Background

Although many time-series studies of ozone and mortality have identified positive associations, others have yielded null or inconclusive results, making the results of these studies difficult to interpret.

Methods

We performed a meta-analysis of 144 effect estimates from 39 time-series studies, and estimated pooled effects by lags, age groups, cause-specific mortality, and concentration metrics. We compared results with pooled estimates from the National Morbidity, Mortality, and Air Pollution Study (NMMAPS), a time-series study of 95 large U.S. urban centers from 1987 to 2000.

Results

Both meta-analysis and NMMAPS results provided strong evidence of a short-term association between ozone and mortality, with larger effects for cardiovascular and respiratory mortality, the elderly, and current-day ozone exposure. In both analyses, results were insensitive to adjustment for particulate matter and model specifications. In the meta-analysis, a 10-ppb increase in daily ozone at single-day or 2-day average of lags 0, 1, or 2 days was associated with an 0.87% increase in total mortality (95% posterior interval = 0.55% to 1.18%), whereas the lag 0 NMMAPS estimate is 0.25% (0.12% to 0.39%). Several findings indicate possible publication bias: meta-analysis results were consistently larger than those from NMMAPS; meta-analysis pooled estimates at lags 0 or 1 were larger when only a single lag was reported than when estimates for multiple lags were reported; and heterogeneity of city-specific estimates in the meta-analysis were larger than with NMMAPS.

Conclusions

This study provides evidence of short-term associations between ozone and mortality as well as evidence of publication bias.

Context

Ozone has been associated with various adverse health effects, including increased rates of hospital admissions and exacerbation of respiratory illnesses. Although numerous time-series studies have estimated associations between day-to-day variation in ozone levels and mortality counts, results have been inconclusive.

Objective

To investigate whether short-term (daily and weekly) exposure to ambient ozone is associated with mortality in the United States.

Design and Setting

Using analytical methods and databases developed for the National Morbidity, Mortality, and Air Pollution Study, we estimated a national average relative rate of mortality associated with short-term exposure to ambient ozone for 95 large US urban communities from 1987-2000. We used distributed-lag models for estimating community-specific relative rates of mortality adjusted for time-varying confounders (particulate matter, weather, seasonality, and long-term trends) and hierarchical models for combining relative rates across communities to estimate a national average relative rate, taking into account spatial heterogeneity.

Main Outcome Measure

Daily counts of total non–injury-related mortality and cardiovascular and respiratory mortality in 95 large US communities during a 14-year period.

Results

A 10-ppb increase in the previous week’s ozone was associated with a 0.52% increase in daily mortality (95% posterior interval [PI], 0.27%-0.77%) and a 0.64% increase in cardiovascular and respiratory mortality (95% PI, 0.31%-0.98%). Effect estimates for aggregate ozone during the previous week were larger than for models considering only a single day’s exposure. Results were robust to adjustment for particulate matter, weather, seasonality, and long-term trends.

Conclusions

These results indicate a statistically significant association between short-term changes in ozone and mortality on average for 95 large US urban communities, which include about 40% of the total US population. The findings indicate that this widespread pollutant adversely affects public health.

Context

Evidence on the health risks associated with short-term exposure to fine particles (particulate matter ≤2.5 μm in aerodynamic diameter [PM2.5]) is limited. Results from the new national monitoring network for PM2.5 make possible systematic research on health risks at national and regional scales.

Objectives

To estimate risks of cardiovascular and respiratory hospital admissions associated with short-term exposure to PM2.5 for Medicare enrollees and to explore heterogeneity of the variation of risks across regions.

Design, Setting, and Participants

A national database comprising daily time-series data daily for 1999 through 2002 on hospital admission rates (constructed from the Medicare National Claims History Files) for cardiovascular and respiratory outcomes and injuries, ambient PM2.5 levels, and temperature and dew-point temperature for 204 US urban counties (population >200 000) with 11.5 million Medicare enrollees (aged >65 years) living an average of 5.9 miles from a PM2.5 monitor.

Main Outcome Measures

Daily counts of county-wide hospital admissions for primary diagnosis of cerebrovascular, peripheral, and ischemic heart diseases, heart rhythm, heart failure, chronic obstructive pulmonary disease, and respiratory infection, and injuries as a control outcome.

Results

There was a short-term increase in hospital admission rates associated with PM2.5 for all of the health outcomes except injuries. The largest association was for heart failure, which had a 1.28% (95% confidence interval, 0.78%–1.78%) increase in risk per 10-μg/m3 increase in same-day PM2.5. Cardiovascular risks tended to be higher in counties located in the Eastern region of the United States, which included the Northeast, the Southeast, the Midwest, and the South.

Conclusion

Short-term exposure to PM2.5 increases the risk for hospital admission for cardiovascular and respiratory diseases.

Aims

A potential role for cardiovascular disease (CVD) risk factors in the aetiology of suicide has not been comprehensively examined. In addition to being small in scale and poorly characterized, existing studies very rarely sample Asian populations in whom risk factor–suicide relationships may plausibly differ to Caucasian groups. We examined the association between a series of CVD risk factors and future mortality from suicide.

Methods and results

The Korean Cancer Prevention Study is a prospective cohort study comprising 1 234 927 individuals (445 022 women) aged 30–95 years with extensive measurement of established CVD risk factors at baseline and subsequent mortality surveillance. Fourteen years of follow-up gave rise to 472 deaths (389 in men and 83 in women) from suicide. After adjustment for a range of covariates, in men, smoking hazard ratio; 95% CI: (current vs. never: 1.69; 1.27, 2.24), alcohol intake (1–24 g/day vs. none: 1.29; 1.00, 1.66), blood cholesterol (≥240 vs. <200 mg/dL: 0.54; 0.36, 0.80), body mass index (underweight vs. normal weight: 2.08; 1.26, 3.45), stature [quartile 1(lowest) vs. 4: 1.68; 1.23, 2.30], socioeconomic status [quartile 1(lowest) vs. 4: 1.65; 1.21, 2.24], and martial status (unmarried vs. other: 1.60; 0.83, 3.06) were related to suicide mortality risk. These associations were generally apparent in women, although of lower magnitude. Exercise and blood pressure were not associated with completed suicide.

Conclusion

In this cohort of Korean men and women, a series of CVD risk factors were associated with an elevated risk of future suicide mortality.

Epidemiologic evidence provides some support for a causal association between maternal secondhand smoke (SHS) exposure during pregnancy and reduction in infant birth weight. The purpose of this cross-sectional study is to examine the magnitude of this association in China, where both prevalence and dose of SHS exposure are thought to be higher than in U.S. populations. Women who gave birth in Beijing and Changchun September 2000–November 2001 were interviewed to quantify self-reported prenatal SHS exposure. Their medical records were reviewed for data on pregnancy complications and birth outcomes. Non-smoking women who delivered term babies (≥37 weeks gestation) were included in the study (N = 2,770). Nearly a quarter of the women (24%) reported daily SHS exposure, 47% reported no prenatal exposure, and 75% denied any SHS exposure from the husband smoking at home. Overall, no deficit in mean birth weight was observed with exposure from all sources of SHS combined (+11 grams, 95% CI: +2, +21). Infants had higher mean birth weights among the exposed than the unexposed for all measures of SHS exposure. Future studies on SHS exposure and infant birth weight in China should emphasize more objective measures of exposure to quantify and account for any exposure misclassification.

Background

Exposure to particulate matter (PM) is a significant risk factor for increased cardiopulmonary morbidity and mortality. The mechanism of PM-mediated pathophysiology remains unknown. However, PM is proinflammatory to the endothelium and increases vascular permeability in vitro and in vivo via ROS generation.

Objectives

We explored the role of tight junction proteins as targets for PM-induced loss of lung endothelial cell (EC) barrier integrity and enhanced cardiopulmonary dysfunction.

Methods

Changes in human lung EC monolayer permeability were assessed by Transendothelial Electrical Resistance (TER) in response to PM challenge (collected from Ft. McHenry Tunnel, Baltimore, MD, particle size >0.1 μm). Biochemical assessment of ROS generation and Ca2+ mobilization were also measured.

Results

PM exposure induced tight junction protein Zona occludens-1 (ZO-1) relocation from the cell periphery, which was accompanied by significant reductions in ZO-1 protein levels but not in adherens junction proteins (VE-cadherin and β-catenin). N-acetyl-cysteine (NAC, 5 mM) reduced PM-induced ROS generation in ECs, which further prevented TER decreases and atteneuated ZO-1 degradation. PM also mediated intracellular calcium mobilization via the transient receptor potential cation channel M2 (TRPM2), in a ROS-dependent manner with subsequent activation of the Ca2+-dependent protease calpain. PM-activated calpain is responsible for ZO-1 degradation and EC barrier disruption. Overexpression of ZO-1 attenuated PM-induced endothelial barrier disruption and vascular hyperpermeability in vivo and in vitro.

Conclusions

These results demonstrate that PM induces marked increases in vascular permeability via ROS-mediated calcium leakage via activated TRPM2, and via ZO-1 degradation by activated calpain. These findings support a novel mechanism for PM-induced lung damage and adverse cardiovascular outcomes.

Recent air pollutant measurement data document unique aspects of the air pollution mixture near roadways, and an expanding body of epidemiological data suggests increased risks for exacerbation of asthma and other respiratory diseases, premature mortality, and certain cancers and birth outcomes from air pollution exposures in populations residing in relatively close proximity to roadways. The Workshop on Traffic, Health, and Infrastructure Planning, held in February 2004, was convened to provide a forum for interdisciplinary discussion of motor vehicle emissions, exposures and potential health effects related to proximity to motor vehicle traffic. This report summarizes the workshop discussions and findings regarding the current science on this issue, identifies planning and policy issues related to localized motor vehicle emissions and health concerns, and provides recommendations for future research and policy directions.

Purpose

To further clarify the relationship between total cholesterol and cancer, which remains unclear.

Methods

We prospectively examined the association between total cholesterol and site-specific and all-cancer incidence among 1,189,719 Korean adults enrolled in the National Health Insurance Corporation who underwent a standardized biennial medical examination in 1992 to 1995 and were observed for 14 years until cancer diagnosis or death.

Results

Over follow-up, 53,944 men and 24,475 women were diagnosed with a primary cancer. Compared with levels less than 160 mg/dL, high total cholesterol (≥ 240 mg/dL) was positively associated with prostate cancer (hazard ratio [HR], 1.24; 95% CI, 1.07 to 1.44; P trend = .001) and colon cancer (HR, 1.12; 95% CI, 1.00 to 1.25; P trend = .05) in men and breast cancer in women (HR, 1.17; 95% CI, 1.03 to 1.33; P trend = .03). Higher total cholesterol was associated with a lower incidence of liver cancer (men: HR, 0.42; 95% CI, 0.38 to 0.45; P trend < .001; women: HR, 0.32; 95% CI, 0.27 to 0.39; P trend < .001), stomach cancer (men: HR, 0.87; 95% CI, 0.82 to 0.93; P trend ≤ .001; women: HR, 0.86; 95% CI, 0.77 to 0.97; P trend = .06), and, in men, lung cancer (HR, 0.89; 95% CI, 0.82 to 0.96; P trend < .001). Results for liver cancer were slightly attenuated after additional adjustment for liver enzyme levels and hepatitis B surface antigen status (men: HR, 0.60; P trend < .001; women: HR, 0.46; P trend = .003) and exclusion of the first 10 years of follow-up (men: HR, 0.59; P trend < .001; women: HR, 0.44; P trend < .001). Total cholesterol was inversely associated with all-cancer incidence in both men (HR, 0.84; 95% CI, 0.81 to 0.86; P trend < .001) and women (HR, 0.91; 95% CI, 0.87 to 0.95; P trend < .001), but these associations were attenuated after excluding incident liver cancers (men: HR, 0.95; P trend < .001; women: HR, 0.98; P trend = .32).

Conclusion

In this large prospective study, we found that total cholesterol was associated with the risk of several different cancers, although these relationships differed markedly by cancer site.

OBJECTIVE

Mounting evidence suggests that smoking is a cause of type 2 diabetes. We explored the association of cigarette smoking with diabetes incidence and mortality in a large cohort of Koreans.

RESEARCH DESIGN AND METHODS

A 14-year prospective cohort study was performed on 1,236,443 Korean men and women, aged 30–95 years at baseline, who underwent standardized biennial medical examinations provided by the National Health Insurance Corporation (NHIC). Incident diabetes was identified on the basis of outpatient visits, hospitalization, or prescription medication treatment for diabetes, as captured in the NHIC database. Diabetes mortality was obtained through the national statistical office. Cox proportional hazards models were used to investigate associations of smoking with indicators of diabetes and diabetes mortality.

RESULTS

Smoking was significantly associated with increased risk for diabetic outpatient treatment, hospitalization, and mortality among both men and women, and the risk among current smokers increased modestly with the number of cigarettes smoked daily (Ptrend < 0.0001 for all associations). Compared with never smokers, current male smokers who smoked ≥20 cigarettes/day had increased risk for incident diabetes defined by outpatient treatment (adjusted hazard ratio 1.55 [1.51–1.60]), incident diabetes defined by ≥3 prescription medications for diabetes (1.71 [1.63–1.80]), and death from diabetes (1.60 [1.25–2.06]). The risks for outpatient treatment among smokers were higher in men than in women with evidence for effect modification by sex and age (Pinteraction < 0.0001).

CONCLUSIONS

Our study provides longitudinal evidence that smoking increases the risk of incident diabetes and mortality.

More than 161,000 lung cancer deaths are projected to occur in the U.S. in 2008. Of these, an estimated 10–15% will be caused by factors other than active smoking, corresponding to 16,000–24,000 deaths annually. Thus lung cancer in never smokers would rank among the most common causes of cancer mortality in the U.S. if considered to be a separate category. Slightly more than half of the lung cancers caused by factors other than active smoking occur in never smokers. As summarized in the accompanying article, lung cancers that occur in never smokers differ from those that occur in smokers in their molecular profile and response to targeted therapy. These recent laboratory and clinical observations highlight the importance of defining the genetic and environmental factors responsible for the development of lung cancer in never-smokers. This article summarizes available data on the clinical epidemiology of lung cancer in never smokers, and the several environmental risk factors that population-based research has implicated in the etiology of these cancers. Primary factors closely tied to lung cancer in never smokers include exposure to known and suspected carcinogens including radon, second-hand tobacco smoke, and other indoor air pollutants. Several other exposures have been implicated. However, a large fraction of lung cancers occurring in never-smokers cannot be definitively associated with established environmental risk factors, highlighting the need for additional epidemiologic research in this area.

Context

Health risks of fine particulate matter of 2.5 µm or less in aerodynamic diameter (PM2.5) have been studied extensively over the last decade. Evidence concerning the health risks of the coarse fraction of greater than 2.5 µm and 10 µm or less in aerodynamic diameter (PM10-2.5) is limited.

Objective

To estimate risk of hospital admissions for cardiovascular and respiratory diseases associated with PM10-2.5 exposure, controlling for PM2.5.

Design, Setting, and Participants

Using a database assembled for 108 US counties with daily cardiovascular and respiratory disease admission rates, temperature and dew-point temperature, and PM10-2.5 and PM2.5 concentrations were calculated with monitoring data as an exposure surrogate from January 1, 1999, through December 31, 2005. Admission rates were constructed from the Medicare National Claims History Files, for a study population of approximately 12 million Medicare enrollees living on average 9 miles (14.4 km) from collocated pairs of PM10 and PM2.5 monitors.

Main Outcome Measures

Daily counts of county-wide emergency hospital admissions for primary diagnoses of cardiovascular or respiratory disease.

Results

There were 3.7 million cardiovascular disease and 1.4 million respiratory disease admissions. A 10-µg/m3 increase in PM10-2.5 was associated with a 0.36% (95% posterior interval [PI], 0.05% to 0.68%) increase in cardiovascular disease admissions on the same day. However, when adjusted for PM2.5, the association was no longer statistically significant (0.25%; 95% PI, −0.11% to 0.60%). A 10-µg/m3 increase in PM10-2.5 was associated with a nonstatistically significant unadjusted 0.33% (95% PI, −0.21% to 0.86%) increase in respiratory disease admissions and with a 0.26% (95% PI, −0.32% to 0.84%) increase in respiratory disease admissions when adjusted for PM2.5. The unadjusted associations of PM2.5 with cardiovascular and respiratory disease admissions were 0.71% (95% PI, 0.45%–0.96%) for same-day exposure and 0.44% (95% PI, 0.06% to 0.82%) for exposure 2 days before hospital admission.

Conclusion

After adjustment for PM2.5, there were no statistically significant associations between coarse particulates and hospital admissions for cardiovascular and respiratory diseases.

This paper provides a perspective on epidemiological research on radiation and cancer, a field that has evolved over its six decade history. The review covers the current framework for assessing radiation risk and persistent questions about the details of these risks: is there a threshold and more generally, what is the shape of the dose-response relationship? How do risks vary over time and with age? What factors modify the risk of radiation? The example of radon progeny and lung cancer is considered as a case study, illustrating the modeling of epidemiological data to derive quantitative models and the coherence of the epidemiological and biological evidence. Finally, the manuscript considers the need for ongoing research, even in the face of research over a 60-year span.

In this introduction to volume 32 of Epidemiologic Reviews, the authors highlight the diversity and complexity of global health concerns, and they frame the 12 articles included in this issue within the diverse topics of research in this emerging and ever-expanding field. The authors emphasize the need for ongoing research related to the methods used in global health and for comprehensive surveillance, and they offer suggestions for future directions in global health research.

Epidemiologic studies have linked exposure to airborne pollutant particulate matter (PM) with increased cardiopulmonary mortality and morbidity. The mechanisms of PM-mediated lung pathophysiology, however, remain unknown. We tested the hypothesis that PM, via enhanced oxidative stress, disrupts lung endothelial cell (EC) barrier integrity, thereby enhancing organ dysfunction. Using PM collected from Ft. McHenry Tunnel (Baltimore, MD), we assessed PM-mediated changes in transendothelial electrical resistance (TER) (a highly sensitive measure of barrier function), reactive oxygen species (ROS) generation, and p38 mitogen-activated protein kinase (MAPK) activation in human pulmonary artery EC. PM induced significant dose (10–100 μg/ml)- and time (0–10 h)-dependent EC barrier disruption reflected by reduced TER values. Exposure of human lung EC to PM resulted in significant ROS generation, which was directly involved in PM-mediated EC barrier dysfunction, as N-acetyl-cysteine (NAC, 5 mM) pretreatment abolished both ROS production and barrier disruption induced by PM. Furthermore, PM induced p38 MAPK activation and HSP27 phosphorylation, events that were both attenuated by NAC. In addition, PM-induced EC barrier disruption was partially prevented by the p38 MAP kinase inhibitor SB203580 (10 μM) as well as by reduced expression of either p38 MAPK β or HSP27 (siRNA). These results demonstrate that PM induces ROS generation in human lung endothelium, resulting in oxidative stress–mediated EC barrier disruption via p38 MAPK- and HSP27-dependent pathways. These findings support a novel mechanism for PM-induced lung dysfunction and adverse cardiopulmonary outcomes.

The authors explored the association of cigarette smoking with tuberculosis incidence, recurrence, and mortality. A 14-year prospective cohort study (1992–2006) was carried out in 1,294,504 South Koreans. Participants were grouped by smoking history, and the authors assessed tuberculosis incidence, mortality, and recurrence risk for each group. Unadjusted and adjusted Cox proportional hazards models were used to investigate the association between smoking history and the 3 outcomes of interest, adjusting for age and alcohol use. Compared with never smokers, current smokers had increased mortality from tuberculosis among both men (adjusted hazard ratio (HR) = 1.6, 95% confidence interval (CI): 1.3, 2.0) and women (HR = 1.6, 95% CI: 1.0, 2.4). Current male smokers had greater risk of incident tuberculosis than former smokers (HR = 1.4, 95% CI: 1.3, 1.5), and risk among current smokers increased with number of cigarettes smoked daily. In females, cigarette smoking was not associated with incident tuberculosis. There was interaction between smoking and sex for incidence (P = 0.00047). The effect of smoking was generally reduced with adjustment for body mass index. Among men, the highest alcohol consumption category (≥100 g/day) was associated with risk of incident tuberculosis (HR = 1.5, 95% CI: 1.3, 1.7). This study provides longitudinal evidence that smoking increases risk of incident tuberculosis, mortality from tuberculosis, and tuberculosis recurrence.

The majority of lung cancers are caused by long term exposure to the several classes of carcinogens present in tobacco smoke. While a significant fraction of lung cancers in never smokers may also be attributable to tobacco, many such cancers arise in the absence of detectable tobacco exposure, and may follow a very different cellular and molecular pathway of malignant transformation. Recent studies summarized here suggest that lung cancers arising in never smokers have a distinct natural history, profile of oncogenic mutations, and response to targeted therapy. The majority of molecular analyses of lung cancer have focused on genetic profiling of pathways responsible for metabolism of primary tobacco carcinogens. Limited research has been conducted evaluating familial aggregation and genetic linkage of lung cancer, particularly among never smokers in whom such associations might be expected to be strongest. Data emerging over the past several years demonstrates that lung cancers in never smokers are much more likely to carry activating mutations of the Epidermal Growth Factor Receptor (EGFR), a key oncogenic factor and direct therapeutic target of several newer anti-cancer drugs. EGFR mutant lung cancers may represent a distinct class of lung cancers, enriched in the never smoking population, and less clearly linked to direct tobacco carcinogenesis. These insights followed initial testing and demonstration of efficacy of EGFR-targeted drugs. Focused analysis of molecular carcinogenesis in lung cancers in never smokers is needed, and may provide additional biologic insight with therapeutic implications for lung cancers in both ever smokers and never smokers.

Background

Evidence on risk of cardiovascular (CVD) hospitalization associated with short-term exposure to outdoor carbon monoxide (CO), an air pollutant primarily generated by traffic, is inconsistent across studies. Uncertainties remain regarding the degree to which associations are attributable to other traffic pollutants and whether effects persist at low levels.

Methods and Results

We conducted a multi-site time-series study to estimate risk of CVD hospitalization associated with short-term CO exposure in 126 U.S. urban counties from 1999–2005 for >9.3 million Medicare enrollees ≥65 years of age. We considered models with adjustment by other traffic-related pollutants: nitrogen dioxide (NO2), fine particles (PM2.5), and Elemental Carbon (EC).

We found a positive and statistically significant association between same day (L0) CO and increased risk of hospitalization for multiple CVD outcomes (ischemic heart disease, heart rhythm disturbances, heart failure, cerebrovascular disease, total CVD). The association remained positive and statistically significant, but was attenuated, with co-pollutant adjustment, especially NO2. A one part per million (ppm) increase in L0 daily 1-hour maximum CO was associated with a 0.96% (95% posterior interval 0.79, 1.12%) increase in risk of CVD admissions. With L0 NO2 adjustment, this estimate is 0.55% (0.36, 0.74%). The risk persisted at low CO levels <1 ppm.

Conclusions

We found evidence of an association between short-term exposure to ambient CO and risk of CVD hospitalizations, even at levels well below current U.S. health-based regulatory standards. This evidence indicates that exposure to current CO levels may still pose a public health threat, particularly for persons with CVD.

Rationale: There are unexplained geographical and seasonal differences in the short-term effects of fine particulate matter (PM2.5) on human health. The hypothesis has been advanced to include the possibility that such differences might be due to variations in the PM2.5 chemical composition, but evidence supporting this hypothesis is lacking.

Objectives: To examine whether variation in the relative risks (RR) of hospitalization associated with ambient exposure to PM2.5 total mass reflects differences in PM2.5 chemical composition.

Methods: We linked two national datasets by county and by season: (1) long-term average concentrations of PM2.5 chemical components for 2000–2005 and (2) RRs of cardiovascular and respiratory hospitalizations for persons 65 years or older associated with a 10-μg/m3 increase in PM2.5 total mass on the same day for 106 U.S. counties for 1999 through 2005.

Measurements and Main Results: We found a positive and statistically significant association between county-specific estimates of the short-term effects of PM2.5 on cardiovascular and respiratory hospitalizations and county-specific levels of vanadium, elemental carbon, or nickel PM2.5 content.

Conclusions: Communities with higher PM2.5 content of nickel, vanadium, and elemental carbon and/or their related sources were found to have higher risk of hospitalizations associated with short-term exposure to PM2.5.

The authors investigated whether short-term effects of fine particulate matter with an aerodynamic diameter ≤2.5 μm (PM2.5) on risk of cardiovascular and respiratory hospitalizations among the elderly varied by region and season in 202 US counties for 1999–2005. They fit 3 types of time-series models to provide evidence for 1) consistent particulate matter effects across the year, 2) different particulate matter effects by season, and 3) smoothly varying particulate matter effects throughout the year. The authors found statistically significant evidence of seasonal and regional variation in estimates of particulate matter effect. Respiratory disease effect estimates were highest in winter, with a 1.05% (95% posterior interval: 0.29, 1.82) increase in hospitalizations per 10-μg/m3 increase in same-day PM2.5. Cardiovascular diseases estimates were also highest in winter, with a 1.49% (95% confidence interval: 1.09, 1.89) increase in hospitalizations per 10-μg/m3 increase in same-day PM2.5, with associations also observed in other seasons. The strongest evidence of a relation between PM2.5 and hospitalizations was in the Northeast for both respiratory and cardiovascular diseases. Heterogeneity of PM2.5 effects on hospitalizations may reflect seasonal and regional differences in emissions and in particles’ chemical constituents. Results can help guide development of hypotheses and further epidemiologic studies on potential heterogeneity in the toxicity of constituents of the particulate matter mixture.

In a cohort of 6,441 volunteers followed over an average of 8.2 years, Naresh Punjabi and colleagues find sleep-disordered breathing to be independently associated with mortality and identify predictive characteristics.

Background

Sleep-disordered breathing is a common condition associated with adverse health outcomes including hypertension and cardiovascular disease. The overall objective of this study was to determine whether sleep-disordered breathing and its sequelae of intermittent hypoxemia and recurrent arousals are associated with mortality in a community sample of adults aged 40 years or older.

Methods and Findings

We prospectively examined whether sleep-disordered breathing was associated with an increased risk of death from any cause in 6,441 men and women participating in the Sleep Heart Health Study. Sleep-disordered breathing was assessed with the apnea–hypopnea index (AHI) based on an in-home polysomnogram. Survival analysis and proportional hazards regression models were used to calculate hazard ratios for mortality after adjusting for age, sex, race, smoking status, body mass index, and prevalent medical conditions. The average follow-up period for the cohort was 8.2 y during which 1,047 participants (587 men and 460 women) died. Compared to those without sleep-disordered breathing (AHI: <5 events/h), the fully adjusted hazard ratios for all-cause mortality in those with mild (AHI: 5.0–14.9 events/h), moderate (AHI: 15.0–29.9 events/h), and severe (AHI: ≥30.0 events/h) sleep-disordered breathing were 0.93 (95% CI: 0.80–1.08), 1.17 (95% CI: 0.97–1.42), and 1.46 (95% CI: 1.14–1.86), respectively. Stratified analyses by sex and age showed that the increased risk of death associated with severe sleep-disordered breathing was statistically significant in men aged 40–70 y (hazard ratio: 2.09; 95% CI: 1.31–3.33). Measures of sleep-related intermittent hypoxemia, but not sleep fragmentation, were independently associated with all-cause mortality. Coronary artery disease–related mortality associated with sleep-disordered breathing showed a pattern of association similar to all-cause mortality.

Conclusions

Sleep-disordered breathing is associated with all-cause mortality and specifically that due to coronary artery disease, particularly in men aged 40–70 y with severe sleep-disordered breathing.

Please see later in the article for the Editors' Summary

Editors' Summary

Background

About 1 in 10 women and 1 in 4 men have a chronic condition called sleep-disordered breathing although most are unaware of their problem. Sleep-disordered breathing, which is commonest in middle-aged and elderly people, is characterized by numerous, brief (10 second or so) interruptions of breathing during sleep. These interruptions, which usually occur when relaxation of the upper airway muscles decreases airflow, lower the level of oxygen in the blood and, as a result, affected individuals are frequently aroused from deep sleep as they struggle to breathe. Symptoms of sleep-disordered breathing include loud snoring and daytime sleepiness. Treatments include lifestyle changes such as losing weight (excess fat around the neck increases airway collapse) and smoking cessation. Affected people can also use special devices to prevent them sleeping on their backs, but for severe sleep-disordered breathing, doctors often recommend continuous positive airway pressure (CPAP), a machine that pressurizes the upper airway through a face mask to keep it open.

Why Was This Study Done?

Sleep-disordered breathing is a serious condition. It is associated with several adverse health conditions including coronary artery disease (narrowing of the blood vessels that supply the heart, a condition that can cause a heart attack) and daytime sleepiness that can affect an individual's driving ability. In addition, several clinic- and community-based studies suggest that sleep-disordered sleeping may increase a person's risk of dying. However, because these studies have been small and have often failed to allow for other conditions and characteristics that affect an individual's risk of dying (“confounding factors”), they provide inconsistent or incomplete information about the potential association between sleep-disordered breathing and the risk of death. In this prospective cohort study (part of the Sleep Heart Health Study, which is researching the effects of sleep-disordered breathing on cardiovascular health), the researchers examine whether sleep-disordered breathing is associated with all-cause mortality (death from any cause) in a large community sample of adults. A prospective cohort study is one in which a group of participants is enrolled and then followed forward in time (in this case for several years) to see what happens to them.

What Did the Researchers Do and Find?

At enrollment, the study participants—more than 6,000 people aged 40 years or older, none of whom were being treated for sleep-disordered breathing—had a health examination. Their night-time breathing, sleep patterns, and blood oxygen levels were also assessed and these data used to calculate each participant's apnea-hypopnea index (AHI)—the number of apneas and hypopneas per hour. During the study follow-up period, 1,047 participants died. Compared to participants without sleep-disordered sleeping, participants with severe sleep-disordered breathing (an AHI of ≥30) were about one and a half times as likely to die from any cause after adjustment for potential confounding factors. People with milder sleep-disordered breathing did not have a statistically significant increased risk of dying. After dividing the participants into subgroups according to their age and sex, men aged 40–70 years with severe sleep-disordered breathing had a statistically increased risk of dying from any cause (twice the risk of men of a similar age without sleep-disordered breathing). Finally, death from coronary artery disease was also associated with sleep-disordered breathing in men but not in women.

What Do These Findings Mean?

These findings indicate that sleep-disordered breathing is associated with an increased risk of all-cause mortality, particularly in men aged 40–70 years, even after allowing for known confounding factors. They also suggest that the increased risk of death is specifically associated with coronary artery disease although further studies are needed to confirm this finding because it was based on the analysis of a small subgroup of study participants. Although this study is much larger than previous investigations into the association between sleep-disordered breathing and all-cause mortality, it has several limitations including its reliance on a single night's measurements for the diagnosis of sleep-disordered breathing. Nevertheless, these findings suggest that clinical trials should now be started to assess whether treatment can reduce the increased risk of death that seems to be associated with this common disorder.

Additional Information

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000132.

The US National Heart Lung and Blood Institute has information (including a video) about sleep-disordered breathing (sleep apnea) (in English and Spanish)

The UK National Heath Service also provides information for patients about sleep apnea

MedlinePlus provides links to further information and advice about sleep-disordered breathing (in English and Spanish)

More information on the Sleep Heart Health Study is available

Background

Population-based studies have estimated health risks of short-term exposure to fine particles using mass of PM2.5 (particulate matter ≤ 2.5 μm in aerodynamic diameter) as the indicator. Evidence regarding the toxicity of the chemical components of the PM2.5 mixture is limited.

Objective

In this study we investigated the association between hospital admission for cardiovascular disease (CVD) and respiratory disease and the chemical components of PM2.5 in the United States.

Methods

We used a national database comprising daily data for 2000–2006 on emergency hospital admissions for cardiovascular and respiratory outcomes, ambient levels of major PM2.5 chemical components [sulfate, nitrate, silicon, elemental carbon (EC), organic carbon matter (OCM), and sodium and ammonium ions], and weather. Using Bayesian hierarchical statistical models, we estimated the associations between daily levels of PM2.5 components and risk of hospital admissions in 119 U.S. urban communities for 12 million Medicare enrollees (≥ 65 years of age).

Results

In multiple-pollutant models that adjust for the levels of other pollutants, an interquartile range (IQR) increase in EC was associated with a 0.80% [95% posterior interval (PI), 0.34–1.27%] increase in risk of same-day cardiovascular admissions, and an IQR increase in OCM was associated with a 1.01% (95% PI, 0.04–1.98%) increase in risk of respiratory admissions on the same day. Other components were not associated with cardiovascular or respiratory hospital admissions in multiple-pollutant models.

Conclusions

Ambient levels of EC and OCM, which are generated primarily from vehicle emissions, diesel, and wood burning, were associated with the largest risks of emergency hospitalization across the major chemical constituents of PM2.5.

Low-dose extrapolation model selection for evaluating the health effects of environmental pollutants is a key component of the risk assessment process. At a workshop held in Baltimore, Maryland, on 23–24 April 2007, sponsored by U.S. Environmental Protection Agency and Johns Hopkins Risk Sciences and Public Policy Institute, a multidisciplinary group of experts reviewed the state of the science regarding low-dose extrapolation modeling and its application in environmental health risk assessments. Participants identified discussion topics based on a literature review, which included examples for which human responses to ambient exposures have been extensively characterized for cancer and/or noncancer outcomes. Topics included the need for formalized approaches and criteria to assess the evidence for mode of action (MOA), the use of human versus animal data, the use of MOA information in biologically based models, and the implications of interindividual variability, background disease processes, and background exposures in threshold versus nonthreshold model choice. Participants recommended approaches that differ from current practice for extrapolating high-dose animal data to low-dose human exposures, including categorical approaches for integrating information on MOA, statistical approaches such as model averaging, and inference-based models that explicitly consider uncertainty and interindividual variability.

Background

Environmental air pollutants are inhaled as complex mixtures, but the long dominant focus of monitoring and research on individual pollutants has provided modest insight into pollutant interactions that may be important to health. Trends toward managing multiple pollutants to maximize aggregate health gains place increasing value on knowing whether the effects of combinations of pollutants are greater than the sum of the effects of individual pollutants (synergy).

Objective

We reviewed selected published literature to determine whether synergistic effects of combinations of pollutants on health outcomes have actually been demonstrated.

Methods and results

We reviewed 36 laboratory studies of combinations of ozone with other pollutants that were reported in the recent U.S. Environmental Protection Agency Ozone Criteria Document. We examined original reports to determine whether the experimental design tested for synergy and whether synergy was demonstrated. Fourteen studies demonstrated synergism, although synergistic, additive, and antagonistic effects were sometimes observed among different outcomes or at different times after exposure.

Conclusions

Synergisms involving O3 have been demonstrated by laboratory studies of humans and animals. We conclude that the plausibility of synergisms among environmental pollutants has been established, although comparisons are limited, and most involved exposure concentrations much higher than typical of environmental pollutants. Epidemiologic research has limited ability to address the issue explicitly.