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Increased particulate matter (PM) air pollutant concentrations have been associated with platelet activation. It was postulated that elevated air pollutant concentrations would be associated with increases in measures of platelet function and that responses would be blunted when taking aspirin and/or fish oil. Data from a sequential therapy trial (30 subjects with type 2 diabetes mellitus), with 4 clinic visits (first: no supplements, second: aspirin, third: omega-3 fatty acid supplements, fourth: aspirin and omega-3 fatty acids) per subject, were utilized. Using linear mixed models, adjusted for relative humidity, temperature, visit number, and season, changes in three platelet function measures including (1) aggregation induced by adenosine diphosphate (ADP), (2) aggregation induced by collagen, and (3) thromboxane B2 production were associated with interquartile range (IQR) increases in mean concentrations of ambient PM2.5, black carbon, ultrafine particles (UFP; 10–100 nm), and accumulation mode particles (AMP; 100–500 nm) in the previous 1–96 h. IQR increases in mean UFP and AMP concentrations were associated with significant decreases in platelet response, with the largest being a –0.43 log(pg/ml) decrease in log(thromboxane B2) (95% CI = –0.8, –0.1) associated with each 582-particles/cm3increase in AMP, and a –1.7 ohm reduction in collagen-induced aggregation (95% CI = –3.1, –0.3) associated with each 2097-particles/cm3increase in UFP in the previous 72 h. This UFP effect on thromboxane B2 was significantly muted in diabetic subjects taking aspirin (–0.01 log[pg/ml]; 95% CI = –0.4, 0.3). The reason for this finding remains unknown, and needs to be investigated in future studies. [ABSTRACT FROM PUBLISHER]

Context: Exposure to ozone has acute respiratory effects, but few human clinical studies have evaluated cardiovascular effects. Objective: We hypothesized that ozone exposure alters pulmonary and systemic vascular function, and cardiac function, with more pronounced effects in subjects with impaired antioxidant defense from deletion of the glutathione- S-transferase M1 gene (GSTM1 null). Methods: Twenty-four young, healthy never-smoker subjects (12 GSTM1 null) inhaled filtered air, 100 ppb ozone and 200 ppb ozone for 3 h, with intermittent exercise, in a double-blind, randomized, crossover fashion. Exposures were separated by at least 2 weeks. Vital signs, spirometry, arterial and venous blood nitrite levels, impedance cardiography, peripheral arterial tonometry, estimation of pulmonary capillary blood volume (Vc), and blood microparticles and platelet activation were measured at baseline and during 4 h after each exposure. Results: Ozone inhalation decreased lung function immediately after exposure (mean ± standard error change in FEV1, air: −0.03 ± 0.04 L; 200 ppb ozone: −0.30 ± 0.07 L; p < 0.001). The immediate post-exposure increase in blood pressure, caused by the final 15-min exercise period, was blunted by 200 ppb ozone exposure (mean ± standard error change for air: 16.7 ± 2.6 mmHg; 100 ppb ozone: 14.5 ± 2.4 mmHg; 200 ppb ozone: 8.5 ± 2.5 mmHg; p = 0.02). We found no consistent effects of ozone on any other measure of cardiac or vascular function. All results were independent of the GSTM1 genotype. Conclusions: We did not find convincing evidence for early acute adverse cardiovascular consequences of ozone exposure in young healthy adults. The ozone-associated blunting of the blood pressure response to exercise is of unclear clinical significance. [ABSTRACT FROM AUTHOR]

Exposure to air pollution is associated with increased morbidity and mortality from cardiovascular disease. We hypothesized that increases in exposure to ambient air pollution are associated with platelet activation and formation of circulating tissue factor-expressing microparticles. We studied 19 subjects with type 2 diabetes, without clinical evidence of cardiovascular disease, who had previously participated in a human clinical study of exposure to ultrafine particles (UFP). Blood was obtained for measurements of platelet activation following an overnight stay in the Clinical Research Center, prior to each of their two pre-exposure visits. Air pollution and meteorological data, including UFP counts, were analyzed for the 5 days prior to the subjects' arrival at the Clinical Research Center. Contrary to expectations, increases in UFP were associated with decreases in surface expression of platelet activation markers. The number of platelet-leukocyte conjugates decreased by −80 (95% confidence interval (CI) −123 to −37, p = 0.001) on the first lag day (20-44 h prior to the blood draw) and by −85 (CI −139 to −31, p = 0.005) on combined lag days 1 to 5, per interquartile range (IQR) increase in UFP particle number (2482). However, levels of soluble CD40L increased 104 (CI 3 to 205, p = 0.04) pg/ml per IQR increase in UFP on lag day 1, a finding consistent with prior platelet activation. We speculate that, in people with diabetes, exposure to UFP activates circulating platelets within hours of exposure, followed by an increase in soluble CD40L and a rebound reduction in circulating platelet surface markers. [ABSTRACT FROM AUTHOR]

Exposure to particulate matter (PM) is associated with systemic health effects, but the cellular and molecular mechanisms are unclear. Objective: We hypothesized that, if circulating mononuclear cells play an important role in mediating systemic effects of PM, they would show gene expression changes following exposure. Materials and methods: Peripheral blood samples were collected before (0 h) and at 24 h from healthy subjects exposed to filtered air (FA) and ultrafine carbon particles (UFPs, 50 µg/m3) for 2 h in a previous study (n = 3 each). RNA from mononuclear cell fraction (>85% lymphocytes) was extracted, amplified and hybridized to Affymetrix HU133 plus 2 microarrays. Selected genes were confirmed in five additional subjects from the same study. Results: We identified 1713 genes (UFP 24 h vs. FA 0 and 24 h, P < 0.05, false discovery rate of 0.01). The top 10 upregulated genes (fold) were CDKN1C (1.86), ZNF12 (1.83), SRGAP2 (1.82), FYB (1.79), LSM14B (1.79), CD93 (1.76), NCSTN (1.70), DUSP6 (1.69), TACC1 (1.68), and H2AFY (1.68). Upregulation of CDKN1C and SRGAP2 was confirmed by real-time-PCR. We entered 1020 genes with a ratio >1.1 or <-1.1 into the Ingenuity Pathway Analysis and identified pathways related to inflammation, tissue growth and host defense against environmental insults, such as, insulin growth factor 1 signaling, insulin receptor signaling and NF-E2-related factor-2-mediated oxidative stress response pathway. Discussion and conclusions: Two-hour exposures to UFP produced gene expression changes in circulating mononuclear cells. These gene changes provide biologically plausible links to PM-induced systemic health effects, especially those in the cardiovascular system and glucose metabolism. [ABSTRACT FROM AUTHOR]

The U.S. Environmental Protection Agency (EPA), under the authority of the Clean Air Act (CAA), is required to promulgate National Ambient Air Quality Standards (NAAQSs) for criteria air pollutants, including ozone. Each NAAQS includes a primary health-based standard and a secondary or welfare-based standard. This paper considers only the science used for revision of the primary standard for ozone in 2008. This paper summarizes deliberations of a small group of scientists who met in June 2007 to review the scientific information informing the EPA Administrator’s proposed revision of the 1997 standard. The Panel recognized that there is no scientific methodology that, in the absence of judgment, can define the precise numerical level, related averaging time, and statistical form of the NAAQS. The selection of these elements of the NAAQS involves policy judgments that should be informed by scientific information and analyses. Thus, the Panel members did not feel it appropriate to offer either their individual or collective judgment on the specific numerical level of the NAAQS for ozone. The Panel deliberations focused on the scientific data available on the health effects of exposure to ambient concentrations of ozone, controlled ozone exposure studies with human volunteers, long-term epidemiological studies, time- series epidemiological studies, human panel studies, and toxicological investigations. The deliberations also dealt with the issue of background levels of ozone of nonanthropogenic origin and issues involved with conducting formal risk assessments of the health impacts of current and prospective levels of ambient ozone. The scientific issues that were central to the EPA Administrator’s 2008 revision of the NAAQS for ozone will undoubtedly also be critical to the next review of the ozone standard. That review should begin very soon if it is to be completed within the 5-year cycle specified in the CAA. It is hoped that this Report will stimulate discussion of these scientific issues, conduct of additional research, and conduct of new analyses that will provide an improved scientific basis for the policy judgment that will have to be made by a future EPA Administrator in considering potential revision of the ozone standard. [ABSTRACT FROM AUTHOR]

The mechanisms underlying the association between air pollution and cardiovascular morbidity and mortality are unknown. This study aimed to determine whether controlled exposure to elemental carbon ultrafine particles (UFP) affects electrocardiogram (ECG) parameters describing heart rate variability; repolarization duration, morphology, and variability; and changes in the ST segment. Two separate controlled studies (12 subjects each) were performed using a crossover design, in which each subject was exposed to filtered air and carbon UFP for 2 hours. The first protocol involved 2 exposures to air and 10 μg/m3 (∼ 2× 106 particles/cm3, count median diameter ∼25 nm, geometric standard deviation ∼1.6), at rest. The second protocol included 3 exposures to air, 10, and 25 μg/m3 UFP (∼ 7× 106 particles/cm3), with repeated exercise. Each subject underwent a continuous digital 12-lead ECG Holter recording to analyze the above ECG parameters. Repeated measures analysis of variance (ANOVA) was used to compare tested parameters between exposures. The observed responses to UFP exposure were small and generally not significant, although there were trends indicating an increase in parasympathetic tone, which is most likely also responsible for trends toward ST elevation, blunted QTc shortening, and increased variability of T-wave complexity after exposure to UFP. Recovery from exercise showed a blunted response of the parasympathetic system after exposure to UFP in comparison to air exposure. In conclusion, transient exposure to 10-25 μ g/m3 ultrafine carbon particles does not cause marked changes in ECG-derived parameters in young healthy subjects. However, trends are observed indicating that some subjects might be susceptible to air pollution, with a response involving autonomic modulation of the heart and repolarization of the ventricular myocardium. [ABSTRACT FROM AUTHOR]

Inhalation of ambient particulate matter increases the risk of cardiovascular disease. Clinical studies play an important role in elucidating mechanisms for pollutant effects, and in establishing ambient air quality standards. Ultrafine particles (UFP; diameter <100 nm) may be important in the cardiovascular effects of ambient PM, yet there are few clinical studies of UFP health effects. Our laboratory has developed an exposure facility for clinical studies of laboratory-generated UFP. We confirmed previous predictions that UFP <50 nm in diameter deposit in the respiratory tract with a high efficiency, and have shown that exercise or the presence of asthma further increases UFP deposition. UFP exposure with exercise reduced expression of selected adhesion molecules on blood leukocytes, and also decreased the pulmonary diffusing capacity for carbon monoxide. These findings are best explained by UFP effects on pulmonary vascular function. These findings provide a possible mechanism by which inhalation of UFP may contribute to cardiopulmonary health effects in susceptible people. [ABSTRACT FROM AUTHOR]

Air exhaled by cigarette smokers contains reduced amounts of nitric oxide (NO). Measurement of NO at different expiratory flow rates permits calculation of NO production by the conducting airways (VawNO) and alveolar concentration of NO (PALV). An independent measurement of diffusing capacity of the alveolar compartment (DLNO) multiplied by PALV allows calculation of NO production by the alveoli (VLNO). Twelve asymptomatic cigarette smokers and 22 age-matched nonsmokers had measurements of DLNO and expired NO at constant expiratory flow rates varying from 60 to 1500 ml/s. VawNO in smokers was only 22 ± 11 nl/min (mean ± standard deviation, SD) compared to 70 ± 37 nl/min in nonsmokers (p < .0001). In contrast, VLNO showed no significant difference (smokers: 203 ± 104 nl/min, nonsmokers: 209 ± 74 nl/min, p = .86). These data show that the diminished NO expired by smokers results from diminished NO production by the tissues of the conducting airways but normal values produced by the alveoli. [ABSTRACT FROM AUTHOR]

Particulate air pollution is associated with asthma exacerbations and increased morbidity and mortality from respiratory causes. Ultrafine particles (particles less than 0.1 μm in diameter) may contribute to these adverse effects because they have a higher predicted pulmonary deposition, greater potential to induce pulmonary inflammation, larger surface area, and enhanced oxidant capacity when compared with larger particles on a mass basis. We hypothesized that ultrafine particle exposure would induce airway inflammation in susceptible humans. This hypothesis was tested in a series of randomized, double-blind studies by exposing healthy subjects and mild asthmatic subjects to carbon ultrafine particles versus filtered air. Both exposures were delivered via a mouthpiece system during rest and moderate exercise. Healthy subjects were exposed to particle concentrations of 10, 25, and 50 μg/m 3 , while asthmatics were exposed to 10 μg/m 3 . Lung function and airway inflammation were assessed by symptom scores, pulmonary function tests, and airway nitric oxide parameters. Airway inflammatory cells were measured via induced sputum analysis in several of the protocols. There were no differences in any of these measurements in normal or asthmatic subjects when exposed to ultrafine particles at concentrations of 10 or 25 μg/m 3 . However, exposing 16 normal subjects to the higher concentration of 50 μg/m 3 caused a reduction in maximal midexpiratory flow rate (-4.34 ± 1.78% [ultrafine particles] vs. +1.08 ± 1.86% [air], p = .042) and carbon monoxide diffusing capacity (-1.76 ± 0.66 ml/min/mm Hg [ultrafine particles] vs. -0.18 ± 0.41 ml/min/mm Hg [air], p = .040) at 21 h after exposure. There were no consistent differences in symptoms, induced sputum, or exhaled nitric oxide parameters in any of these studies. These results suggest that exposure to carbon ultrafine particles results in mild small-airways dysfunction together with impaired alveolar gas exchange in normal subjects. These effects do not appear related to airway inflammation. Additional studies are required to confirm these findings in normal subjects, compare them with additional susceptible patient populations, and determine their pathophysiologic mechanisms. [ABSTRACT FROM AUTHOR]

Ultrafine particles (diameter < 100 nm) may be important in the health effects of air pollution, in part because of their predicted high respiratory deposition. However, there are few measurements of ultrafine particle deposition during spontaneous breathing. The fractional deposition for the total respiratory tract of ultrafine carbon particles (count median diameter = 26 nm, geometric standard deviation = 1.6) was measured in 12 healthy subjects (6 female, 6 male) at rest (minute ventilation 9.0 ± 1.3 L/min) using a mouthpiece exposure system. The mean ± SD fractional deposition was 0.66 ± 0.11 by particle number and 0.58 ± 0.13 by particle mass concentration, similar to model predictions. The number deposition fraction increased as particle size decreased, reaching 0.80 ± 0.09 for the smallest particles (midpoint count median diameter = 8.7 nm). No gender differences were observed. In an additional 7 subjects (2 female, 5 male) alternating rest with moderate exercise (minute ventilation 38.1 ± 9.5 L/min), the deposition fraction during exercise increased to 0.83 ± 0.04 and 0.76 ± 0.06 by particle number and mass concentration, respectively, and reached 0.94 ± 0.02 for the smallest particles. Experimental deposition data exceeded model predictions during exercise. The total number of deposited particles was more than 4.5-fold higher during exercise than at rest because of the combined increase in deposition fraction and minute ventilation. Fractional deposition of ultrafine particles during mouth breathing is high in healthy subjects, and increases further with exercise. [ABSTRACT FROM AUTHOR]

A recent series of epidemiologic reports have shown associations between fine particulate matter (PM) levels and increased cardiovascular morbidity and mortality. Elevated PM levels have been linked with cardiac events, including serious ventricular arrhythmias and myocardial infarction. A workshop brought together epidemiologists, cardiologists, and toxicologists from academia, government, and industry to examine plausible mechanisms that could be responsible for such effects, and to consider the armamentarium of noninvasive tests available to examine these relationships. Possible mechanisms considered by the participants include: (a) effects on the autonomic nervous system; (b) alterations on ion channel function in myocardial cells; (c) ischemic responses in the myocardium; and (d) inflammatory responses triggering endothelial dysfunction, atherosclerosis, and thrombosis. A large number of tests were identified to assess specific mechanistic pathways underlying the cardiovascular effects of air pollution and include: (a) autonomic control of the cardiovascular system assessed primarily by heart-rate variability; (b) myocardial substrate and vulnerability assessed by the electrocardiogram and estimations of ejection fraction and wall motion abnormalities in imaging studies; and (c) endothelial function, atherosclerosis, and thrombosis assessed by clotting parameters, cytokines, lipid profiles, and forearm blood flow. A variety of approaches ranging from molecular and genetic investigations to human clinical studies were recommended to further investigate the important epidemiologic associations. [ABSTRACT FROM AUTHOR]

Exposure to ozone injures respiratory epithelium, and the mechanisms may involve the generation of reactive oxygen species (ROS). This study tested the hypothesis that ozone exposure increases the airway burden of ROS to a greater degree in smokers than nonsmokers, and that this effect is independent of ozone-induced changes in spirometry. Healthy subjects were selected as either responders (decrement in FEV[sub 1] > 15%) or non responders (decrement in FEV[sub 1] < 5%) to ozone; each underwent 2 exposures to ozone and 1 to air, with bronchoalveolar lavage (BAL) performed 30 min (early) and 18 h (late) after exposure. Release of superoxide anion (O[sub 2][sup -]) was used as a measure of ROS release by all BAL cells, and flow cytometry was used to detect ROS production in alveolar macrophages (AM) only. Recovery of AM was approximately threefold greater in smokers than nonsmokers. Unstimulated, but not stimulated, cells obtained by BAL from smokers released approximately twofold greater amounts of O[sub 2][sup -] than cells from non smokers, both early and late after ozone exposure (p = .012 and p = .046, respectively). Stimulated, but not unstimulated, ROS generation by AM from smokers increased following ozone exposure, but the ozone effect was not significant. ROS production by AM decreased in nonsmokers (air vs. ozone late, p = .014). Total protein, albumin, and immunoglobulin M (IgM) increased in BAL fluid, consistent with an increase in epithelial permeability. In addition, the concentration of α[sub 2]-macroglobulin increased approximately threefold 18 h after exposure in nonsmokers (p < .001). No relationship was found between measures of ROS production and lung function responsiveness to ozone. These studies suggest the airways of smokers experience a greater burden of ROS than those of nonsmokers following ozone exposure. [ABSTRACT FROM AUTHOR]

The oxidative burst in circulating polymorphonuclear leukocytes (PMN) plays a fundamental role in pulmonary defense and injury. Flow cytometric techniques have been developed for quantitation of oxidative burst activity at the single cell level using 2',7'dichlorofluorescin (DCFH). However, the specific reactive oxidant species being measured using this method are not clearly defined. Isolated human PMN were loaded with DCFH diacetate, stimulated with phorbol myristate acetate (PMA) in the presence or absence of specific reagents, and analyzed using flow cytometry. Addition of PMA resulted in a 90-fold increase in the fluorescence intensity of DCFH-loaded neutrophils (p < .01). Inhibition of NADPH oxidase activity using a calmodulin antagonist (W-13) decreased PMA-induced DCFH oxidation by 70% (p < .05). Inhibition of nitric oxide synthase using N[sup G] -monomethyl-L-arginine (NMMA) did not significantly reduce DCFH oxidation, and did not alter the action of W-13. Addition of superoxide dismutase (SOD) had no effect, but catalase, with or without SOD, suppressed DCFH oxidation by 90% (p < .01). These data suggest that hydrogen peroxide, and not NO, is primarily responsible for the PMA-induced oxidation of DCFH in human PMN under these conditions. [ABSTRACT FROM AUTHOR]

Discusses factors that may determine individual susceptibility to particulate matter. Reasons why susceptibility for a given health effect may not confer susceptibility to a different health effect; Role played by dosimetry in determining individual susceptibility; Techniques and tools that may be used for identifying and modifying genetic susceptibility in human beings.

Nitrogen dioxide (NO2) exposure has been linked with increased respiratory illness and infection. The objective of this study was to determine whether exposure at peak indoor levels causes airway inflammation or impairs local or systemic host defense in humans either immediately or 18 h after exposure. In an initial phase, 12 volunteers were exposed to purified air or a targeted concentration of 2.0 ppm NO2 for 6 h, with intermittent exercise, and underwent bronchoalveolar lavage (BAL) 18 h after exposure. In a second phase, 12 volunteers participated in an identical exposure protocol but BAL was performed immediately after exposure. Eighteen hours after exposure to NO2, polymorphonuclear leukocytes recovered by BAL increased from 2.2 +/- 0.3 to 3.1 +/- 0.4% (p = .005) and small decreases were found in the percentage of blood CD8+ T lymphocytes ( p = .01) and in blood T lymphocytes expressing neither CD4 nor CD8 (p = .03). These variables were not significantly different immediately after NO2 exposure. Nitrogen dioxide exposure did not alter lymphocyte subsets in BAL or alveolar macrophage function at either time point. Exposure to 2.0 ppm NO2 for 6 h with exercise causes airway inflammation and may alter blood lymphocyte populations 18 h after exposure. [ABSTRACT FROM AUTHOR]