung mechanics and caused persistent noninflammatory airway hyperresponsiveness. Such findings suggest to us that humans might also respond to VOCs through physiopathological pathways different from those chiefly involved in typical cigarette smoke–driven emphysema in chronic obstructive pulmonary disease (COPD). If so, this study could form the basis for a novel disease mechanism for lasting respiratory disease following inhalational exposure to catastrophic fuel oil spills. https://doi.org/10.1289/EHP4178

Background: Aluminum (Al) is the most abundant and ubiquitous metal in the environment. The main route of human exposure to Al is through food and water intake. Although human exposure to Al is com...

Background: Reductions in ambient concentrations of fine particulate matter (PM2.5) have contributed to reductions in cardiovascular (CV) mortality. Objectives: We examined changes in CV mortality attributed to reductions in emissions from mobile, point, areal, and nonroad sources through changes in concentrations of PM2.5 and its major components [nitrates, sulfates, elemental carbon (EC), and organic carbon (OC)] in 2,132 U.S. counties between 1990 and 2010. Methods: Using Community Multiscale Air Quality model estimated PM2.5 total and component concentrations, we calculated population-weighted annual averages for each county. We estimated PM2.5 total- and component-related CV mortality, adjusted for county-level population characteristics and baseline PM2.5 concentrations. Using the index of Emission Mitigation Efficiency for primary emission-to-particle pathways, we expressed changes in particle-related mortality in terms of precursor emissions by each sector. Results: PM2.5 reductions represented 5.7% of the overall decline in CV mortality. Large point source emissions of sulfur dioxide accounted for 6.685 [95% confidence interval (CI): 5.703, 7.667] fewer sulfate-related CV deaths per 100,000 people. Mobile source emissions of primary EC and nitrous oxides accounted for 3.396 (95% CI: 2.772, 4.020) and 3.984 (95% CI: 2.472, 5.496) fewer CV deaths per 100,000 people respectively. Increased EC and OC emissions from areal sources increased carbon-related CV mortality by 0.788 (95% CI: −0.540, 2.116) and 0.245 (95% CI: −0.697, 1.187) CV deaths per 100,000 people. Discussion: In a nationwide epidemiological study of emission sector contribution to PM2.5–related mortality, we found that reductions in sulfur-dioxide emissions from large point sources and nitrates and EC emissions from mobile sources contributed the largest reduction in particle-related mortality rates respectively. https://doi.org/10.1289/EHP5692

Background: The association between long-term exposure to ambient fine particulate matter with aerodynamic diameter ≤2.5μm (PM2.5) and lung function in young people remains uncertain, particularly in Asia, where air pollution is generally a serious problem. Objectives: This study investigated the association between long-term exposure to ambient PM2.5 and lung function in Taiwanese children, adolescents, and young adults. Methods: This study comprised 24,544 participants 6–24 years of age, with 33,506 medical observations made between 2000 and 2014. We used a spatiotemporal model to estimate PM2.5 concentrations at participants’ addresses. Spirometry parameters, i.e., forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and maximum midexpiratory flow (MMEF), were determined. A generalized linear mixed model was used to examine the associations between long-term exposure to ambient PM2.5 and lung function. The odds ratios (ORs) of poor lung function were also calculated after adjusting for a range of covariates. Results: Every 10-μg/m3 increase in the 2-y average PM2.5 concentration was associated with decreases of 2.22% [95% confidence interval (CI): −2.60, −1.85], 2.94 (95% CI: −3.36, −2.51), and 2.79% (95% CI: −3.15, −2.41) in the FVC, FEV1, and MMEF, respectively. Furthermore, it was associated with a 20% increase in the prevalence of poor lung function (OR: 1.20; 95% CI: 1.12, 1.29). Conclusions: Two-year ambient PM2.5 concentrations were inversely associated with lung function and positively associated with the prevalence of poor lung function in children, adolescents, and young adults in Taiwan. https://doi.org/10.1289/EHP5220

Background: Studies on the effect of air pollutions on kidney diseases are still limited. Objective: We aimed to investigate the associations between particulate matter (PM) exposures and renal function among adults. Methods: We recruited 21,656 adults as participants from 2007 to 2009. The Taiwanese Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to derive the estimated glomerular filtration rate (eGFR). Subjects with an eGFR lower than 60 mL/min/1.73 m2 were defined as having chronic kidney disease (CKD). Land use regression (LUR) models were used to estimate individual exposures to PM with an aerodynamic diameter < 10 μm (PM10), coarse particles (PMCoarse), fine particles (PM2.5), and PM2.5Absorbance. Generalized linear and logistic regression models were used to estimate the associations between PM exposure and renal function. Results: An IQR increase in PM10 (5.83 μg/m3) was negatively associated with eGFR by –0.69 (95% CI: –0.89, –0.48) mL/min/1.73 m2 and positively associated with the prevalence of CKD with adjusted OR = 1.15 (95% CI: 1.07, 1.23). An IQR increase in PMCoarse (6.59 μg/m3) was significantly associated with lower eGFR by –1.07 (95% CI: –1.32, –0.81) mL/min/1.73 m2 and CKD with OR = 1.26 (95% CI: 1.15, 1.38). In contrast, neither outcome was significantly associated with PM2.5 or PM2.5Absorbance. Stratified analyses indicated that associations of CKD with both PM10 and PMCoarse were limited to participants < 65 years of age, and were stronger (for PM10) or limited to (PMCoarse) women. Associations also appeared to be stronger in those without (vs. with) hypertension, and in normal versus overweight participants. Conclusions: Exposure during the previous year to PM10 and PMCoarse, but not PM2.5 or PM2.5Absorbance, was associated with reduced renal function among Taiwanese adults. Citation: Yang YR, Chen YM, Chen SY, Chan CC. 2017. Associations between long-term particulate matter exposure and adult renal function in the Taipei metropolis. Environ Health Perspect 125:602–607; http://dx.doi.org/10.1289/EHP302

Background: There is a positive association between ambient fine particulate matter ≤ 2.5 μm in aerodynamic diameter (PM2.5) and incidence and mortality of lung cancer (LC), but few studies have assessed the relationship between ambient PM2.5 and LC among never smokers. Objectives: We assessed the association between PM2.5 and risk of LC using the Adventist Health and Smog Study-2 (AHSMOG-2), a cohort of health conscious nonsmokers where 81% have never smoked. Methods: A total of 80,285 AHSMOG-2 participants were followed for an average of 7.5 years with respect to incident LC identified through linkage with U.S. state cancer registries. Estimates of ambient air pollution levels at participants’ residences were obtained for 2000 and 2001, the years immediately prior to the start of the study. Results: A total of 250 incident LC cases occurred during 598,927 person-years of follow-up. For each 10-μg/m3 increment in PM2.5, adjusted hazard ratio (HR) with 95% confidence interval (CI) for LC incidence was 1.43 (95% CI: 1.11, 1.84) in the two-pollutant multivariable model with ozone. Among those who spent > 1 hr/day outdoors or who had lived 5 or more years at their enrollment address, the HR was 1.68 (95% CI: 1.28, 2.22) and 1.54 (95% CI: 1.17, 2.04), respectively. Conclusion: Increased risk estimates of LC were observed for each 10-μg/m3 increment in ambient PM2.5 concentration. The estimate was higher among those with longer residence at enrollment address and those who spent > 1 hr/day outdoors. Citation: Gharibvand L, Shavlik D, Ghamsary M, Beeson WL, Soret S, Knutsen R, Knutsen SF. 2017. The association between ambient fine particulate air pollution and lung cancer incidence: results from the AHSMOG-2 study. Environ Health Perspect 125:378–384; http://dx.doi.org/10.1289/EHP124Citation: Gharibvand L, Shavlik D, Ghamsary M, Beeson WL, Soret S, Knutsen R, Knutsen SF. 2017. The association between ambient fine particulate air pollution and lung cancer incidence: results from the AHSMOG-2 study. Environ Health Perspect 125:378–384; http://dx.doi.org/10.1289/EHP124

Background: The current single-chemical-as-carcinogen risk assessment paradigm might underestimate or miss the cumulative effects of exposure to chemical mixtures, as highlighted in recent work from the Halifax Project. This is particularly important for chemical exposures in the low-dose range that may be affecting crucial cancer hallmark mechanisms that serve to enable carcinogenesis. Objective: Could ongoing low-dose exposures to a mixture of commonly encountered environmental chemicals produce effects in concert that lead to carcinogenesis? A workshop held at the NIEHS in August 2015 evaluated the scientific support for the low-dose mixture hypothesis of carcinogenesis and developed a research agenda. Here we describe the science that supports this novel theory, identify knowledge gaps, recommend future methodologies, and explore preventative risk assessment and policy decision-making that incorporates cancer biology, environmental health science, translational toxicology, and clinical epidemiology. Discussion and Conclusions: The theoretical merits of the low-dose carcinogenesis hypothesis are well founded with clear biological relevance, and therefore, the premise warrants further investigation. Expert recommendations include the need for better insights into the ways in which noncarcinogenic constituents might combine to uniquely affect the process of cellular transformation (in vitro) and environmental carcinogenesis (in vivo), including investigations of the role of key defense mechanisms in maintaining transformed cells in a dormant state. The scientific community will need to acknowledge limitations of animal-based models in predicting human responses; evaluate biological events leading to carcinogenesis both spatially and temporally; examine the overlap between measurable cancer hallmarks and characteristics of carcinogens; incorporate epigenetic biomarkers, in silico modelling, high-performance computing and high-resolution imaging, microbiome, metabolomics, and transcriptomics into future research efforts; and build molecular annotations of network perturbations. The restructuring of many existing regulatory frameworks will require adequate testing of relevant environmental mixtures to build a critical mass of evidence on which to base policy decisions. Citation: Miller MF, Goodson WH III, Manjili MH, Kleinstreuer N, Bisson WH, Lowe L. 2017. Low-Dose Mixture Hypothesis of Carcinogenesis Workshop: scientific underpinnings and research recommendations. Environ Health Perspect 125:163–169; http://dx.doi.org/10.1289/EHP411

Background: Vegetation fires can release substantial quantities of fine particles (PM2.5), which are harmful to health. The fire smoke may be transported over long distances and can cause adverse health effects over wide areas. Objective: We aimed to assess annual mortality attributable to short-term exposures to vegetation fire–originated PM2.5 in different regions of Europe. Methods: PM2.5 emissions from vegetation fires in Europe in 2005 and 2008 were evaluated based on Moderate Resolution Imaging Spectroradiometer (MODIS) satellite data on fire radiative power. Atmospheric transport of the emissions was modeled using the System for Integrated modeLling of Atmospheric coMposition (SILAM) chemical transport model. Mortality impacts were estimated for 27 European countries based on a) modeled daily PM2.5 concentrations and b) population data, both presented in a 50 × 50 km2 spatial grid; c) an exposure–response function for short-term PM2.5 exposure and daily nonaccidental mortality; and d) country-level data for background mortality risk. Results: In the 27 countries overall, an estimated 1,483 and 1,080 premature deaths were attributable to the vegetation fire–originated PM2.5 in 2005 and 2008, respectively. Estimated impacts were highest in southern and eastern Europe. However, all countries were affected by fire-originated PM2.5, and even the lower concentrations in western and northern Europe contributed substantially (~ 30%) to the overall estimate of attributable mortality. Conclusions: Our assessment suggests that air pollution caused by PM2.5 released from vegetation fires is a notable risk factor for public health in Europe. Moreover, the risk can be expected to increase in the future as climate change proceeds. This factor should be taken into consideration when evaluating the overall health and socioeconomic impacts of these fires., published version, peerReviewed

Background: The autonomic nervous system plays a key role in maintaining homeostasis and responding to external stimuli. In adults, exposure to fine particulate matter (PM2.5) has been associated with reduced heart rate variability (HRV), an indicator of cardiac autonomic control. Objectives: Our goal was to investigate the associations of exposure to fine particulate matter (PM2.5) with HRV as an indicator of cardiac autonomic control during early development. Methods: We studied 237 maternal–infant pairs in a Boston-based birth cohort. We estimated daily residential PM2.5 using satellite data in combination with land-use regression predictors. In infants at 6 months of age, we measured parasympathetic nervous system (PNS) activity using continuous electrocardiogram monitoring during the Repeated Still-Face Paradigm, an experimental protocol designed to elicit autonomic reactivity in response to maternal interaction and disengagement. We used multivariable linear regression to examine average PM2.5 exposure across pregnancy in relation to PNS withdrawal and activation, indexed by changes in respiration-corrected respiratory sinus arrhythmia (RSAc)—an established metric of HRV that reflects cardiac vagal tone. We examined interactions with infant sex using cross-product terms. Results: In adjusted models we found that a 1-unit increase in PM2.5 (in micrograms per cubic meter) was associated with a 3.53% decrease in baseline RSAc (95% CI: −6.96, 0.02). In models examining RSAc change between episodes, higher PM2.5 was generally associated with reduced PNS withdrawal during stress and reduced PNS activation during recovery; however, these associations were not statistically significant. We did not observe a significant interaction between PM2.5 and sex. Discussion: Prenatal exposure to PM2.5 may disrupt cardiac vagal tone during infancy. Future research is needed to replicate these preliminary findings. https://doi.org/10.1289/EHP4434

Background: Health-risk issues are raised concerning inhalation of particulate pollutants that are thought to have potential hazardous effects on the central nervous system. The brain is presented as a direct target of particulate matter (PM) exposure because of the nose-to-brain pathway involvement. The main cause of contamination in nuclear occupational activities is related to exposure to aerosols containing radionuclides, particularly uranium dust. It has been previously demonstrated that instilled solubilized uranium in the rat nasal cavity is conveyed to the brain via the olfactory nerve. Objective: The aim of this study was to analyze the anatomical localization of uranium compounds in the olfactory system after in vivo exposure to a polydisperse aerosol of uranium tetraoxide (UO4) particles. Methods: The olfactory neuroepithelium (OE) and selected brain structures—olfactory bulbs (OB), frontal cortex (FC), hippocampus (HIP), cerebellum (Cer), and brainstem (BS)—were microdissected 4 h after aerosol inhalation via a nose-only system in adult rats. Tissues were subjected to complementary analytical techniques. Results: Uranium concentrations measured by inductively coupled plasma mass spectrometry (ICP-MS) were significantly higher in all brain structures from exposed animals compared with their respective controls. We observed that cerebral uranium concentrations followed an anteroposterior gradient with typical accumulation in the OB, characteristic of a direct olfactory transfer of inhaled compounds. Secondary ion mass spectrometry (SIMS) microscopy and transmission electron microscopy coupled with energy-dispersive X-ray spectroscopy (TEM-EDX) were used in order to track elemental uranium in situ in the olfactory epithelium. Elemental uranium was detected in precise anatomical regions: olfactory neuron dendrites, paracellular junctions of neuroepithelial cells, and olfactory nerve tracts (around axons and endoneural spaces). Conclusion: These neuroanatomical observations in a rat model are consistent with the transport of elemental uranium in different physicochemical forms (solubilized, nanoparticles) along olfactory nerve bundles after inhalation of UO4 microparticles. This work contributes to knowledge of the mechanistic actions of particulate pollutants on the brain. https://doi.org/10.1289/EHP4927

Background: Ambient fine particulate air pollution with aerodynamic diameter ≤2.5 μm (PM2.5) is an important contributor to the global burden of disease. Information on the shape of the concentration–response relationship at low concentrations is critical for estimating this burden, setting air quality standards, and in benefits assessments. Objectives: We examined the concentration–response relationship between PM2.5 and nonaccidental mortality in three Canadian Census Health and Environment Cohorts (CanCHECs) based on the 1991, 1996, and 2001 census cycles linked to mobility and mortality data. Methods: Census respondents were linked with death records through 2016, resulting in 8.5 million adults, 150 million years of follow-up, and 1.5 million deaths. Using annual mailing address, we assigned time-varying contextual variables and 3-y moving-average ambient PM2.5 at a 1×1 km spatial resolution from 1988 to 2015. We ran Cox proportional hazards models for PM2.5 adjusted for eight subject-level indicators of socioeconomic status, seven contextual covariates, ozone, nitrogen dioxide, and combined oxidative potential. We used three statistical methods to examine the shape of the concentration–response relationship between PM2.5 and nonaccidental mortality. Results: The mean 3-y annual average estimate of PM2.5 exposure ranged from 6.7 to 8.0 μg/m3 over the three cohorts. We estimated a hazard ratio (HR) of 1.053 [95% confidence interval (CI): 1.041, 1.065] per 10-μg/m3 change in PM2.5 after pooling the three cohort-specific hazard ratios, with some variation between cohorts (1.041 for the 1991 and 1996 cohorts and 1.084 for the 2001 cohort). We observed a supralinear association in all three cohorts. The lower bound of the 95% CIs exceeded unity for all concentrations in the 1991 cohort, for concentrations above 2 μg/m3 in the 1996 cohort, and above 5 μg/m3 in the 2001 cohort. Discussion: In a very large population-based cohort with up to 25 y of follow-up, PM2.5 was associated with nonaccidental mortality at concentrations as low as 5 μg/m3. https://doi.org/10.1289/EHP5204

Background: The autonomic nervous system plays a key role in maintaining homeostasis and responding to external stimuli. In adults, exposure to fine particulate matter (PM2.5) has been associated w...

Background: Acute exposure to ambient particulate matter

BACKGROUND: Lung cancer rates among never-smoking women in Xuanwei and Fuyuan in China are among the highest in the world and have been attributed to the domestic use of smoky (bituminous) coal for heating and cooking. However, the key components of coal that drive lung cancer risk have not been identified. OBJECTIVES: We aimed to investigate the relationship between lifelong exposure to the constituents of smoky coal (and other fuel types) and lung cancer. METHODS: Using a population-based case-control study of lung cancer among 1,015 never-smoking female cases and 485 controls, we examined the association between exposure to 43 household air pollutants and lung cancer. Pollutant predictions were derived from a comprehensive exposure assessment study, which included methylated polycyclic aromatic hydrocarbons (PAHs), which have never been directly evaluated in an epidemiological study of any cancer. Hierarchical clustering and penalized regression were applied in order to address high colinearity in exposure variables. RESULTS: The strongest association with lung cancer was for a cluster of 25 PAHs [odds ratio (OR): 2.21; 95% confidence interval (CI): 1.67, 2.87 per 1 standard deviation (SD) change], within which 5-methylchrysene (5-MC), a mutagenic and carcinogenic PAH, had the highest individual observed OR (5.42; 95% CI: 0.94, 27.5). A positive association with nitrogen dioxide ([Formula: see text]) was also observed (OR: 2.06; 95% CI: 1.19, 3.49). By contrast, neither benzo(a)pyrene (BaP) nor fine particulate matter with aerodynamic diameter [Formula: see text] ([Formula: see text]) were associated with lung cancer in the multipollutant models. CONCLUSIONS: To our knowledge, this is the first study to comprehensively evaluate the association between lung cancer and household air pollution (HAP) constituents estimated over the entire life course. Given the global ubiquity of coal use domestically for indoor cooking and heating and commercially for electric power generation, our study suggests that more extensive monitoring of coal combustion products, including methylated PAHs, may be warranted to more accurately assess health risks and develop prevention strategies from this exposure. https://doi.org/10.1289/EHP4913.

In 2013, China released the Air Pollution Prevention and Control Action Plan (Action Plan), which set the roadmap for national air pollution control actions for the period of 2013 to 2017. A decrease in the fine particulate matter with aerodynamic diameter [Formula: see text] ([Formula: see text]) concentration may lead to a substantial benefit for human health.We aimed to quantify the relative contributions four factors: emission reductions, changed meteorology, population growth, and a change in baseline mortality rates to the reduced [Formula: see text]-related mortality ([Formula: see text]-mortality) during the 2013-2017 period and evaluate the importance of emission controls for human health protection in China.The integrated exposure-response function was adopted to estimate the chronic health effects of [Formula: see text]. The annual [Formula: see text] concentrations were estimated from chemical transport model simulations combined with surface observations for 2013 and 2017. Relative contributions to [Formula: see text]-mortality from emission reductions and the three factors were individually quantified through scenario analysis.The estimated total [Formula: see text]-mortality in China was 1.389 million [95% confidence interval (CI): 1.005 million, 1.631 million] in 2013 but was substantially reduced to 1.102 million (95% CI: 0.755 million, 1.337 million) in 2017. Emission controls contributed 88.7% to this reduction in [Formula: see text]-mortality, while changed meteorology, the change in baseline mortality rates, and population growth during 2013-2017 contributed 9.6, 3.8, and [Formula: see text], respectively.The implementation of the Action Plan has significantly reduced the [Formula: see text] concentration in regions of China where population density is high, dominating the decline in [Formula: see text]-mortality during 2013-2017. However, the health burden of [Formula: see text] pollution in China is still extremely high compared with that in other developed countries. An aggressive air pollution control strategy should be implemented in densely populated areas to further reduce the health burden. https://doi.org/10.1289/EHP4157.

Studies found approximately linear short-term associations between particulate matter (PM) and mortality in Western communities. However, in China, where the urban PM levels are typically considerably higher than in Western communities, some studies suggest nonlinearity in this association. Health impact assessments (HIA) of PM in China have generally not incorporated nonlinearity in the concentration-response (C-R) association, which could result in large discrepancies in estimates of excess deaths if the true association is nonlinear.We investigated nonlinearity in the C-R associations between with PM with aerodynamic diameter [Formula: see text] ([Formula: see text]) and mortality in Beijing, China, and the sensitivity of HIA to linearity assumptions.We modeled the C-R association between [Formula: see text] and cause-specific mortality in Beijing, China (2009-2012), using generalized linear models (GLM). [Formula: see text] was included through either linear, piecewise-linear, or spline functions to investigate evidence of nonlinearity. To determine the sensitivity of HIA to linearity assumptions, we estimated [Formula: see text]-attributable deaths using both linear- and nonlinear-based C-R associations between [Formula: see text] and mortality.We found some evidence that, for nonaccidental and circulatory mortality, the shape of the C-R association was relatively flat at lower concentrations of [Formula: see text], but then had a positive slope at higher concentrations, indicating nonlinearity. Conversely, the shape for respiratory mortality was positive and linear at lower concentrations of [Formula: see text], but then leveled off at the higher concentrations. Estimates of excess deaths attributable to short-term [Formula: see text] exposure were, in some cases, very sensitive to the linearity assumption in the association, but in other cases robust to this assumption.Our results demonstrate some evidence of nonlinearity in [Formula: see text]-mortality associations and that an assumption of linearity in this association can influence HIAs, highlighting the importance of understanding potential nonlinearity in the [Formula: see text]-mortality association at the high concentrations of [Formula: see text] in developing megacities like Beijing. https://doi.org/10.1289/EHP4464.

Background: Pulmonary inflammation is believed to be central to the pathogenesis due to exposure to fine particulate matter with aerodynamic diameter ≤2.5 μm (PM2.5). This central role, however, has not yet been systemically examined. Objective: In the present study, we exploited a lung epithelial cell-specific inhibitor κB kinase 2 (IKK2) knockout mouse model to determine the role of pulmonary inflammation in the pathophysiology due to exposure to diesel exhaust particulate matter (DEP). Methods: SFTPC -rtTA+/−tetO -cre+/−IKK2flox/flox (lung epithelial cell-specific IKK2 knockout, KO) and SFTPC -rtTA+/−tetO -cre+/−IKK2flox/flox (wild-type, tgWT) mice were intratracheally instilled with either vehicle or DEP for 4 months, and their inflammatory response and glucose homeostasis were then assessed. Results: In comparison with tgWT mice, lung epithelial cell-specific IKK2-deficient mice had fewer DEP exposure-induced bronchoalveolar lavage fluid immune cells and proinflammatory cytokines as well as fewer DEP exposure-induced circulating proinflammatory cytokines. Glucose and insulin tolerance tests revealed that lung epithelial cell-specific IKK2 deficiency resulted in markedly less DEP exposure–induced insulin resistance and greater glucose tolerance. Akt phosphorylation analyses of insulin-responsive tissues showed that DEP exposure primarily targeted hepatic insulin sensitivity. Lung epithelial cell–specific IKK2-deficient mice had significantly lower hepatic insulin resistance than tgWT mice had. Furthermore, this difference in insulin resistance was accompanied by consistent differences in hepatic insulin receptor substrate 1 serine phosphorylation and inflammatory marker expression. Discussion: Our findings suggest that in a tissue-specific knockout mouse model, an IKK2-dependent pulmonary inflammatory response was essential for the development of abnormal glucose homeostasis due to exposure to DEP. https://doi.org/10.1289/EHP4591

The effects of exposure to fine particulate matter ([Formula: see text]) during wildland fires are not well understood in comparison with [Formula: see text] exposures from other sources.We examined the cardiopulmonary effects of short-term exposure to [Formula: see text] on smoke days in the United States to evaluate whether health effects are consistent with those during non-smoke days.We examined cardiopulmonary hospitalizations among adults [Formula: see text] y of age, in U.S. counties ([Formula: see text]) within [Formula: see text] of 123 large wildfires during 2008-2010. We evaluated associations during smoke and non-smoke days and examined variability with respect to modeled and observed exposure metrics. Poisson regression was used to estimate county-specific effects at lag days 0-6 (L0-6), adjusted for day of week, temperature, humidity, and seasonal trend. We used meta-analyses to combine county-specific effects and estimate overall percentage differences in hospitalizations expressed per [Formula: see text] increase in [Formula: see text].Exposure to [Formula: see text], on all days and locations, was associated with increased hospitalizations on smoke and non-smoke days using modeled exposure metrics. The estimated effects persisted across multiple lags, with a percentage increase of 1.08% [95% confidence interval (CI): 0.28, 1.89] on smoke days and 0.67% (95% CI: [Formula: see text], 1.44) on non-smoke days for respiratory and 0.61% (95% CI: 0.09, 1.14) on smoke days and 0.69% (95% CI: 0.19, 1.2) on non-smoke days for cardiovascular outcomes on L1. For asthma-related hospitalizations, the percentage increase was greater on smoke days [6.9% (95% CI: 3.71, 10.11)] than non-smoke days [1.34% (95% CI: [Formula: see text], 3.77)] on L1.The increased risk of [Formula: see text]-related cardiopulmonary hospitalizations was similar on smoke and non-smoke days across multiple lags and exposure metrics, whereas risk for asthma-related hospitalizations was higher during smoke days. https://doi.org/10.1289/EHP3860.

Coarse particulate matter with aerodynamic diameter between 2.5 and [Formula: see text] ([Formula: see text]) air pollution is a severe environmental problem in developing countries, but its challenges to public health were rarely evaluated.We aimed to investigate the associations between day-to-day changes in [Formula: see text] and cause-specific mortality in China.We conducted a nationwide daily time-series analysis in 272 main Chinese cities from 2013 to 2015. The associations between [Formula: see text] concentrations and mortality were analyzed in each city using overdispersed generalized additive models. Two-stage Bayesian hierarchical models were used to estimate national and regional average associations, and random-effect models were used to pool city-specific concentration-response curves. Two-pollutant models were adjusted for fine particles with aerodynamic diameter [Formula: see text] ([Formula: see text]) or gaseous pollutants.Overall, we observed positive and approximately linear concentration-response associations between [Formula: see text] and daily mortality. A [Formula: see text] increase in [Formula: see text] was associated with higher mortality due to nonaccidental causes [0.23%; 95% posterior interval (PI): 0.13, 0.33], cardiovascular diseases (CVDs; 0.25%; 95% PI: 0.13, 0.37), coronary heart disease (CHD; 0.21%; 95% PI: 0.05, 0.36), stroke (0.21%; 95% PI: 0.08, 0.35), respiratory diseases (0.26%; 95% PI: 0.07, 0.46), and chronic obstructive pulmonary disease (COPD; 0.34%; 95% PI: 0.12, 0.57). Associations were stronger for cities in southern vs. northern China, with significant differences for total and cardiovascular mortality. Associations with [Formula: see text] were of similar magnitude to those for [Formula: see text] in both single- and two-pollutant models with mutual adjustment. Associations were robust to adjustment for gaseous pollutants other than nitrogen dioxide and sulfur dioxide. Meta-regression indicated that a larger positive correlation between [Formula: see text] and [Formula: see text] predicted stronger city-specific associations between [Formula: see text] and total mortality.This analysis showed significant associations between short-term [Formula: see text] exposure and daily nonaccidental and cardiopulmonary mortality based on data from 272 cities located throughout China. Associations appeared to be independent of exposure to [Formula: see text], carbon monoxide, and ozone. https://doi.org/10.1289/EHP2711.

Background: Many cohort studies have reported associations between PM2.5 and the hazard of dying, but few have used formal causal modeling methods, estimated marginal effects, or directly modeled the loss of life expectancy. Objective: Our goal was to directly estimate the effect of PM2.5 on the distribution of life span using causal modeling techniques. Methods: We derived nonparametric estimates of the distribution of life expectancy as a function of PM2.5 using data from 16,965,154 Medicare beneficiaries in the Northeastern and mid-Atlantic region states (129,341,959 person-years of follow-up and 6,334,905 deaths). We fit separate inverse probability-weighted logistic regressions for each year of age to estimate the risk of dying at that age given the average PM2.5 concentration at each subject’s residence ZIP code in the same year, and we used Monte Carlo simulations to estimate confidence intervals. Results: The estimated mean age at death for a population with an annual average PM2.5 exposure of 12 μg/m3 (the 2012 National Ambient Air Quality Standard) was 0.89 y less (95% CI: 0.88, 0.91) than estimated for a counterfactual PM2.5 exposure of 7.5 μg/m3. In comparison, life expectancy at 65 y of age increased by 0.9 y between 2004 and 2013 in the United States. We estimated that 23.5% of the Medicare population would die before 76 y of age if exposed to PM2.5 at 12 μg/m3 compared with 20.1% if exposed to an annual average of 7.5 μg/m3. Conclusions: We believe that this is the first study to directly estimate the effect of PM2.5 on the distribution of age at death using causal modeling techniques to control for confounding. We find that reducing PM2.5 concentrations below the 2012 U.S. annual standard would substantially increase life expectancy in the Medicare population. https://doi.org/10.1289/EHP3130

Summary: Per- and polyfluoroalkyl substances (PFASs) are a group of fluorinated substances of interest to researchers, regulators, and the public due to their widespread presence in the environment. A few PFASs have comparatively extensive amounts of human epidemiological, exposure, and experimental animal toxicity data (e.g., perfluorooctanoic acid), whereas little toxicity and exposure information exists for much of the broader set of PFASs. Given that traditional approaches to generate toxicity information are resource intensive, new approach methods, including in vitro high-throughput toxicity (HTT) testing, are being employed to inform PFAS hazard characterization and further (in vivo) testing. The U.S. Environmental Protection Agency (EPA) and the National Toxicology Program (NTP) are collaborating to develop a risk-based approach for conducting PFAS toxicity testing to facilitate PFAS human health assessments. This article describes the construction of a PFAS screening library and the process by which a targeted subset of 75 PFASs were selected. Multiple factors were considered, including interest to the U.S. EPA, compounds within targeted categories, structural diversity, exposure considerations, procurability and testability, and availability of existing toxicity data. Generating targeted HTT data for PFASs represents a new frontier for informing priority setting. https://doi.org/10.1289/EHP4555

Particulate matter (PM) air pollution has been associated with decreased pulmonary function, but the exposure–response relationship in chronic obstructive pulmonary disease (COPD) patients is uncertain, and most studies have only focused on exposures to ambient pollution.We aimed to assess associations between pulmonary function and indoor and ambient PM [Formula: see text] ([Formula: see text]) and black carbon (BC).Between November 2012 and December 2014, 125 patients with COPD (mean age, 73.4 y) who were not currently smoking and without known indoor BC sources were recruited. Indoor BC and [Formula: see text] were measured in each home for a week in each season, up to four times a year, followed by in-person spirometry pre- and post-bronchodilator. Ambient exposures were available from a central site monitor. Multivariable adjusted mixed effects regression models were used to assess associations scaled per interquartile range (IQR) of exposure.There were 367 study visits; the median (IQR) indoor BC and [Formula: see text] were 0.19 (0.22) [Formula: see text] and 6.67 (5.80) [Formula: see text], respectively. Increasing indoor exposures to BC were associated with decreases in pre-bronchodilator forced expiratory volume in 1 s [Formula: see text] and forced vital capacity (FVC), and [Formula: see text]. For example, in multivariable adjusted models, each IQR increase in indoor BC from the weekly integrated filter was associated with a [Formula: see text] [95% confidence interval (CI): [Formula: see text], [Formula: see text]] decrease in pre-bronchodilator [Formula: see text]. Increases in indoor [Formula: see text] were associated with decreases in [Formula: see text] and FVC of smaller magnitude than those for indoor BC; however, the results were less precise. Ambient BC was not associated with pre-bronchodilator pulmonary function, ambient [Formula: see text] was only associated with decreases in FVC and increases in [Formula: see text], and neither indoor nor ambient BC or [Formula: see text] were associated with post-bronchodilator pulmonary function.Low-level exposures to indoor BC and [Formula: see text], but not ambient exposures, were consistently associated with decreases in pre-bronchodilator pulmonary function. There was no association between exposures and post-bronchodilator pulmonary function. https://doi.org/10.1289/EHP3668.

Background: Many cohort studies have reported associations between PM2.5 and the hazard of dying, but few have used formal causal modeling methods, estimated marginal effects, or directly modeled t...

Background: Previous studies have associated short-term air pollution exposure with depression. Although an animal study showed an association between long-term exposure to particulate matter ≤ 2.5 μm (PM2.5) and depression, epidemiological studies assessing the long-term association are scarce. Objective: We aimed to determine the association between long-term PM2.5 exposure and major depressive disorder (MDD). Methods: A total of 27,270 participants 15–79 years of age who maintained an address within the same districts in Seoul, Republic of Korea, throughout the entire study period (between 2002 and 2010) and without a previous MDD diagnosis were analyzed. We used three district-specific exposure indices as measures of long-term PM2.5 exposure. Cox proportional hazards models adjusted for potential confounding factors and measured at district and individual levels were constructed. We further conducted stratified analyses according to underlying chronic diseases such as diabetes mellitus, cardiovascular disease, and chronic obstructive pulmonary disease. Results: The risk of MDD during the follow-up period (2008–2010) increased with an increase of 10 μg/m3 in PM2.5 in 2007 [hazard ratio (HR) = 1.44; 95% CI: 1.17, 1.78], PM2.5 between 2007 and 2010 (HR = 1.59; 95% CI: 1.02, 2.49), and 12-month moving average of PM2.5 until an event or censor (HR = 1.47; 95% CI: 1.14, 1.90). The association between long-term PM2.5 exposure and MDD was greater in participants with underlying chronic diseases than in participants without these diseases. Conclusion: Long-term PM2.5 exposure increased the risk of MDD among the general population. Individuals with underlying chronic diseases are more vulnerable to long-term PM2.5 exposure. Citation: Kim KN, Lim YH, Bae HJ, Kim M, Jung K, Hong YC. 2016. Long-term fine particulate matter exposure and major depressive disorder in a community-based urban cohort. Environ Health Perspect 124:1547–1553; http://dx.doi.org/10.1289/EHP192

Background: Prenatal exposure to ambient PM2.5, (i.e., fine particulate matter, aerodynamic diameter ≤ 2.5 μm) has been associated with preterm birth and low birth weight. The association between prenatal PM2.5 exposure and intrauterine inflammation (IUI), an important risk factor for preterm birth and neurodevelopmental outcomes, has not been evaluated. Objectives: We aimed to investigate the association between maternal exposure to PM2.5 and IUI in the Boston Birth Cohort, a predominantly urban low-income minority population. Methods: This analysis included 5,059 mother–infant pairs in the Boston Birth Cohort. IUI was assessed based on intrapartum fever and placenta pathology. PM2.5 exposure was assigned using data from the U.S. EPA’s Air Quality System. Odds ratios (OR) and 95% confidence intervals (CI) quantified the association of maternal PM2.5 exposure during preconception and various periods of pregnancy with IUI. Results: Comparing the highest with the lowest PM2.5 exposure quartiles, the multi-adjusted association with IUI was significant for all exposure periods considered, including 3 months before conception (OR = 1.52; 95% CI: 1.22, 1.89), first trimester (OR = 1.93; 95% CI: 1.55, 2.40), second trimester (OR = 1.67; 95% CI: 1.35, 2.08), third trimester (OR = 1.53; 95% CI: 1.24, 1.90), and whole pregnancy (OR = 1.92; 95% CI: 1.55, 2.37). Conclusions: Despite relatively low exposures, our results suggest a monotonic positive relationship between PM2.5 exposure during preconception and pregnancy and IUI. IUI may be a sensitive biomarker for assessing early biological effect of PM2.5 exposure on the developing fetus. Citation: Nachman RM, Mao G, Zhang X, Hong X, Chen Z, Soria CS, He H, Wang G, Caruso D, Pearson C, Biswal S, Zuckerman B, Wills-Karp M, Wang X. 2016. Intrauterine inflammation and maternal exposure to ambient PM2.5 during preconception and specific periods of pregnancy: the Boston Birth Cohort. Environ Health Perspect 124:1608–1615; http://dx.doi.org/10.1289/EHP243

Background: The workplace is one of the major locations outside of the home for nonsmokers’ exposure to secondhand smoke (SHS). New policies in many U.S. states and localities restrict or prohibit smoking in the workplace, and information on current trends in the exposure of nonsmokers to SHS across various occupational groups is therefore needed. Objective: We evaluated temporal trends in SHS exposure among nonsmoking workers in the United States and identified those occupations with workers with the highest levels of SHS exposure. Methods: We combined serum cotinine (sCOT) measurements and questionnaire data from five survey cycles of the National Health and Nutrition Examination Survey (NHANES: 2001–2010). Trends in SHS exposure by occupations were determined from percent changes and least-squares geometric means (LSGMs) of sCOT concentrations computed using sample-weighted multiple regression models. Results: Between NHANES 2001–2002 and NHANES 2009–2010, LSGMs of sCOT levels had changed –25% (95% CI: –39, –7%) in nonsmoking workers. The largest decrease was identified among food preparation workers [–54% (95% CI: –74, –19%)], followed by white-collar [–40%, (95% CI: –56, –19%)] and blue-collar workers (–32%, 95% CI: –51, –5%). LSGMs of sCOT remained highest in food preparation workers in all survey cycles, but the gap between occupations narrowed in the latest survey cycle (2009–2010). For example, the gap in LSGMs of sCOT between food preparation and science/education workers dropped > 70% during 2000 to 2010. Conclusions: During the period from 2001 to 2010, the overall SHS exposure in nonsmoking workers declined with substantial drops in food preparation/service and blue-collar workers. Although disparities persist in SHS exposure, the gaps among occupations have narrowed. Citation: Wei B, Bernert JT, Blount BC, Sosnoff CS, Wang L, Richter P, Pirkle JL. 2016. Temporal trends of secondhand smoke exposure: nonsmoking workers in the United States (NHANES 2001–2010). Environ Health Perspect 124:1568–1574; http://dx.doi.org/10.1289/EHP165