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Background: Prior studies have examined the association between fine particulate matter [PM ≤2.5μm in aerodynamic diameter (PM2.5)] and fetal growth with either limited spatial or temporal resolution. Objectives: In this study, we examined the association between PM2.5 exposure during pregnancy and fetal growth measures (ultrasound parameters and birth weight) in a pregnancy cohort using spatiotemporally resolved PM2.5 in Eastern Massachusetts, USA. Methods: We used ultrasound measures of biparietal diameter (BPD), head circumference, femur length, and abdominal circumference (AC), in addition to birth weight, from 9,446 pregnancies that were delivered at the Beth Israel Deaconess Medical Center from 2011–2016. We used linear mixed-effects models to examine the associations of PM2.5 in two exposure windows (the first 16 wk of pregnancy and the cumulative exposure up until the assessment of fetal growth) with anatomic scans (ultrasound measures at

Background: Studies have shown that air pollution exposures during pregnancy are associated with an increased risk of autism spectrum disorder (ASD) in children, and the risk appears to be greater for boys. However, studies assessing gestational windows of susceptibility have been mostly limited by trimesters. Objective: We identified sensitive windows of exposure to regional air pollution and risk of ASD and examined sex differences in a large birth cohort. Methods: This population-based retrospective cohort study included 294,937 mother–child pairs with singleton deliveries in Kaiser Permanente Southern California (KPSC) hospitals from 2001 to 2014. Children were followed using electronic medical records until clinical ASD diagnosis, non-KPSC membership, death, or 31 December 2019, whichever came first. Weekly mean fine particulate matter [PM with an aerodynamic diameter of ≤2.5μm (PM2.5)], nitrogen dioxide (NO2), and ozone (O3) pregnancy exposures were estimated using spatiotemporal prediction models. Cox proportional hazard models with distributed lags were used to estimate weekly pollutant exposure associations with ASD risk for the entire cohort, and separately for boys and for girls. Models were adjusted for child sex (for full cohort), maternal race/ethnicity, maternal age at delivery, parity, maternal education, maternal comorbidities, medical center, census tract median household income, birth year, and season. Results: There were 5,694 ASD diagnoses (4,636 boys, 1,058 girls). Sensitive PM2.5 exposure windows associated with ASD were found early in pregnancy, statistically significant throughout the first two trimesters [1–27 wk of gestation, cumulative hazard ratio (HR)=1.14 [95% confidence interval (CI): 1.06, 1.23] per interquartile range (IQR) (7.4-μg/m3) increase]. O3 exposure during 34–37 wk of gestation was associated with increased risk [HR=1.06 (95% CI: 1.01, 1.11) per IQR (17.4 ppb) increase] but with reduced risk during 20–28 wk of gestation [HR=0.93 (95% CI: 0.89, 0.98)]. No associations were observed with NO2. Sex-stratified early gestational PM2.5 associations were stronger among boys [boys HR=1.16 (95% CI: 1.08, 1.26); girls HR=1.06 (95% CI: 0.89, 1.26)]. O3 associations in later gestation were observed only in boys [boys HR=1.10 (95% CI: 1.04, 1.16); girls HR=0.94 (95% CI: 0.84, 1.05)]. Conclusions: Exposures to PM2.5 in the first two gestational trimesters were associated with increased ASD risk in children, with stronger associations observed for boys. The role of O3 exposure on ASD risk merits further investigation. https://doi.org/10.1289/EHP9509

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: Although many time-series studies have established associations of daily pollution variations with daily deaths, there are fewer at low concentrations, or focused on locally generated pollution, which is becoming more important as regulations reduce regional transport. Causal modeling approaches are also lacking. Objective: We used causal modeling to estimate the impact of local air pollution on mortality at low concentrations. Methods: Using an instrumental variable approach, we developed an instrument for variations in local pollution concentrations that is unlikely to be correlated with other causes of death, and examined its association with daily deaths in the Boston, Massachusetts, area. We combined height of the planetary boundary layer and wind speed, which affect concentrations of local emissions, to develop the instrument for particulate matter ≤ 2.5 μm (PM2.5), black carbon (BC), or nitrogen dioxide (NO2) variations that were independent of year, month, and temperature. We also used Granger causality to assess whether omitted variable confounding existed. Results: We estimated that an interquartile range increase in the instrument for local PM2.5 was associated with a 0.90% increase in daily deaths (95% CI: 0.25, 1.56). A similar result was found for BC, and a weaker association with NO2. The Granger test found no evidence of omitted variable confounding for the instrument. A separate test confirmed the instrument was not associated with mortality independent of pollution. Furthermore, the association remained when all days with PM2.5 concentrations > 30 μg/m3 were excluded from the analysis (0.84% increase in daily deaths; 95% CI: 0.19, 1.50). Conclusions: We conclude that there is a causal association of local air pollution with daily deaths at concentrations below U.S. EPA standards. The estimated attributable risk in Boston exceeded 1,800 deaths during the study period, indicating that important public health benefits can follow from further control efforts. Citation: Schwartz J, Bind MA, Koutrakis P. 2017. Estimating causal effects of local air pollution on daily deaths: effect of low levels. Environ Health Perspect 125:23–29; http://dx.doi.org/10.1289/EHP232

Background: Previous literature suggests that higher ambient temperature may play a role in increasing the risk of suicide. However, no multi-country study has explored the shape of the association and the role of moderate and extreme heat across different locations. Objectives: We examined the short-term temperature–suicide relationship using daily time-series data collected for 341 locations in 12 countries for periods ranging from 4 to 40 y. Methods: We conducted a two-stage meta-analysis. First, we performed location-specific time-stratified case-crossover analyses to examine the temperature–suicide association for each location. Then, we used a multivariate meta-regression to combine the location-specific lag-cumulative nonlinear associations across all locations and by country. Results: A total of 1,320,148 suicides were included in this study. Higher ambient temperature was associated with an increased risk of suicide in general, and we observed a nonlinear association (inverted J-shaped curve) with the highest risk at 27°C. The relative risk (RR) for the highest risk was 1.33 (95% CI: 1.30, 1.36) compared with the risk at the first percentile. Country-specific results showed that the nonlinear associations were more obvious in northeast Asia (Japan, South Korea, and Taiwan). The temperature with the highest risk of suicide ranged from the 87th to 88th percentiles in the northeast Asian countries, whereas this value was the 99th percentile in Western countries (Canada, Spain, Switzerland, the UK, and the United States) and South Africa, where nearly linear associations were estimated. The country-specific RRs ranged from 1.31 (95% CI: 1.19, 1.44) in the United States to 1.65 (95% CI: 1.40, 1.93) in Taiwan, excluding countries where the results were substantially uncertain. Discussion: Our findings showed that the risk of suicide increased with increasing ambient temperature in many countries, but to varying extents and not necessarily linearly. This temperature–suicide association should be interpreted cautiously, and further evidence of the relationship and modifying factors is needed. https://doi.org/10.1289/EHP4898, This study was partly supported by the Global Research Lab (K21004000001-10A0500-00710) the Mid-Career Research grant (2019R1A2C1086194) of the National Research Foundation, the Ministry of Science, Information and Communication Technologies in South Korea; by the Medical Research Council UK (MR/M022625/1 and MR/R013349/1) and the Natural Environment Research Council (NE/R0093894/1) in the UK; by the National Institutes of Health/National Institute of Environmental Health Sciences–funded Health and Exposome Research Center at Emory (HERCULES) Center (P30ES019776) and the USEPA grant RD-83587201 in the United States; by the National Health Research Institute (NHRI-EM-106-SP03) in Taiwan; by the Environment Research and Technology Development Fund (S-14) of the Ministry of the Environment in Japan; by the Joint Usage/Research Center on Tropical Disease, Institute of Tropical Medicine, School of Tropical Medicine and Global Health, Nagasaki University in Japan; by the Japan Society for the Promotion of Science (JSPS) Invitational Fellowships for Research (S18149) in Japan; and by the JSPS Grants-in-Aid for Scientific Research (KAKENHI; JP16K19773, JP19K17104, and 19H03900) in Japan.

There is strong experimental evidence that physiologic stress from high temperatures is greater if humidity is higher. However, heat indices developed to allow for this have not consistently predicted mortality better than dry-bulb temperature.We aimed to clarify the potential contribution of humidity an addition to temperature in predicting daily mortality in summer by using a large multicountry dataset.In 445 cities in 24 countries, we fit a time-series regression model for summer mortality with a distributed lag nonlinear model (DLNM) for temperature (up to lag 3) and supplemented this with a range of terms for relative humidity (RH) and its interaction with temperature. City-specific associations were summarized using meta-analytic techniques.Adding a linear term for RH to the temperature term improved fit slightly, with an increase of 23% in RH (the 99th percentile anomaly) associated with a 1.1% [95% confidence interval (CI): 0.8, 1.3] decrease in mortality. Allowing curvature in the RH term or adding terms for interaction of RH with temperature did not improve the model fit. The humidity-related decreased risk was made up of a positive coefficient at lag 0 outweighed by negative coefficients at lags of 1-3 d. Key results were broadly robust to small model changes and replacing RH with absolute measures of humidity. Replacing temperature with apparent temperature, a metric combining humidity and temperature, reduced goodness of fit slightly.The absence of a positive association of humidity with mortality in summer in this large multinational study is counter to expectations from physiologic studies, though consistent with previous epidemiologic studies finding little evidence for improved prediction by heat indices. The result that there was a small negative average association of humidity with mortality should be interpreted cautiously; the lag structure has unclear interpretation and suggests the need for future work to clarify. https://doi.org/10.1289/EHP5430.

A few studies suggest that air pollution may decrease fertility, but prospective studies and examinations of windows of susceptibility remain unclear.We aimed to examine the association between time-varying exposure to nitrogen dioxide ([Formula: see text]), ozone ([Formula: see text]), fine particulate matter [Formula: see text] ([Formula: see text]), and black carbon (BC) onWe included 345 women (522 IVF cycles) for the [Formula: see text], [Formula: see text], and [Formula: see text] analyses and 339 women (512 IVF cycles) for the BC analysis enrolled in a prospective cohort at a Boston fertility center (2004–2015). We used validated spatiotemporal models to estimate daily residential exposure to [Formula: see text], [Formula: see text], [Formula: see text], and BC. Multivariable discrete time Cox proportional hazards models with four periods [ovarian stimulation (OS), oocyte retrieval to embryo transfer (ET), ET to implantation, implantation to live birth] estimated odds ratios (OR) and 95% confidence intervals (CI) of failing at IVF. Time-dependent interactions were used to identify vulnerable periods.An interquartile range (IQR) increase in [Formula: see text], [Formula: see text], and BC throughout the IVF cycle was associated with an elevated odds of failing at IVF prior to live birth ([Formula: see text], 95% CI: 0.95, 1.23 for [Formula: see text]; [Formula: see text], 95% CI: 0.88, 1.28 for [Formula: see text]; and [Formula: see text], 95% CI: 0.96, 1.41 for BC). This relationship significantly varied across the IVF cycle such that the association with higher exposure to air pollution during OS was strongest for early IVF failures. An IQR increase in [Formula: see text], [Formula: see text], and BC exposure during OS was associated with 1.42 (95% CI: 1.20, 1.69), 1.26 (95% CI: 0.96, 1.67), and 1.23 (95% CI: 0.96, 1.59) times the odds of failing prior to oocyte retrieval, and 1.32 (95% CI: 1.13, 1.54), 1.27 (95% CI: 0.98, 1.65), and 1.32 (95% CI: 1.10, 1.59) times the odds of failing prior to ET.Increased exposure to traffic-related pollutants was associated with higher odds of early IVF failure. https://doi.org/10.1289/EHP4601.

Background: The link between particulate matter (PM) exposure and adverse health outcomes has been widely evaluated using large cohort studies. However, the possibility of residual confounding and lack of information about the health effects of PM in rural and suburban areas are unsolved issues. Objective: Our aim was to estimate the effect of annual PM≤10 μm (PM10) exposure on cause-specific mortality in the Latium region (central Italy, of which Rome is the main city) during 2006–2012 using a difference-in-differences approach. Methods: We estimated daily PM10 concentrations for each 1 km2 of the region from 2006 to 2012 by use of satellite data, land-use predictors, and meteorological parameters. For each of the 378 regional municipalities and each year, we averaged daily PM10 values to obtain annual mean PM10 exposures. We applied a variant of the difference-in-differences approach to estimate the association between PM10 and cause-specific mortality by focusing on within-municipality fluctuations of mortality rates and annual PM exposures around municipality means, therefore controlling by design for confounding from all spatial and temporal potential confounders. Analyses were also stratified by population size of the municipalities to obtain effect estimates in rural and suburban areas of the region. Results: In the period 2006–2012, we observed deaths due to three causes: 347,699 nonaccidental; 92,787 cardiovascular; and 16,509 respiratory causes. The annual average (standard deviation, SD) PM10 concentration was 21.9 (±4.9) μg/m3 in Latium. For each 1-μg/m3 increase in annual PM10 we estimated increases of 0.8% (95% confidence intervals (CIs): 0.2%, 1.3%), 0.9% (0.0%, 1.8%), and 1.4% (−0.4%, 3.3%) in nonaccidental, cardiovascular, and respiratory mortality, respectively. Similar results were found when we excluded the metropolitan area of Rome from the analysis. Higher effects were estimated in the smaller municipalities, e.g., those with population

Background: The evidence and method are limited for the associations between mortality and temperature variability (TV) within or between days. Objectives: We developed a novel method to calculate TV and investigated TV-mortality associations using a large multicountry data set. Methods: We collected daily data for temperature and mortality from 372 locations in 12 countries/regions (Australia, Brazil, Canada, China, Japan, Moldova, South Korea, Spain, Taiwan, Thailand, the United Kingdom, and the United States). We calculated TV from the standard deviation of the minimum and maximum temperatures during the exposure days. Two-stage analyses were used to assess the relationship between TV and mortality. In the first stage, a Poisson regression model allowing over-dispersion was used to estimate the community-specific TV-mortality relationship, after controlling for potential confounders. In the second stage, a meta-analysis was used to pool the effect estimates within each country. Results: There was a significant association between TV and mortality in all countries, even after controlling for the effects of daily mean temperature. In stratified analyses, TV was still significantly associated with mortality in cold, hot, and moderate seasons. Mortality risks related to TV were higher in hot areas than in cold areas when using short TV exposures (0–1 days), whereas TV-related mortality risks were higher in moderate areas than in cold and hot areas when using longer TV exposures (0–7 days). Conclusions: The results indicate that more attention should be paid to unstable weather conditions in order to protect health. These findings may have implications for developing public health policies to manage health risks of climate change. © 2016, Public Health Services, US Dept of Health and Human Services. All rights reserved., This work was supported by the University of Queensland (Australia) (Y.G.); the National Health and Medical Research Council (Australia) (grant 553043) (S.T.); the Australian Research Council (Australia) (grant DP110100651) (S.T.); the Medical Research Council-UK (grant G1002296) (A.G.); the Ministry of Education, Spain (grant PRX12/00515) (A.T.); the Ministry of the Environment, Japan (M.H. and Y.H.); and the National Research Foundation of Korea (grant K21004000001-10A0500-00710) (H.K.).

Background: Long-term air pollution exposure has been associated with age-related cognitive impairment, possibly because of enhanced inflammation. Leukocytes with longer telomere length (TL) are more responsive to inflammatory stimuli, yet TL has not been evaluated in relation to air pollution and cognition. Objectives: We assessed whether TL modifies the association of 1-year exposure to black carbon (BC), a marker of traffic-related air pollution, with cognitive function in older men, and we examined whether this modification is independent of age and of C-reactive protein (CRP), a marker of inflammation. Methods: Between 1999 and 2007, we conducted 1–3 cognitive examinations of 428 older men in the Veterans Affairs (VA) Normative Aging Study. We used covariate-adjusted repeated-measure logistic regression to estimate associations of 1-year BC exposure with relative odds of being a low scorer (≤ 25) on the Mini-Mental State Examination (MMSE), which is a proxy of poor cognition. Confounders included age, CRP, and lifestyle and sociodemographic factors. Results: Each doubling in BC level was associated with 1.57 (95% CI: 1.20, 2.05) times higher odds of low MMSE scores. The BC-MMSE association was greater only among individuals with longer blood TL (5th quintile) (OR = 3.23; 95% CI: 1.37, 7.59; p = 0.04 for BC-by-TL-interaction). TL and CRP were associated neither with each other nor with MMSE. However, CRP modified the BC-MMSE relationship, with stronger associations only at higher CRP (5th quintile) and reference TL level (1st quintile) (OR = 2.68; 95% CI: 1.06, 6.79; p = 0.04 for BC-by-CRP-interaction). Conclusions: TL and CRP levels may help predict the impact of BC exposure on cognitive function in older men. Citation: Colicino E, Wilson A, Frisardi MC, Prada D, Power MC, Hoxha M, Dioni L, Spiro A III, Vokonas PS, Weisskopf MG, Schwartz JD, Baccarelli AA. 2017. Telomere length, long-term black carbon exposure, and cognitive function in a cohort of older men: the VA Normative Aging Study. Environ Health Perspect 125:76–81; http://dx.doi.org/10.1289/EHP241

Background: Previous studies have observed associations between air pollution and heart disease. Susceptibility to air pollution effects has been examined mostly with a test of effect modification, but little evidence is available whether air pollution distorts cardiovascular risk factor distribution. Objectives: This paper aims to examine distributional and heterogeneous effects of air pollution on known cardiovascular biomarkers. Methods: A total of 1,112 men from the Normative Aging Study and residents of the greater Boston, Massachusetts, area with mean age of 69 years at baseline were included in this study during the period 1995–2013. We used quantile regression and random slope models to investigate distributional effects and heterogeneity in the traffic-related responses on blood pressure, heart rate variability, repolarization, lipids, and inflammation. We considered 28-day averaged exposure to particle number, PM2.5 black carbon, and PM2.5 mass concentrations (measured at a single monitor near the site of the study visits). Results: We observed some evidence suggesting distributional effects of traffic-related pollutants on systolic blood pressure, heart rate variability, corrected QT interval, low density lipoprotein (LDL) cholesterol, triglyceride, and intercellular adhesion molecule-1 (ICAM-1). For example, among participants with LDL cholesterol below 80 mg/dL, an interquartile range increase in PM2.5 black carbon exposure was associated with a 7-mg/dL (95% CI: 5, 10) increase in LDL cholesterol, while among subjects with LDL cholesterol levels close to 160 mg/dL, the same exposure was related to a 16-mg/dL (95% CI: 13, 20) increase in LDL cholesterol. We observed similar heterogeneous associations across low versus high percentiles of the LDL distribution for PM2.5 mass and particle number. Conclusions: These results suggest that air pollution distorts the distribution of cardiovascular risk factors, and that, for several outcomes, effects may be greatest among individuals who are already at high risk. Citation: Bind MA, Peters A, Koutrakis P, Coull B, Vokonas P, Schwartz J. 2016. Quantile regression analysis of the distributional effects of air pollution on blood pressure, heart rate variability, blood lipids, and biomarkers of inflammation in elderly American men: the Normative Aging Study. Environ Health Perspect 124:1189–1198; http://dx.doi.org/10.1289/ehp.1510044

Background MicroRNAs (miRNAs) are post-transcriptional gene suppressors and potential mediators of environmental effects. In addition to human miRNAs, viral miRNAs expressed from latent viral sequences are detectable in human cells. Objective In a highly exposed population in Beijing, China, we evaluated the associations of particulate air pollution exposure on blood miRNA profiles. Methods The Beijing Truck Driver Air Pollution Study (BTDAS) included 60 truck drivers and 60 office workers. We investigated associations of short-term air pollution exposure, using measures of personal PM2.5 (particulate matter ≤ 2.5 μm) and elemental carbon (EC), and ambient PM10 (≤ 10 μm), with blood NanoString nCounter miRNA profiles at two exams separated by 1–2 weeks. Results No miRNA was significantly associated with personal PM2.5 at a false discovery rate (FDR) of 20%. Short-term ambient PM10 was associated with the expression of 12 miRNAs in office workers only (FDR < 20%). Short-term EC was associated with differential expression of 46 human and 7 viral miRNAs, the latter including 3 and 4 viral miRNAs in office workers and truck drivers, respectively. EC-associated miRNAs differed between office workers and truck drivers with significant effect modification by occupational group. Functional interaction network analysis suggested enriched cellular proliferation/differentiation pathways in truck drivers and proinflammation pathways in office workers. Conclusions Short-term EC exposure was associated with the expression of human and viral miRNAs that may influence immune responses and other biological pathways. Associations between EC exposure and viral miRNA expression suggest that latent viral miRNAs are potential mediators of air pollution–associated health effects. PM2.5/PM10 exposures showed no consistent relationships with miRNA expression. Citation Hou L, Barupal J, Zhang W, Zheng Y, Liu L, Zhang X, Dou C, McCracken JP, Díaz A, Motta V, Sanchez-Guerra M, Wolf KR, Bertazzi PA, Schwartz JD, Wang S, Baccarelli AA. 2016. Particulate air pollution exposure and expression of viral and human microRNAs in blood: the Beijing Truck Driver Air Pollution Study. Environ Health Perspect 124:344–350; http://dx.doi.org/10.1289/ehp.1408519

Background: It is unknown if ambient fine particulate matter (PM2.5) is associated with lower renal function, a cardiovascular risk factor. Objective: We investigated whether long-term PM2.5 exposure was associated with estimated glomerular filtration rate (eGFR) in a cohort of older men living in the Boston Metropolitan area. Methods: This longitudinal analysis included 669 participants from the Veterans Administration Normative Aging Study with up to four visits between 2000 and 2011 (n = 1,715 visits). Serum creatinine was measured at each visit, and eGFR was calculated according to the Chronic Kidney Disease Epidemiology Collaboration equation. One-year exposure to PM2.5 prior to each visit was assessed using a validated spatiotemporal model that utilized satellite remote-sensing aerosol optical depth data. eGFR was modeled in a time-varying linear mixed-effects regression model as a continuous function of 1-year PM2.5, adjusting for important covariates. Results: One-year PM2.5 exposure was associated with lower eGFRs; a 2.1-μg/m3 interquartile range higher 1-year PM2.5 was associated with a 1.87 mL/min/1.73 m2 lower eGFR [95% confidence interval (CI): –2.99, –0.76]. A 2.1 μg/m3-higher 1-year PM2.5 was also associated with an additional annual decrease in eGFR of 0.60 mL/min/1.73 m2 per year (95% CI: –0.79, –0.40). Conclusions: In this longitudinal sample of older men, the findings supported the hypothesis that long-term PM2.5 exposure negatively affects renal function and increases renal function decline. Citation: Mehta AJ, Zanobetti A, Bind MC, Kloog I, Koutrakis P, Sparrow D, Vokonas PS, Schwartz JD. 2016. Long-term exposure to ambient fine particulate matter and renal function in older men: the VA Normative Aging Study. Environ Health Perspect 124:1353–1360; http://dx.doi.org/10.1289/ehp.1510269

Background PM2.5 (particulate matter ≤ 2.5 μm) has been associated with adverse cardiovascular outcomes, but it is unclear whether specific PM2.5 components, particularly metals, may be responsible for cardiovascular effects. Objectives We aimed to determine which PM2.5 components are associated with blood pressure in a longitudinal cohort. Methods We fit linear mixed-effects models with the adaptive LASSO penalty to longitudinal data from 718 elderly men in the Veterans Affairs Normative Aging Study, 1999–2010. We controlled for PM2.5 mass, age, body mass index, use of antihypertensive medication (ACE inhibitors, non-ophthalmic beta blockers, calcium channel blockers, diuretics, and angiotensin receptor antagonists), smoking status, alcohol intake, years of education, temperature, and season as fixed effects in the models, and additionally applied the adaptive LASSO method to select PM2.5 components associated with blood pressure. Final models were identified by the Bayesian Information Criterion (BIC). Results For systolic blood pressure (SBP), nickel (Ni) and sodium (Na) were selected by the adaptive LASSO, whereas only Ni was selected for diastolic blood pressure (DBP). An interquartile range increase (2.5 ng/m3) in 7-day moving-average Ni was associated with 2.48-mmHg (95% CI: 1.45, 3.50 mmHg) increase in SBP and 2.22-mmHg (95% CI: 1.69, 2.75 mmHg) increase in DBP, respectively. Associations were comparable when the analysis was restricted to study visits with PM2.5 below the 75th percentile of the distribution (12 μg/m3). Conclusions Our study suggested that exposure to ambient Ni was associated with increased blood pressure independent of PM2.5 mass in our study population of elderly men. Further research is needed to confirm our findings, assess generalizability to other populations, and identify potential mechanisms for Ni effects. Citation Dai L, Koutrakis P, Coull BA, Sparrow D, Vokonas PS, Schwartz JD. 2016. Use of the adaptive LASSO method to identify PM2.5 components associated with blood pressure in elderly men: the Veterans Affairs Normative Aging Study. Environ Health Perspect 124:120–125; http://dx.doi.org/10.1289/ehp.1409021

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: Particulate matter (PM) air pollution has been associated with decreased pulmonary function, but the exposure–response relationship in chronic obstructive pulmonary disease (COPD) patie...

BACKGROUND: Epigenetic variability is hypothesized as a regulatory pathway through which prenatal exposures may influence child development and health. OBJECTIVE: We sought to examine the associations of residential proximity to roadways at birth and epigenome-wide DNA methylation. We also assessed associations of differential methylation with child cognitive outcomes. METHODS: We estimated residential proximity to roadways at birth using a geographic information system (GIS) and cord blood methylation using Illumina’s HumanMethylation450-array in 482 mother–child pairs in Project Viva. We identified individual CpGs associated with residential-proximity-to-roadways at birth using robust linear regression [false discovery rate ðFDRÞ < 0:05]. We also estimated association between proximity-to-roadways at birth and methylation of the same sites in blood samples collected at age 7–11 y (N = 415). We ran the same analyses in the Generation R Study for replication (N = 641). In Project Viva, we investigated associations of differential methylation at birth with midchildhood cognition using linear regression. RESULTS: Living closer to major roadways at birth was associated with higher cord blood (and—more weakly—midchildhood blood) methylation of four sites in LAMB2. For each halving of residential-proximity-to-major-roadways, we observed a 0.82% increase in DNA methylation at cg05654765 [95% confidence interval (CI): (0.54%, 1.10%)], 0.88% at cg14099457 [95% CI: (0.56%, 1.19%)], 0.19% at cg03732535 [95% CI: (0.11%, 0.28)], and 1.08% at cg02954987 [95% CI: (0.65%, 1.51%)]. Higher cord blood methylation of these sites was associated with lower midchildhood nonverbal cognitive scores. Our results did not replicate in the Generation R Study. CONCLUSIONS: Our discovery results must be interpreted with caution, given that they were not replicated in a separate cohort. However, living close to major roadways at birth was associated with cord blood methylation of sites in LAMB2—a gene known to be linked to axonal development—in our U.S. cohort. Higher methylation of these sites associated with lower nonverbal cognitive scores at age 7–11 y in the same children. © 2018, Public Health Services, US Dept of Health and Human Services. All rights reserved.

Studies have long associated [Formula: see text] with daily mortality, but few applied causal-modeling methods, or at low exposures. Short-term exposure to [Formula: see text], a marker of local traffic, has also been associated with mortality but is less studied. We previously found a causal effect between local air pollution and mortality in Boston.We aimed to estimate the causal effects of local pollution, [Formula: see text], and [Formula: see text] on mortality in 135 U.S. cities.We used three methods which, under different assumptions, provide causal marginal estimates of effect: a marginal structural model, an instrumental variable analysis, and a negative exposure control. The instrumental approach used planetary boundary layer, wind speed, and air pressure as instruments for concentrations of local pollutants; the marginal structural model separated the effects of [Formula: see text] from the effects of [Formula: see text], and the negative exposure control provided protection against unmeasured confounders.In 7.3 million deaths, the instrumental approach estimated that mortality increased 1.5% [95% confidence interval (CI): 1.1%, 2.0%] per [Formula: see text] increase in local pollution indexed as [Formula: see text]. The negative control exposure was not associated with mortality. Restricting our analysis to days with [Formula: see text] below [Formula: see text], we found a 1.70% (95% CI 1.11%, 2.29%) increase. With marginal structural models, we found positive significant increases in deaths with both [Formula: see text] and [Formula: see text]. On days with [Formula: see text] below [Formula: see text], we found a 0.83% (95% CI 0.39%, 1.27%) increase. Including negative exposure controls changed estimates minimally.Causal-modeling techniques, each subject to different assumptions, demonstrated causal effects of locally generated pollutants on daily deaths with effects at concentrations below the current EPA daily [Formula: see text] standard. https://doi.org/10.1289/EHP2732.

In a recently published paper using space-time satellite data to determine air temperature (Ta), Kloog et al. concluded that Ta during pregnancy was associated with lower birth weight and shorter gestational age in the study population. The results obtained pointed to associations between Ta and birth weight during the last trimester, and between Ta and preterm delivery and low birth weight during the entire pregnancy. These results agree with those obtained by Dadvand et al. (2014), indicating Ta has a stressful role influencing low birth weight. There are many epidemiological studies reporting a nonlinear J- or U-shaped relationship between Ta and health indicators such as mortality (Basu and Samet 2002) and morbidity (Ye et al. 2012), with different response times for heat and cold waves (Gasparrini et al. 2015). When Kloog et al. performed linear and logistic models, Ta was introduced with a linear component in multiple time windows before birth. Models also were adjusted for different environmental and sociodemographic factors. However, the authors did not control for heat and cold episodes during pregnancy. From our point of view, a similar nonlinear behavior could be expected or would at least be worth analyzing in the case of adverse birth variables. As a susceptible population group, pregnant women may be more sensitive to changes in temperature and may be at a greater risk of heat stress, because during pregnancy the increase in fat deposition and associated decrease in the ratio of body surface area to body mass result in less capacity for heat loss to the environment (Wells and Cole 2002). A study conducted in Rome with time-series analysis methodology (Schifano et al. 2013) showed that heat, as measured by the maximum temperature during warmer periods, was associated in the short term with preterm birth. This association with temperature was not observed in the cold periods. Similar results were obtained in Madrid (Linares et al. in press). This study considered daily maximum temperatures during heat waves (defined in Madrid during 2001–2009 as daily maximum temperatures above 34°C) and during cold waves (defined in Madrid during 2001–2009 as daily maximum temperatures below –2°C). The results for the influence of high temperatures on low birth weight were similar to those found in Rome, with the same short-term association between temperature rise and increased cases of premature birth and, consequently, low birth weight. This suggests heat waves are an acute stressor on pregnant women, not the chronic stressor described by Kloog et al. The mechanism is unclear by which high temperatures may increase the risk of preterm birth, but there is evidence in the literature that supports a relationship (Carolan-Olah and Frankowska 2014). This short-term effect of Ta on adverse birth outcomes is similar to that already described for traffic noise as a factor in adverse birth outcomes in Madrid (Diaz and Linares in press). Although Kloog et al. introduced Ta values with linear components, from our point of view introducing Ta as a linear component and not taking into account the effects of heat and cold separately minimizes the authors’ ability to draw conclusions about potential impacts. The effects of high temperatures may be offset by cold temperatures. Therefore, it would be interesting to improve the analysis of Kloog et al. by taking into account the effect of Ta, but separating its effect by warm and cold seasons, especially for days within heat and cold waves.

Background Air pollution has been related to mean changes in outcomes, including DNA methylation. However, mean regression analyses may not capture associations that occur primarily in the tails of the outcome distribution. Objectives In this study, we examined whether the association between particulate air pollution and DNA methylation differs across quantiles of the methylation distribution. We focused on methylation of candidate genes related to coagulation and inflammation: coagulation factor III (F3), intercellular adhesion molecule 1 (ICAM-1), interferon gamma (IFN-γ), interleukin-6 (IL-6), and toll-like receptor 2 (TRL-2). Methods We measured gene-specific blood DNA methylation repeatedly in 777 elderly men participating in the Normative Aging Study (1999–2010). We fit quantile regressions for longitudinal data to investigate whether the associations of particle number, PM2.5 (diameter ≤ 2.5 μm)black carbon, and PM2.5 mass concentrations (4-week moving average) with DNA methylation [expressed as the percentage of methylated cytosines over the sum of methylated and unmethylated cytosines at position 5 (%5mC)] varied across deciles of the methylation distribution. We reported the quantile regression coefficients that corresponded to absolute differences in DNA methylation (expressed in %5mC) associated with an interquartile range increase in air pollution concentration. Results Interquartile range increases in particle number, PM2.5 black carbon, and PM2.5 mass concentrations were associated with significantly lower methylation in the lower tails of the IFN-γ and ICAM-1 methylation distributions. For instance, a 3.4-μg/m3 increase in PM2.5 mass concentration was associated with a 0.18%5mC (95% CI: –0.30, –0.06) decrease on the 20th percentile of ICAM-1 methylation, but was not significantly related to the 80th percentile (estimate: 0.07%5mC, 95% CI: –0.09, 0.24). Conclusions In our study population of older men, air pollution exposures were associated with a left shift in the lower tails of the IFN-γ and ICAM-1 methylation distributions. Citation Bind MA, Coull BA, Peters A, Baccarelli AA, Tarantini L, Cantone L, Vokonas PS, Koutrakis P, Schwartz JD. 2015. Beyond the mean: quantile regression to explore the association of air pollution with gene-specific methylation in the Normative Aging Study. Environ Health Perspect 123:759–765; http://dx.doi.org/10.1289/ehp.1307824

Background Both short- and long-term exposures to fine particulate matter (≤ 2.5 μm; PM2.5) are associated with mortality. However, whether the associations exist at levels below the new U.S. Environmental Protection Agency (EPA) standards (12 μg/m3 of annual average PM2.5, 35 μg/m3 daily) is unclear. In addition, it is not clear whether results from previous time series studies (fit in larger cities) and cohort studies (fit in convenience samples) are generalizable. Objectives We estimated the effects of low-concentration PM2.5 on mortality. Methods High resolution (1 km × 1 km) daily PM2.5 predictions, derived from satellite aerosol optical depth retrievals, were used. Poisson regressions were applied to a Medicare population (≥ 65 years of age) in New England to simultaneously estimate the acute and chronic effects of exposure to PM2.5, with mutual adjustment for short- and long-term exposure, as well as for area-based confounders. Models were also restricted to annual concentrations < 10 μg/m3 or daily concentrations < 30 μg/m3. Results PM2.5 was associated with increased mortality. In the study cohort, 2.14% (95% CI: 1.38, 2.89%) and 7.52% (95% CI: 1.95, 13.40%) increases were estimated for each 10-μg/m3 increase in short- (2 day) and long-term (1 year) exposure, respectively. The associations held for analyses restricted to low-concentration PM2.5 exposure, and the corresponding estimates were 2.14% (95% CI: 1.34, 2.95%) and 9.28% (95% CI: 0.76, 18.52%). Penalized spline models of long-term exposure indicated a larger effect for mortality in association with exposures ≥ 6 μg/m3 versus those < 6 μg/m3. In contrast, the association between short-term exposure and mortality appeared to be linear across the entire exposure distribution. Conclusions Using a mutually adjusted model, we estimated significant acute and chronic effects of PM2.5 exposure below the current U.S. EPA standards. These findings suggest that improving air quality with even lower PM2.5 than currently allowed by U.S. EPA standards may benefit public health. Citation Shi L, Zanobetti A, Kloog I, Coull BA, Koutrakis P, Melly SJ, Schwartz JD. 2016. Low-concentration PM2.5 and mortality: estimating acute and chronic effects in a population-based study. Environ Health Perspect 124:46–52; http://dx.doi.org/10.1289/ehp.1409111

Background Long-term exposure to fine particles (particulate matter ≤ 2.5 μm; PM2.5) has been consistently linked to heart and lung disease. Recently, there has been increased interest in examining the effects of air pollution on the nervous system, with evidence showing potentially harmful effects on neurodegeneration. Objective Our objective was to assess the potential impact of long-term PM2.5 exposure on event time, defined as time to first admission for dementia, Alzheimer’s (AD), or Parkinson’s (PD) diseases in an elderly population across the northeastern United States. Methods We estimated the effects of PM2.5 on first hospital admission for dementia, AD, and PD among all Medicare enrollees ≥ 65 years in 50 northeastern U.S. cities (1999–2010). For each outcome, we first ran a Cox proportional hazards model for each city, adjusting for prior cardiopulmonary-related hospitalizations and year, and stratified by follow-up time, age, sex, and race. We then pooled the city-specific estimates by employing a random effects meta-regression. Results We followed approximately 9.8 million subjects and observed significant associations of long-term PM2.5 city-wide exposure with all three outcomes. Specifically, we estimated a hazard ratio (HR) of 1.08 (95% CI: 1.05, 1.11) for dementia, an HR of 1.15 (95% CI: 1.11, 1.19) for AD, and an HR of 1.08 (95% CI: 1.04, 1.12) for PD admissions per 1-μg/m3 increase in annual PM2.5 concentrations. Conclusions To our knowledge, this is the first study to examine the relationship between long-term exposure to PM2.5 and time to first hospitalization for common neurodegenerative diseases. We found strong evidence of association for all three outcomes. Our findings provide the basis for further studies, as the implications of such exposures could be crucial to public health. Citation Kioumourtzoglou MA, Schwartz JD, Weisskopf MG, Melly SJ, Wang Y, Dominici F, Zanobetti A. 2016. Long-term PM2.5 exposure and neurological hospital admissions in the northeastern United States. Environ Health Perspect 124:23–29; http://dx.doi.org/10.1289/ehp.1408973

Background Influences of prenatal and early-life exposures to air pollution on cognition are not well understood. Objectives We examined associations of gestational and childhood exposure to traffic-related pollution with childhood cognition. Methods We studied 1,109 mother–child pairs in Project Viva, a prospective birth cohort study in eastern Massachusetts (USA). In mid-childhood (mean age, 8.0 years), we measured verbal and nonverbal intelligence, visual motor abilities, and visual memory. For periods in late pregnancy and childhood, we estimated spatially and temporally resolved black carbon (BC) and fine particulate matter (PM2.5) exposures, residential proximity to major roadways, and near-residence traffic density. We used linear regression models to examine associations of exposures with cognitive assessment scores, adjusted for potential confounders. Results Compared with children living ≥ 200 m from a major roadway at birth, those living < 50 m away had lower nonverbal IQ [–7.5 points; 95% confidence interval (CI): –13.1, –1.9], and somewhat lower verbal IQ (–3.8 points; 95% CI: –8.2, 0.6) and visual motor abilities (–5.3 points; 95% CI: –11.0, 0.4). Cross-sectional associations of major roadway proximity and cognition at mid-childhood were weaker. Prenatal and childhood exposure to traffic density and PM2.5 did not appear to be associated with poorer cognitive performance. Third-trimester and childhood BC exposures were associated with lower verbal IQ in minimally adjusted models; but after adjustment for socioeconomic covariates, associations were attenuated or reversed. Conclusions Residential proximity to major roadways during gestation and early life may affect cognitive development. Influences of pollutants and socioeconomic conditions on cognition may be difficult to disentangle. Citation Harris MH, Gold DR, Rifas-Shiman SL, Melly SJ, Zanobetti A, Coull BA, Schwartz JD, Gryparis A, Kloog I, Koutrakis P, Bellinger DC, White RF, Sagiv SK, Oken E. 2015. Prenatal and childhood traffic-related pollution exposure and childhood cognition in the Project Viva cohort (Massachusetts, USA). Environ Health Perspect 123:1072–1078; http://dx.doi.org/10.1289/ehp.1408803

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Background: Heat wave and health warning systems are activated based on forecasts of health-threatening hot weather. Objective: We estimated heat–mortality associations based on forecast and observed weather data in Detroit, Michigan, and compared the accuracy of forecast products for predicting heat waves. Methods: We derived and compared apparent temperature (AT) and heat wave days (with heat waves defined as ≥ 2 days of daily mean AT ≥ 95th percentile of warm-season average) from weather observations and six different forecast products. We used Poisson regression with and without adjustment for ozone and/or PM10 (particulate matter with aerodynamic diameter ≤ 10 μm) to estimate and compare associations of daily all-cause mortality with observed and predicted AT and heat wave days. Results: The 1-day-ahead forecast of a local operational product, Revised Digital Forecast, had about half the number of false positives compared with all other forecasts. On average, controlling for heat waves, days with observed AT = 25.3°C were associated with 3.5% higher mortality (95% CI: –1.6, 8.8%) than days with AT = 8.5°C. Observed heat wave days were associated with 6.2% higher mortality (95% CI: –0.4, 13.2%) than non–heat wave days. The accuracy of predictions varied, but associations between mortality and forecast heat generally tended to overestimate heat effects, whereas associations with forecast heat waves tended to underestimate heat wave effects, relative to associations based on observed weather metrics. Conclusions: Our findings suggest that incorporating knowledge of local conditions may improve the accuracy of predictions used to activate heat wave and health warning systems. Citation: Zhang K, Chen YH, Schwartz JD, Rood RB, O’Neill MS. 2014. Using forecast and observed weather data to assess performance of forecast products in identifying heat waves and estimating heat wave effects on mortality. Environ Health Perspect 122:912–918; http://dx.doi.org/10.1289/ehp.1306858

Background: Epidemiological studies have examined the association between PM2.5 and mortality, but uncertainty remains about the seasonal variations in PM2.5-related effects and the relative importance of species. Objectives: We estimated the effects of PM2.5 species on mortality and how infiltration rates may modify the association. Methods: Using city–season specific Poisson regression, we estimated PM2.5 effects on approximately 4.5 million deaths for all causes, cardiovascular disease (CVD), myocardial infarction (MI), stroke, and respiratory diseases in 75 U.S. cities for 2000–2006. We added interaction terms between PM2.5 and monthly average species-to-PM2.5 proportions of individual species to determine the relative toxicity of each species. We combined results across cities using multivariate meta-regression, and controlled for infiltration. Results: We estimated a 1.18% (95% CI: 0.93, 1.44%) increase in all-cause mortality, a 1.03% (95% CI: 0.65, 1.41%) increase in CVD, a 1.22% (95% CI: 0.62, 1.82%) increase in MI, a 1.76% (95% CI: 1.01, 2.52%) increase in stroke, and a 1.71% (95% CI: 1.06, 2.35%) increase in respiratory deaths in association with a 10-μg/m3 increase in 2-day averaged PM2.5 concentration. The associations were largest in the spring. Silicon, calcium, and sulfur were associated with more all-cause mortality, whereas sulfur was related to more respiratory deaths. County-level smoking and alcohol were associated with larger estimated PM2.5 effects. Conclusions: Our study showed an increased risk of mortality associated with PM2.5, which varied with seasons and species. The results suggest that mass alone might not be sufficient to evaluate the health effects of particles. Citation: Dai L, Zanobetti A, Koutrakis P, Schwartz JD. 2014. Associations of fine particulate matter species with mortality in the United States: a multicity time-series analysis. Environ Health Perspect 122:837–842; http://dx.doi.org/10.1289/ehp.1307568

Background: Exposure to fine particulate matter (PM with diameter ≤ 2.5 μm; PM2.5) has been linked to type 2 diabetes mellitus, but associations with hyperglycemia in pregnancy have not been well studied. Methods: We studied Boston, Massachusetts–area pregnant women without known diabetes. We identified impaired glucose tolerance (IGT) and gestational diabetes mellitus (GDM) during pregnancy from clinical glucose tolerance tests at median 28.1 weeks gestation. We used residential addresses to estimate second-trimester PM2.5 and black carbon exposure via a central monitoring site and spatiotemporal models. We estimated residential traffic density and roadway proximity as surrogates for exposure to traffic-related air pollution. We performed multinomial logistic regression analyses adjusted for sociodemographic covariates, and used multiple imputation to account for missing data. Results: Of 2,093 women, 65 (3%) had IGT and 118 (6%) had GDM. Second-trimester spatiotemporal exposures ranged from 8.5 to 15.9 μg/m3 for PM2.5 and from 0.1 to 1.7 μg/m3 for black carbon. Traffic density was 0–30,860 vehicles/day × length of road (kilometers) within 100 m; 281 (13%) women lived ≤ 200 m from a major road. The prevalence of IGT was elevated in the highest (vs. lowest) quartile of exposure to spatiotemporal PM2.5 [odds ratio (OR) = 2.63; 95% CI: 1.15, 6.01] and traffic density (OR = 2.66; 95% CI: 1.24, 5.71). IGT also was positively associated with other exposure measures, although associations were not statistically significant. No pollutant exposures were positively associated with GDM. Conclusions: Greater exposure to PM2.5 and other traffic-related pollutants during pregnancy was associated with IGT but not GDM. Air pollution may contribute to abnormal glycemia in pregnancy. Citation: Fleisch AF, Gold DR, Rifas-Shiman SL, Koutrakis P, Schwartz JD, Kloog I, Melly S, Coull BA, Zanobetti A, Gillman MW, Oken E. 2014. Air pollution exposure and abnormal glucose tolerance during pregnancy: the Project Viva Cohort. Environ Health Perspect 122:378–383; http://dx.doi.org/10.1289/ehp.1307065

Background: Exposure to ambient air pollution, particularly from traffic, has been associated with adverse cognitive outcomes, but the association with depressive symptoms remains unclear. Objectives: We investigated the association between exposure to ambient air and traffic pollution and the presence of depressive symptoms among 732 Boston-area adults ≥ 65 years of age (78.1 ± 5.5 years, mean ± SD). Methods: We assessed depressive symptoms during home interviews using the Revised Center for Epidemiological Studies Depression Scale (CESD-R). We estimated residential distance to the nearest major roadway as a marker of long-term exposure to traffic pollution and assessed short-term exposure to ambient fine particulate matter (PM2.5), sulfates, black carbon (BC), ultrafine particles, and gaseous pollutants, averaged over the 2 weeks preceding each assessment. We used generalized estimating equations to estimate the odds ratio (OR) of a CESD-R score ≥ 16 associated with exposure, adjusting for potential confounders. In sensitivity analyses, we considered CESD-R score as a continuous outcome and mean annual residential BC as an alternate marker of long-term exposure to traffic pollution. Results: We found no evidence of a positive association between depressive symptoms and long-term exposure to traffic pollution or short-term changes in pollutant levels. For example, we found an OR of CESD-R score ≥ 16 of 0.67 (95% CI: 0.46, 0.98) per interquartile range (3.4 μg/m3) increase in PM2.5 over the 2 weeks preceding assessment. Conclusions: We found no evidence suggesting that ambient air pollution is associated with depressive symptoms among older adults living in a metropolitan area in attainment of current U.S. regulatory standards. Citation: Wang Y, Eliot MN, Koutrakis P, Gryparis A, Schwartz JD, Coull BA, Mittleman MA, Milberg WP, Lipsitz LA, Wellenius GA. 2014. Ambient air pollution and depressive symptoms in older adults: results from the MOBILIZE Boston Study. Environ Health Perspect 122:553–558; http://dx.doi.org/10.1289/ehp.1205909

Background: Extreme weather and air pollution are associated with increased cardiovascular risk in people with diabetes. Objectives: In a population with diabetes, we conducted a novel assessment of vascular brachial artery responses both to ambient pollution and to weather (temperature and water vapor pressure, a measure of humidity). Methods: Sixty-four 49- to 85-year-old Boston residents with type 2 diabetes completed up to five study visits (279 repeated measures). Brachial artery diameter (BAD) was measured by ultrasound before and after brachial artery occlusion [i.e., flow-mediated dilation (FMD)] and before and after nitroglycerin-mediated dilation (NMD). Ambient concentrations of fine particulate mass (PM2.5), black carbon (BC), organic carbon (OC), elemental carbon, particle number, and sulfate were measured at our monitoring site; ambient concentrations of carbon monoxide, nitrogen dioxide, and ozone were obtained from state monitors. Particle exposure in the home and during each trip to the clinic (home/trip exposure) was measured continuously and as a 5-day integrated sample. We used linear models with fixed effects for participants, adjusting for date, season, temperature, and water vapor pressure on the day of each visit, to estimate associations between our outcomes and interquartile range increases in exposure. Results: Baseline BAD was negatively associated with particle pollution, including home/trip–integrated BC (–0.02 mm; 95% CI: –0.04, –0.003, for a 0.28 μg/m3 increase in BC), OC (–0.08 mm; 95% CI: –0.14, –0.03, for a 1.61 μg/m3 increase) as well as PM2.5, 5-day average ambient PM2.5, and BC. BAD was positively associated with ambient temperature and water vapor pressure. However, exposures were not consistently associated with FMD or NMD. Conclusion: Brachial artery diameter, a predictor of cardiovascular risk, decreased in association with particle pollution and increased in association with ambient temperature in our study population of adults with type 2 diabetes. Citation: Zanobetti A, Luttmann-Gibson H, Horton ES, Cohen A, Coull BA, Hoffmann B, Schwartz JD, Mittleman MA, Li Y, Stone PH, de Souza C, Lamparello B, Koutrakis P, Gold DR. 2014. Brachial artery responses to ambient pollution, temperature, and humidity in people with type 2 diabetes: a repeated-measures study. Environ Health Perspect 122:242–248; http://dx.doi.org/10.1289/ehp.1206136

Background: Few studies have been performed on pulmonary effects of air pollution in the elderly—a vulnerable population with low reserve capacity—and mechanisms and susceptibility factors for potential effects are unclear. Objectives: We evaluated the lag structure of air pollutant associations with lung function and potential effect modification by DNA methylation (< or ≥ median) at 26 individual CpG sites in nine candidate genes in a well-characterized cohort of elderly men. Methods: We measured forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1), and blood DNA methylation one to four times between 1999 and 2009 in 776 men from the Normative Aging Study. Air pollution was measured at fixed monitors 4 hr to 28 days before lung function tests. We used linear mixed-effects models to estimate the main effects of air pollutants and effect modification by DNA methylation. Results: An interquartile range (IQR) increase in subchronic exposure (3 to 28 days cumulated), but not in acute exposure (during the previous 4 hr, or the current or previous day), to black carbon, total and nontraffic particles with aerodynamic diameter ≤ 2.5 μm (PM2.5), carbon monoxide, and nitrogen dioxide was associated with a 1–5% decrease in FVC and FEV1 (p < 0.05). Slope estimates were greater for FVC than FEV1, and increased with cumulative exposure. The estimates slopes for air pollutants (28 days cumulated) were higher in participants with low (< median) methylation in TLR2 at position 2 and position 5 and high (≥ median) methylation in GCR. Conclusions: Subchronic exposure to traffic-related pollutants was associated with significantly reduced lung function in the elderly; nontraffic pollutants (particles, ozone) had weaker associations. Epigenetic mechanisms related to inflammation and immunity may influence these associations. Citation: Lepeule J, Bind MAC, Baccarelli AA, Koutrakis P, Tarantini L, Litonjua A, Sparrow D, Vokonas P, Schwartz JD. 2014. Epigenetic influences on associations between air pollutants and lung function in elderly men: the Normative Aging Study. Environ Health Perspect 122:566–572; http://dx.doi.org/10.1289/ehp.1206458

Background: Low-level environmental cadmium exposure in children may be associated with adverse neurodevelopmental outcomes. Objective: Our aim was to evaluate associations between urinary cadmium concentration and reported learning disability (LD), special education utilization, and attention deficit hyperactivity disorder (ADHD) in U.S. children using National Health and Nutrition Examination Survey (NHANES) data. Methods: We analyzed data from a subset of participants in NHANES (1999–2004) who were 6–15 years of age and had spot urine samples analyzed for cadmium. Outcomes were assessed by parent or proxy-respondent report. We fit multivariable-adjusted logistic regression models to estimate associations between urinary cadmium and the outcomes. Results: When we compared children in the highest quartile of urinary cadmium with those in the lowest quartile, odds ratios adjusted for several potential confounders were 3.21 [95% confidence interval (CI): 1.43, 7.17] for LD, 3.00 (95% CI: 1.12, 8.01) for special education, and 0.67 (95% CI: 0.28, 1.61) for ADHD. There were no significant interactions with sex, but associations with LD and special education were somewhat stronger in males, and the trend in the ADHD analysis was only evident among those with blood lead levels above the median. Conclusions: These findings suggest that children who have higher urinary cadmium concentrations may have increased risk of both LD and special education. Importantly, we observed these associations at exposure levels that were previously considered to be without adverse effects, and these levels are common among U.S. children.

Background: Household cleaning products are associated with adverse respiratory health outcomes, but the cardiovascular health effects are largely unknown. Objective: We determined if long-term use of household sprays and scented products at home was associated with reduced heart rate variability (HRV), a marker of autonomic cardiac dysfunction. Methods: We recorded 24-hr electrocardiograms in a cross-sectional survey of 581 Swiss adults, ≥ 50 years of age, who answered a detailed questionnaire regarding their use of household cleaning products in their homes. The adjusted average percent changes in standard deviation of all normal-to-normal intervals in 24 hr (24-hr SDNN) and total power (TP) were estimated in multiple linear regression in association with frequency [< 1, 1–3, or 4–7 days/week, unexposed (reference)] of using cleaning sprays, air freshening sprays, and scented products. Results: Decreases in 24-hr SDNN and TP were observed with frequent use of all product types, but the strongest reductions were associated with air freshening sprays. Compared with unexposed participants, we found that using air freshening sprays 4–7 days/week was associated with 11% [95% confidence interval (CI): –20%, –2%] and 29% (95% CI: –46%, –8%) decreases in 24-hr SDNN and TP, respectively. Inverse associations of 24-SDNN and TP with increased use of cleaning sprays, air freshening sprays, and scented products were observed mainly in participants with obstructive lung disease (p < 0.05 for interactions). Conclusions: In predominantly older adult women, long-term frequent use of household spray and scented products was associated with reduced HRV, which suggests an increased risk of cardiovascular health hazards. People with preexisting pulmonary conditions may be more susceptible.

Background: Traffic-related particles (TRPs) are associated with adverse cardiovascular events. The exact mechanisms are unclear, but systemic inflammatory responses likely play a role. Objectives: We conducted a repeated measures study among male participants of the Normative Aging Study in the greater Boston, Massachusetts, area to determine whether individual-level residential black carbon (BC), a marker of TRPs, is associated with systemic inflammation and whether coronary heart disease (CHD), diabetes, and obesity modify associations. Methods: We quantified markers of inflammation in 1,163 serum samples from 580 men. Exposure to BC up to 4 weeks prior was predicted from a validated spatiotemporal land-use regression model. Linear mixed effects models estimated the effects of BC on each marker while adjusting for potential confounders. Results: Associations between BC and blood markers were not observed in main effects models or when stratified by obesity status. However, BC was positively associated with markers of inflammation in men with CHD (particularly vascular endothelial growth factor) and in men with diabetes (particularly interleukin-1β and tumor necrosis factor-α). Significant exposure time windows varied by marker, although in general the strongest associations were observed with moving averages of 2–7 days after a lag of several days. Conclusions: In an elderly male population, estimated BC exposures were positively associated with markers of systemic inflammation but only in men with CHD or diabetes.

Background: Most toxicologic studies focus on a single agent, although this does not reflect real-world scenarios in which humans are exposed to multiple chemicals. Objectives: We prospectively studied manganese–lead interactions in early childhood to examine whether manganese–lead coexposure is associated with neurodevelopmental deficiencies that are more severe than expected based on effects of exposure to each metal alone. Methods: Four hundred fifty-five children were enrolled at birth in an longitudinal cohort study in Mexico City, provided blood samples, and were followed until 36 months of age. We measured lead and manganese at 12 and 24 months and assessed neurodevelopment at 6-month intervals from 12 to 36 months of age using Bayley Scales of Infant Development–II. Results: Mean (± SD) blood concentrations at 12 and 24 months were, respectively, 24.7 ± 5.9 μg/L and 21.5 ± 7.4 μg/L for manganese and 5.1 ± 2.6 μg/dL and 5.0 ± 2.9 μg/dL for lead. Mixed-effects models, including Bayley scores at five time points, showed a significant interaction over time: highest manganese quintile × continuous lead; mental development score, β = –1.27 [95% confidence interval (CI): –2.18, –0.37]; psychomotor development score, β = –0.92 (95% CI: –1.76, –0.09). Slopes for the estimated 12-month lead effect on 18-month mental development and 24- through 36-month psychomotor development scores were steeper for children with high manganese than for children with midrange manganese levels. Conclusions: We observed evidence of synergism between lead and manganese, whereby lead toxicity was increased among children with high manganese coexposure. Findings highlight the importance of understanding health effects of mixed exposures, particularly during potentially sensitive developmental stages such as early childhood.

Background: Health risks differ by fine particle (aerodynamic diameter ≤ 2.5 μm) component, although with substantial variability. Traditional methods to assess component-specific risks are limited, suggesting the need for alternative methods. Objectives: We examined whether the odds of daily hospital admissions differ by pollutant chemical properties. Methods: We categorized pollutants by chemical properties and examined their impacts on the odds of daily hospital admissions among Medicare recipients > 64 years of age in counties in Atlanta, Georgia, for 1998–2006. We analyzed data in two stages. In the first stage we applied a case-crossover analysis to simultaneously estimate effects of 65 pollutants measured in the Aerosol Research and Inhalation Epidemiology Study on cause-specific hospital admissions, controlling for temperature and ozone. In the second stage, we regressed pollutant-specific slopes from the first stage on pollutant properties. We calculated uncertainty estimates using a bootstrap procedure. We repeated the two-stage analyses using coefficients from first-stage models that included single pollutants plus ozone and meteorological variables only. We based our primary analyses on exposures on day of admission. Results: We found that 24-hr transition metals and alkanes were associated with increased odds [0.26%; 95% confidence interval (CI), 0.02–0.48; and 0.37%; 95% CI, 0.04–0.72, respectively] of hospital admissions for cardiovascular disease (CVD). Transition metals were significantly associated with increased hospital admissions for ischemic heart disease, congestive heart failure, and atrial fibrillation. Increased respiratory-related hospital admissions were significantly associated with alkanes. Aromatics and microcrystalline oxides were significantly associated with decreased CVD- and respiratory-related hospital admissions. Conclusions: The two-stage approach showed transition metals to be consistently associated with increased odds of CVD-related hospital admissions.

Background: Arsenic, cadmium, mercury, and lead are associated with cardiovascular disease in epidemiologic research. These associations may be mediated by direct effects of the metals on blood pressure (BP) elevation. Manganese is associated with cardiovascular dysfunction and hypotension in occupational cohorts. Objectives: We hypothesized that chronic arsenic, cadmium, mercury, and lead exposures elevate BP and that manganese lowers BP. Methods: We conducted a cross-sectional analysis of associations between toenail metals and BP among older men from the Normative Aging Study (n = 639), using linear regression and adjusting for potential confounders. Results: An interquartile range increase in toenail arsenic was associated with higher systolic BP [0.93 mmHg; 95% confidence interval (CI): 0.25, 1.62] and pulse pressure (0.76 mmHg; 95% CI: 0.22, 1.30). Positive associations between arsenic and BP and negative associations between manganese and BP were strengthened in models adjusted for other toenail metals. Conclusions: Our findings suggest associations between BP and arsenic and manganese. This may be of public health importance because of prevalence of both metal exposure and cardiovascular disease. Results should be interpreted cautiously given potential limitations of toenails as biomarkers of metal exposure.

Background: DNA methylation is a potential pathway linking environmental exposures to disease. Exposure to particulate air pollution has been associated with increased cardiovascular morbidity and mortality, and lower blood DNA methylation has been found in processes related to cardiovascular morbidity. Objective: We hypothesized that prolonged exposure to particulate pollution would be associated with hypomethylation of repetitive DNA elements and that this association would be modified by genes involved in glutathione metabolism and other host characteristics. Methods: DNA methylation of the long interspersed nucleotide element–1 (LINE-1) and the short interspersed nucleotide element Alu were measured by quantitative polymerase chain reaction pyrosequencing in 1,406 blood samples from 706 elderly participants in the Normative Aging Study. We estimated changes in repetitive element DNA methylation associated with ambient particles (particulate matter ≤ 2.5 µm in aerodynamic diameter), black carbon (BC), and sulfates (SO4), with mixed models. We examined multiple exposure windows (1–6 months) before DNA methylation measurement. We investigated whether this association was modified by genotype and phenotype. Results: An interquartile range (IQR) increase in BC over a 90-day period was associated with a decrease of 0.31% 5-methylcytosine (5mC) (95% confidence interval, 0.12–0.50%) in Alu. An IQR increase in SO4 over a 90-day period was associated with a decrease of 0.27% 5mC (0.02–0.52%) in LINE-1. The glutathione S-transferase mu-1–null genotype strengthened the association between BC and Alu hypomethylation. Conclusion: Prolonged exposure to BC and SO4 particles was associated with hypomethylation of two types of repetitive elements.

Background: A large body of evidence suggests that fine particulate matter (PM) air pollution is a cause of cardiovascular disease, but little is known in particular about the cardiovascular effects of indoor air pollution from household use of solid fuels in developing countries. RESPIRE (Randomized Exposure Study of Pollution Indoors and Respiratory Effects) was a randomized trial of a chimney woodstove that reduces wood smoke exposure. Objectives: We tested the hypotheses that the stove intervention, compared with open fire use, would reduce ST-segment depression and increase heart rate variability (HRV). Methods: We used two complementary study designs: a) between-groups comparisons based on randomized stove assignment, and b) before-and-after comparisons within control subjects who used open fires during the trial and received chimney stoves after the trial. Electrocardiogram sessions that lasted 20 hr were repeated up to three times among 49 intervention and 70 control women 38–84 years of age, and 55 control subjects were also assessed after receiving stoves. HRV and ST-segment values were assessed for each 30-min period. ST-segment depression was defined as an average value below –1.00 mm. Personal fine PM [aerodynamic diameter ≤ 2.5 μm (PM2.5)] exposures were measured for 24 hr before each electrocardiogram. Results: PM2.5 exposure means were 266 and 102 μg/m3 during the trial period in the control and intervention groups, respectively. During the trial, the stove intervention was associated with an odds ratio of 0.26 (95% confidence interval, 0.08–0.90) for ST-segment depression. We found similar associations with the before-and-after comparison. The intervention was not significantly associated with HRV. Conclusions: The stove intervention was associated with reduced occurrence of nonspecific ST-segment depression, suggesting that household wood smoke exposures affect ventricular repolarization and potentially cardiovascular health.

Background Traffic-related particles induce oxidative stress and may exert adverse effects on central nervous system function, which could manifest as cognitive impairment. Objective We assessed the association between black carbon (BC), a marker of traffic-related air pollution, and cognition in older men. Methods A total of 680 men (mean ± SD, 71 ± 7 years of age) from the U.S. Department of Veterans Affairs Normative Aging Study completed a battery of seven cognitive tests at least once between 1996 and 2007. We assessed long-term exposure to traffic-related air pollution using a validated spatiotemporal land-use regression model for BC. Results The association between BC and cognition was nonlinear, and we log-transformed BC estimates for all analyses [ln(BC)]. In a multivariable-adjusted model, for each doubling in BC on the natural scale, the odds of having a Mini-Mental State Examination (MMSE) score ≤ 25 was 1.3 times higher [95% confidence interval (CI), 1.1 to 1.6]. In a multivariable-adjusted model for global cognitive function, which combined scores from the remaining six tests, a doubling of BC was associated with a 0.054 SD lower test score (95% CI, −0.103 to −0.006), an effect size similar to that observed with a difference in age of 1.9 years in our data. We found no evidence of heterogeneity by cognitive test. In sensitivity analyses adjusting for past lead exposure, the association with MMSE scores was similar (odds ratio = 1.3; 95% CI, 1.1 to 1.7), but the association with global cognition was somewhat attenuated (−0.038 per doubling in BC; 95% CI, −0.089 to 0.012). Conclusions Ambient traffic-related air pollution was associated with decreased cognitive function in older men.

Background Shortened leukocyte telomere length (LTL) is a marker of cardiovascular risk that has been recently associated with long-term exposure to ambient particulate matter (PM). However, LTL is increased during acute inflammation and allows for rapid proliferation of inflammatory cells. Whether short-term exposure to proinflammatory exposures such as PM increases LTL has never been evaluated. Objectives We investigated the effects of acute exposure to metal-rich PM on blood LTL, as well as molecular mechanisms contributing to LTL regulation in a group of steel workers with high PM exposure. Methods We measured LTL, as well as mRNA expression and promoter DNA methylation of the telomerase catalytic enzyme gene [human telomerase reverse transcriptase (hTERT)] in blood samples obtained from 63 steel workers on the first day of a workweek (baseline) and after 3 days of work (postexposure). Results LTL was significantly increased in postexposure (mean ± SD, 1.43 ± 0.51) compared with baseline samples (1.23 ± 0.28, p-value < 0.001). Postexposure LTL was positively associated with PM10 (β = 0.30, p-value = 0.002 for 90th vs. 10th percentile exposure) and PM1 (β = 0.29, p-value = 0.042) exposure levels in regression models adjusting for multiple covariates. hTERT expression was lower in postexposure samples (1.31 ± 0.75) than at baseline (1.68 ± 0.86, p-value < 0.001), but the decrease in hTERT expression did not show a dose–response relationship with PM. We found no exposure-related differences in the methylation of any of the CpG sites investigated in the hTERT promoter. Conclusions Short-term exposure to PM caused a rapid increase in blood LTL. The LTL increase did not appear to be mediated by PM-related changes in hTERT expression and methylation.

Methylmercury (MeHg) is a widespread and particularly toxic form of mercury (Hg). It results from the conversion of inorganic Hg to a methylated form by aquatic microorganisms and can bioaccumulate in the aquatic food web. Dietary intake of MeHg, primarily through ingestion of contaminated fish and seafood, is recognized as a significant public health concern, primarily because of its well-studied neurodevelopmental toxicity in fetuses and children. However, a growing body of evidence suggests that MeHg exposure may also lead to increased risks of adverse cardiovascular impacts in exposed populations. In a comprehensive review of MeHg-related health effects in 2000, the National Research Council (NRC) concluded that neurodevelopmental impacts from prenatal MeHg exposures are the most sensitive and best-documented end points (NRC 2000). The report also found limited evidence of adverse cardiovascular effects at similar levels of exposure but did not reach firm conclusions on the cardiovascular impact of MeHg intake. Since the publication of the NRC report, the U.S. Environmental Protection Agency (EPA) benefits assessments of rules controlling Hg emissions, such as the Clean Air Mercury Rule, have quantified neurodevelopmental benefits of reducing MeHg exposures to fetuses and children (U.S. EPA 2005). [For a diagram outlining the U.S. EPA’s benefits assessment process, see Supplemental Material, Figure 1 (doi:10.1289/ehp.1003012).] However, Rice et al. (2010) developed a probabilistic analysis that characterized the plausible distribution of health and economic benefits associated with a reduction in MeHg exposure and reported that 80% of the benefits were associated with reductions in fatal heart attacks, and the remainder with IQ gains. Therefore, omitting these effects, if real, could result in a significant downward bias on the economic value of benefits ascribed to rules that control Hg emissions. Other assessments have reviewed the evidence for cardiovascular risk from MeHg exposure (Mozaffarian 2009; Stern 2005) and the balance of cardiovascular risks and benefits from MeHg exposure in conjunction with fish intake (Mozaffarian and Rimm 2006). However, previous assessments have not addressed the full range of potential cardiovascular health effects and have not focused on the development of dose–response relationships between MeHg and these individual cardiovascular effects. In January 2010, the U.S. EPA convened a workshop in Washington, DC, to review the current science concerning cardiovascular impacts of MeHg exposures and to elicit recommendations about whether these effects should be included in benefits assessments of future Hg rules [for a list of questions posed by the U.S. EPA to workshop participants, see Supplemental Material (doi:10.1289/ehp.1003012)]. The invited panel consisted of nine individuals, all coauthors of this article, with expertise spanning epidemiology, clinical medicine, toxicology, risk and exposure assessment, biostatistics, and uncertainty analysis. This article discusses the current literature and presents the recommendations of the assembled panel. In brief, we recommend the development of a dose–response function relating MeHg exposures with myocardial infarction (MI), for use in regulatory benefits analyses of future rules targeting Hg emissions.

Background Telomere length reflects biological age and is inversely associated with risk of cardiovascular disease (CVD). Ambient air pollution is associated with CVD, but its effect on telomere length is unknown. Objective We investigated whether ambient black carbon (BC), a marker for traffic-related particles, is associated with telomere length in the Normative Aging Study (NAS). Methods Among 165 never-smoking men from the NAS, leukocyte telomere length (LTL) was measured repeatedly approximately every 3 years from 1999 through 2006 using quantitative real-time polymerase chain reaction (qRT-PCR). BC concentration at their residences during the year before each LTL measurement was estimated based on a spatiotemporal model calibrated with BC measurements from 82 locations within the study area. Results The median [interquartile range (IQR)] annual moving-average BC concentration was 0.32 (0.20–0.45) μg/m3. LTL, expressed as population-standardized ratio of telomere repeat to single-copy gene copy numbers, had a geometric mean (geometric SD) of 1.25 (1.42). We used linear mixed-effects models including random subject intercepts and adjusted for several potential confounders. We used inverse probability of response weighting to adjust for potential selection bias due to loss to follow-up. An IQR increase in annual BC (0.25 μg/m3) was associated with a 7.6% decrease (95% confidence interval, −12.8 to −2.1) in LTL. We found evidence of effect modification, with a stronger association among subjects ≥ 75 years of age compared with younger participants (p = 0.050) and statin medications appearing protective of the effects of BC on LTL (p = 0.050). Conclusions Telomere attrition, linked to biological aging, may be associated with long-term exposures to airborne particles, particularly those rich in BC, which are primarily related to automobile traffic.

Parkinson’s disease (PD) is a complex disease for which a number of genetic and environmental risks have been identified. Twin studies suggest that environmental risk factors may be particularly important in patients whose illness begins after 50 years of age (Tanner et al. 1999). Although much of the research into environmental contributors to PD has focused on pesticides, other toxicants have been explored as well (Elbaz and Moisan 2008; Lai et al. 2002). Lead is known to disrupt dopaminergic function in experimental studies and can induce oxidative stress (Ercal et al. 2001), which is a candidate hypothesis for the etiology of PD (Jenner 2003). The assessment of exposure to lead, particularly cumulative exposure, however, can be difficult. Lead can be measured easily in blood, but its half-life is approximately 30 days, rendering this biomarker a better indicator of recent exposure than of cumulative exposure. Cumulative exposure, however, might be more relevant than recent exposure for the development of PD. Prior studies of lead and PD have generally relied on self-reported exposure or on work histories from which cumulative exposures are reconstructed. Although these studies have suggested an association with cumulative exposure to lead, biomarkers of cumulative exposure could provide a more robust exposure measure. Circulating lead is deposited in bone, where it has a half-life on the order of years to decades, making it an excellent biomarker of cumulative lead exposure (Hu et al. 1998). Bone lead can be assessed with the K-shell X-ray fluorescence (KXRF) technique, but only one study has examined the association of this biomarker with PD, finding a suggestive but not quite significant [odds ratio (OR) = 1.62; 95% confidence intervals (CI), 0.83–3.17] association in an analysis involving 121 PD patients and 414 controls (Coon et al. 2006). We examined the association between cumulative exposure to lead—as measured by lead in bone with KXRF—and odds of PD in a case–control study based in Boston, Massachusetts.

Background Black carbon (BC) is a marker of traffic pollution that has been associated with blood pressure (BP), but findings have been inconsistent. MicroRNAs (miRNAs) are emerging as key regulators of gene expression, but whether polymorphisms in genes involved in processing of miRNAs to maturity influence susceptibility to BC has not been elucidated. Objectives We investigated the association between BC and BP, as well as potential effect modification by single nucleotide polymorphisms (SNPs) in miRNA processing genes. Methods Repeated measures analyses were performed using data from the VA Normative Aging Study. Complete covariate data were available for 789 participants with one to six study visits between 1995 and 2008. In models of systolic and diastolic BP, we examined SNP-by-BC interactions with 19 miRNA-related variants under recessive models of inheritance. Mixed-effects models were adjusted for potential confounders including clinical characteristics, lifestyle, and meteorologic factors. Results A 1-SD increase in BC (0.415 μg/m3) was associated with 3.04 mmHg higher systolic (95% confidence interval (CI), 2.29–3.79) and 2.28 mmHg higher diastolic BP (95% CI, 1.88–2.67). Interactions modifying BC associations were observed with SNPs in the DICER, GEMIN4, and DiGeorge critical region-8 (DGCR8) genes, and in GEMIN3 and GEMIN4, predicting diastolic and systolic BP, respectively. Conclusions We observed evidence of effect modification of the association between BP and 7-day BC moving averages by SNPs associated with miRNA processing. Although the mechanisms underlying these associations are not well understood, they suggest a role for miRNA genesis and processing in influencing BC effects.

Background Acute exposure to ambient air pollution has been associated with acute changes in cardiac outcomes, often within hours of exposure. Objectives We examined the effects of air pollutants on heart-rate–corrected QT interval (QTc), an electrocardiographic marker of ventricular repolarization, and whether these associations were modified by participant characteristics and genetic polymorphisms related to oxidative stress. Methods We studied repeated measurements of QTc on 580 men from the Veterans Affairs Normative Aging Study (NAS) using mixed-effects models with random intercepts. We fitted a quadratic constrained distributed lag model to estimate the cumulative effect on QTc of ambient air pollutants including fine particulate matter ≤ 2.5 μm in aerodynamic diameter (PM2.5), ozone (O3), black carbon (BC), nitrogen dioxide (NO2), carbon monoxide (CO), and sulfur dioxide (SO2) concentrations during the 10 hr before the visit. We genotyped polymorphisms related to oxidative stress and analyzed pollution–susceptibility score interactions using the genetic susceptibility score (GSS) method. Results Ambient traffic pollutant concentrations were related to longer QTc. An interquartile range (IQR) change in BC cumulative during the 10 hr before the visit was associated with increased QTc [1.89 msec change; 95% confidence interval (CI), −0.16 to 3.93]. We found a similar association with QTc for an IQR change in 1-hr BC that occurred 4 hr before the visit (2.54 msec change; 95% CI, 0.28–4.80). We found increased QTc for IQR changes in NO2 and CO, but the change was statistically insignificant. In contrast, we found no association between QTc and PM2.5, SO2, and O3. The association between QTc and BC was stronger among participants who were obese, who had diabetes, who were nonsmokers, or who had higher GSSs. Conclusions Traffic-related pollutants may increase QTc among persons with diabetes, persons who are obese, and nonsmoking elderly individuals; the number of genetic variants related to oxidative stress increases this effect.

Introduction Ambient particulate pollution and traffic have been linked to myocardial infarction and cardiac death risk. Possible mechanisms include autonomic cardiac dysfunction. Methods In a repeated-measures study of 46 patients 43–75 years of age, we investigated associations of central-site ambient particulate pollution, including black carbon (BC) (a marker for regional and local traffic), and report of traffic exposure with changes in half-hourly averaged heart rate variability (HRV), a marker of autonomic function measured by 24-hr Holter electrocardiogram monitoring. Each patient was observed up to four times within 1 year after a percutaneous intervention for myocardial infarction, acute coronary syndrome without infarction, or stable coronary artery disease (4,955 half-hour observations). For each half-hour period, diary data defined whether the patient was home or not home, or in traffic. Results A decrease in high frequency (HF; an HRV marker of vagal tone) of −16.4% [95% confidence interval (CI), −20.7 to −11.8%] was associated with an interquartile range of 0.3-μg/m3 increase in prior 5-day averaged ambient BC. Decreases in HF were independently associated both with the previous 2-hr averaged BC (−10.4%; 95% CI, −15.4 to −5.2%) and with being in traffic in the previous 2 hr (−38.5%; 95% CI, −57.4 to −11.1%). We also observed independent responses for particulate air matter with aerodynamic diameter ≤ 2.5 μm and for gases (ozone or nitrogen dioxide). Conclusion After hospitalization for coronary artery disease, both particulate pollution and being in traffic, a marker of stress and pollution, were associated with decreased HRV.

Introduction Systemic inflammation may be one of the mechanisms mediating the association between ambient air pollution and cardiovascular morbidity and mortality. Interleukin-6 (IL-6) and fibrinogen are biomarkers of systemic inflammation that are independent risk factors for cardiovascular disease. Objective We investigated the association between ambient air pollution and systemic inflammation using baseline measurements of IL-6 and fibrinogen from controlled human exposure studies. Methods In this retrospective analysis we used repeated-measures data in 45 nonsmoking subjects. Hourly and daily moving averages were calculated for ozone, nitrogen dioxide, sulfur dioxide, and particulate matter ≤ 2.5 μm in aerodynamic diameter (PM2.5). Linear mixed-model regression determined the effects of the pollutants on systemic IL-6 and fibrinogen. Effect modification by season was considered. Results We observed a positive association between IL-6 and O3 [0.31 SD per O3 interquartile range (IQR); 95% confidence interval (CI), 0.08–0.54] and between IL-6 and SO2 (0.25 SD per SO2 IQR; 95% CI, 0.06–0.43). We observed the strongest effects using 4-day moving averages. Responses to pollutants varied by season and tended to be higher in the summer, particularly for O3 and PM2.5. Fibrinogen was not associated with pollution. Conclusions This study demonstrates a significant association between ambient pollutant levels and baseline levels of systemic IL-6. These findings have potential implications for controlled human exposure studies. Future research should consider whether ambient pollution exposure before chamber exposure modifies IL-6 response.

Background DNA methylation is an epigenetic mark that regulates gene expression. Changes in DNA methylation within white blood cells may result from cumulative exposure to environmental metals such as lead. Bone lead, a marker of cumulative exposure, may therefore better predict DNA methylation than does blood lead. Objective In this study we compared associations between lead biomarkers and DNA methylation. Methods We measured global methylation in participants of the Normative Aging Study (all men) who had archived DNA samples. We measured patella and tibia lead levels by K-X-Ray fluorescence and blood lead by atomic absorption spectrophotometry. DNA samples from blood were used to determine global methylation averages within CpG islands of long interspersed nuclear elements-1 (LINE-1) and Alu retrotransposons. A mixed-effects model using repeated measures of Alu or LINE-1 as the dependent variable and blood/bone lead (tibia or patella in separate models) as the primary exposure marker was fit to the data. Results Overall mean global methylation (± SD) was 26.3 ± 1.0 as measured by Alu and 76.8 ± 1.9 as measured by LINE-1. In the mixed-effects model, patella lead levels were inversely associated with LINE-1 (β = −0.25; p < 0.01) but not Alu (β = −0.03; p = 0.4). Tibia lead and blood lead did not predict global methylation for either Alu or LINE-1. Conclusion Patella lead levels predicted reduced global DNA methylation within LINE-1 elements. The association between lead exposure and LINE-1 DNA methylation may have implications for the mechanisms of action of lead on health outcomes, and also suggests that changes in DNA methylation may represent a biomarker of past lead exposure.

Background Low-level exposure to lead and to chronic stress may independently influence cognition. However, the modifying potential of psychosocial stress on the neurotoxicity of lead and their combined relationship to aging-associated decline have not been fully examined. Objectives We examined the cross-sectional interaction between stress and lead exposure on Mini-Mental State Examination (MMSE) scores among 811 participants in the Normative Aging Study, a cohort of older U.S. men. Methods We used two self-reported measures of stress appraisal—a self-report of stress related to their most severe problem and the Perceived Stress Scale (PSS). Indices of lead exposure were blood lead and bone (tibia and patella) lead. Results Participants with higher self-reported stress had lower MMSE scores, which were adjusted for age, education, computer experience, English as a first language, smoking, and alcohol intake. In multivariable-adjusted tests for interaction, those with higher PSS scores had a 0.57-point lower (95% confidence interval, −0.90 to 0.24) MMSE score for a 2-fold increase in blood lead than did those with lower PSS scores. In addition, the combination of high PSS scores and high blood lead categories on one or both was associated with a 0.05–0.08 reduction on the MMSE for each year of age compared with those with low PSS score and blood lead level (p < 0.05). Conclusions Psychological stress had an independent inverse association with cognition and also modified the relationship between lead exposure and cognitive performance among older men. Furthermore, high stress and lead together modified the association between age and cognition.