Background/Aim: Many time-series studies have established associations between short-term exposure to ambient fine particles (PM2.5) or ozone and increased mortality. However, those studies have generally been limited to large cities, and evidence for the associations below the current National Ambient Air Quality Standards (NAAQS) is limited. Also, many previous studies had inadequate power to identify susceptible sub-groups.We examined the association of acute exposure to ambient PM2.5 and ozone with mortality using the case-crossover approach, on a large nationwide sample consisting of all Medicare participants in the U.S. Methods: We conducted national case-crossover analyses to estimate the effects of PM2.5 and ozone on over 22 million deaths of Medicare participants during 2000 to 2012. Daily PM2.5 and ozone levels were assessed by previously published and validated prediction models. Daily exposures were matched to every ZIP code. We used conditional logistical regression to examine the association between mortality and PM2.5 and ozone in two-pollutant models. Effect modification by age, race, sex, socio-economic status (SES), and population density was also examined. In addition, we estimated the dose-response curves for PM2.5 and ozone. Results: We found that mortality increased by 1.04% [95% confidence interval (CI): 0.95%, 1.14%] and 0.51% (95% CI: 0.41%, 0.61%) for every 10 µg/m3 and 10 ppb increase in PM2.5 and ozone, respectively. Sub-group analyses showed that blacks, people with a low SES, elders and females had higher risk estimates associated with air pollution. We observed a dose-response curve that showed linearity at low doses and attenuated at higher doses for the relationship between mortality and both PM2.5 and ozone. Conclusions: Exposures to PM2.5 and ozone were significantly associated with higher risk of mortality, even at levels below current U.S. standards. Disadvantaged groups are more susceptible to air pollution. Tighter air quality standards are needed to protect public health.

Background: Fine particulate matter (PM2.5) represents a mixture of components with potentially different toxicities. However, little is known about the relative effects of PM2.5 mass and PM2.5 components on mitochondrial DNA (mtDNA) abundance, which may lie on the pathway of PM2.5-associated disease.Methods: We studied 646 elderly male participants in the Normative Aging Study from Greater Boston to investigate associations of long-term exposure to PM2.5 mass and PM2.5 components with mtDNA abundance. We estimated concentrations of pollutants for the 365-day preceding examination at each participant's address using spatial- and temporal-resolved chemical transport models. We measured blood mtDNA abundance using RT-PCR. We applied a shrinkage and selection method (adaptive LASSO) to identify components most predictive of mtDNA abundance, and fit multipollutant linear mixed-effects models with subject-specific intercept to estimate the relative effects of individual PM component.Results: MtDNA abundance was negatively associated with PM2.5 mass in the previous year and-after adjusting for PM2.5 mass-several PM2.5 components, including organic carbon, sulfate (marginally), and nitrate. In multipollutant models including as independent variables PM2.5 mass and PM2.5 components selected by LASSO, nitrate was associated with mtDNA abundance. An SD increase in annual PM2.5-associated nitrate was associated with a 0.12 SD (95% confidence intervals [CI] = -0.18, -0.07) decrease in mtDNA abundance. Analyses restricted to PM2.5 annual concentration below the current 1-year U.S. Environmental Protection Agency standard produced similar results.Conclusions: Long-term exposures to PM2.5-associated nitrate were related to decreased mtDNA abundance independent of PM2.5 mass. Mass alone may not fully capture the potential of PM2.5 to oxidize the mitochondrial genome. See video abstract at, http://links.lww.com/EDE/B274.

We tested whether genetic variation in miRNA processing genes modified the association of PM2.5 with DNA methylation (DNAm) age. Patients & methods: We conducted a repeated measures study based on 552 participants from the Normative Aging Study with multiple visits between 2000 and 2011 (n = 940 visits). Address-level 1-year PM2.5 exposures were estimated using the GEOS-chem model. DNAm-age and a panel of 14 SNPs in miRNA processing genes were measured from participant blood samples. Results & conclusion: In fully adjusted linear mixed-effects models, having at least one copy of the minor rs4961280 [AGO2] allele was associated with a lower DNAm-age (beta = -1.13; 95% CI: -2.26 to -0.002). However, the association of PM2.5 with DNAm-age was significantly (P-interaction = 0.01) weaker in homozygous carriers of the major rs4961280 [AGO2] allele (beta = 0.38; 95% CI: -0.20 to 0.96) when compared with all other participants (beta = 1.58; 95% CI: 0.76 to 2.39). Our results suggest that miRNA processing impacts DNAmage relationships. Graphical abstract: miRNA processing AGO2 polymorphism (rs4961280) modifies the association of long-term ambient fine particle exposure with blood DNA methylation age [GRAPHICS] The graph depicts lines from a fully adjusted linear regression model with fine particle exposure levels ranging from the tenth to the ninetieth percentile, all other continuous variables held constant at their means, and all other categorical variables held at their most frequent level.

Background: Long-term PM2.5 exposure and aging have been implicated in multiple shared diseases; studying their relationship is a promising strategy to further understand the adverse impact of PM2.5 on human health.Objective: We assessed the relationship of major PM2.5 component species (ammonium, elemental carbon, organic carbon, nitrate, and sulfate) with Horvath and Hannum DNA methylation (DNAm) age, two DNA methylation-based predictors of chronological age.Methods: This analysis included 552 participants from the Normative Aging Study with multiple visits between 2000 and 2011 (n = 940 visits). We estimated 1-year PM2.5 species levels at participants' addresses using the GEOS-chem transport model. Blood DNAm-age was calculated using CpG sites on the Illumina HumanMethylation450 BeadChip. We fit linear mixed-effects models, controlling for PM2.5 mass and lifestyle/environmental factors as fixed effects, with the adaptive LASSO penalty to identify PM2.5 species associated with DNAm-age.Results: Sulfate and ammonium were selected by the LASSO in the Horvath DNAm-age models. In a fully-adjusted multiple-species model, interquartile range increases in both 1-year sulfate (95%CI: 0.28, 0.74, P < 0.0001) and ammonium (95%CI: 0.02, 0.70, P = 0.04) levels were associated with at least a 0.36-year increase in Horvath DNAm-age. No PM2.5 species were selected by the LASSO in the Hannum DNAm-age models. Our findings persisted in sensitivity analyses including only visits with 1-year PM2.5 levels within US EPA national quality standards.Conclusion: Our results demonstrate that sulfate and ammonium were most associated with Horvath DNAm-age and suggest that DNAm-age measures differ in their sensitivity to ambient particle exposures and potentially disease. Published by Elsevier Ltd.

Importance The US Environmental Protection Agency is required to reexamine its National Ambient Air Quality Standards (NAAQS) every 5 years, but evidence of mortality risk is lacking at air pollution levels below the current daily NAAQS in unmonitored areas and for sensitive subgroups. Objective To estimate the association between short-term exposures to ambient fine particulate matter (PM2.5) and ozone, and at levels below the current daily NAAQS, and mortality in the continental United States. Design, Setting, and Participants Case-crossover design and conditional logistic regression to estimate the association between short-term exposures to PM2.5 and ozone (mean of daily exposure on the same day of death and 1 day prior) and mortality in 2-pollutant models. The study included the entire Medicare population from January 1, 2000, to December 31, 2012, residing in 39 182 zip codes. Exposures Daily PM2.5 and ozone levels in a 1-km × 1-km grid were estimated using published and validated air pollution prediction models based on land use, chemical transport modeling, and satellite remote sensing data. From these gridded exposures, daily exposures were calculated for every zip code in the United States. Warm-season ozone was defined as ozone levels for the months April to September of each year. Main Outcomes and Measures All-cause mortality in the entire Medicare population from 2000 to 2012. Results During the study period, there were 22 433 862 million case days and 76 143 209 control days. Of all case and control days, 93.6% had PM2.5 levels below 25 &mgr;g/m3, during which 95.2% of deaths occurred (21 353 817 of 22 433 862), and 91.1% of days had ozone levels below 60 parts per billion, during which 93.4% of deaths occurred (20 955 387 of 22 433 862). The baseline daily mortality rates were 137.33 and 129.44 (per 1 million persons at risk per day) for the entire year and for the warm season, respectively. Each short-term increase of 10 &mgr;g/m3 in PM2.5 (adjusted by ozone) and 10 parts per billion (10−9) in warm-season ozone (adjusted by PM2.5) were statistically significantly associated with a relative increase of 1.05% (95% CI, 0.95%-1.15%) and 0.51% (95% CI, 0.41%-0.61%) in daily mortality rate, respectively. Absolute risk differences in daily mortality rate were 1.42 (95% CI, 1.29-1.56) and 0.66 (95% CI, 0.53-0.78) per 1 million persons at risk per day. There was no evidence of a threshold in the exposure-response relationship. Conclusions and Relevance In the US Medicare population from 2000 to 2012, short-term exposures to PM2.5 and warm-season ozone were significantly associated with increased risk of mortality. This risk occurred at levels below current national air quality standards, suggesting that these standards may need to be reevaluated.

Recent studies have reported robust associations of long-term PM2.5 exposure with DNA methylation-based measures of aging; yet, the molecular implications of these relationships remain poorly understood. We evaluated if genetic variation in 3 biological pathways implicated in PM2.5-related disease-oxidative stress, endothelial function, and metal processing-could modify the effect of PM2.5 on DNAm-age, one prominent DNA methylation-based measure of biological age. This analysis was based on 552 individuals from the Normative Aging Study with at least one visit between 2000 and 2011 (n = 940 visits). A genetic-score approach was used to calculate aging-risk variant scores for endothelial function, oxidative stress, and metal processing pathways. One-year PM2.5 and PM2.5 component (sulfate and ammonium) levels at participants' addresses were estimated using the GEOS-chem transport model. Blood DNAm-age was calculated using CpG sites on the Illumina HumanMethylation450 BeadChip. In fully-adjusted linear mixed-effects models, the effects of sulfate on DNAm-age (in years) were greater in individuals with high aging-risk endothelial function variant scores when compared with individuals with low aging-risk endothelial function variant scores (Pinteraction = 0.0007; βHigh = 1.09, 95% CIHigh: 0.70, 1.48; βLow = 0.40, 95% CILow: 0.14, 0.67). Similar trends were observed in fully adjusted models of ammonium and total PM2.5 alone. No effect modification was observed by oxidative stress and metal processing variant scores. Secondary analyses revealed significant associations of serum endothelial markers, intercellular adhesion molecule-1 (β = 0.01, 95% CI: 0.002, 0.012) and vascular cell adhesion molecule-1 (β = 0.002, 95% CI: 0.0005, 0.0026), with DNAm-age. Our results add novel evidence that endothelial physiology may be important to DNAm-age relationships, but further research is required to establish their generalizability.

The mitochondrial genome has long been implicated in age-related disease, but no studies have examined its role in the relationship of long-term fine particle (PM2.5) exposure and DNA methylation age (DNAm-age)-a novel measure of biological age. In this analysis based on 940 observations between 2000 and 2011 from 552 Normative Aging Study participants, we determined the roles of mitochondrial DNA haplogroup variation and mitochondrial genome abundance in the relationship of PM2.5 with DNAm-age. We used the GEOS-chem transport model to estimate address-specific, one-year PM2.5 levels for each participant. DNAm-age and mitochondrial DNA markers were measured from participant blood samples. Nine haplogroups (H, I, J, K, T, U, V, W, and X) were present in the population. In fully adjusted linear mixed-effects models, the association of PM2.5 with DNAm-age (in years) was significantly diminished in carriers of haplogroup V (Pinteraction = 0.01; β = 0.18, 95%CI: -0.41, 0.78) compared to noncarriers (β = 1.25, 95%CI: 0.58, 1.93). Mediation analysis estimated that decreases in mitochondrial DNA copy number, a measure of mitochondrial genome abundance, mediated 12% of the association of PM2.5 with DNAm-age. Our data suggests that the mitochondrial genome plays a role in DNAm-age relationships particularly in the context of long-term PM2.5 exposure.

Although there is growing evidence that exposure to ambient particulate matter is associated with global DNA methylation and gene-specific methylation, little is known regarding epigenome-wide changes in DNA methylation in relation to particles and, especially, particle components. Using the Illumina Infinium HumanMethylation450 BeadChip, we examined the relationship between one-year moving averages of PM2.5 species (Al, Ca, Cu, Fe, K, Na, Ni, S, Si, V, and Zn) and DNA methylation at 484,613 CpG probes in a longitudinal cohort that included 646 subjects. Bonferroni correction was applied to adjust for multiple comparisons. Bioinformatics analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment was also performed. We observed 20 Bonferroni significant (P-value < 9.4× 10-9) CpGs for Fe, 8 for Ni, and 1 for V. Particularly, methylation at Schlafen Family Member 11 (SLFN11) cg10911913 was positively associated with measured levels of all 3 species. The SLFN11 gene codes for an interferon-induced protein that inhibits retroviruses and sensitizes cancer cells to DNA-damaging agents. Bioinformatics analysis suggests that gene targets may be relevant to pathways including cancers, signal transduction, and cell growth and death. Ours is the first study to examine the epigenome-wide association between ambient particles species and DNA methylation. We found that long-term exposures to specific components of ambient particle pollution, especially particles emitted during oil combustion, were associated with methylation changes in genes relevant to immune responses. Our findings provide insight into potential biologic mechanisms on an epigenetic level.

Few studies have examined the association between ambient temperature and cognitive function, or used exposure to temperature at a given address instead of a single stationary monitor. The existing literature on the temperature-cognition relationship has mostly consisted of experimental studies that involve a small sample size and a few specific temperature values. In the current study, we examined the association between residential air temperature and Mini-Mental State Examination (MMSE) scores, a quantitative measurement of cognitive function, in a longitudinal cohort of elderly men. Residential air temperature was estimated by a novel spatiotemporal approach that incorporates satellite remote sensing, land use regression, meteorological variables and spatial smoothing in the Northeastern USA. We then applied logistic regression generalized estimating equations to examine the relationship between residential temperature (range: −5.8–25.7 °C), and the risk of low MMSE scores (MMSE scores ≤25) among 594 elderly men (1085 visits in total) from the Veterans Affairs Normative Aging Study, 2000–2008. Sensitivity analysis on visits wherein subjects lived within 30 km of the clinic center in Massachusetts or aged ≥70 years was also evaluated. A statistically significant, U-shaped association between residential air temperature and low MMSE score (p-value=0.036) was observed. Sensitivity analysis suggested that the estimated effect remains among individuals aged ≥70 years. In conclusion, the data suggest that risk of low MMSE scores is highest when temperature is either high or low, and lowest when ambient temperature is approximately within 10–15 °C in a cohort of elderly men. Further research is needed to confirm our findings and assess generalizability to other populations.

Studies have found associations between PM 2.5 and cardiovascular events. The role of different components of PM 2.5 is not well understood. We used linear mixed-effects models with the adaptive LASSO penalty to select PM 2.5 species and source(s), separately, that may be associated with markers of inflammation and endothelial dysfunction, with adjustment for age, obesity, smoking, statin use, diabetes mellitus, temperature, and season as fixed effects in a large longitudinal cohort of elderly men. We also analyzed these associations with source apportionment models and examined genetic pathway–air pollution interactions within three relevant pathways (oxidative stress, metal processing, and endothelial function). We found that independent of PM 2.5 mass vanadium (V) was associated with intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). An IQR increase (3.2 ng/m 3 ) in 2-day moving average V was associated with a 2.5% (95% CI: 1.2–3.8%) change in ICAM-1 and a 3.9% (95% CI: 2.2–5.7%) change in VCAM-1, respectively. In addition, an oil combustion source rich in V was linked to these adhesion molecules. People with higher allelic risk profiles related to oxidative stress may have greater associations ( P -value of interaction=0.11). Our findings suggest that particles derived from oil combustion may be associated with inflammation and endothelial dysfunction, and it is likely that oxidative stress plays a role in the associations.

BACKGROUND: PM2.5 (particulate matter <= 2.5 mu m) 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/m(3)) 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 mu g/m(3)).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.

Lingzhen Dai, Antonella Zanobetti, Petros Koutrakis, and Joel D. Schwartz Environ Health Perspect 122(8):837–842 (2014), http://dx.doi.org/10.1289/ehp.1307568 In Table S1, the authors incorrectly inverted the titles of the column headers for temperature and PM2.5. In the original supplemental materials, the last two column headings were titled Temperature (°C) and PM2.5 (μg/m3), but should have been PM2.5 (μg/m3) and Temperature (°C), respectively. The authors also noticed the following misspelling: Saint Diego, CA, should be spelled San Diego, CA. These corrections to Table S1 appear in this erratum. These typographical errors do not affect the information presented in the article. The authors regret the errors. A Section 508–conformant HTML version of this article is available at http://dx.doi.org/10.1289/EHP301.

OBJECTIVETo study the associations between daily mortality and the status of exposure to air pollution.METHODSA time-series analysis was conducted to assess the relations between acute mortality and exposure to respiratory particulate matter (PM(10)), sulfur-dioxide (SO2) and nitrogen dioxide (NO2) in urban residents of Guangzhou (2004 - 2008), using Poisson regression.RESULTSThrough controlling the factors as temperature, relative humidity, age, gender and time, significant increases were observed in all-cause mortality of 0.94% (0.79 - 1.09) for PM(10), 1.55% (1.31 - 1.78) for NO2, and 1.09% (0.91 - 1.27) for SO2, per 10 µg/m(3), when increase of the lagging 2-day average concentrations of air pollution was seen, in Guangzhou. Stronger effects of exposure to air pollution were found on cardiovascular and respiratory mortality, as well as in elderly (≥ 65 years) and female population.CONCLUSIONOur results suggested that exposure to ambient pollution was significantly associated with the increase of excess risks, on total and cardio-respiratory mortality in the residents of Guangzhou.

The authors conducted a time-series analysis to examine seasonal variation of mortality risk in association with particulate matter less than 2.5 μm in aerodynamic diameter (PM(2.5)) and chemical species in Xi'an, China, using daily air pollution and all-cause and cause-specific mortality data (2004-2008). Poisson regression incorporating natural splines was used to estimate mortality risks of PM(2.5) and its chemical components, adjusting for day of the week, time trend, and meteorologic effects. Increases of 2.29% (95% confidence interval: 0.83, 3.76) for all-cause mortality and 3.08% (95% confidence interval: 0.94, 5.26) for cardiovascular mortality were associated with an interquartile range increase of 103.0 μg/m(3) in lagged 1-2 day PM(2.5) exposure. Stronger effects were observed for the elderly (≥65 years), males, and cardiovascular diseases groups. Secondary components (sulfate and ammonium), combustion species (elemental carbon, sulfur, chlorine), and transition metals (chromium, lead, nickel, and zinc) appeared most responsible for increased risk, particularly in the cold months. The authors concluded that differential association patterns observed across species and seasons indicated that PM(2.5)-related effects might not be sufficiently explained by PM(2.5) mass alone. Future research is needed to examine spatial and temporal varying factors that might play important roles in modifying the PM(2.5)-mortality association.

Background and objectives: Epidemiologic studies have attributed adverse health effects to air pollution; however, controversy remains regarding the relationship between ambient oxidants [ozone (O3) and nitrogen dioxide (NO2)] and mortality, especially in Asia. We conducted a four-city time-series study to investigate acute effects of O3 and NO2 in the Pearl River Delta (PRD) of southern China, using data from 2006 through 2008. Methods: We used generalized linear models with Poisson regression incorporating natural spline functions to analyze acute mortality in association with O3 and NO2, with PM10 (particulate matter ≤ 10 μm in diameter) included as a major confounder. Effect estimates were determined for individual cities and for the four cities as a whole. We stratified the analysis according to high- and low- exposure periods for O3. Results: We found consistent positive associations between ambient oxidants and daily mortality across the PRD cities. Overall, 10-μg/m3 increases in average O3 and NO2 concentrations over the previous 2 days were associated with 0.81% [95% confidence interval (CI): 0.63%, 1.00%] and 1.95% (95% CI: 1.62%, 2.29%) increases in total mortality, respectively, with stronger estimated effects for cardiovascular and respiratory mortality. After adjusting for PM10, estimated effects of O3 on total and cardiovascular mortality were stronger for exposure during high-exposure months (September through November), whereas respiratory mortality was associated with O3 exposure during nonpeak exposure months only. Conclusions: Our findings suggest significant acute mortality effects of O3 and NO2 in the PRD and strengthen the rationale for further limiting the ambient pollution levels in the area.

Objective To study associations between daily mortality and exposure to air pollution.Methods A time-series analysis was conducted to assess the acute mortality effects of respirable particulate matter(PM10),nitrogen dioxide(NO2)and sulfur dioxide(SO2) in urban Xi'an residents,using Poisson regression.Temperature,relative humidity,age,gender and day of week were controlled in the models.Results Per 10 μg/m3 increases in 2-day average concentrations of air pollution,significant increases were observed in all-cause mortality of 0.35%(95%CI: 0.11%-0.58%) for PM10,2.42%(95%CI: 1.57%-3.27%) for NO2,and 0.60%(95%CI: 0.16%-1.05%) for SO2.Stronger effects of air pollution were observed on cardio-respiratory mortality.Seasonal variations in pollution associated mortality effects were found between centralized heating(November 15 to March 15) and non-heating(March 16 to November 14) periods.Conclusion Exposure to ambient pollution was significantly associated with the increases in excess risk of total and cardio-respiratory mortality in Xi'an residents.

Objectives: Several studies reported acute mortality and morbidity effects of exposure to carbon monoxide (CO); which, however, has been least studied in Chinese population at regional scale.Methods: We conducted a time-series analysis assessing mortality effects of CO in four cities located in the Pearl River Delta (PRD) of China, a labor and resource intensive city cluster, using daily mortality and air pollution data (2006-2008). Generalized linear model with Poisson regression incorporating natural spline functions was used to analyze the effects of exposure to ambient CO on total (nonaccidental), cardiovascular and respiratory mortality. Effect estimates were determined first for individual cities, and then focused for the mega-city Guangzhou.Results: We found exposure to CO was significantly associated with increased mortality in the mega-city of Guangzhou and medium-sized industrial city of Foshan. In specific, per 0.5 ppm increase in the average lag 1-2 (previous two days) exposure to CO was associated with 3.04% [95% confidence interval (CI), 2.18-3.90%], 3.62% (95% CI, 2.20-5.06%) and 3.72% (95% CI, 1.71-5.76%) increases in excessive risks (ERs) of total, cardiovascular and respiratory mortality, in Guangzhou. Further, we observed significant heterogeneity in mortality effects of exposure to CO among the four PRO cities of different development levels: stronger mortality effects were found in larger, more developed and industrialized cities.Conclusions: Exposure to ambient CO is associated with significant increases in total, cardiovascular and respiratory mortality in Chinese population. CO is an established biologic toxicant, whereas the effects and possible mechanisms of exposure to ambient level of CO and co-pollutants warrant further investigation. (C) 2011 Elsevier B.V. All rights reserved.