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1.  Living Near Major Traffic Roads and Risk of Deep Vein Thrombosis 
Circulation  2009;119(24):3118-3124.
Particulate air pollution has been consistently linked to increased risk of arterial cardiovascular disease. Few data on air pollution exposure and risk of venous thrombosis are available. We investigated whether living near major traffic roads increases the risk of deep vein thrombosis (DVT), using distance from roads as a proxy for traffic exposure.
Methods and Results
Between 1995-2005, we examined 663 patients with DVT of the lower limbs and 859 age-matched controls from cities with population>15,000 inhabitants in Lombardia Region, Italy. We assessed distance from residential addresses to the nearest major traffic road using geographic information system methodology. The risk of DVT was estimated from logistic regression models adjusting for multiple clinical and environmental covariates.
The risk of DVT was increased (Odds Ratio [OR]=1.33; 95% CI 1.03-1.71; p=0.03 in age-adjusted models; OR=1.47; 95%CI 1.10-1.96; p=0.008 in models adjusted for multiple covariates) for subjects living near a major traffic road (3 meters, 10th centile of the distance distribution) compared to those living farther away (reference distance of 245 meters, 90th centile). The increase in DVT risk was approximately linear over the observed distance range (from 718 to 0 meters), and was not modified after adjusting for background levels of particulate matter (OR=1.47; 95%CI 1.11-1.96; p=0.008 for 10th vs. 90th distance centile in models adjusting for area levels of particulate matter <10 μm in aerodynamic diameter [PM10] in the year before diagnosis).
Living near major traffic roads is associated with increased risk of DVT.
PMCID: PMC2895730  PMID: 19506111
Deep vein thrombosis; air pollution; risk factors; coagulation
2.  The Absolute Risk of Venous Thrombosis after Air Travel: A Cohort Study of 8,755 Employees of International Organisations 
PLoS Medicine  2007;4(9):e290.
The risk of venous thrombosis is approximately 2- to 4-fold increased after air travel, but the absolute risk is unknown. The objective of this study was to assess the absolute risk of venous thrombosis after air travel.
Methods and Findings
We conducted a cohort study among employees of large international companies and organisations, who were followed between 1 January 2000 and 31 December 2005. The occurrence of symptomatic venous thrombosis was linked to exposure to air travel, as assessed by travel records provided by the companies and organisations. A long-haul flight was defined as a flight of at least 4 h and participants were considered exposed for a postflight period of 8 wk. A total of 8,755 employees were followed during a total follow-up time of 38,910 person-years (PY). The total time employees were exposed to a long-haul flight was 6,872 PY. In the follow-up period, 53 thromboses occurred, 22 of which within 8 wk of a long-haul flight, yielding an incidence rate of 3.2/1,000 PY, as compared to 1.0/1,000 PY in individuals not exposed to air travel (incidence rate ratio 3.2, 95% confidence interval 1.8–5.6). This rate was equivalent to a risk of one event per 4,656 long-haul flights. The risk increased with exposure to more flights within a short time frame and with increasing duration of flights. The incidence was highest in the first 2 wk after travel and gradually decreased to baseline after 8 wk. The risk was particularly high in employees under age 30 y, women who used oral contraceptives, and individuals who were particularly short, tall, or overweight.
The risk of symptomatic venous thrombosis after air travel is moderately increased on average, and rises with increasing exposure and in high-risk groups.
In a cohort study of 8,755 employees of large international organizations followed for 38,910 person-years, Suzanne Cannegieter and colleagues find a risk of one thrombosis per 4,656 long-haul flights.
Editors' Summary
Blood normally flows smoothly throughout the human body, supplying the brain and other vital organs with oxygen and nutrients. When an injury occurs, proteins called clotting factors make the blood gel or coagulate at the injury site. The resultant blood clot (thrombus) plugs the wound and prevents blood loss. Sometimes, however, a thrombus forms inside an uninjured blood vessel and partly or completely blocks the blood flow. A clot inside one of the veins (vessels that take blood to the heart) deep within the body is called a deep vein thrombosis (DVT). Symptoms of DVT (which usually occurs in the deep veins of the leg) include pain, swelling, and redness in one leg. DVT is usually treated with heparin and warfarin, two anticoagulant drugs that stop the blood clot growing. If left untreated, part of the clot (an embolus) can break off and travel to the lungs, where it can cause a life-threatening condition called pulmonary embolism (PE). Fortunately, DVT and PE are rare but having an inherited blood clotting disorder, taking an oral contraceptive, and some types of surgery are all risk factors for them. In addition, long-haul plane travel increases the risk of DVT and PE, known collectively as venous thrombosis (VT) 2- to 4-fold, in part because the enforced immobilization during flights slows down blood flow.
Why Was This Study Done?
Although the link between air travel and VT was first noticed in the 1950s, exactly how many people will develop DVT and PE (the absolute risk of developing VT) after a long flight remains unknown. This information is needed so that travelers can be given advice about their actual risk and can make informed decisions about trying to reduce that risk by, for example, taking small doses of anticoagulant medicine before a flight. In this study, the researchers have determined the absolute risk of VT during and after long-haul air travel in a large group of business travelers.
What Did the Researchers Do and Find?
The researchers enrolled almost 9,000 employees from several international companies and organizations and followed them for an average of 4.4 years. The details of flights taken by each employee were obtained from company records, and employees completed a Web-based questionnaire about whether they had developed VT and what risk factors they had for the condition. Out of 53 thrombi that occurred during the study, 22 occurred within eight weeks of a long-haul flight (a flight of more than four hours). From this and data on the total time employees spent on long-haul flights, the researchers calculated that these flights tripled the risk of developing VT, and that the absolute risk (the probability of something occurring in a certain time period) of a VT occurring shortly after such travel was one event per 4,656 flights. They also calculated that the risk of VT was increased by exposure to more flights during a short period and to longer flights and was greatest in the first two weeks after a flight. In addition, the risk of VT was particularly high in young employees, women taking oral contraceptives, and people who were short, tall or overweight.
What Do These Findings Mean?
The main finding of this study is that the absolute risk of VT after of a long-haul flight is low—only one passenger out of nearly 5,000 is likely to develop VT because of flying. However, the study included only healthy people without previous VT whose average age was 40 years, so the absolute risk of VT after long-haul flights might be higher in the general traveling population. Even so, this finding strongly suggests that prophylactic (preventative) use of anticoagulants by all long-haul travelers may not be justified because these drugs have potentially dangerous side effects (for example, they can cause uncontrolled bleeding). Subgroups of travelers with additional risk factors for VT might, however, benefit from the use of this and other prophylactic measures, but randomized trials are needed to find out who would benefit most from which prophylactic measure.
Additional Information.
Please access these Web sites via the online version of this summary at
MedlinePlus encyclopedia pages on blood clots, deep vein thrombosis, and pulmonary embolism (in English and Spanish)
Information from the US National Heart Lung and Blood Institute on deep vein thrombosis, including an animation of how DVT causes pulmonary embolisms
Information for patients from the UK National Health Service Direct health encyclopedia on deep vein thrombosis (in several languages)
Information for travelers on DVT from the US Centers for Disease Control and Prevention and from the UK National Travel Health Network and Centre
This study came out of the WHO Research Into Global Hazards of Travel (WRIGHT) project, and WHO's WRIGHT project on Air Travel and Venous Thromboembolism, of which his study forms a part, has a Web site
PMCID: PMC1989755  PMID: 17896862
3.  Air Pollution and the Microvasculature: A Cross-Sectional Assessment of In Vivo Retinal Images in the Population-Based Multi-Ethnic Study of Atherosclerosis (MESA) 
PLoS Medicine  2010;7(11):e1000372.
Sara Adar and colleagues show that residing in locations with higher air pollution concentrations and experiencing daily increases in air pollution are associated with narrower retinal arteriolar diameters in older individuals, thus providing a link between air pollution and cardiovascular disease.
Long- and short-term exposures to air pollution, especially fine particulate matter (PM2.5), have been linked to cardiovascular morbidity and mortality. One hypothesized mechanism for these associations involves microvascular effects. Retinal photography provides a novel, in vivo approach to examine the association of air pollution with changes in the human microvasculature.
Methods and Findings
Chronic and acute associations between residential air pollution concentrations and retinal vessel diameters, expressed as central retinal arteriolar equivalents (CRAE) and central retinal venular equivalents (CRVE), were examined using digital retinal images taken in Multi-Ethnic Study of Atherosclerosis (MESA) participants between 2002 and 2003. Study participants (46 to 87 years of age) were without clinical cardiovascular disease at the baseline examination (2000–2002). Long-term outdoor concentrations of PM2.5 were estimated at each participant's home for the 2 years preceding the clinical exam using a spatio-temporal model. Short-term concentrations were assigned using outdoor measurements on the day preceding the clinical exam. Residential proximity to roadways was also used as an indicator of long-term traffic exposures. All associations were examined using linear regression models adjusted for subject-specific age, sex, race/ethnicity, education, income, smoking status, alcohol use, physical activity, body mass index, family history of cardiovascular disease, diabetes status, serum cholesterol, glucose, blood pressure, emphysema, C-reactive protein, medication use, and fellow vessel diameter. Short-term associations were further controlled for weather and seasonality. Among the 4,607 participants with complete data, CRAE were found to be narrower among persons residing in regions with increased long- and short-term levels of PM2.5. These relationships were observed in a joint exposure model with −0.8 µm (95% confidence interval [CI] −1.1 to −0.5) and −0.4 µm (95% CI −0.8 to 0.1) decreases in CRAE per interquartile increases in long- (3 µg/m3) and short-term (9 µg/m3) PM2.5 levels, respectively. These reductions in CRAE are equivalent to 7- and 3-year increases in age in the same cohort. Similarly, living near a major road was also associated with a −0.7 µm decrease (95% CI −1.4 to 0.1) in CRAE. Although the chronic association with CRAE was largely influenced by differences in exposure between cities, this relationship was generally robust to control for city-level covariates and no significant differences were observed between cities. Wider CRVE were associated with living in areas of higher PM2.5 concentrations, but these findings were less robust and not supported by the presence of consistent acute associations with PM2.5.
Residing in regions with higher air pollution concentrations and experiencing daily increases in air pollution were each associated with narrower retinal arteriolar diameters in older individuals. These findings support the hypothesis that important vascular phenomena are associated with small increases in short-term or long-term air pollution exposures, even at current exposure levels, and further corroborate reported associations between air pollution and the development and exacerbation of clinical cardiovascular disease.
Please see later in the article for the Editors' Summary
Editors' Summary
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a common cause of illness and death among adults in developed countries. In the United States, for example, the leading cause of death is coronary heart disease, a CVD in which narrowing of the heart's arteries by atherosclerotic plaques (fatty deposits that build up with age) slows the blood supply to the heart and may eventually cause a heart attack (myocardial infarction). Other types of CVD include stroke (in which atherosclerotic plaques interrupt the brain's blood supply) and peripheral arterial disease (in which the blood supply to the limbs is blocked). Smoking, high blood pressure, high blood levels of cholesterol (a type of fat), having diabetes, being overweight, and being physically inactive all increase a person's risk of developing CVD. Treatments for CVD include lifestyle changes and taking drugs that lower blood pressure or blood cholesterol levels.
Why Was This Study Done?
Another risk factor for CVD is exposure to long-term and/or short-term air pollution. Fine particle pollution or PM2.5 is particularly strongly associated with an increased risk of CVD. PM2.5—particulate matter 2.5 µm in diameter or 1/30th the diameter of a human hair—is mainly produced by motor vehicles, power plants, and other combustion sources. Why PM2.5 increases CVD risk is not clear but one possibility is that it alters the body's microvasculature (fine blood vessels known as capillaries, arterioles, and venules), thereby impairing the blood flow through the heart and brain. In this study, the researchers use noninvasive digital retinal photography to investigate whether there is an association between air pollution and changes in the human microvasculature. The retina—a light-sensitive layer at the back of the eye that converts images into electrical messages and sends them to the brain—has a dense microvasculature. Retinal photography is used to check the retinal microvasculature for signs of potentially blinding eye diseases such as diabetic retinopathy. Previous studies have found that narrower than normal retinal arterioles and wider than normal retinal venules are associated with CVD.
What Did the Researchers Do and Find?
The researchers used digital retinal photography to measure the diameters of retinal blood vessels in the participants of the Multi-Ethnic Study of Atherosclerosis (MESA). This study is investigating CVD progression in people aged 45–84 years of various ethnic backgrounds who had no CVD symptoms when they enrolled in the study in 2000–2002. The researchers modeled the long-term outdoor concentration of PM2.5 at each participant's house for the 2-year period preceding the retinal examination (which was done between 2002 and 2003) using data on PM2.5 levels collected by regulatory monitoring stations as well as study-specific air samples collected outside of the homes and in the communities of study participants. Outdoor PM2.5 measurements taken the day before the examination provided short-term PM2.5 levels. Among the 4,607 MESA participants who had complete data, retinal arteriolar diameters were narrowed among those who lived in regions with increased long- and short-term PM2.5 levels. Specifically, an increase in long-term PM2.5 concentrations of 3 µg/m3 was associated with a 0.8 µm decrease in arteriolar diameter, a reduction equivalent to that seen for a 7-year increase in age in this group of people. Living near a major road, another indicator of long-term exposure to PM2.5 pollution, was also associated with narrowed arterioles. Finally, increased retinal venular diameters were weakly associated with long-term high PM2.5 concentrations.
What Do These Findings Mean?
These findings indicate that living in areas with long-term air pollution or being exposed to short-term air pollution is associated with narrowing of the retinal arterioles in older individuals. They also show that widening of retinal venules is associated with long-term (but not short-term) PM2.5 pollution. Together, these findings support the hypothesis that long- and short-term air pollution increases CVD risk through effects on the microvasculature. However, they do not prove that PM2.5 is the constituent of air pollution that drives microvascular changes—these findings could reflect the toxicity of another pollutant or the pollution mixture as a whole. Importantly, these findings show that microvascular changes can occur at the PM2.5 levels that commonly occur in developed countries, which are well below those seen in developing countries. Worryingly, they also suggest that the deleterious cardiovascular effects of air pollution could occur at levels below existing regulatory standards.
Additional Information
Please access these Web sites via the online version of this summary at 10.1371/journal.pmed.1000372.
The American Heart Association provides information for patients and caregivers on all aspects of cardiovascular disease (in several languages), including information on air pollution, heart disease, and stroke
The US Centers for Disease Control and Prevention has information on heart disease and on stroke
Information is available from the British Heart Foundation on cardiovascular disease
The UK National Health Service Choices website provides information for patients and caregivers about cardiovascular disease
MedlinePlus provides links to other sources of information on heart disease and on vascular disease (in English and Spanish)
The AIRNow site provides information about US air quality and about air pollution and health
The Air Quality Archive has up-to-date information about air pollution in the UK and information about the health effects of air pollution
The US Environmental Protection Agency has information on PM2.5
The following Web sites contain information available on the MESA and MESA Air studies
PMCID: PMC2994677  PMID: 21152417
4.  Traffic exposure and incident venous thromboembolism in the Atherosclerosis Risk in Communities (ARIC) Study 
Two recent case-control studies in Italy reported that long-term exposure to particulate air pollution or living near major traffic roads was associated with an increased risk of deep vein thrombosis (DVT). No prospective evidence exists about long-term traffic-related air pollution and incident venous thromboembolism (VTE).
To examine the association between long-term traffic exposure and incident VTE in a population-based prospective cohort study.
We studied 13,143 middle-aged men and women in the Atherosclerosis Risk in Communities Study without history of DVT or pulmonary embolus (PE) at baseline examination (1987-1989). Geographical Information System (GIS)-mapped traffic density and distance to major roads in the four study communities served as measures of traffic exposure. We examined the association between traffic exposure and incident VTE using proportional hazards regression models.
405 subjects developed VTE through 2005. Traffic density was not significantly associated with VTE. Relative to those in the lowest quartile of traffic density, the adjusted hazard ratios across increasing quartiles were 1.18 (95%CI 0.88-1.57), 0.99 (95%CI 0.74-1.34) and 1.14 (95%CI 0.86-1.51) (p for trend across quartiles = 0.64). For residents living within 150 meters of major roads compared to subjects living further away, the adjusted hazard ratio was 1.16 (95%CI 0.95-1.42, p=0.14).
This first prospective study in the general population does not support an association between air pollution exposure or traffic proximity and risk of DVT. More data may be needed to clarify whether traffic or air pollution influences the risk of VTE.
PMCID: PMC3071427  PMID: 21255249
traffic exposure; VTE; air pollution; cohort
5.  Long-Term Exposure to Air Pollution and Cardiorespiratory Disease in the California Teachers Study Cohort 
Rationale: Several studies have linked long-term exposure to particulate air pollution with increased cardiopulmonary mortality; only two have also examined incident circulatory disease.
Objectives: To examine associations of individualized long-term exposures to particulate and gaseous air pollution with incident myocardial infarction and stroke, as well as all-cause and cause-specific mortality.
Methods: We estimated long-term residential air pollution exposure for more than 100,000 participants in the California Teachers Study, a prospective cohort of female public school professionals. We linked geocoded residential addresses with inverse distance-weighted monthly pollutant surfaces for two measures of particulate matter and for several gaseous pollutants. We examined associations between exposure to these pollutants and risks of incident myocardial infarction and stroke, and of all-cause and cause-specific mortality, using Cox proportional hazards models.
Measurements and Main Results: We found elevated hazard ratios linking long-term exposure to particulate matter less than 2.5 μm in aerodynamic diameter (PM2.5), scaled to an increment of 10 μg/m3 with mortality from ischemic heart disease (IHD) (1.20; 95% confidence interval [CI], 1.02–1.41) and, particularly among postmenopausal women, incident stroke (1.19; 95% CI, 1.02–1.38). Long-term exposure to particulate matter less than 10 μm in aerodynamic diameter (PM10) was associated with elevated risks for IHD mortality (1.06; 95% CI, 0.99–1.14) and incident stroke (1.06; 95% CI, 1.00–1.13), while exposure to nitrogen oxides was associated with elevated risks for IHD and all cardiovascular mortality.
Conclusions: This study provides evidence linking long-term exposure to PM2.5 and PM10 with increased risks of incident stroke as well as IHD mortality; exposure to nitrogen oxides was also related to death from cardiovascular diseases.
PMCID: PMC3208653  PMID: 21700913
particulate matter; cardiovascular diseases; air pollutants; epidemiology
6.  Cardiorespiratory Biomarker Responses in Healthy Young Adults to Drastic Air Quality Changes Surrounding the 2008 Beijing Olympics 
Associations between air pollution and cardiorespiratory mortality and morbidity have been well established, but data to support biologic mechanisms underlying these associations are limited. We designed this study to examine several prominently hypothesized mechanisms by assessing Beijing residents’ biologic responses, at the biomarker level, to drastic changes in air quality brought about by unprecedented air pollution control measures implemented during the 2008 Beijing Olympics.
To test the hypothesis that changes in air pollution levels are associated with changes in biomarker levels reflecting inflammation, hemostasis, oxidative stress, and autonomic tone, we recruited and retained 125 nonsmoking adults (19 to 33 years old) free of cardiorespiratory and other chronic diseases. Using the combination of a quasi-experimental design and a panel-study approach, we measured biomarkers of autonomic dysfunction (heart rate [HR*] and heart rate variability [HRV]), of systemic inflammation and oxidative stress (plasma C-reactive protein [CRP], fibrinogen, blood cell counts and differentials, and urinary 8-hydroxy-2′-deoxyguanosine [8-OHdG]), of pulmonary inflammation and oxidative stress (fractional exhaled nitric oxide [FeNO], exhaled breath condensate [EBC] pH, EBC nitrate, EBC nitrite, EBC nitrite+nitrate [sum of the concentrations of nitrite and nitrate], and EBC 8-isoprostane), of hemostasis (platelet activation [plasma sCD62P and sCD40L], platelet aggregation, and von Willebrand factor [vWF]), and of blood pressure (systolic blood pressure [SBP] and diastolic blood pressure [DBP]). These biomarkers were measured on each subject twice before, twice during, and twice after the Beijing Olympics. For each subject, repeated measurements were separated by at least one week to avoid potential residual effects from a prior measurement. We measured a large suite of air pollutants (PM2.5 [particulate matter ≤ 2.5 μm in aerodynamic diameter] and constituents, sulfur dioxide [SO2], carbon monoxide [CO], nitrogen dioxide [NO2], and ozone [O3]) throughout the study at a central Beijing site near the residences and workplaces of the subjects on a daily basis. Total particle number (TPN) was also measured at a separate site. We used a time-series analysis to assess changes in pollutant concentration by period (pre-, during-, and post-Olympics periods). We used mixed-effects models to assess changes in biomarker levels by period and to estimate changes associated with increases in pollutant concentrations, controlling for ambient temperature, relative humidity (RH), sex, and the day of the week of the biomarker measurements. We conducted sensitivity analyses to assess the impact of potential temporal confounding and exposure misclassification.
We observed reductions in mean concentrations for all measured pollutants except O3 from the pre-Olympics period to the during-Olympics period. On average, elemental carbon (EC) changed by −36%, TPN by −22%, SO2 by −60%, CO by −48%, and NO2 by −43% (P < 0.05 for all these pollutants). Reductions were observed in mean concentrations of PM2.5 (by −27%), sulfate (SO42−) (by −13%), and organic carbon (OC) (by −23%); however, these values were not statistically significant. Both 24-hour averages and 1-hour maximums of O3 increased (by 20% and 17%, respectively) from the pre-Olympics to the during-Olympics period. In the post-Olympics period after the pollution control measures were relaxed, mean concentrations of most pollutants (with the exception of SO42− and O3) increased to levels similar to or higher than pre-Olympics levels.
Concomitantly and consistent with the hypothesis, we observed, from the pre-Olympics to the during-Olympics period, statistically significant (P ≤ 0.05) or marginally significant (0.05 < P < 0.1) decreases in HR (−1 bpm or −1.7% [95% CI, −3.4 to −0.1]), SBP (−1.6 mmHg or − 1.8% [95% CI, −3.9 to 0.4]), 8-OHdG (−58.3% [95% CI, −72.5 to −36.7]), FeNO (−60.3% [95% CI, −66.0 to −53.6]), EBC nitrite (−30.0% [95% CI, −39.3 to −19.3]), EBC nitrate (−21.5% [95% CI, −35.5 to −4.5]), EBC nitrite+nitrate (−17.6% [95% CI, −28.4 to −5.1]), EBC hydrogen ions (−46% [calculated from EBC pH], or +3.5% in EBC pH [95% CI, 2.2 to 4.9]), sCD62P (−34% [95% CI, −38.4 to −29.2]), sCD40L (−5.7% [95% CI, −10.5 to −0.7]), and vWF (−13.1% [95% CI, −18.6 to −7.5]). Moreover, the percentages of above-detection values out of all observations were significantly lower for plasma CRP and EBC 8-isoprostane in the during-Olympics period compared with the pre-Olympics period. In the post-Olympics period, the levels of the following biomarkers reversed (increased, either with or without statistical significance) from those in the during-Olympics period: SBP (10.7% [95% CI, 2.8 to 18.6]), fibrinogen (4.3% [95% CI, −1.7 to 10.2), neutrophil count (4.7% [95% CI, −7.7 to 17.0]), 8-OHdG (315% [95% CI, 62.0 to 962]), FeNO (130% [95% CI, 62.5 to 225]), EBC nitrite (159% [95% CI, 71.8 to 292]), EBC nitrate (161% [95% CI, 48.0 to 362]), EBC nitrite+nitrate (124% [95% CI, 50.9 to 233]), EBC hydrogen ions (146% [calculated from EBC pH] or −4.8% in EBC pH [95% CI, −9.4 to −0.2]), sCD62P (33.7% [95% CI, 17.7 to 51.8]), and sCD40L (9.1% [95% CI, −3.7 to 23.5]).
Furthermore, these biomarkers also showed statistically significant associations with multiple pollutants across different lags after adjusting for meteorologic parameters. The associations were in the directions hypothesized and were consistent with the findings from the comparisons between periods, providing further evidence that the period effects were due to changes in air quality, independent of season and meteorologic conditions or other potential confounders. Contrary to our hypothesis, however, we observed increases in platelet aggregation, red blood cells (RBCs) and white blood cells (WBCs) associated with the during-Olympics period, as well as significant negative associations of these biomarkers with pollutant concentrations. We did not observe significant changes in any of the HRV indices and DBP by period. However, we observed associations between a few HRV indices and pollutant concentrations.
Changes in air pollution levels during the Beijing Olympics were associated with acute changes in biomarkers of pulmonary and systemic inflammation, oxidative stress, and hemostasis and in measures of cardiovascular physiology (HR and SBP) in healthy, young adults. These changes support the prominently hypothesized mechanistic pathways underlying the cardiorespiratory effects of air pollution.
PMCID: PMC4086245  PMID: 23646463
7.  Air Pollution, Smoking, and Plasma Homocysteine 
Environmental Health Perspectives  2006;115(2):176-181.
Mild hyperhomocysteinemia is independently associated with an increased risk of cardiovascular disease. Air pollution exposure induces short-term inflammatory changes that may determine hyperhomocysteinemia, particularly in the presence of a preexisting proinflammatory status such as that found in cigarette smokers.
We examined the relation of air pollution levels with fasting and postmethionine-load total homocysteine (tHcy) in 1,213 normal subjects from Lombardia, Italy.
We obtained hourly concentrations of particulate matter < 10 μm in aerodynamic diameter (PM10) and gaseous pollutants (carbon monoxide, nitrogen dioxide, sulfur dioxide, ozone) from 53 monitoring sites covering the study area. We applied generalized additive models to compute standardized regression coefficients controlled for age, sex, body mass index, smoking, alcohol, hormone use, temperature, day of the year, and long-term trends.
The estimated difference in tHcy associated with an interquartile increase in average PM10 concentrations in the 24 hr before the study was nonsignificant [0.4%; 95% confidence interval (CI), −2.4 to 3.3 for fasting; and 1.1%, 95% CI, −1.5 to 3.7 for postmethionine-load tHcy]. In smokers, 24-hr PM10 levels were associated with 6.3% (95% CI, 1.3 to 11.6; p < 0.05) and 4.9% (95% CI, 0.5 to 9.6; p < 0.05) increases in fasting and postmethionine-load tHcy, respectively, but no association was seen in nonsmokers (p-interaction = 0.005 for fasting and 0.039 for postmethionine-load tHcy). Average 24-hr O3 concentrations were associated with significant differences in fasting tHcy (6.7%; 95% CI, 0.9 to 12.8; p < 0.05), but no consistent associations were found when postmethionine-load tHcy and/or 7-day average O3 concentrations were considered.
Air particles may interact with cigarette smoking and increase plasma homocysteine in healthy subjects.
PMCID: PMC1831519  PMID: 17384761
air pollution; cardiovascular risk; generalized additive models; homocysteine; particulate matter; smoking
8.  Synergistic Effects of Hypofibrinolysis and Genetic and Acquired Risk Factors on the Risk of a First Venous Thrombosis 
PLoS Medicine  2008;5(5):e97.
Previously, we demonstrated that hypofibrinolysis, a decreased capacity to dissolve a blood clot as measured with an overall clot lysis assay, increases the risk of venous thrombosis. Here, we investigated the combined effect of hypofibrinolysis with established risk factors associated with hypercoagulability.
Methods and Findings
Fibrinolytic potential was determined with a plasma-based clot lysis assay in 2,090 patients with venous thrombosis and 2,564 control participants between 18 and 70 y of age enrolled in the Multiple Environmental and Genetic Assessment (MEGA) of risk factors for venous thrombosis study, a population-based case-control study on venous thrombosis. Participants completed a standardized questionnaire on acquired risk factors.
Hypofibrinolysis alone, i.e., clot lysis time (CLT) in the fourth quartile (longest CLT) (in absence of the other risk factor of interest) increased thrombosis risk about 2-fold relative to individuals with CLT in the first quartile (shortest CLT). Oral contraceptive use in women with CLT in the first quartile gave an odds ratio (OR) of 2.6 (95% confidence interval [CI] 1.6 to 4.0), while women with hypofibrinolysis who used oral contraceptives had an over 20-fold increased risk of venous thrombosis (OR 21.8, 95% CI 10.2 to 46.7). For immobilization alone the OR was 4.3 (95% CI 3.2 to 5.8) and immobilization with hypofibrinolysis increased the risk 10.3-fold (95% CI 7.7 to 13.8). Factor V Leiden alone increased the risk 3.5-fold (95% CI 2.3 to 5.5), and hypofibrinolysis in factor V Leiden carriers gave an OR of 8.1 (95% CI 5.3 to 12.3). The combination of hypofibrinolysis and the prothrombin 20210A mutation did not synergistically increase the risk. All ORs and 95% CIs presented are relative to individuals with CLT in the first quartile and without the other risk factor of interest.
The combination of hypofibrinolysis with oral contraceptive use, immobilization, or factor V Leiden results in a risk of venous thrombosis that exceeds the sum of the individual risks.
Frits Rosendaal and colleagues show that the combination of hypofibrinolysis with oral contraceptive use, immobilization, or factor V Leiden results in a risk of venous thrombosis that exceeds the sum of the individual risks.
Editors' Summary
When a blood vessel is injured, proteins in the blood called clotting factors “coagulate” (solidify) the blood at the injury site. The resultant clot (thrombus) plugs the wound and prevents blood loss. When the injury has healed, other proteins dissolve the clot, a process called “fibrinolysis.” Sometimes, however, a thrombus develops inside an undamaged blood vessel and partly or completely blocks the blood flow. A clot that occurs in one of the veins (vessels that take the blood to the heart) deep within the body (usually in the leg) is a deep vein thrombosis (DVT). Some DVTs have no symptoms; others cause pain, swelling, and tenderness in one leg. They are usually treated with heparin and warfarin, anticoagulant drugs that stop the clot growing. If left untreated, part of the clot (an embolus) can break off and travel to the lungs, where it can cause a life-threatening condition called a pulmonary embolism (PE).
Why Was This Study Done?
Most people are very unlikely to develop venous thrombosis (the collective term for DVT and PE), but anything that makes blood “hypercoagulable” (prone to clotting) increases this risk. Genetic risk factors can be inherited changes in blood clotting proteins (for example, a mutation in a gene coding for one protein, factor V, which is involved in clotting, is known as factor V Leiden—Leiden, The Netherlands, was where it was first described). There are also acquired risk factors such as taking oral contraceptives or being immobilized (for example, during bed rest). These risk factors often act in such a way that the risk of developing venous thrombosis for a person with multiple risk factors is greater than the sum of the individual risks. Another recently identified but little studied risk factor for venous thrombosis is “hypofibrinolysis,” a decreased capacity to dissolve blood clots. In this study (part of the “MEGA” study on risk factors for venous thrombosis), the researchers investigate the combined effect of hypofibrinolysis and established risk factors associated with hypercoagulability on the risk of developing venous thrombosis.
What Did the Researchers Do and Find?
The researchers collected blood from more than 2,000 individuals after their first DVT or PE and from a similar number of persons without venous thrombosis (controls). For each blood sample, they measured the time it took to dissolve a clot generated from that blood in a test tube (the clot lysis time or CLT) and determined which participants had the factor V Leiden mutation or a genetic change in the clotting factor prothrombin that also increases blood coagulability. The study participants also completed a questionnaire about acquired risk factors for venous thrombosis. The researchers divided the participants into four equal-sized groups (quartiles) based on their CLT and used the quartile with the lowest CLT as the reference group for their statistical analyses; hypofibrinolysis was defined as a CLT in the highest quartile (the longest times). Participants with hypofibrinolysis alone were twice as likely to develop venous thrombosis as those with a CLT in the lowest quartile (the shortest times). Oral contraceptive use alone increased the risk of venous thrombosis 2.5-fold, whereas the combination of oral contraceptive use and hypofibrinolysis increased the risk 20-fold. The researchers also found synergistic effects on thrombosis risk for hypofibrinolysis combined with immobilization or with the factor V Leiden mutation but not with the prothrombin mutation.
What Do These Findings Mean?
These findings confirm that persons with hypofibrinolysis and hence longer CLTs have a greater risk of developing venous thrombosis than those with short CLTs. Because CLTs were measured after venous thrombosis had occurred, hypofibrinolysis could be an effect rather than a cause of this condition. However, this is unlikely because there was no association between how long after the venous thrombosis the blood sample was taken and the measured CLT. These findings also show that the combination of hypofibrinolysis with immobilization, the factor V Leiden mutation, and oral contraceptive use greatly increases the risk of venous thrombosis. This new information about the risk factors for venous thrombosis should help physicians to advise patients about reducing their chances of developing this life-threatening condition.
Additional Information.
Please access these Web sites via the online version of this summary at
The MedlinePlus encyclopedia has pages on blood clots, deep vein thrombosis, and pulmonary embolism (in English and Spanish)
The US National Heart Lung and Blood Institute provides information on deep vein thrombosis, including an animation about how DVT causes pulmonary embolisms
The UK National Health Service Direct health encyclopedia provides information for patients on deep vein thrombosis (in several languages)
More information about the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study is available on the Leiden University Medical Center Web site
Wikipedia has pages on coagulation and on fibrinolysis (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC2365975  PMID: 18462012
9.  Oral Cleft Defects and Maternal Exposure to Ambient Air Pollutants in New Jersey 
Evidence links exposure to ambient air pollution during pregnancy, particularly gaseous pollutants and particulate matter, to an increased risk of adverse reproductive outcomes but the results for birth defects have been inconsistent.
We compared estimated exposure to ambient air pollutants during early pregnancy among mothers of children with oral cleft defects (cases) to that among mothers of controls, adjusting for available risk factors from birth certificates. We obtained ambient air pollutant data from air monitoring sites in New Jersey for carbon monoxide (CO), nitrogen dioxide (NO2), ozone (O3), sulfur dioxide (SO2), particulate matter less than 10 µm in aerodynamic diameter (PM10) and particulate matter less than 2.5 µm in aerodynamic diameter (PM2.5). We used values from the nearest monitor (within 40 km of the residence at birth) for controls, cleft lip with or without cleft palate (CLP) and cleft palate only (CPO).
Based on logistic regression analyses for each contaminant and all contaminants together, there were no consistent elevated associations between selected air pollutants and cleft malformations. Quartile of CO concentration showed a consistent protective association with CPO (p<.01). For other contaminants, confidence intervals (95%) of the odds ratios for some quartiles excluded one. CLP showed limited evidence of an association with increasing SO2 exposure while CPO showed weak associations with increasing O3 exposure.
There was little consistent evidence associating cleft malformations with maternal exposure to ambient air pollutants. Evaluating particular pollutants or disease subgroups would require more detailed measurement of exposure and classification of cleft defects.
PMCID: PMC2862481  PMID: 20146378
10.  In-Traffic Air Pollution Exposure and CC16, Blood Coagulation, and Inflammation Markers in Healthy Adults 
Environmental Health Perspectives  2011;119(10):1384-1389.
Background: Exposure to traffic-related air pollution is a risk factor for cardiovascular events, probably involving mechanisms of inflammation and coagulation. Little is known about effects of the short exposures encountered while participating in traffic.
Objectives: The objective of the study was to examine effects of exposure of commuters to air pollution on cardiovascular biomarkers.
Methods: Thirty-four healthy adult volunteers commuted for 2 hr by bus, car, or bicycle during the morning rush hour. During the commute, exposure to particle number, particulate matter (PM) ≤ 2.5 µm in aerodynamic diameter (PM2.5), PM ≤ 10 µm in diameter (PM10), and soot was measured. We estimated inhaled doses based on heart rate monitoring. Shortly before exposure and 6 hr after exposure, blood samples were taken and analyzed for CC16 (Clara cell protein 16), blood cell count, coagulation markers, and inflammation markers. Between June 2007 and June 2008, 352 pre- and postexposure blood samples were collected on 47 test days. We used mixed models to analyze the associations between exposure and changes in health parameters.
Results: We observed no consistent associations between the air pollution exposures and doses and the various biomarkers that we investigated.
Conclusions: Air pollution exposure during commuting was not consistently associated with acute changes in inflammation markers, blood cell counts, or blood coagulation markers.
PMCID: PMC3230432  PMID: 21665568
air epidemiology; Clara cell protein 16; coagulation; inflammation; interleukins; outdoor air; particulate matter; ultrafine particles
11.  Lung Function and Incidence of Chronic Obstructive Pulmonary Disease after Improved Cooking Fuels and Kitchen Ventilation: A 9-Year Prospective Cohort Study 
PLoS Medicine  2014;11(3):e1001621.
Pixin Ran, Nanshan Zhong, and colleagues report that cleaner cooking fuels and improved ventilation were associated with better lung function and reduced COPD among a cohort of villagers in Southern China.
Please see later in the article for the Editors' Summary
Biomass smoke is associated with the risk of chronic obstructive pulmonary disease (COPD), but few studies have elaborated approaches to reduce the risk of COPD from biomass burning. The purpose of this study was to determine whether improved cooking fuels and ventilation have effects on pulmonary function and the incidence of COPD.
Methods and Findings
A 9-y prospective cohort study was conducted among 996 eligible participants aged at least 40 y from November 1, 2002, through November 30, 2011, in 12 villages in southern China. Interventions were implemented starting in 2002 to improve kitchen ventilation (by providing support and instruction for improving biomass stoves or installing exhaust fans) and to promote the use of clean fuels (i.e., biogas) instead of biomass for cooking (by providing support and instruction for installing household biogas digesters); questionnaire interviews and spirometry tests were performed in 2005, 2008, and 2011. That the interventions improved air quality was confirmed via measurements of indoor air pollutants (i.e., SO2, CO, CO2, NO2, and particulate matter with an aerodynamic diameter of 10 µm or less) in a randomly selected subset of the participants' homes. Annual declines in lung function and COPD incidence were compared between those who took up one, both, or neither of the interventions.
Use of clean fuels and improved ventilation were associated with a reduced decline in forced expiratory volume in 1 s (FEV1): decline in FEV1 was reduced by 12 ml/y (95% CI, 4 to 20 ml/y) and 13 ml/y (95% CI, 4 to 23 ml/y) in those who used clean fuels and improved ventilation, respectively, compared to those who took up neither intervention, after adjustment for confounders. The combined improvements of use of clean fuels and improved ventilation had the greatest favorable effects on the decline in FEV1, with a slowing of 16 ml/y (95% CI, 9 to 23 ml/y). The longer the duration of improved fuel use and ventilation, the greater the benefits in slowing the decline of FEV1 (p<0.05). The reduction in the risk of COPD was unequivocal after the fuel and ventilation improvements, with an odds ratio of 0.28 (95% CI, 0.11 to 0.73) for both improvements.
Replacing biomass with biogas for cooking and improving kitchen ventilation are associated with a reduced decline in FEV1 and risk of COPD.
Trial Registration
Chinese Clinical Trial Register ChiCTR-OCH-12002398
Please see later in the article for the Editors' Summary
Editors' Summary
Nearly 3 billion people in developing countries heat their homes and cook by burning biomass—wood, crop waste, and animal dung—in open fires and leaky stoves. Burning biomass this way releases pollutants into the home that impair lung function and that are responsible for more than a million deaths from chronic obstructive pulmonary disease (COPD) every year. COPD is a group of diseases that interfere with breathing. Normally, air is breathed in through the nose or mouth and travels down the windpipe into two bronchial tubes (airways) in the lungs. These tubes branch into smaller tubes (bronchioles) that end in bunches of tiny air sacs (alveoli). Oxygen in the air passes through the thin walls of these sacs into small blood vessels and is taken to the heart for circulation round the body. The two main types of COPD—chronic bronchitis (long-term irritation and swelling of the bronchial tubes) and emphysema (damage to the walls of the alveoli)—make it hard for people to breathe. Most people with COPD have both chronic bronchitis and emphysema, both of which are caused by long-term exposure to cigarette smoke, indoor air pollution, and other lung irritants. Symptoms of COPD include breathlessness during exercise and a persistent cough that produces large amounts of phlegm (mucus). There is no cure for COPD, but drugs and oxygen therapy can relieve its symptoms, and avoiding lung irritants can slow disease progression.
Why Was This Study Done?
Exposure to indoor air pollution has been associated with impaired lung function and COPD in several studies. However, few studies have assessed the long-term effects on lung function and on the incidence of COPD (the proportion of a population that develops COPD each year) of replacing biomass with biogas (a clean fuel produced by bacterial digestion of biodegradable materials) for cooking and heating, or of improving kitchen ventilation during cooking. Here, the researchers undertook a nine-year prospective cohort study in rural southern China to investigate whether these interventions are associated with any effects on lung function and on the incidence of COPD. A prospective cohort study enrolls a group of people, determines their characteristics at baseline, and follows them over time to see whether specific characteristic are associated with specific outcomes.
What Did the Researchers Do and Find?
The researchers offered nearly 1,000 people living in 12 villages in southern China access to biogas and to improved kitchen ventilation. All the participants, who adopted these interventions according to personal preferences, completed a questionnaire about their smoking habits and occupational exposure to pollutants and had their lung function measured using a spirometry test at the start and end of the study. Some participants also completed a questionnaire and had their lung function measured three and six years into the study. Finally, the researchers measured levels of indoor air pollution in a randomly selected subset of homes at the end of the study to confirm that the interventions had reduced indoor air pollution. Compared with non-use, the use of clean fuels and of improved ventilation were both associated with a reduction in the decline in lung function over time after adjusting for known characteristics that affect lung function, such as smoking. The use of both interventions reduced the decline in lung function more markedly than either intervention alone, and the benefits of using the interventions increased with length of use. Notably, the combined use of both interventions reduced the risk of COPD occurrence among the study participants.
What Do These Findings Mean?
These findings suggest that, among people living in rural southern China, the combined interventions of use of biogas instead of biomass and improved kitchen ventilation were associated with a reduced decline in lung function over time and with a reduced risk of COPD. Because participants were not randomly allocated to intervention groups, the people who adopted the interventions may have shared other unknown characteristics (confounders) that affected their lung function (for example, having a healthier lifestyle). Thus, it is not possible to conclude that either intervention actually caused a reduction in the decline in lung function. Nevertheless, these findings suggest that the use of biogas as a substitute for biomass for cooking and heating and improvements in kitchen ventilation might lead to a reduction in the global burden of COPD associated with biomass smoke.
Additional Information
Please access these websites via the online version of this summary at
The US National Heart, Lung, and Blood Institute provides detailed information for the public about COPD
The US Centers for Disease Control and Prevention provides information about COPD and links to other resources (in English and Spanish)
The UK National Health Service Choices website provides information for patients and carers about COPD, personal stories, and links to other resources
The British Lung Foundation, a not-for-profit organization, provides information about COPD in several languages
The Global Initiative for Chronic Obstructive Lung Disease works to improve prevention and treatment of COPD around the world
The World Health Organization provides information about all aspects of indoor air pollution and health (in English, French, and Spanish)
MedlinePlus provides links to other information about COPD (in English and Spanish)
PMCID: PMC3965383  PMID: 24667834
12.  Short-Term Mortality Rates during a Decade of Improved Air Quality in Erfurt, Germany 
Environmental Health Perspectives  2008;117(3):448-454.
Numerous studies have shown associations between ambient air pollution and daily mortality.
Our goal was to investigate the association of ambient air pollution and daily mortality in Erfurt, Germany, over a 10.5-year period after the German unification, when air quality improved.
We obtained daily mortality counts and data on mass concentrations of particulate matter (PM) < 10 μm in aerodynamic diameter (PM10), gaseous pollutants, and meteorology in Erfurt between October 1991 and March 2002. We obtained ultrafine particle number concentrations (UFP) and mass concentrations of PM < 2.5 μm in aerodynamic diameter (PM2.5) from September 1995 to March 2002. We analyzed the data using semiparametric Poisson regression models adjusting for trend, seasonality, influenza epidemics, day of the week, and meteorology. We evaluated cumulative associations between air pollution and mortality using polynomial distributed lag (PDL) models and multiday moving averages of air pollutants. We evaluated changes in the associations over time in time-varying coefficient models.
Air pollution concentrations decreased over the study period. Cumulative exposure to UFP was associated with increased mortality. An interquartile range (IQR) increase in the 15-day cumulative mean UFP of 7,649 cm−3 was associated with a relative risk (RR) of 1.060 [95% confidence interval (CI), 1.008–1.114] for PDL models and an RR/IQR of 1.055 (95% CI, 1.011–1.101) for moving averages. RRs decreased from the mid-1990s to the late 1990s.
Results indicate an elevated mortality risk from short-term exposure to UFP. They further suggest that RRs for short-term associations of air pollution decreased as pollution control measures were implemented in Eastern Germany.
PMCID: PMC2661916  PMID: 19337521
accountability research; air pollution; improved air quality; mortality; particulate matter; ultrafine particles
13.  PM(10) exposure, gaseous pollutants, and daily mortality in Inchon, South Korea. 
Environmental Health Perspectives  1999;107(11):873-878.
To evaluate the relative importance of various measures of particulate and gaseous air pollution as predictors of daily mortality in Inchon, South Korea, the association between total daily mortality and air pollution was investigated for a 20-month period (January 1995 through August 1996). Poisson regression was used to regress daily death counts on each air pollutant, controlling for time trends, season, and meteorologic influences such as temperature and relative humidity. Regression coefficients of a 5-day moving average of particulate matter less than or = to 10 microm in aerodynamic diameter (PM(10)) on total mortality were positively significant when considered separately and simultaneously with other pollutants in the model. PM(10) remained significant when the models were confined to cardiovascular or respiratory mortality. Sulfur dioxide (SO(2)) and carbon monoxide (CO) were significantly related to respiratory mortality in the single-pollutant model. Ozone exposure was not statistically significant with regard to mortality in the above models, and graphic analysis showed that the relationship was nonlinear. A combined index of PM(10), nitrogen dioxide, SO(2), and CO seemed to better explain the exposure-response relationship with total mortality than an individual air pollutant. Pollutants should be considered together in the risk assessment of air pollution, as opposed to measuring the risk of individual pollutants.
PMCID: PMC1566699  PMID: 10544154
14.  Ambient air pollution exposure and full-term birth weight in California 
Environmental Health  2010;9:44.
Studies have identified relationships between air pollution and birth weight, but have been inconsistent in identifying individual pollutants inversely associated with birth weight or elucidating susceptibility of the fetus by trimester of exposure. We examined effects of prenatal ambient pollution exposure on average birth weight and risk of low birth weight in full-term births.
We estimated average ambient air pollutant concentrations throughout pregnancy in the neighborhoods of women who delivered term singleton live births between 1996 and 2006 in California. We adjusted effect estimates of air pollutants on birth weight for infant characteristics, maternal characteristics, neighborhood socioeconomic factors, and year and season of birth.
3,545,177 singleton births had monitoring for at least one air pollutant within a 10 km radius of the tract or ZIP Code of the mother's residence. In multivariate models, pollutants were associated with decreased birth weight; -5.4 grams (95% confidence interval -6.8 g, -4.1 g) per ppm carbon monoxide, -9.0 g (-9.6 g, -8.4 g) per pphm nitrogen dioxide, -5.7 g (-6.6 g, -4.9 g) per pphm ozone, -7.7 g (-7.9 g, -6.6 g) per 10 μg/m3 particulate matter under 10 μm, -12.8 g (-14.3 g, -11.3 g) per 10 μg/m3 particulate matter under 2.5 μm, and -9.3 g (-10.7 g, -7.9 g) per 10 μg/m3 of coarse particulate matter. With the exception of carbon monoxide, estimates were largely unchanged after controlling for co-pollutants. Effect estimates for the third trimester largely reflect the results seen from full pregnancy exposure estimates; greater variation in results is seen in effect estimates specific to the first and second trimesters.
This study indicates that maternal exposure to ambient air pollution results in modestly lower infant birth weight. A small decline in birth weight is unlikely to have clinical relevance for individual infants, and there is debate about whether a small shift in the population distribution of birth weight has broader health implications. However, the ubiquity of air pollution exposures, the responsiveness of pollutant levels to regulation, and the fact that the highest pollution levels in California are lower than those regularly experienced in other countries suggest that precautionary efforts to reduce pollutants may be beneficial for infant health from a population perspective.
PMCID: PMC2919523  PMID: 20667084
15.  Assessing the impact of race, social factors and air pollution on birth outcomes: a population-based study 
Environmental Health  2014;13:4.
Both air pollution exposure and socioeconomic status (SES) are important indicators of children’s health. Using highly resolved modeled predictive surfaces, we examine the joint effects of air pollution exposure and measures of SES in a population level analysis of pregnancy outcomes in North Carolina (NC).
Daily measurements of particulate matter <2.5 μm in aerodynamic diameter (PM2.5) and ozone (O3) were calculated through a spatial hierarchical Bayesian model which produces census-tract level point predictions. Using multilevel models and NC birth data from 2002–2006, we examine the association between pregnancy averaged PM2.5 and O3, individual and area-based SES indicators, and birth outcomes.
Maternal race and education, and neighborhood household income were associated with adverse birth outcomes. Predicted concentrations of PM2.5 and O3 were also associated with an additional effect on reductions in birth weight and increased risks of being born low birth weight and small for gestational age.
This paper builds on and complements previous work on the relationship between pregnancy outcomes and air pollution exposure by using 1) highly resolved air pollution exposure data; 2) a five-year population level sample of pregnancies; and 3) including personal and areal level measures of social determinants of pregnancy outcomes. Results show a stable and negative association between air pollution exposure and adverse birth outcomes. Additionally, the more socially disadvantaged populations are at a greater risk; controlling for both SES and environmental stressors provides a better understanding of the contributing factors to poor children’s health outcomes.
PMCID: PMC3922656  PMID: 24476365
Air pollution; Exposure predictions; Pregnancy outcomes; Socioeconomic status
16.  Traffic-related Particles Are Associated with Elevated Homocysteine 
Rationale: Recent epidemiologic studies have shown that homocysteine, a sulfur-containing amino acid formed during the metabolism of methionine, is a risk factor for atherosclerosis, myocardial infarction, stroke, and thrombosis. Particulate air pollution has been related to cardiovascular death and hospital admission, but the underlying mechanisms are not fully elucidated.
Objectives: We examined the associations between ambient particulate air pollution and plasma concentrations of homocysteine among 960 community-residing older men (mean age, 73.6 ± 6.9 yr).
Methods: Total homocysteine in plasma, measured using high-performance liquid chromatography with fluorescence detection, was regressed on each ambient particulate pollutant (black carbon, organic carbon, sulfate or PM2.5), and effect modification by plasma and dietary B vitamins (folate, B6, and B12) was examined.
Measurements and Main Results: The median concentration of total homocysteine was 10.6 μmol/L. Statistically significant positive associations of total homocysteine were observed with traffic-related particles (black carbon and organic carbon). No association was observed with sulfate, an indicator of coal combustion particles, or PM2.5 (particulate matter ≤ 2.5 μm in aerodynamic diameter). The effects of black carbon and organic carbon were more pronounced in persons with low concentrations of plasma folate and vitamin B12.
Conclusions: Exposures to ambient particles, particularly from traffic, are associated with elevated plasma total homocysteine. Homocysteine may be a component or biological marker of the oxidation pathways underlying the effect of ambient particles on the cardiovascular system.
PMCID: PMC2542426  PMID: 18467508
air pollution; folate; homocysteine; traffic particles; vitamin B12
17.  Rapid DNA Methylation Changes after Exposure to Traffic Particles 
Rationale: Exposure to particulate air pollution has been related to increased hospitalization and death, particularly from cardiovascular disease. Lower blood DNA methylation content is found in processes related to cardiovascular outcomes, such as oxidative stress, aging, and atherosclerosis.
Objectives: We evaluated whether particulate pollution modifies DNA methylation in heavily methylated sequences with high representation throughout the human genome.
Methods: We measured DNA methylation of long interspersed nucleotide element (LINE)-1 and Alu repetitive elements by quantitative polymerase chain reaction–pyrosequencing of 1,097 blood samples from 718 elderly participants in the Boston area Normative Aging Study. We used covariate-adjusted mixed models to account for within-subject correlation in repeated measures. We estimated the effects on DNA methylation of ambient particulate pollutants (black carbon, particulate matter with aerodynamic diameter ≤ 2.5 μm [PM2.5], or sulfate) in multiple time windows (4 h to 7 d) before the examination. We estimated standardized regression coefficients (β) expressing the fraction of a standard deviation change in DNA methylation associated with a standard deviation increase in exposure.
Measurements and Main Results: Repetitive element DNA methylation varied in association with time-related variables, such as day of the week and season. LINE-1 methylation decreased after recent exposure to higher black carbon (β = −0.11; 95% confidence interval [CI], −0.18 to −0.04; P = 0.002) and PM2.5 (β = −0.13; 95% CI, −0.19 to −0.06; P < 0.001 for the 7-d moving average). In two-pollutant models, only black carbon, a tracer of traffic particles, was significantly associated with LINE-1 methylation (β = −0.09; 95% CI, −0.17 to −0.01; P = 0.03). No association was found with Alu methylation (P > 0.12).
Conclusions: We found decreased repeated-element methylation after exposure to traffic particles. Whether decreased methylation mediates exposure-related health effects remains to be determined.
PMCID: PMC2720123  PMID: 19136372
epigenetic processes; air pollution; inhalation exposure; interspersed repetitive sequences
18.  Traffic-related air toxics and preterm birth: a population-based case-control study in Los Angeles county, California 
Environmental Health  2011;10:89.
Numerous studies have associated air pollutant exposures with adverse birth outcomes, but there is still relatively little information to attribute effects to specific emission sources or air toxics. We used three exposure data sources to examine risks of preterm birth in Los Angeles women when exposed to high levels of traffic-related air pollutants - including specific toxics - during pregnancy.
We identified births during 6/1/04-3/31/06 to women residing within five miles of a Southern California Air Quality Management District (SCAQMD) Multiple Air Toxics Exposure Study (MATES III) monitoring station. We identified preterm cases and, using a risk set approach, matched cases to controls based on gestational age at birth. Pregnancy period exposure averages were estimated for a number of air toxics including polycyclic aromatic hydrocarbons (PAHs), source-specific PM2.5 (fine particulates with aerodynamic diameter less than 2.5 μm) based on a Chemical Mass Balance model, criteria air pollutants based on government monitoring data, and land use regression (LUR) estimates of nitric oxide (NO), nitrogen dioxide (NO2) and nitrogen oxides (NOx). Associations between these metrics and odds of preterm birth were estimated using conditional logistic regression.
Odds of preterm birth increased 6-21% per inter-quartile range increase in entire pregnancy exposures to organic carbon (OC), elemental carbon (EC), benzene, and diesel, biomass burning and ammonium nitrate PM2.5, and 30% per inter-quartile increase in PAHs; these pollutants were positively correlated and clustered together in a factor analysis. Associations with LUR exposure metrics were weaker (3-4% per inter-quartile range increase).
These latest analyses provide additional evidence of traffic-related air pollution's impact on preterm birth for women living in Southern California and indicate PAHs as a pollutant of concern that should be a focus of future studies. Other PAH sources besides traffic were also associated with higher odds of preterm birth, as was ammonium nitrate PM2.5, the latter suggesting potential importance of secondary pollutants. Future studies should focus on accurate modeling of both local and regional spatial and temporal distributions, and incorporation of source information.
PMCID: PMC3204282  PMID: 21981989
19.  Long-Term Exposure to Ambient Air Pollution and Mortality Due to Cardiovascular Disease and Cerebrovascular Disease in Shenyang, China 
PLoS ONE  2011;6(6):e20827.
The relationship between ambient air pollution exposure and mortality of cardiovascular and cerebrovascular diseases in human is controversial, and there is little information about how exposures to ambient air pollution contribution to the mortality of cardiovascular and cerebrovascular diseases among Chinese. The aim of the present study was to examine whether exposure to ambient-air pollution increases the risk for cardiovascular and cerebrovascular disease.
Methodology/Principal Findings
We conducted a retrospective cohort study among humans to examine the association between compound-air pollutants [particulate matter <10 µm in aerodynamic diameter (PM10), sulfur dioxide (SO2) and nitrogen dioxide (NO2)] and mortality in Shenyang, China, using 12 years of data (1998–2009). Also, stratified analysis by sex, age, education, and income was conducted for cardiovascular and cerebrovascular mortality. The results showed that an increase of 10 µg/m3 in a year average concentration of PM10 corresponds to 55% increase in the risk of a death cardiovascular disease (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.51 to 1.60) and 49% increase in cerebrovascular disease (HR, 1.49; 95% CI, 1.45 to 1.53), respectively. The corresponding figures of adjusted HR (95%CI) for a 10 µg/m3 increase in NO2 was 2.46 (2.31 to 2.63) for cardiovascular mortality and 2.44 (2.27 to 2.62) for cerebrovascular mortality, respectively. The effects of air pollution were more evident in female that in male, and nonsmokers and residents with BMI<18.5 were more vulnerable to outdoor air pollution.
Long-term exposure to ambient air pollution is associated with the death of cardiovascular and cerebrovascular diseases among Chinese populations.
PMCID: PMC3112212  PMID: 21695220
20.  Baseline Repeated Measures from Controlled Human Exposure Studies: Associations between Ambient Air Pollution Exposure and the Systemic Inflammatory Biomarkers IL-6 and Fibrinogen 
Environmental Health Perspectives  2009;118(1):120-124.
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.
We investigated the association between ambient air pollution and systemic inflammation using baseline measurements of IL-6 and fibrinogen from controlled human exposure studies.
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.
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.
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.
PMCID: PMC2831955  PMID: 20056584
air pollution; epidemiology; fibrinogen; inflammation; interleukin-6
21.  Particulate matter and risk of parkinson disease in a large prospective study of women 
Environmental Health  2014;13(1):80.
Exposure to air pollution has been implicated in a number of adverse health outcomes and the effect of particulate matter (PM) on the brain is beginning to be recognized. Yet, no prospective study has examined the association between PM and risk of Parkinson Disease. Thus, our goal was assess if exposure to particulate matter air pollution is related to risk of Parkinson’s disease (PD) in the Nurses’ Health Study (NHS), a large prospective cohort of women.
Cumulative average exposure to different size fractions of PM up to 2 years before the onset of PD, was estimated using a spatio-temporal model by linking each individual’s places of residence throughout the study with location-specific air pollution levels. We prospectively followed 115,767 women in the NHS, identified 508 incident PD cases and used multivariable Cox proportional hazards models to estimate the risk of PD associated with each size fraction of PM independently.
In models adjusted for age in months, smoking, region, population density, caffeine and ibuprofen intake, we observed no statistically significant associations between exposure to air pollution and PD risk. The relative risk (RR) comparing the top quartile to the bottom quartile of PM exposure was 0.99 (95% Confidence Intervals (CI): 0.84,1.16) for PM10 (≤10 microns in diameter), 1.08 (95% CI: 0.81, 1.45) for PM2.5 (≤2.5 microns in diameter), and 0.92 (95% CI: 0.71, 1.19) for PM10–2.5 (2.5 to 10 microns in diameter).
In this study, we found no evidence that exposure to air pollution is a risk factor for PD.
PMCID: PMC4201741  PMID: 25294559
Epidemiology; Cohort studies; Incidence studies; Parkinson disease/Parkinsonism
22.  Chronic exposure to outdoor air pollution and diagnosed cardiovascular disease: meta-analysis of three large cross-sectional surveys 
Environmental Health  2009;8:30.
Higher exposure to outdoor air pollution is associated with increased cardiopulmonary deaths, but there is limited evidence about the association between outdoor air pollution and diagnosed cardiovascular disease. Our study aimed to estimate the size of the association between long term exposure to outdoor air pollution and prevalent cardiovascular disease.
We carried out a cross-sectional analysis of data on more than 19,000 white adults aged 45 and older who participated in three representative surveys of the English population in 1994, 1998 and 2003, examining the relationship between self-reported doctor-diagnosed cardiovascular disease and exposure to outdoor air pollutants using multilevel regression techniques and meta-analysis.
The combined estimates suggested that an increase of 1 μg m-3 in concentration of particulate matter less than 10 microns in diameter was associated with an increase of 2.9% (95% CI -0.6% to 6.5%) in prevalence of cardiovascular disease in men, and an increase of 1.6% (95%CI -2.1% to 5.5%) in women. The year-specific analyses showed strongly positive associations in 2003 between odds of cardiovascular disease in both men and women and exposure to particulate matter but not in 1994 or 1998. We found no consistent associations between exposure to gaseous air pollutants and doctor-diagnosed cardiovascular disease.
The associations of prevalent cardiovascular disease with concentration of particulate matter less than 10 microns in diameter, while only weakly positive, were consistent with the effects reported in cohort studies. The results provide evidence of the size of the association between particulate air pollution and the prevalence of cardiovascular disease but no evidence for an association with gaseous pollutants. We found strongly positive associations between particulate matter and cardiovascular disease in 2003 only, which highlights the importance of replicating findings in more than one population.
PMCID: PMC2716315  PMID: 19594904
23.  Enhanced pre-operative thrombolytic status is associated with the incidence of deep venous thrombosis in patients undergoing total knee arthroplasty 
Thrombosis Journal  2014;12:11.
Deep venous thrombosis (DVT), which is often associated with pulmonary embolism (PE), is a serious complication after total knee arthroplasty (TKA). In the present study, we examined the overall thrombotic and thrombolytic status using Global Thrombosis Test (GTT) in non-anticoagulated blood of patients undergoing TKA to develop the predictable marker for the incidence of DVT.
DVT was diagnosed using doppler ultrasonography a day after the surgery in 31 patients with osteoarthritis (n = 24), rheumatoid arthritis (n = 6) and ankylosing spondylitis (n = 1) by the well-trained operator. We measured overall thrombotic and thrombolytic status using GTT and other biomarkers, which is associated with blood coagulation and fibrinolysis, before and immediately after the surgery.
Newly-generated DVT during the operation was detected in 11 of 31 patients (35.4%) 1 day after TKA. There were no differences in markers of coagulation (PT and APTT), platelet activity (platelet aggregation-induced by ADP and collagen) and fibrinolysis (FDP and D-dimer) between non-DVT and DVT group both before and after the surgery. Both Pre- and Post-operative GTT-occlusion times (OT), an index of platelet reactivity, were tended to be shorter, but not significant, in DVT group compared with non-DVT group. Pre-operative GTT-lysis time (LT), an index of thrombolytic activity, was significantly shorter in DVT group compared with non-DVT group, while there were no differences in post-operative value of this index between DVT group and non-DVT group, suggesting overall thrombolytic activity was enhanced in DVT group before surgery.
Our data suggest that enhancement of pre-operative thrombolytic activity assessed by GTT may be a predictable marker for the incidence of DVT after TKA.
PMCID: PMC4094920  PMID: 25024643
Deep venous thrombosis; Global thrombosis test; Thrombolysis
24.  The Effect of Ambient Air Pollution during Early Pregnancy on Fetal Ultrasonic Measurements during Mid-Pregnancy 
Environmental Health Perspectives  2007;116(3):362-369.
Over the past decade there has been mounting evidence that ambient air pollution during pregnancy influences fetal growth.
This study was designed to examine possible associations between fetal ultrasonic measurements collected from 15,623 scans (13–26 weeks gestation) and ambient air pollution during early pregnancy.
We calculated mothers’ average monthly exposures over the first 4 months of pregnancy for the following pollutants: particulate matter < 10 μm aerodynamic diameter (PM10), ozone, nitrogen dioxide, and sulfur dioxide. We examined associations with fetal femur length (FL), biparietal diameter (BPD), head circumference (HC), and abdominal circumference (AC). Final analyses included scans from only those women within 2 km of an air pollution monitoring site. We controlled for long-term trend, season, temperature, gestation, mother’s age, socioeconomic status, and fetal sex.
A reduction in fetal AC was associated with O3 during days 31–60 [−1.42 mm; 95% confidence interval (CI), −2.74 to −0.09], SO2 during days 61–90 (−1.67 mm; 95% CI, −2.94 to −0.40), and PM10 during days 91–120 (−0.78 mm; 95% CI, −1.49 to −0.08). Other results showed a reduction in BPD (−0.68 mm; 95% CI, −1.09 to −0.27) associated with SO2 during days 0–30, a reduction in HC (−1.02 mm; 95% CI, −1.78 to −0.26) associated with PM10 during days 91–120, and a reduction in FL associated with PM10 during days 0–30 (−0.28 mm; 95% CI, −0.48 to −0.08) and 91–120 (−0.23; 95% CI, −0.42 to −0.04).
We found strong effects of ambient air pollution on ultrasound measures. Future research, including more individually detailed data, is needed to confirm our results.
PMCID: PMC2265059  PMID: 18335104
air pollution; fetal growth; pregnancy; temperature; ultrasound
25.  An Association Between Long-Term Exposure to Ambient Air Pollution and Mortality From Lung Cancer and Respiratory Diseases in Japan 
Journal of Epidemiology  2011;21(2):132-143.
Evidence for a link between long-term exposure to air pollution and lung cancer is limited to Western populations. In this prospective cohort study, we examined this association in a Japanese population.
The study comprised 63 520 participants living in 6 areas in 3 Japanese prefectures who were enrolled between 1983 and 1985. Exposure to particulate matter less than 2.5 µm in aerodynamic diameter (PM2.5), sulfur dioxide (SO2), and nitrogen dioxide (NO2) was assessed using data from monitoring stations located in or nearby each area. The Cox proportional hazards model was used to calculate the hazard ratios associated with the average concentrations of these air pollutants.
The 10-year average concentrations of PM2.5, SO2, and NO2 before recruitment (1974–1983) were 16.8 to 41.9 µg/m3, 2.4 to 19.0 ppb, and 1.2 to 33.7 ppb, respectively (inter-area range). During an average follow-up of 8.7 years, there were 6687 deaths, including 518 deaths from lung cancer. The hazard ratios for lung cancer mortality associated with a 10-unit increase in PM2.5 (µg/m3), SO2 (ppb), and NO2 (ppb) were 1.24 (95% confidence interval: 1.12–1.37), 1.26 (1.07–1.48), and 1.17 (1.10–1.26), respectively, after adjustment for tobacco smoking and other confounding factors. In addition, a significant increase in risk was observed for male smokers and female never smokers. Respiratory diseases, particularly pneumonia, were also significantly associated with all the air pollutants.
Long-term exposure to air pollution is associated with lung cancer and respiratory diseases in Japan.
PMCID: PMC3899505  PMID: 21325732
air pollution; lung neoplasms; nitrogen dioxide; particulate matter; sulfur dioxide

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