[... formula ...] and [... formula ...] Exposures and Lung Function in Swiss Adults: Estimated Effects of Short-Term Exposures and Long-Term Exposures with and without Adjustment for Short-Term Deviations

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     

Associations between Blood Lead Levels and Coronary Artery Stenosis Measured Using Coronary Computed Tomography Angiography

Background: Lead exposure is a risk factor for increased blood pressure and cardiovascular disease, even when blood lead levels (BLLs) are within the normal range.Objective: This study aimed to investigate the association between BLL and coronary artery stenosis (CAS) in asymptomatic adults using 128-slice dual-source coronary computed tomography (CT) angiography.Methods: We analyzed medical records data from 2,193 adults (1,461 men and 732 women) who elected to complete a screening health examination, coronary CT angiography, and BLL measurement during 2011–2018 and had no history of CAS symptoms, cardiovascular disease, or occupational exposure to lead. Logistic regression models were used to estimate associations between moderate-to-severe CAS (≥25% stenosis) and a 1-μg/dL increase in blood lead, with and without adjustment for age, sex, hypertension, diabetes mellitus, dyslipidemia, body mass index, regular exercise, smoking status, and alcohol drinking.Results: BLLs ranged from 0.12 to 10.14μg/dL, with an arithmetic mean of 2.71±1.26μg/dL. The arithmetic mean was higher for men than for women (2.98±1.26μg/dL vs. 2.18±1.08μg/dL, p<0.001) and higher in the moderate-to-severe CAS group than in the no-CAS or <25% stenosis group (3.02±1.44μg/dL vs. 2.67±1.23μg/dL, p<0.001). Moderate-to-severe CAS was significantly associated with BLL before and after adjustment, with an adjusted odds ratio for a 1-μg/dL increase in BLL of 1.14 (95% CI: 1.02, 1.26), p=0.017.Conclusions: BLL was positively associated with the prevalence of moderate-to-severe CAS in Korean adults who completed an elective screening examination for early cardiovascular disease, 94% of whom had a BLL of <5μg/dL. More efforts and a strict health policy are needed to further reduce BLLs in the general population. https://doi.org/10.1289/EHP7351     

Assessing Indoor Dust Interference with Human Nuclear Hormone Receptors in Cell-Based Luciferase Reporter Assays

Background: Per- and polyfluoroalkyl substances (PFAS), organophosphate esters (OPEs), and polybrominated diphenyl ethers (PBDEs) are hormone-disrupting chemicals that migrate from building materials into air and dust.Objectives: We aimed to quantify the hormonal activities of 46 dust samples and identify chemicals driving the observed activities.Methods: We evaluated associations between hormonal activities of extracted dust in five cell-based luciferase reporter assays and dust concentrations of 42 measured PFAS, OPEs, and PBDEs, transformed as either raw or potency-weighted concentrations based on Tox21 high-throughput screening data.Results: All dust samples were hormonally active, showing antagonistic activity toward peroxisome proliferator-activated receptor (PPARγ2) (100%; 46 of 46 samples), thyroid hormone receptor (TRβ) (89%; 41 samples), and androgen receptor (AR) (87%; 40 samples); agonist activity on estrogen receptor (ERα) (96%; 44 samples); and binding competition with thyroxine (T4) on serum transporter transthyretin (TTR) (98%; 45 samples). Effects were observed with as little as 4μg of extracted dust. In regression models for each chemical class, interquartile range increases in potency-weighted or unknown-potency chemical concentrations were associated with higher hormonal activities of dust extracts (potency-weighted: ΣPFAS–TRβ, ↑28%, p<0.05; ΣOPEs–TRβ, ↑27%, p=0.08; ΣPBDEs–TRβ, ↑20%, p<0.05; ΣPBDEs–ERα, ↑7.7%, p=0.08; unknown-potency: ΣOPEs–TTR, ↑34%, p<0.05; ΣOPEs–AR, ↑13%, p=0.06), adjusted for chemicals with active, inactive, and unknown Tox21 designations.Discussion: All indoor dust samples exhibited hormonal activities, which were associated with PFAS, PBDE, and OPE levels. Reporter gene cell-based assays are relatively inexpensive, health-relevant evaluations of toxic loads of chemical mixtures that building occupants are exposed to. https://doi.org/10.1289/EHP8054     

Folic Acid Supplementation and the Association between Maternal Airborne Particulate Matter Exposure and Preterm Delivery: A National Birth Cohort Study in China

Background: Potential modification of the association between maternal particulate matter (PM) exposure and preterm delivery (PTD) by folic acid (FA) supplementation has not been studied.Objective: We examined whether FA supplementation could reduce the risk of PTD associated with maternal exposure to PM in ambient air during pregnancy.Method: In a cohort study covering 30 of the 31 provinces of mainland China in 2014, 1,229,556 primiparas of Han ethnicity were followed until labor. We collected information on their FA supplementation and pregnancy outcomes and estimated each participant’s exposure to PM with diameters of ≤10μm (PM10), 2.5μm (PM2.5), and 1μm (PM1) using satellite remote-sensing based models. Cox proportional hazard regression models were used to examine interactions between FA supplementation and PM exposures, after controlling for individual characteristics.Results: Participants who initiated FA ≥3 months prior to pregnancy (38.1%) had a 23% [hazard ratio (HR)=0.77 (95% CI: 0.76, 0.78)] lower risk of PTD than women who did not use preconception FA. Participants with PM concentrations in the highest quartile had a higher risk of PTD [HR=1.29 (95% CI: 1.26, 1.32) for PM1, 1.52 (95% CI: 1.46, 1.58) for PM2.5, and 1.22 (95% CI: 1.17, 1.27) for PM10] than those with exposures in the lowest PM quartiles. Estimated associations with a 10-μg/m3 increase in PM1 and PM2.5 were significantly lower among women who initiated FA ≥3 months prior to pregnancy [HR=1.09 (95% CI: 1.08, 1.10) for both exposures] than among women who did not use preconception FA [HR=1.12 (95% CI: 1.11, 1.13) for both exposures; pinteraction<0.001]. The corresponding association was also significantly lower for a 10-μg/m3 increase in PM10 [HR=1.03 (95% CI: 1.02, 1.03) for FA ≥3 months before pregnancy vs. 1.04 (95% CI: 1.03, 1.04) for no preconception FA; pinteraction<0.001].Conclusion: Our findings require confirmation in other populations, but they suggest that initiating FA supplementation ≥3 months prior to pregnancy may lessen the risk of PTD associated with PM exposure during pregnancy among primiparas of Han ethnicity. https://doi.org/10.1289/EHP6386     

Fluoride in Drinking Water,Diet, and Urine in Relation to Bone Mineral Density and Fracture Incidence in Postmenopausal Women

Background: Although randomized controlled trials (RCTs) have demonstrated that high fluoride increases bone mineral density (BMD) and skeletal fragility, observational studies of low-dose chronic exposure through drinking water (<1.5mg/L, the maximum recommended by the World Health Organization) have been inconclusive.Objective: We assessed associations of fluoride in urine, and intake via diet and drinking water, with BMD and fracture incidence in postmenopausal women exposed to drinking water fluoride ≤1mg/L.Methods: Data were from participants in the Swedish Mammography Cohort–Clinical, a population-based prospective cohort study. At baseline (2004–2009), fluoride exposure was assessed based on urine concentrations (n=4,306) and estimated dietary intake (including drinking water) (n=4,072), and BMD was measured using dual energy X-ray absorptiometry. Incident fractures were ascertained via register-linkage through 2017. Residential history was collected to identify women with long-term consistent drinking water exposures prior to baseline.Results: At baseline, mean urine fluoride was 1.2mg/g creatinine (±1.9) and mean dietary intake was 2.2mg/d (±0.9), respectively. During follow-up, 850, 529, and 187 cases of any fractures, osteoporotic fractures, and hip fractures, respectively, were ascertained. Baseline BMD was slightly higher among women in the highest vs. lowest tertiles of exposure. Fluoride exposures were positively associated with incident hip fractures, with multivariable-adjusted hazard ratios of 1.50 (95% CI: 1.04, 2.17) and 1.59 (95% CI: 1.10, 2.30), for the highest vs. lowest tertiles of urine fluoride and dietary fluoride, respectively. Associations with other fractures were less pronounced for urine fluoride, and null for dietary fluoride. Restricting the analyses to women with consistent long-term drinking water exposures prior to baseline strengthened associations between fractures and urinary fluoride.Discussion: In this cohort of postmenopausal women, the risk of fractures was increased in association with two separate indicators of fluoride exposure. Our findings are consistent with RCTs and suggest that high consumption of drinking water with a fluoride concentration of ∼1mg/L may increase both BMD and skeletal fragility in older women. https://doi.org/10.1289/EHP7404     

Ambient Fine Particulate Matter Air Pollution and Risk of Weight Gain and Obesity in United States Veterans: An Observational Cohort Study

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)≥30kg/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 (4.54kg) increase in weight [HR=1.07 (95% CI: 1.06, 1.08)] and with higher intra-individual changes in BMI [0.140kg/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 12μg/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     

Assessing the Distribution of Air Pollution Health Risks within Cities: A Neighborhood-Scale Analysis Leveraging High-Resolution Data Sets in the Bay Area,California

Background: Air pollution-attributable disease burdens reported at global, country, state, or county levels mask potential smaller-scale geographic heterogeneity driven by variation in pollution levels and disease rates. Capturing within-city variation in air pollution health impacts is now possible with high-resolution pollutant concentrations.Objectives: We quantified neighborhood-level variation in air pollution health risks, comparing results from highly spatially resolved pollutant and disease rate data sets available for the Bay Area, California.Methods: We estimated mortality and morbidity attributable to nitrogen dioxide (NO2), black carbon (BC), and fine particulate matter [PM ≤2.5μm in aerodynamic diameter (PM2.5)] using epidemiologically derived health impact functions. We compared geographic distributions of pollution-attributable risk estimates using concentrations from a) mobile monitoring of NO2 and BC; and b) models predicting annual NO2, BC and PM2.5 concentrations from land-use variables and satellite observations. We also compared results using county vs. census block group (CBG) disease rates.Results: Estimated pollution-attributable deaths per 100,000 people at the 100-m grid-cell level ranged across the Bay Area by a factor of 38, 4, and 5 for NO2 [mean=30 (95% CI: 9, 50)], BC [mean=2 (95% CI: 1, 2)], and PM2.5, [mean=49 (95% CI: 33, 64)]. Applying concentrations from mobile monitoring and land-use regression (LUR) models in Oakland neighborhoods yielded similar spatial patterns of estimated grid-cell–level NO2-attributable mortality rates. Mobile monitoring concentrations captured more heterogeneity [mobile monitoring mean=64 (95% CI: 19, 107) deaths per 100,000 people; LUR mean=101 (95% CI: 30, 167)]. Using CBG-level disease rates instead of county-level disease rates resulted in 15% larger attributable mortality rates for both NO2 and PM2.5, with more spatial heterogeneity at the grid-cell–level [NO2 CBG mean=41 deaths per 100,000 people (95% CI: 12, 68); NO2 county mean=38 (95% CI: 11, 64); PM2.5 CBG mean=59 (95% CI: 40, 77); and PM2.5 county mean=55 (95% CI: 37, 71)].Discussion: Air pollutant-attributable health burdens varied substantially between neighborhoods, driven by spatial variation in pollutant concentrations and disease rates. https://doi.org/10.1289/EHP7679     

Prenatal Lead (Pb) Exposure and Peripheral Blood DNA Methylation (5mC) and Hydroxymethylation (5hmC) in Mexican Adolescents from the ELEMENT Birth Cohort

Background: Gestational lead (Pb) exposure can adversely affect offspring health through multiple mechanisms, including epigenomic alterations via DNA methylation (5mC) and hydroxymethylation (5hmC), an intermediate in oxidative demethylation. Most current methods do not distinguish between 5mC and 5hmC, limiting insights into their individual roles.Objective: Our study sought to identify the association of trimester-specific (T1, T2, T3) prenatal Pb exposure with 5mC and 5hmC levels at multiple cytosine-phosphate-guanine sites within gene regions previously associated with prenatal Pb (HCN2, NINJ2, RAB5A, TPPP) in whole blood leukocytes of children ages 11–18 years of age.Methods: Participants from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) birth cohorts were selected (n=144) for pyrosequencing analysis following oxidative or standard sodium bisulfite treatment. This workflow directly quantifies total methylation (5mC+5hmC) and 5mC only; 5hmC is estimated by subtraction.Results: Participants were 51% male, and mean maternal blood lead levels (BLL) were 6.43±5.16μg/dL in Trimester 1 (T1), 5.66±5.21μg/dL in Trimester 2 (T2), and 5.86±4.34μg/dL in Trimester 3 (T3). In addition, 5hmC levels were calculated for HCN2 (mean±standard deviation(SD), 2.08±4.18%), NINJ2 (G/C: 2.01±5.95; GG: 0.90±3.97), RAB5A (0.66±0.80%), and TPPP (1.11±6.67%). Furthermore, 5mC levels were measured in HCN2 (81.3±9.63%), NINJ2 (heterozygotes: 38.6±7.39%; GG homozygotes: 67.3±9.83%), RAB5A (1.41±1.21%), and TPPP (92.5±8.03%). Several significant associations between BLLs and 5mC/5hmC were identified: T1 BLLs with 5mC in HCN2 (β=−0.37, p=0.03) and 5hmC in NINJ2 (β=0.49, p=0.003); T2 BLLs with 5mC in HCN2 (β=0.37, p=0.03) and 5hmC in NINJ2 (β=0.27, p=0.008); and T3 BLLs with 5mC in HCN2 (β=0.50, p=0.01) and NINJ2 (β=−0.35, p=0.004) and 5hmC in NINJ2 (β=0.45, p<0.001). NINJ2 5mC was negatively correlated with gene expression (Pearson r=−0.5, p-value=0.005), whereas 5hmC was positively correlated (r=0.4, p-value=0.04).Discussion: These findings suggest there is variable 5hmC in human whole blood and that prenatal Pb exposure is associated with gene-specific 5mC and 5hmC levels at adolescence, providing evidence to consider 5hmC as a regulatory mechanism that is responsive to environmental exposures. https://doi.org/10.1289/EHP8507     

Associations of Pre- and Postnatal Air Pollution Exposures with Child Blood Pressure and Modification by Maternal Nutrition: A Prospective Study in the CANDLE Cohort

Background: Limited data suggest air pollution exposures may contribute to pediatric high blood pressure (HBP), a known predictor of adult cardiovascular diseases.Methods: We investigated this association in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) study, a sociodemographically diverse pregnancy cohort in the southern United States with participants enrolled from 2006 to 2011. We included 822 mother–child dyads with available address histories and a valid child blood pressure measurement at 4–6 y. Systolic (SBP) and diastolic blood pressures (DBP) were converted to age-, sex-, and height-specific percentiles for normal-weight U.S. children. HBP was classified based on SBP or DBP ≥90th percentile. Nitrogen dioxide (NO2) and particulate matter ≤2.5μm in aerodynamic diameter (PM2.5) estimates in both pre- and postnatal windows were obtained from annual national models and spatiotemporal models, respectively. We fit multivariate Linear and Poisson regressions and explored multiplicative joint effects with maternal nutrition, child sex, and maternal race using interaction terms.Results: Mean PM2.5 and NO2 in the prenatal period were 10.8 [standard deviation (SD): 0.9] μg/m3 and 10.0 (SD: 2.4) ppb, respectively, and 9.9 (SD: 0.6) μg/m3 and 8.8 (SD: 1.9) ppb from birth to the 4-y-old birthday. On average, SBP percentile increased by 14.6 (95% CI: 4.6, 24.6), and DBP percentile increased by 8.7 (95% CI: 1.4, 15.9) with each 2-μg/m3 increase in second-trimester PM2.5. PM2.5 averaged over the prenatal period was only significantly associated with higher DBP percentiles [β= 11.6 (95% CI: 2.9, 20.2)]. Positive associations of second-trimester PM2.5 with SBP and DBP percentiles were stronger in children with maternal folate concentrations in the lowest quartile (pinteraction= 0.05 and 0.07, respectively) and associations with DBP percentiles were stronger in female children (pinteraction= 0.05). We did not detect significant association of NO2, road proximity, and postnatal PM2.5 with any outcomes.Conclusions: The findings suggest that higher prenatal PM2.5 exposure, particularly in the second trimester, is associated with elevated early childhood blood pressure. This adverse association could be modified by pregnancy folate concentrations. https://doi.org/10.1289/EHP7486     

Interaction between Long-Term Exposure to Fine Particulate Matter and Physical Activity,and Risk of Cardiovascular Disease and Overall Mortality in U.S. Women

Background: Increased respiration during physical activity may increase air pollution dose, which may attenuate the benefits of physical activity on cardiovascular disease (CVD) risk and overall mortality.Objectives: We aimed to examine the multiplicative interaction between long-term ambient residential exposure to fine particulate matter <2.5 microns (PM2.5) and physical activity in the association with CVD risk and overall mortality.Methods: We followed 104,990 female participants of the U.S.-based prospective Nurses’ Health Study from 1988 to 2008. We used Cox proportional hazards models to assess the independent associations of 24-months moving average residential PM2.5 exposure and physical activity updated every 4 y and the multiplicative interaction of the two on CVD (myocardial infarction and stroke) risk and overall mortality, after adjusting for demographics and CVD risk factors.Results: During 20 years of follow-up, we documented 6,074 incident CVD cases and 9,827 deaths. In fully adjusted models, PM2.5 exposure was associated with modest increased risks of CVD [hazard ratio (HR) for fifth quintile ≥16.5μg/m3 compared to first quintile <10.7μg/m3: 1.09, 95% confidence interval (CI): 0.99, 1.20; ptrend=0.05] and overall mortality (HR fifth compared to first quintile: 1.10, 95% CI: 1.02, 1.19; ptrend=0.07). Higher overall physical activity was associated with substantially lower risk of CVD [HR fourth quartile, which was ≥24.4 metabolic equivalent of task (MET)-h/wk, compared to first quartile (<3.7MET-h/wk): 0.61, 95% CI: 0.57, 0.66; ptrend<0.0001] and overall mortality (HR fourth compared to first quartile: 0.40, 95% CI: 0.37, 0.42; ptrend<0.0001). We observed no statistically significant interactions between PM2.5 exposure and physical activity (overall, walking, vigorous activity) in association with CVD risk and overall mortality.Discussion: In this study of U.S. women, we observed no multiplicative interaction between long-term PM2.5 exposure and physical activity; higher physical activity was strongly associated with lower CVD risk and overall mortality at all levels of PM2.5 exposure. https://doi.org/10.1289/EHP7402     

Boiled or Bottled: Regional and Seasonal Exposures to Drinking Water Contamination and Household Air Pollution in Rural China

Background: Inadequate access to safe drinking water remains a global health problem, particularly in rural areas. Boiling is the most commonly used form of point-of-use household water treatment (HWT) globally, although the use of bottled water in low- and middle-income countries (LMICs) is increasing rapidly.Objectives: We assessed the regional and seasonal prevalence of HWT practices (including bottled water use) in low-income rural areas in two Chinese provinces, evaluated the microbiological safety of drinking water and associated health outcomes, and estimated the air pollution burden associated with the use of solid fuels for boiling.Methods: We conducted cross-sectional surveys and collected drinking water samples from 1,033 rural households in Guangxi and Henan provinces. Temperature sensors affixed to pots and electric kettles were used to corroborate self-reported boiling frequencies and durations, which were used to model household air pollution (HAP) in terms of estimated particulate matter ≤2.5μm in aerodynamic diameter (PM2.5) concentrations.Results: Based on summer data collection in both provinces, after controlling for covariates, boiling with electric kettles was associated with the largest log reduction in thermotolerant coliforms (TTCs) (−0.66 log10 TTC most probable number/100mL), followed by boiling with pots (−0.58), and bottled water use (−0.39); all were statistically significant (p<0.001). Boiling with electric kettles was associated with a reduced risk of TTC contamination [risk ratio (RR)=0.25, p<0.001] and reported diarrhea (RR=0.80, p=0.672). TTCs were detected in 51% (n=136) of bottled water samples. For households boiling with biomass, modeled PM2.5 concentrations averaged 79μg/m3 (standard deviation=21).Discussion: Our findings suggest that where boiling is already common and electricity access is widespread, the promotion of electricity-based boiling may represent a pragmatic stop-gap means of expanding safe water access until centralized, or decentralized, treated drinking water is available; displacing biomass use for water boiling could also reduce HAP concentrations and exposures. Our results also highlight the risks of increasing bottled water use in rural areas, and its potential to displace other sources of safe drinking water, which could in turn hamper efforts in China and other LMICs toward universal and affordable safe water access. https://doi.org/10.1289/EHP7124     

Cadmium Exposure and Coronary Artery Atherosclerosis: A Cross-Sectional Population-Based Study of Swedish Middle-Aged Adults

Background: The general population is ubiquitously exposed to the toxic metal cadmium through the diet and smoking. Cadmium exposure is associated with increased morbidity and mortality in myocardial infarction and stroke. Atherosclerosis is the main underlying mechanism of myocardial infarction. However, associations between cadmium and coronary artery atherosclerosis have not been examined.Objectives: Our study sought to examine the hypothesis that blood cadmium (B-Cd) is positively associated with coronary artery calcification, as a measure of coronary artery atherosclerosis in the population-based Swedish SCAPIS study.Methods: Our analysis included 5,627 individuals (51% women), age 50–64 y, enrolled from 2013 to 2018. The coronary artery calcium score (CACS) was obtained from computed tomography. Blood cadmium was determined by inductively coupled plasma mass spectrometry (ICP-MS). Associations between B-Cd and coronary artery calcium score (CACS Agatston score) were evaluated using prevalence ratios (PRs) in models adjusted for sex, age, smoking, hypertension, diabetes, low-density cholesterol/high-density cholesterol ratio, and family history.Results: The median B-Cd concentration was 0.24μg/L. The prevalence of positive coronary artery calcium (CACS>0) was 41% and the prevalence of CACS≥100 was 13%. Relative to the lowest quartile (Q) of B-Cd (<0.16μg/L), the highest quartile (median 0.63μg/L) was associated with a small but significant increase in CACS>0 (PR 1.1; 95% CI: 1.0, 1.3), and a greater relative increase in CACS≥100 (PR 1.6; 95% CI: 1.3, 2.0). When restricted to 2,446 never-smokers, corresponding PRs were 1.1 (95% CI 0.9, 1.3) for CACS>0 (63 cases in Q4) and 1.7 (95% CI 1.1, 2.7) for CACS≥100 (17 cases in Q4).Discussion: Blood cadmium in the highest quartile was associated with CACS in a general population sample with low to moderate cadmium exposure. This supports the hypothesis that atherosclerosis is an important mechanism underlying the associations between cadmium and incident cardiovascular disease. The findings suggest that public health measures to reduce cadmium exposure are warranted. https://doi.org/10.1289/EHP8523     

[... formula ...] and Lung Function: An in Vivo Exploration of Potential Climate Change Implications

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Atmospheric carbon dioxide (CO2) hit a milestone in 2015, when global average concentrations reached 400ppm for the first time in recorded history.1 By 2100, the global average could more than double if emissions remain unabated, according to the RCP8.5 (“business as usual”) scenario used by the Intergovernmental Panel on Climate Change in its assessments.2 Although much attention has been paid to the effect of CO2 as a climate forcing agent, multiple reports suggest this greenhouse gas also may have direct health effects.3 A recent report in Environmental Health Perspectives used a mouse model to assess the pulmonary effects of chronic exposure to ambient CO2 at concentrations comparable to those projected by climate modeling.4Open in a separate windowHumans have been exposed to atmospheric CO2 concentrations averaging roughly 230ppm since the time of our earliest ancestor.9^,10 However, intensified human activity and associated CO2 emissions have led to increases of 2–3ppm per year for the past 50 years. In its most recent update as of this writing, Hawaii’s Mauna Loa Observatory reported a seasonally adjusted CO2 concentration of 414.88ppm for the month of December 2020.11 Image: National Aeronautics and Space Administration. Based on data from Lüthi et al. (2008).12A 2019 review in Nature Sustainability summarized evidence on the effects on lung function of very high (>1,000ppm), acute CO2 exposures.3 In contrast, current report is the first known study to directly assess the physiological impact of long-term exposure to CO2 concentrations that are realistically possible in the near future, says first author Alexander Larcombe, an associate professor at the Telethon Kids Institute and Wal-yan Respiratory Research Center in Nedlands, Australia.In the new study, investigators exposed adult female mice and their offspring to either control (approximately465ppm) or elevated (approximately890ppm) concentrations of CO2. Dams began exposure with a 1-week acclimation period before mating, and offspring were exposed from preconception to adulthood. At postnatal week 12, the investigators assessed the offspring’s respiratory function and lung structure. To compare the effects of exposure during lung development versus exposure during adulthood, they also examined the dams’ lung function.Their results indicate that, among female offspring, exposures to high ambient CO2 caused modest measurable changes in lung function and structure compared with exposure to control CO2 levels. The fact that deficits were seen only in offspring suggests the differences were developmental rather than adaptational.Lung development impairment is well documented to occur in a low-oxygen environment (hypoxia);5 however, the exposure model used in this study did not mimic hypoxic conditions, where oxygen levels are significantly lower while CO2 levels remain unchanged. In the lung, gas exchange occurs in tiny air sacs called alveoli, and perturbations in ambient CO2 levels would be expected to result in increased lung area through alveolarization,6 which in the mouse develops almost exclusively after birth.7 Consistent with this notion, male mice exhibited higher numbers of alveoli; conversely, females showed decreased alveolarization. Other markers of lung function suggested that high CO2 exposure affected female mice exclusively.The authors proposed respiratory acidosis, a change in blood chemistry that results from CO2 exposure, as a possible basis for impaired lung function in female mice. However, they explored no foundation for the sex-specific effects.The findings reported by the authors might not rule out an effect on male mice given the relatively small sample size and inherent animal-to-animal variability, cautions Darryl Zeldin, head of the Environmental Cardiopulmonary Disease Group and scientific director of the National Institute of Environmental Health Sciences. Zeldin was not involved in the study.An additional caveat to the study is the choice of animal model. As burrowing animals, mice are more tolerant to elevated CO2 than animals that stay aboveground.8 Larcombe suggests that future studies should address whether similar outcomes occur in larger, nonburrowing mammals, which would help to give further insight into potential implications for human health.     

Breast Cancer Risk in Association with Atmospheric Pollution Exposure: A Meta-Analysis of Effect Estimates Followed by a Health Impact Assessment

Background: The epidemiological literature of associations between atmospheric pollutant exposure and breast cancer incidence has recently strongly evolved.Objectives: We aimed to perform a) a meta-analysis of studies considering this relationship, correcting for publication bias and taking menopausal status and cancer hormone responsiveness into account; and b) for the pollutants most likely to affect breast cancer, an assessment of the corresponding number of attributable cases in France and of the related economic costs.Methods: We conducted a literature review and random-effects meta-analyses of epidemiological studies examining the association of fine particulate matter with aerodynamic diameter less than or equal to 2.5μm (PM2.5), particulate matter with aerodynamic diameter less than or equal to 10 μm (PM10), and NO2 long-term exposure with breast cancer incidence; additional analyses were stratified on menopausal status and on tumor hormone responsiveness status. The resulting dose–response functions were combined with modeled atmospheric pollutant exposures in 2013 for France, cancer treatments costs, lost productivity, and years of life lost, to estimate the number of breast cancers attributable to atmospheric pollution and related economic costs in France.Results: The review identified 32, 27, and 36 effect estimates for PM2.5, PM10, and NO2, respectively. The meta-analytical relative risk estimates of breast cancer corrected for publication bias were 1.006 [95% confidence interval (CI): 0.941, 1.076], 1.047 (95% CI: 0.984, 1.113), and 1.023 (95% CI: 1.005, 1.041), respectively. NO2 estimated effects appeared higher in premenopausal than in postmenopausal women and higher for hormone responsive positive (ER+/PR+) than negative (ER–/PR–) breast cancers. Assuming a causal effect of NO2, we estimated that 1,677 (95% CI: 374, 2,914) new breast cancer cases were attributable to NO2 annually in France, or 3.15% (95% CI: 0.70, 5.48) of the incident cases. The corresponding tangible and intangible costs were estimated to be €825 million (low, high: 570, 1,080) per year.Conclusion: These findings suggest that decreasing long-term NO2 exposure or correlated air pollutant exposures could lower breast cancer risk. https://doi.org/10.1289/EHP8419     

Bias due to Selection on Live Births in Studies of Environmental Exposures during Pregnancy: A Simulation Study

Background: Studies of the effects of prenatal environmental exposures on postnatal outcomes are particularly vulnerable to live birth bias; i.e., the bias that arises from the necessary restriction of the analysis to live births when that is influenced by both the exposure under study A and unmeasured factors U that also affect the outcome.Objectives: In the context of a recent publication of nitrogen dioxide (NO2) and autism spectrum disorder (ASD) that found an odds ratio (OR) of 0.77 per 5.85 ppb NO2 during pregnancy, we aimed to examine what parameters would be needed to account for this protective association through live birth bias.Methods: We simulated the magnitude of bias under two selection mechanisms and when both mechanisms co-occur, assuming a true null effect. Simulation input parameters were based on characteristics of the original study and a range of plausible values for the prevalence of unmeasured factor U and the ORs for the selection effects (i.e., the effects of NO2 and U on loss and of U on ASD). Each scenario was simulated 1,000 times.Results: We found that the magnitude of bias was small when NO2 and U independently influenced pregnancy loss (collider-stratification without interaction), was stronger when NO2-induced loss preferentially occurred in U=1 (depletion of susceptibles), and was strongest when both mechanisms worked together. For example, ORs of 3.0 for NO2-loss, U-loss, U-ASD, and U prevalence=0.75 yielded NO2-ASD ORs per 5.85 ppb NO2 of 0.95, 0.89, and 0.75 for the three scenarios, respectively. The bias is amplified with multiple Us, yielding ORs as low as 0.51.Discussion: Our simulations illustrate that live birth bias may lead to exposure–outcome associations that are biased downward, where the extent of the bias depends on the fetal selection mechanism, the strength of that selection, and the prevalence of U. https://doi.org/10.1289/EHP7961     

Mouse Lung Structure and Function after Long-Term Exposure to an Atmospheric Carbon Dioxide Level Predicted by Climate Change Modeling

Background: Climate change models predict that atmospheric carbon dioxide [CO2] levels will be between 700 and 900 ppm within the next 80 y. Despite this, the direct physiological effects of exposure to slightly elevated atmospheric CO2 (as compared with ∼410 ppm experienced today), especially when exposures extend from preconception to adulthood, have not been thoroughly studied.Objectives: In this study we aimed to assess the respiratory structure and function effects of long-term exposure to 890 ppm CO2 from preconception to adulthood using a mouse model.Methods: We exposed mice to CO2 (∼890 ppm) from prepregnancy, through the in utero and early life periods, until 3 months of age, at which point we assessed respiratory function using the forced oscillation technique, and lung structure.Results: CO2 exposure resulted in a range of respiratory impairments, particularly in female mice, including higher tissue elastance, longer chord length, and lower lung compliance. Importantly, we also assessed the lung function of the dams that gave birth to our experimental subjects. Even though these mice had been exposed to the same level of increased CO2 for a similar amount of time (∼8wk), we measured no impairments in lung function. This suggests that the early life period, when lungs are undergoing rapid growth and development, is particularly sensitive to CO2.Discussion: To the best of our knowledge, this study, for the first time, shows that long-term exposure to environmentally relevant levels of CO2 can impact respiratory function in the mouse. https://doi.org/10.1289/EHP7305     

Air Pollution and Polyclonal Elevation of Serum Free Light Chains: An Assessment of Adaptive Immune Responses in the Prospective Heinz Nixdorf Recall Study

Background: Residential exposure to air pollution (AP) has been shown to activate the immune system (IS). Although innate immune responses to AP have been studied extensively, investigations on the adaptive IS are scarce.Objectives: The aim of this study was to investigate the association between short- to long-term AP exposure and polyclonal free light chains (FLC) produced by plasma cells.Methods: We used repeated data from three examinations (t0: 2000–2003; t1: 2006–2008; and t2: 2011–2015) of the population-based German Heinz Nixdorf Recall cohort of initially 4,814 participants (45–75 y old). Residential exposure to total and source-specific particulate matter (PM) with an aerodynamic diameter of 10 or 2.5μm (PM10 and PM2.5 respectively), nitrogen dioxide (NO2), and particle number concentrations (accumulation mode; PNAM) was estimated using a chemistry transport model with different time windows (1- to 365-d mean ± standard deviation) before blood draw. We applied linear mixed models with a random participant intercept to estimate associations between total, traffic- and industry-related AP exposures and log-transformed FLC, controlling for examination time, sociodemographic and lifestyle variables, estimated glomerular filtration rate and season.Results: Analyzing 9,933 observations from 4,455 participants, we observed generally positive associations between AP exposures and FLC. We observed strongest associations with middle-term exposures, e.g., 3.0% increase in FLC (95% confidence interval: 1.8%, 4.3%) per interquartile range increase in 91-d mean of NO2 (14.1μg/m³). Across the different pollutants, NO2 showed strongest associations with FLC, followed by PM10 and PNAM. Effect estimates for traffic-related exposures were mostly higher compared with total exposures. Although NO2 and PNAM estimates remained stable upon adjustment for PM, PM estimates decreased considerably upon adjustment for NO2 and PNAM.Discussion: Our results suggest that middle-term AP exposures in particular might be positively associated with activation of the adaptive IS. Traffic-related PM, PNAM, and NO2 showed strongest associations. https://doi.org/10.1289/EHP7164     

Long-Term Ambient Air Pollution Exposures and Circulating and Stimulated Inflammatory Mediators in a Cohort of Midlife Adults

Background: Chronic exposure to air pollution may prime the immune system to be reactive, increasing inflammatory responses to immune stimulation and providing a pathway to increased risk for inflammatory diseases, including asthma and cardiovascular disease. Although long-term exposure to ambient air pollution has been associated with increased circulating markers of inflammation, it is unknown whether it also relates to the magnitude of inflammatory response.Objectives: The aim of this study was to examine associations between chronic ambient pollution exposures and circulating and stimulated levels of inflammatory mediators in a cohort of healthy adults.Methods: Circulating interleukin (IL)-6, C-reactive protein (CRP) (n=392), and lipopolysaccharide stimulated production of IL-1β, IL-6, and tumor necrosis factor (TNF)-α (n=379) were measured in the Adult Health and Behavior II cohort. Fine particulate matter [particulate matter with aerodynamic diameter less than or equal to 2.5 μm (PM2.5)] and constituents [black carbon (BC), and lead (Pb), manganese (Mn), zinc (Zn), and iron (Fe)] were estimated for each residential address using hybrid dispersion land use regression models. Associations between pollutant exposures and inflammatory measures were examined using linear regression; models were adjusted for age, sex, race, education, smoking, body mass index, and month of blood draw.Results: There were no significant correlations between circulating and stimulated measures of inflammation. Significant positive associations were found between exposure to PM2.5 and BC with stimulated production of IL-6, IL-1β, and TNF-α. Pb, Mn, Fe, and Zn exposures were positively associated with stimulated production of IL-1β and TNF-α. No pollutants were associated with circulating IL-6 or CRP levels.Discussion: Exposure to PM2.5, BC, Pb, Mn, Fe, and Zn was associated with increased production of inflammatory mediators by stimulated immune cells. In contrast, pollutant exposure was not related to circulating markers of inflammation. These results suggest that chronic exposure to some pollutants may prime immune cells to mount larger inflammatory responses, possibly contributing to increased risk for inflammatory disease. https://doi.org/10.1289/EHP7089     

Rare,Protein-Altering Variants in AS3MT and Arsenic Metabolism Efficiency: A Multi-Population Association Study

Background: Common genetic variation in the arsenic methyltransferase (AS3MT) gene region is known to be associated with arsenic metabolism efficiency (AME), measured as the percentage of dimethylarsinic acid (DMA%) in the urine. Rare, protein-altering variants in AS3MT could have even larger effects on AME, but their contribution to AME has not been investigated.Objectives: We estimated the impact of rare, protein-coding variation in AS3MT on AME using a multi-population approach to facilitate the discovery of population-specific and shared causal rare variants.Methods: We generated targeted DNA sequencing data for the coding regions of AS3MT for three arsenic-exposed cohorts with existing data on arsenic species measured in urine: Health Effects of Arsenic Longitudinal Study (HEALS, n=2,434), Strong Heart Study (SHS, n=868), and New Hampshire Skin Cancer Study (NHSCS, n=666). We assessed the collective effects of rare (allele frequency <1%), protein-altering AS3MT variants on DMA%, using multiple approaches, including a test of the association between rare allele carrier status (yes/no) and DMA% using linear regression (adjusted for common variants in 10q24.32 region, age, sex, and population structure).Results: We identified 23 carriers of rare-protein-altering AS3MT variant across all cohorts (13 in HEALS and 5 in both SHS and NHSCS), including 6 carriers of predicted loss-of-function variants. DMA% was 6–10% lower in carriers compared with noncarriers in HEALS [β=−9.4 (95% CI: −13.9, −4.8)], SHS [β=−6.9 (95% CI: −13.6, −0.2)], and NHSCS [β=−8.7 (95% CI: −15.6, −2.2)]. In meta-analyses across cohorts, DMA% was 8.7% lower in carriers [β=−8.7 (95% CI: −11.9, −5.4)].Discussion: Rare, protein-altering variants in AS3MT were associated with lower mean DMA%, an indicator of reduced AME. Although a small percentage of the population (0.5–0.7%) carry these variants, they are associated with a 6–10% decrease in DMA% that is consistent across multiple ancestral and environmental backgrounds. https://doi.org/10.1289/EHP8152