Effects of short-term increases in personal and ambient pollutant concentrations on pulmonary and cardiovascular function: A panel study analysis of the Multicenter Ozone Study in oldEr subjects (MOSES 2).

BACKGROUND: The cardiovascular effects of ozone exposure are unclear. Using measurements from the 87 participants in the Multicenter Ozone Study of oldEr Subjects (MOSES), we examined whether personal and ambient pollutant exposures before the controlled exposure sessions would be associated with adverse changes in pulmonary and cardiovascular function. METHODS: We used mixed effects linear regression to evaluate associations between increased personal exposures and ambient pollutant concentrations in the 96 h before the pre-exposure visit, and 1) biomarkers measured at pre-exposure, and 2) changes in biomarkers from pre-to post-exposure. RESULTS: Decreases in pre-exposure forced expiratory volume in 1 s (FEV1) were associated with interquartile-range increases in concentrations of particulate matter ≤2.5 µm (PM2.5) 1 h before the pre-exposure visit (-0.022 L; 95% CI -0.037 to -0.006; p = 0.007), carbon monoxide (CO) in the prior 3 h (-0.046 L; 95% CI -0.076 to -0.016; p = 0.003), and nitrogen dioxide (NO2) in the prior 72 h (-0.030 L; 95% CI -0.052 to -0.008; p = 0.007). From pre-to post-exposure, increases in FEV1 were marginally significantly associated with increases in personal ozone exposure (0.010 L; 95% CI 0.004 to 0.026; p = 0.010), and ambient PM2.5 and CO at all lag times. Ambient ozone concentrations in the prior 96 h were associated with both decreased pre-exposure high frequency (HF) heart rate variability (HRV) and increases in HF HRV from pre-to post-exposure. CONCLUSIONS: We observed associations between increased ambient PM2.5, NO2, and CO levels and reduced pulmonary function, and increased ambient ozone concentrations and reduced HRV. Pulmonary function and HRV increased across the exposure sessions in association with these same pollutant increases, suggesting a "recovery" during the exposure sessions. These findings support an association between short term increases in ambient PM2.5, NO2, and CO and decreased pulmonary function, and increased ambient ozone and decreased HRV.

Multicenter Ozone Study in oldEr Subjects (MOSES): Part 2. Effects of Personal and Ambient Concentrations of Ozone and Other Pollutants on Cardiovascular and Pulmonary Function.

INTRODUCTION: The Multicenter Ozone Study of oldEr Subjects (MOSES) was a multi-center study evaluating whether short-term controlled exposure of older, healthy individuals to low levels of ozone (O3) induced acute changes in cardiovascular biomarkers. In MOSES Part 1 (MOSES 1), controlled O3 exposure caused concentration-related reductions in lung function with evidence of airway inflammation and injury, but without convincing evidence of effects on cardiovascular function. However, subjects' prior exposures to indoor and outdoor air pollution in the few hours and days before each MOSES controlled O3 exposure may have independently affected the study biomarkers and/or modified biomarker responses to the MOSES controlled O3 exposures. METHODS: MOSES 1 was conducted at three clinical centers (University of California San Francisco, University of North Carolina, and University of Rochester Medical Center) and included healthy volunteers 55 to 70 years of age. Consented participants who successfully completed the screening and training sessions were enrolled in the study. All three clinical centers adhered to common standard operating procedures and used common tracking and data forms. Each subject was scheduled to participate in a total of 11 visits: screening visit, training visit, and three sets of exposure visits consisting of the pre-exposure day, the exposure day, and the post-exposure day. After completing the pre-exposure day, subjects spent the night in a nearby hotel. On exposure days, the subjects were exposed for 3 hours in random order to 0 ppb O3 (clean air), 70 ppb O3, and 120 ppm O3. During the exposure period the subjects alternated between 15 minutes of moderate exercise and 15 minutes of rest. A suite of cardiovascular and pulmonary endpoints was measured on the day before, the day of, and up to 22 hours after each exposure.In MOSES Part 2 (MOSES 2), we used a longitudinal panel study design, cardiopulmonary biomarker data from MOSES 1, passive cumulative personal exposure samples (PES) of O3 and nitrogen dioxide (NO2) in the 72 hours before the pre-exposure visit, and hourly ambient air pollution and weather measurements in the 96 hours before the pre-exposure visit. We used mixed-effects linear regression and evaluated whether PES O3 and NO2 and these ambient pollutant concentrations in the 96 hours before the pre-exposure visit confounded the MOSES 1 controlled O3 exposure effects on the pre- to post-exposure biomarker changes (Aim 1), whether they modified these pre- to post-exposure biomarker responses to the controlled O3 exposures (Aim 2), whether they were associated with changes in biomarkers measured at the pre-exposure visit or morning of the exposure session (Aim 3), and whether they were associated with differences in the pre- to post-exposure biomarker changes independently of the controlled O3 exposures (Aim 4). RESULTS: Ambient pollutant concentrations at each site were low and were regularly below the National Ambient Air Quality Standard levels. In Aim 1, the controlled O3 exposure effects on the pre- to post-exposure biomarker differences were little changed when PES or ambient pollutant concentrations in the previous 96 hours were included in the model, suggesting these were not confounders of the controlled O3 exposure/biomarker difference associations. In Aim 2, effects of MOSES controlled O3 exposures on forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were modified by ambient NO2 and carbon monoxide (CO), and PES NO2, with reductions in FEV1 and FVC observed only when these concentrations were "Medium" or "High" in the 72 hours before the pre-exposure visit. There was no such effect modification of the effect of controlled O3 exposure on any other cardiopulmonary biomarker.As hypothesized for Aim 3, increased ambient O3 concentrations were associated with decreased pre-exposure heart rate variability (HRV). For example, high frequency (HF) HRV decreased in association with increased ambient O3 concentrations in the 96 hours before the pre-exposure visit (-0.460 ln[ms2]; 95% CI, -0.743 to -0.177 for each 10.35-ppb increase in O3; P = 0.002). However, in Aim 4 these increases in ambient O3 were also associated with increases in HF and low frequency (LF) HRV from pre- to post-exposure, likely reflecting a "recovery" of HRV during the MOSES O3 exposure sessions. Similar patterns across Aims 3 and 4 were observed for LF (the other primary HRV marker), and standard deviation of normal-to-normal sinus beat intervals (SDNN) and root mean square of successive differences in normal-to-normal sinus beat intervals (RMSSD) (secondary HRV markers).Similar Aim 3 and Aim 4 patterns were observed for FEV1 and FVC in association with increases in ambient PM with an aerodynamic diameter ≤ 2.5 µm (PM2.5), CO, and NO2 in the 96 hours before the pre-exposure visit. For Aim 3, small decreases in pre-exposure FEV1 were significantly associated with interquartile range (IQR) increases in PM2.5 concentrations in the 1 hour before the pre-exposure visit (-0.022 L; 95% CI, -0.037 to -0.006; P = 0.007), CO in the 3 hours before the pre-exposure visit (-0.046 L; 95% CI, -0.076 to -0.016; P = 0.003), and NO2 in the 72 hours before the pre-exposure visit (-0.030 L; 95% CI, -0.052 to -0.008; P = 0.007). However, FEV1 was not associated with ambient O3 or sulfur dioxide (SO2), or PES O3 or NO2 (Aim 3). For Aim 4, increased FEV1 across the exposure session (post-exposure minus pre-exposure) was marginally significantly associated with each 4.1-ppb increase in PES O3 concentration (0.010 L; 95% CI, 0.004 to 0.026; P = 0.010), as well as ambient PM2.5 and CO at all lag times. FVC showed similar associations, with patterns of decreased pre-exposure FVC associated with increased PM2.5, CO, and NO2 at most lag times, and increased FVC across the exposure session also associated with increased concentrations of the same pollutants, reflecting a similar recovery. However, increased pollutant concentrations were not associated with adverse changes in pre-exposure levels or pre- to post-exposure changes in biomarkers of cardiac repolarization, ST segment, vascular function, nitrotyrosine as a measure of oxidative stress, prothrombotic state, systemic inflammation, lung injury, or sputum polymorphonuclear leukocyte (PMN) percentage as a measure of airway inflammation. CONCLUSIONS: Our previous MOSES 1 findings of controlled O3 exposure effects on pulmonary function, but not on any cardiovascular biomarker, were not confounded by ambient or personal O3 or other pollutant exposures in the 96 and 72 hours before the pre-exposure visit. Further, these MOSES 1 O3 effects were generally not modified, blunted, or lessened by these same ambient and personal pollutant exposures. However, the reductions in markers of pulmonary function by the MOSES 1 controlled O3 exposure were modified by ambient NO2 and CO, and PES NO2, with reductions observed only when these pollutant concentrations were elevated in the few hours and days before the pre-exposure visit. Increased ambient O3 concentrations were associated with reduced HRV, with "recovery" during exposure visits. Increased ambient PM2.5, NO2, and CO were associated with reduced pulmonary function, independent of the MOSES-controlled O3 exposures. Increased pollutant concentrations were not associated with pre-exposure or pre- to post-exposure changes in other cardiopulmonary biomarkers. Future controlled exposure studies should consider the effect of ambient pollutants on pre-exposure biomarker levels and whether ambient pollutants modify any health response to a controlled pollutant exposure.

Multicenter Ozone Study in oldEr Subjects (MOSES): Part 1. Effects of Exposure to Low Concentrations of Ozone on Respiratory and Cardiovascular Outcomes.

INTRODUCTION: Exposure to air pollution is a well-established risk factor for cardiovascular morbidity and mortality. Most of the evidence supporting an association between air pollution and adverse cardiovascular effects involves exposure to particulate matter (PM). To date, little attention has been paid to acute cardiovascular responses to ozone, in part due to the notion that ozone causes primarily local effects on lung function, which are the basis for the current ozone National Ambient Air Quality Standards (NAAQS). There is evidence from a few epidemiological studies of adverse health effects of chronic exposure to ambient ozone, including increased risk of mortality from cardiovascular disease. However, in contrast to the well-established association between ambient ozone and various nonfatal adverse respiratory effects, the observational evidence for impacts of acute (previous few days) increases in ambient ozone levels on total cardiovascular mortality and morbidity is mixed.Ozone is a prototypic oxidant gas that reacts with constituents of the respiratory tract lining fluid to generate reactive oxygen species (ROS) that can overwhelm antioxidant defenses and cause local oxidative stress. Pathways by which ozone could cause cardiovascular dysfunction include alterations in autonomic balance, systemic inflammation, and oxidative stress. These initial responses could lead ultimately to arrhythmias, endothelial dysfunction, acute arterial vasoconstriction, and procoagulant activity. Individuals with impaired antioxidant defenses, such as those with the null variant of glutathione S-transferase mu 1 (GSTM1), may be at increased risk for acute health effects.The Multicenter Ozone Study in oldEr Subjects (MOSES) was a controlled human exposure study designed to evaluate whether short-term exposure of older, healthy individuals to ambient levels of ozone induces acute cardiovascular responses. The study was designed to test the a priori hypothesis that short-term exposure to ambient levels of ozone would induce acute cardiovascular responses through the following mechanisms: autonomic imbalance, systemic inflammation, and development of a prothrombotic vascular state. We also postulated a priori the confirmatory hypothesis that exposure to ozone would induce airway inflammation, lung injury, and lung function decrements. Finally, we postulated the secondary hypotheses that ozone-induced acute cardiovascular responses would be associated with: (a) increased systemic oxidative stress and lung effects, and (b) the GSTM1-null genotype. METHODS: The study was conducted at three clinical centers with a separate Data Coordinating and Analysis Center (DCAC) using a common protocol. All procedures were approved by the institutional review boards (IRBs) of the participating centers. Healthy volunteers 55 to 70 years of age were recruited. Consented participants who successfully completed the screening and training sessions were enrolled in the study. All three clinical centers adhered to common standard operating procedures (SOPs) and used common tracking and data forms. Each subject was scheduled to participate in a total of 11 visits: screening visit, training visit, and three sets of exposure visits, each consisting of the pre-exposure day, the exposure day, and the post-exposure day. The subjects spent the night in a nearby hotel the night of the pre-exposure day.On exposure days, the subjects were exposed for three hours in random order to 0 ppb ozone (clean air), 70 ppb ozone, and 120 ppm ozone, alternating 15 minutes of moderate exercise with 15 minutes of rest. A suite of cardiovascular and pulmonary endpoints was measured on the day before, the day of, and up to 22 hours after, each exposure. The endpoints included: (1) electrocardiographic changes (continuous Holter monitoring: heart rate variability [HRV], repolarization, and arrhythmia); (2) markers of inflammation and oxidative stress (C-reactive protein [CRP], interleukin-6 [IL-6], 8-isoprostane, nitrotyrosine, and P-selectin); (3) vascular function measures (blood pressure [BP], flow-mediated dilatation [FMD] of the brachial artery, and endothelin-1 [ET-1]; (4) venous blood markers of platelet activation, thrombosis, and microparticle-associated tissue factor activity (MP-TFA); (5) pulmonary function (spirometry); (6) markers of airway epithelial cell injury (increases in plasma club cell protein 16 [CC16] and sputum total protein); and (7) markers of lung inflammation in sputum (polymorphonuclear leukocytes [PMN], IL-6, interleukin-8 [IL-8], and tumor necrosis factor-alpha [TNF-α]). Sputum was collected only at 22 hours after exposure.The analyses of the continuous electrocardiographic monitoring, the brachial artery ultrasound (BAU) images, and the blood and sputum samples were carried out by core laboratories. The results of all analyses were submitted directly to the DCAC.The variables analyzed in the statistical models were represented as changes from pre-exposure to post-exposure (post-exposure minus pre-exposure). Mixed-effect linear models were used to evaluate the impact of exposure to ozone on the prespecified primary and secondary continuous outcomes. Site and time (when multiple measurements were taken) were controlled for in the models. Three separate interaction models were constructed for each outcome: ozone concentration by subject sex; ozone concentration by subject age; and ozone concentration by subject GSTM1 status (null or sufficient). Because of the issue of multiple comparisons, the statistical significance threshold was set a priori at P < 0.01. RESULTS: Subject recruitment started in June 2012, and the first subject was randomized on July 25, 2012. Subject recruitment ended on December 31, 2014, and testing of all subjects was completed by April 30, 2015. A total of 87 subjects completed all three exposures. The mean age was 59.9 ± 4.5 years, 60% of the subjects were female, 88% were white, and 57% were GSTM1 null. Mean baseline body mass index (BMI), BP, cholesterol (total and low-density lipoprotein), and lung function were all within the normal range.We found no significant effects of ozone exposure on any of the primary or secondary endpoints for autonomic function, repolarization, ST segment change, or arrhythmia. Ozone exposure also did not cause significant changes in the primary endpoints for systemic inflammation (CRP) and vascular function (systolic blood pressure [SBP] and FMD) or secondary endpoints for systemic inflammation and oxidative stress (IL-6, P-selectin, and 8-isoprostane). Ozone did cause changes in two secondary endpoints: a significant increase in plasma ET-1 (P = 0.008) and a marginally significant decrease in nitrotyrosine (P = 0.017). Lastly, ozone exposure did not affect the primary prothrombotic endpoints (MP-TFA and monocyte-platelet conjugate count) or any secondary markers of prothrombotic vascular status (platelet activation, circulating microparticles [MPs], von Willebrand factor [vWF], or fibrinogen.).Although our hypothesis focused on possible acute cardiovascular effects of exposure to low levels of ozone, we recognized that the initial effects of inhaled ozone involve the lower airways. Therefore, we looked for: (a) changes in lung function, which are known to occur during exposure to ozone and are maximal at the end of exposure; and (b) markers of airway injury and inflammation. We found an increase in forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) after exposure to 0 ppb ozone, likely due to the effects of exercise. The FEV1 increased significantly 15 minutes after 0 ppb exposure (85 mL; 95% confidence interval [CI], 64 to 106; P < 0.001), and remained significantly increased from pre-exposure at 22 hours (45 mL; 95% CI, 26 to 64; P < 0.001). The increase in FVC followed a similar pattern. The increase in FEV1 and FVC were attenuated in a dose-response manner by exposure to 70 and 120 ppb ozone. We also observed a significant ozone-induced increase in the percentage of sputum PMN 22 hours after exposure at 120 ppb compared to 0 ppb exposure (P = 0.003). Plasma CC16 also increased significantly after exposure to 120 ppb (P < 0.001). Sputum IL-6, IL-8, and TNF-α concentrations were not significantly different after ozone exposure. We found no significant interactions with sex, age, or GSTM1 status regarding the effect of ozone on lung function, percentage of sputum PMN, or plasma CC16. CONCLUSIONS: In this multicenter clinical study of older healthy subjects, ozone exposure caused concentration-related reductions in lung function and presented evidence for airway inflammation and injury. However, there was no convincing evidence for effects on cardiovascular function. Blood levels of the potent vasoconstrictor, ET-1, increased with ozone exposure (with marginal statistical significance), but there were no effects on BP, FMD, or other markers of vascular function. Blood levels of nitrotyrosine decreased with ozone exposure, the opposite of our hypothesis. Our study does not support acute cardiovascular effects of low-level ozone exposure in healthy older subjects. Inclusion of only healthy older individuals is a major limitation, which may affect the generalizability of our findings. We cannot exclude the possibility of effects with higher ozone exposure concentrations or more prolonged exposure, or the possibility that subjects with underlying vascular disease, such as hypertension or diabetes, would show effects under these conditions.

Childhood exposure to ambient polycyclic aromatic hydrocarbons is linked to epigenetic modifications and impaired systemic immunity in T cells.

BACKGROUND: Evidence suggests that exposure to polycyclic aromatic hydrocarbons (PAHs) increases atopy; it is unclear how PAH exposure is linked to increased severity of atopic diseases. OBJECTIVE: We hypothesized that ambient PAH exposure is linked to impairment of immunity in atopic children (defined as children with asthma and/or allergic rhinitis) from Fresno, California, an area with elevated ambient PAHs. METHODS: We recruited 256 subjects from Fresno, CA. Ambient PAH concentrations (ng/m(3) ) were measured using a spatial-temporal regression model over multiple time periods. Asthma diagnosis was determined by current NHLBI criteria. Phenotyping and functional immune measurements were performed from isolated cells. For epigenetic measurements, DNA was isolated and pyrosequenced. RESULTS: We show that higher average PAH exposure was significantly associated with impaired Treg function and increased methylation in the forkhead box protein 3 (FOXP3) locus (P < 0.05), conditional on atopic status. These epigenetic modifications were significantly linked to differential protein expression of FOXP3 (P < 0.001). Methylation was associated with cellular functional changes, specifically Treg dysfunction, and an increase in total plasma IgE levels. Protein expression of IL-10 decreased and IFN-γ increased as the extent of PAH exposure increased. The strength of the associations generally increased as the time window for average PAH exposure increased from 24 hr to 1 year, suggesting more of a chronic response. Significant associations with chronic PAH exposure and immune outcomes were also observed in subjects with allergic rhinitis. CONCLUSIONS AND CLINICAL RELEVANCE: Collectively, these results demonstrate that increased ambient PAH exposure is associated with impaired systemic immunity and epigenetic modifications in a key locus involved in atopy: FOXP3, with a higher impact on atopic children. The results suggest that increased atopic clinical symptoms in children could be linked to increased PAH exposure in air pollution.

Household air pollution and COPD: cause and effect or confounding by other aspects of poverty?

SETTING: Household air pollution (HAP) and chronic obstructive pulmonary disease (COPD) are both major public health problems, reported to cause around 4 million and 3 million deaths every year, respectively. The great majority of these deaths, as well as the burden of disease during life is felt by people in low- and middle-income countries (LMICs).OBJECTIVE and DESIGN: The extent to which HAP causes COPD is controversial; we therefore undertook this review to offer a viewpoint on this from the Global Initiative for COPD (GOLD).RESULTS: We find that while COPD is well-defined in many studies on COPD and HAP, there are major limitations to the definition and measurement of HAP. It is thus difficult to disentangle HAP from other features of poverty that are themselves associated with COPD. We identify other limitations to primary research studies, including the use of cross-sectional designs that limit causal inference.CONCLUSION: There is substantial preventable morbidity and mortality associated with HAP, COPD and poverty, separately and together. Although it may not be possible to define clear causal links between HAP and COPD, there is a clear urgency to reduce the avoidable burden of disease these inflict on the world´s poor.

Chronic respiratory disease in adult outpatients in three African countries: a cross-sectional study.

BACKGROUND: The greatest burden of chronic respiratory disease is in low- and middle-income countries, with recent population-based studies reporting substantial levels of obstructive and restrictive lung function.OBJECTIVE: To characterise the common chronic respiratory diseases encountered in hospital outpatient clinics in three African countries.METHODS This was a cross-sectional study of consecutive adult patients with chronic respiratory symptoms (>8 weeks) attending hospital outpatient departments in Ethiopia, Kenya and Sudan. Patients were assessed using a respiratory questionnaire, spirometry and chest radiography. The diagnoses of the reviewing clinicians were ascertained.RESULT: A total of 519 patients (209 Kenya, 170 Ethiopia, 140 Sudan) participated; the mean age was 45.2 years (SD 16.2); 53% were women, 83% had never smoked. Reviewing clinicians considered that 36% (95% CI 32-40) of patients had asthma, 25% (95% CI 21-29) had chronic bronchitis, 8% (95% CI 6-11) chronic obstructive pulmonary disease (COPD), 5% (95% CI 4-8) bronchiectasis and 4% (95% CI 3-6) post-TB lung disease. Spirometry consistent with COPD was present in 35% (95% CI 30-39). Restriction was evident in 38% (95% CI 33-43). There was evidence of sub-optimal diagnosis of asthma and COPD.CONCLUSION: In Ethiopia, Kenya and Sudan, asthma, COPD and chronic bronchitis account for the majority of diagnoses in non-TB patients with chronic respiratory symptoms. The suboptimal diagnosis of these conditions will require the widespread use of spirometry.

Intervention study to improve smoking cessation during hospitalization.

OBJECTIVES: In France, hospitals have been smoke free since February 2007. A period of hospitalization may be a good time to enhance a smoker's motivation to quit. This study aimed to assess whether training medical staff in smoking cessation management might improve the rate of smoking cessation during hospitalization. STUDY DESIGN: Non-randomized intervention study. METHODS: Staff of the participating care units either received (intervention group) or did not receive (control group) training in smoking cessation management. The dependent variable was the proportion of inpatients that continued to smoke before (Period 1) and after (Period 2) the training session. RESULTS: In total, 358 patients were included. In Period 1, 55.6% and 50% of the smokers from the intervention and control groups stopped smoking, respectively; the corresponding rates in Period 2 were 64.3% and 48.1%. In Period 2, 36.4% and 31.8% of the smokers from the intervention and control groups claimed that they had received motivational counselling. In the intervention group, the request rate for nicotine replacement therapy (NRT) was higher (41.7%) compared with the control group (11.1%). In both groups, patients asked for NRT more often (P < 0.001) when they had received motivational counselling. CONCLUSIONS: This study was not able to demonstrate that training medical staff in smoking cessation management has a significant impact on smoking cessation in hospitalized smokers. The delivery of medium-intensity support to all smokers appears to be out of reach of physician/nurse teams. New strategies are needed, including a team specifically dedicated to the problems of addiction.

Diurnal variability of fine-particulate pollution concentrations: data from 14 low- and middle-income countries.

BACKGROUND: Scientific understanding of indoor air pollution is predominately based on research carried out in cities in high-income countries (HICs). Less is known about how pollutant concentrations change over the course of a typical day in cities in low- and middle-income countries (LMICs).OBJECTIVE: To understand how concentrations of fine particulate matter smaller than 2.5 microns in diameter (PM2.5) change over the course of the day outdoors (across a range of countries) and indoors (using measurements from Dhaka, Bangladesh).DESIGN: Data on PM2.5 concentrations were gathered from 779 households in Dhaka as part of the MCLASS II (Muslim Communities Learning About Second-hand Smoke in Bangladesh) project, and compared to outdoor PM2.5 concentrations to determine the temporal variation in exposure to air pollution. Hourly PM2.5 data from 23 cities in 14 LMICs, as well as London (UK), Paris (France) and New York (NY, USA), were extracted from publicly available sources for comparison.RESULTS: PM2.5 in homes in Dhaka demonstrated a similar temporal pattern to outdoor measurements, with greater concentrations at night than in the afternoon. This pattern was also evident in 19 of 23 LMIC cities.CONCLUSION: PM2.5 concentrations are greater at night than during the afternoon in homes in Dhaka. Diurnal variations in PM2.5 in LMICs is substantial and greater than in London, Paris or New York. This has implications for public health community approaches to health effects of air pollution in LMICs.

Air pollution interventions and respiratory health: a systematic review.

BACKGROUND: Indoor and ambient air pollution exposure is a major risk to respiratory health worldwide, particularly in low- and middle-income countries (LMICs). Interventional trials have mainly focused on alternatives to cooking stoves, with mixed results. Beyond cooking, additional sources of particulate matter also contribute to the burden of air pollution exposure. This review explores evidence from current randomised controlled trials (RCTs) on the clinical effectiveness of interventions to reduce particulate matter in LMICs.METHODS: Twelve databases and the grey literature (e.g., Government reports and policy papers) were searched. Eligible studies were RCTs conducted in LMICs aiming to reduce particulate exposure from any source and reporting on at least one clinical respiratory outcome (respiratory symptoms, lung function or clinical diagnoses). Data from relevant studies were systematically extracted, the risk of bias assessed and narrative synthesis provided.RESULTS: Of the 14 included studies, 12 tested 'improved' cookstoves, most using biomass, but solar and bioethanol cookers were also included. One trial used solar lamps and another was an integrated intervention incorporating behavioural and environmental components for the treatment and prevention of chronic obstructive pulmonary disease. Of the six studies reporting child pneumonia outcomes, none demonstrated significant benefit in intention-to-treat analysis. Ten studies reported respiratory symptom outcomes with some improvements seen, but self-reporting made these outcomes highly vulnerable to bias. Substantial inter-study clinical and methodological heterogeneity precluded calculation of pooled effect estimates.CONCLUSION: Evidence from the RCTs performed to date suggests that individual household-level interventions for air pollution exposure reduction have limited benefits for respiratory health. More comprehensive approaches to air pollution exposure reduction must be developed so their potential health benefits can be assessed.

Occupational exposures and the risk of COPD: dusty trades revisited.

BACKGROUND: The contribution of occupational exposures to chronic obstructive pulmonary disease (COPD) and, in particular, their potential interaction with cigarette smoking remains underappreciated. METHODS: Data from the FLOW study of 1202 subjects with COPD (of which 742 had disease classified as stage II or above by Global Obstructive Lung Disease (GOLD) criteria) and 302 referent subjects matched by age, sex and race recruited from a large managed care organisation were analysed. Occupational exposures were assessed using two methods: self-reported exposure to vapours, gas, dust or fumes on the longest held job (VGDF) and a job exposure matrix (JEM) for probability of exposure based on occupation. Multivariate analysis was used to control for age, sex, race and smoking history. The odds ratio (OR) and adjusted population attributable fraction (PAF) associated with occupational exposure were calculated. RESULTS: VGDF exposure was associated with an increased risk of COPD (OR 2.11; 95% CI 1.59 to 2.82) and a PAF of 31% (95% CI 22% to 39%). The risk associated with high probability of workplace exposure by JEM was similar (OR 2.27; 95% CI 1.46 to 3.52), although the PAF was lower (13%; 95% CI 8% to 18%). These estimates were not substantively different when the analysis was limited to COPD GOLD stage II or above. Joint exposure to both smoking and occupational factors markedly increased the risk of COPD (OR 14.1; 95% CI 9.33 to 21.2). CONCLUSIONS: Workplace exposures are strongly associated with an increased risk of COPD. On a population level, prevention of both smoking and occupational exposure, and especially both together, is needed to prevent the global burden of disease.

Performance of self-reported occupational exposure compared to a job-exposure matrix approach in asthma and chronic rhinitis.

OBJECTIVES: Self-reported exposure to vapours, gas, dust or fumes (VGDF) has been widely used as an occupational exposure metric in epidemiological studies of chronic lung diseases. Our objective was to characterise the performance of VGDF for repeatability, systematic misclassification, and sensitivity and specificity against exposure likelihood by a job-exposure matrix (JEM). METHODS: We analysed data from two interviews, 24 months apart, of adults with asthma and chronic rhinitis. Using distinct job as the unit of analysis, we tested a single response item (exposure to VGDF) against assignment using a JEM. We further analysed VGDF and the JEM among a subset of 199 subjects who reported the same job at both interviews, using logistic regression analysis to test factors associated with VGDF inconsistency and discordance with the JEM. RESULTS: VGDF was reported for 193 (44%) of 436 distinct jobs held by the 348 subjects studied; moderate to high exposure likelihood by JEM was assigned to 120 jobs (28%). The sensitivity and specificity of VGDF against JEM were 71% and 66%, respectively. Among 199 subjects with the same job at both interviews, 32% had a discordant VGDF status (kappa = 0.35). Those with chronic rhinitis without concomitant asthma compared to asthma alone were more likely to have a VGDF report discordant with the JEM (OR 3.6, 95% CI 1.4 to 9.0; p = 0.01). Rhinitis was also associated with reported VGDF in a job classified by the JEM as low exposure (OR 3.9, 95% CI 1.6 to 9.4; p = 0.003). CONCLUSION: The VGDF item is moderately sensitive measured against JEM as a benchmark. The measure is a useful assessment method for epidemiological studies of occupational exposure risk.

Machine-learned modeling of PM2.5 exposures in rural Lao PDR.

This study presents a machine-learning-enhanced method of modeling PM2.5 personal exposures in a data-scarce, rural, solid fuel use context. Data collected during a cookstove (Africa Clean Energy (ACE)-1 solar-battery-powered stove) intervention program in rural Lao PDR are presented and leveraged to explore advanced techniques for predicting personal exposures to particulate matter with aerodynamic diameter smaller than 2.5 µm (PM2.5). Mean 48-h PM2.5 exposure concentrations for female cooks were measured for the pre- and post-intervention periods (the "Before" and "After" periods, respectively) as 123 µg/m3 and 81 µg/m3. Mean 48-h PM2.5 kitchen air pollution ("KAP") concentrations were measured at 462 µg/m3 Before and 124 µg/m3 After. Application of machine learning and ensemble modeling demonstrated cross-validated personal exposure predictions that were modest at the individual level but reasonably strong at the group level, with the best models producing an observed vs. predicted r2 between 0.26 and 0.31 (r2 = 0.49 when using a smaller, un-imputed dataset) and mean Before estimates of 119-120 µg/m3 and After estimates of 86-88 µg/m3. This offered improvement over one typical method of predicting exposure - using a kitchen exposure factor (the ratio of exposure to KAP)- which demonstrated an r2 ~ 0.03 and poorly estimated group average values. The results of these analyses highlight areas of methodological improvement for future exposure assessments of household air pollution and provide evidence for researchers to explore the advantages of further incorporating machine learning methods into similar research across wider geographic and cultural contexts.

Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial.

BACKGROUND: Evidence has accumulated from observational studies that people eating more fruits and vegetables, which are rich in beta-carotene (a violet to yellow plant pigment that acts as an antioxidant and can be converted to vitamin A by enzymes in the intestinal wall and liver) and retinol (an alcohol chemical form of vitamin A), and people having higher serum beta-carotene concentrations had lower rates of lung cancer. The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate (vitamin A) taken daily against placebo in 18314 men and women at high risk of developing lung cancer. The CARET intervention was stopped 21 months early because of clear evidence of no benefit and substantial evidence of possible harm; there were 28% more lung cancers and 17% more deaths in the active intervention group (active = the daily combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate). Promptly after the January 18, 1996, announcement that the CARET active intervention had been stopped, we published preliminary findings from CARET regarding cancer, heart disease, and total mortality. PURPOSE: We present for the first time results based on the pre-specified analytic method, details about risk factors for lung cancer, and analyses of subgroups and of factors that possibly influence response to the intervention. METHODS: CARET was a randomized, double-blinded, placebo-controlled chemoprevention trial, initiated with a pilot phase and then expanded 10-fold at six study centers. Cigarette smoking history and status and alcohol intake were assessed through participant self-report. Serum was collected from the participants at base line and periodically after randomization and was analyzed for beta-carotene concentration. An Endpoints Review Committee evaluated endpoint reports, including pathologic review of tissue specimens. The primary analysis is a stratified logrank test for intervention arm differences in lung cancer incidence, with weighting linearly to hypothesized full effect at 24 months after randomization. Relative risks (RRs) were estimated by use of Cox regression models; tests were performed for quantitative and qualitative interactions between the intervention and smoking status or alcohol intake. O'Brien-Fleming boundaries were used for stopping criteria at interim analyses. Statistical significance was set at the .05 alpha value, and all P values were derived from two-sided statistical tests. RESULTS: According to CARET's pre-specified analysis, there was an RR of 1.36 (95% confidence interval [CI] = 1.07-1.73; P = .01) for weighted lung cancer incidence for the active intervention group compared with the placebo group, and RR = 1.59 (95% CI = 1.13-2.23; P = .01) for weighted lung cancer mortality. All subgroups, except former smokers, had a point estimate of RR of 1.10 or greater for lung cancer. There are suggestions of associations of the excess lung cancer incidence with the highest quartile of alcohol intake (RR = 1.99; 95% CI = 1.28-3.09; test for heterogeneity of RR among quartiles of alcohol intake has P = .01, unadjusted for multiple comparisons) and with large-cell histology (RR = 1.89; 95% CI = 1.09-3.26; test for heterogeneity among histologic categories has P = .35), but not with base-line serum beta-carotene concentrations. CONCLUSIONS: CARET participants receiving the combination of beta-carotene and vitamin A had no chemopreventive benefit and had excess lung cancer incidence and mortality. The results are highly consistent with those found for beta-carotene in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study in 29133 male smokers in Finland.

The beta-carotene and retinol efficacy trial (CARET) for chemoprevention of lung cancer in high risk populations: smokers and asbestos-exposed workers.

CARET is a multicenter, two-armed, double-masked randomized chemoprevention trial in Seattle, Portland, San Francisco, Baltimore, Connecticut, and Irvine, to test whether oral administration of beta-carotene (30 mg/day) plus retinyl palmitate (25,000 IU/day) can decrease the incidence of lung cancer in high risk populations, namely, heavy smokers and asbestos-exposed workers. The intervention combines the antioxidant action of beta-carotene and the tumor suppressor mechanism of vitamin A. As of April 30, 1993, CARET had randomized 1,845 participants in the 1985-1988 pilot phase plus 13,260 "efficacy" participants since 1989; of these, 4,000 are asbestos-exposed males and 11,105 are smokers and former smokers (44% female). Accrual is complete everywhere except Irvine, which was the last center added (1991), and the safety profile of the regimen to date has been excellent. With 14,420 smokers, 4,010 asbestos-exposed participants, and 114,100 person-years through February 1998, we expect CARET to be capable of detecting a 23% reduction in lung cancer incidence in the two populations combined and 27, 49, 32, and 35% reductions in the smokers, female smokers, male smokers, and asbestos-exposed subgroups, respectively. CARET is highly complementary to the alpha-tocopherol-beta-carotene study in Finland and the Harvard Physicians Health Study (beta-carotene alone) in the National Cancer Institute portfolio of major cancer chemoprevention trials.

Contraction of human colonic circular smooth muscle cells is inhibited by the calcium channel blocker pinaverium bromide.

UNLABELLED: The effects of L-type calcium channel blockers (CCBs) selective for the gastrointestinal tract (pinaverium) or non-selective (nicardipine and diltiazem), were investigated on CCK-, CCh- or KCl-induced contraction of smooth muscle cells (SMC) isolated from the circular muscle layer of normal or of inflamed human colons. In the normal tissue colon, whatever the contractile agent used, CCK-8 (1nM), CCh (1nM) or KCl (20mM), a micromolar concentration of pinaverium significantly inhibited contraction (88.36%, 93.10%, 93.92% inhibition respectively); this effect was concentration-dependent for CCh (IC50 = 0.73 +/- 0.08nM) and for CCK (IC50 = 0.92 +/- 0.12nM). In parallel, both nicardipine and diltiazem inhibit significantly contraction of isolated SMC. In inflamed colons, pinaverium (1 microM) display a significant higher efficacy than diltiazem or nicardipine to reduce cell contraction induced by CCK-8 or by KCl. In addition, RT-PCR experiments were performed to evidence tissue specificity of the L-type calcium channel. They revealed the expression of the messenger of the a-1 subunit L-type calcium channel (binding site of such CCBs), consistent with the expression of the rbC-2 splice variant of the alpha1-C gene. IN CONCLUSION: (i) the inhibition by calcium channel blockers of agonist-induced contractile activity suggest a modulation of SMC contraction upon extracellular calcium via 'L-type' voltage-dependent calcium channel; (ii) this study provides a rationale for the clinical use of pinaverium in colonic motor disoders affecting the contractility of SMC, since it appeared to decrease the contraction even in pathological situation; and (iii) RT-PCR experiments confirms the presence in human colon SMC of the alpha-1 subunit mRNA of calcium channel.

Impaired fibrinolytic capacity in patients with inflammatory bowel disease.

The venous occlusion test was applied to 17 patients with inflammatory bowel disease (IBD; 7 cases of Crohn's disease, 10 cases of ulcerative colitis). Results were compared to those obtained in 20 healthy matched control subjects. Patients with IBD had significantly decreased t-PA Ag release (p less than 0.001) and had no significant vWF Ag release. Residual PAI activity was evidenced after venous stasis in the IBD group but not in the control group. Hypofibrinolysis was more important in patients with an evolutive IBD than in patients with IBD in remission. Impaired systemic fibrinolytic capacity might contribute to an increased risk for thromboembolic complications and to the pathogenesis of inflammatory bowel disease.

Calcitonin gene-related peptide-induced relaxation of isolated human colonic smooth muscle cells through different intracellular pathways.

Calcitonin gene-related peptide (CGRP) plays a significant role in the non-adrenergic non-cholinergic (NANC) regulation of intestinal tract motility. In this work, the contractile properties of enzymatically isolated circular smooth muscle cells (SMC) from human colon in response to CGRP were evaluated. Relaxation by CGRP (1 microM) was determined in cells maximally contracted by carbachol (CCh, 1 nM). Simultaneously, cGMP contents of SMC were measured by radioimmunoassay. CCh-induced contraction was inhibited by 1 microM CGRP (maximum: 69+/-5% within 60 sec); similarly, exposure of cells to sodium nitroprussiate (SNP), 1 microM, fully inhibited contraction (maximum: 89+/-8% within 30 sec). In the same time-course as for relaxation, CGRP and sodium nitroprussiate caused significant increase in intracellular cGMP levels (2- and 10-fold that of the basal level, respectively, P < 0.01). The nitric oxide synthase (NOS) inhibitor, L-N5(I-iminoethyl)ornithine, dihydrochloride, (L-NIO), 1 microM, partly inhibited SMC relaxation induced by CGRP (78.26%); the protein kinase inhibitor, N-(2-aminoethyl)-5-isoquinolinesulfonamide hydrochloride (H9), 1 microM, and the selective cAMP-dependent protein kinase inhibitor, adenosine-3',5'-monophosphorothioate triethylammonium salt, Rp isomer, (Rp-cAMP(S)), 1 microM, also caused inhibition of relaxation (70.30% and 28.6%, respectively). In parallel, the increase in cGMP caused by CGRP was partly reduced by L-NIO (65.47%) and by H9 (55%). In conclusion, the nitric oxide generation following exposure of human colonic SMC to sodium nitroprussiate causes relaxation through the cGMP pathway; on the other hand, exposure of SMC to CGRP causes relaxation in part by activation of nitric oxide synthase and guanylate cyclase and in part through the cAMP pathway.

The role of ozone exposure in the epidemiology of asthma.

Asthma is a clinical condition characterized by intermittent respiratory symptoms, nonspecific airway hyperresponsiveness, and reversible airway obstruction. Although the pathogenesis of asthma is incompletely understood, it is clear that airway inflammation is a paramount feature of the condition. Because inhalation of ozone by normal, healthy subjects causes increased airway responsiveness and inflammation, it is somewhat surprising that most controlled human exposure studies that have involved asthmatic subjects have not shown them to be especially sensitive to ozone. The acute decrement in lung function that is the end point traditionally used to define sensitivity to ozone in these studies may be due more to neuromuscular mechanisms limiting deep inspiration than to bronchoconstriction. The frequency of asthma attacks following ozone exposures may be a more relevant end point. Epidemiologic studies, rather than controlled human exposure studies, are required to determine whether ozone pollution increases the risk of asthma exacerbations. Asthma affects approximately 10 million people in the United States and, thus, the answer to this question is of considerable public health importance. Both the prevalence and severity of asthma appear to be increasing in many countries. Although increased asthma morbidity and mortality are probably of multifactorial etiology, a contributory role of urban air pollution is plausible. The epidemiologic database to support an association between asthma and ozone exposure is limited, but the results of several studies suggest such an association. Some potential approaches to further investigation of the relationship between asthma and ozone, including those that would link controlled human exposures to population-based studies, are considered.

Occupational asthma: a review.

Occupational asthma is the most common form of occupational lung disease in the developed world at the present time. In this review, the epidemiology, pathogenesis/mechanisms, clinical presentations, management, and prevention of occupational asthma are discussed. The population attributable risk of asthma due to occupational exposures is considerable. Current understanding of the mechanisms by which many agents cause occupational asthma is limited, especially for low-molecular-weight sensitizers and irritants. The diagnosis of occupational asthma is generally established on the basis of a suggestive history of a temporal association between exposure and the onset of symptoms and objective evidence that these symptoms are related to airflow limitation. Early diagnosis, elimination of exposure to the responsible agent, and early use of inhaled steroids may play important roles in the prevention of long-term persistence of asthma. Persistent occupational asthma is often associated with substantial disability and consequent impacts on income and quality of life. Prevention of new cases is the best approach to reducing the burden of asthma attributable to occupational exposures. Future research needs are identified.