Jon Berntsen

Concentrated Ambient Ultrafine Particle Exposure Induces Cardiac Changes in Young Healthy Volunteers

RATIONALE Exposure to ambient ultrafine particles has been associated with cardiopulmonary toxicity and mortality. Adverse effects specifically linked to ultrafine particles include loss of sympathovagal balance and altered hemostasis. OBJECTIVES To characterize the effects of acute exposure to ambient ultrafine particles in young healthy humans. METHODS Nineteen healthy nonsmoking male and female subjects between the ages of 18 and 35 were exposed to filtered air or to an atmosphere in which captured ultrafine (<0.16 microm) particles were concentrated by a factor of up to 20-fold over ambient levels with the use of particle concentrators fitted with size-selective outlets (ultrafine concentrated ambient particles [UFCAPs]). Subjects underwent bronchoalveolar lavage 18 hours after each exposure. Cardiovascular endpoints measured included pulmonary function, clinical chemistry, and hematological parameters, as well as heart rate variability and repolarization indices. MEASUREMENTS AND MAIN RESULTS Exposure to UFCAPs was statistically associated with an increase in frequency domain markers of heart rate variability, specifically indicative of elevated vagal input to the heart. Consistent with this finding were increases in the variance associated with the duration of the QT interval. In addition, UFCAP exposure resulted in a significant increase in blood levels of the fibrin degradation product D-dimer as well as a modest elevation in the inflammatory chemokine IL-8 recovered in the lavage fluid. CONCLUSIONS These findings show mild inflammatory and prothrombic responses and are suggestive of alterations in cardiac repolarization induced by UFCAP inhalation.

Exposure to wood smoke particles produces inflammation in healthy volunteers

Objectives Human exposure to wood smoke particles (WSP) impacts on human health through changes in indoor air quality, exposures from wild fires, burning of biomass and air pollution. This investigation tested the postulate that healthy volunteers exposed to WSP would demonstrate evidence of both pulmonary and systemic inflammation. Methods Ten volunteers were exposed to filtered air and, 3 weeks or more later, WSP. Each exposure included alternating 15 min of exercise and 15 min of rest for a total duration of 2 h. Wood smoke was generated by heating an oak log on an electric element and then delivered to the exposure chamber. Endpoints measured in the volunteers included symptoms, pulmonary function tests, measures of heart rate variability and repolarisation, blood indices and analysis of cells and fluid obtained during bronchoalveolar lavage. Results Mean particle mass for the 10 exposures to air and WSP was measured using the mass of particles collected on filters and found to be below the detectable limit and 485±84 μg/m3, respectively (mean±SD). There was no change in either symptom prevalence or pulmonary function with exposure to WSP. At 20 h after wood smoke exposure, blood tests demonstrated an increased percentage of neutrophils, and bronchial and bronchoalveolar lavage revealed a neutrophilic influx. Conclusions We conclude that exposure of healthy volunteers to WSP may be associated with evidence of both systemic and pulmonary inflammation.

A Comparison of Studies on the Effects of Controlled Exposure to Fine, Coarse and Ultrafine Ambient Particulate Matter from a Single Location

Particle size has been implicated by epidemiological and toxicological studies as an important determinant of the toxicity of ambient particulate matter (PM). In an effort to characterize the cardiovascular, hematological and pulmonary effects of different PM size fractions in humans, we have conducted controlled human exposures of normal volunteers to ultrafine-, fine- and coarse- fraction PM concentrated from ambient air in Chapel Hill, North Carolina. Healthy non-smoking male and female subjects between the ages of 18 and 35 participated in these studies. Exposures were undertaken with the use of particle concentrators fitted with size-selective outlets. These devices are capable of generating concentration factors between 10- and 20-fold over ambient levels. Cardiovascular endpoints measured include heart rate variability and T-wave alternans, as well as pulmonary function parameters. Subjects underwent bronchoscopy and bronchoalveolar lavage 18 hrs following exposure to PM or to clean air. Lavage fluids and blood samples were assayed for a battery of markers of hematological, cytotoxic and inflammatory injury. The design of these studies permits direct comparison of the effects of concentrated ambient PM as a function of particle size. The data to be presented reveal modest size fraction-dependent effects of concentrated PM exposure on cardiovascular, pulmonary and hematological parameters in normal adult human subjects. These findings have relevant implications for the design of future chamber studies and the role of particle size fraction in the adverse health effects of PM exposure in humans.

Omega-3 fatty acid supplementation appears to attenuate particulate air pollution-induced cardiac effects and lipid changes in healthy middle-aged adults.

Background: Air pollution exposure has been associated with adverse cardiovascular health effects. Findings of a recent epidemiological study suggested that omega-3 fatty acid (fish oil) supplementation blunted cardiac responses to air pollution exposure. Objectives: We conducted a randomized, controlled exposure study to evaluate the efficacy of fish oil supplements in attenuating adverse cardiac effects of exposure to concentrated ambient fine and ultrafine particulate matter (CAP). Methods: Twenty-nine healthy middle-aged participants (mean, 58 ± 1 years of age) were supplemented in a randomized, double-blinded manner with 3 g/day of either fish oil or olive oil for 4 weeks before sequential chamber exposure to filtered air and CAP (mean mass concentration 278 ± 19 µg/m3) for 2 hr. Cardiac responses were assessed by comparing time and frequency domain changes in heart rate variability (HRV) and electrocardiographic repolarization changes measured before, immediately after, and 20 hr after exposure. Changes in plasma lipids were also evaluated at these time points. Results: Fish oil supplementation appeared to attenuate CAP-induced reductions in high-frequency/low-frequency ratio, as well as elevations in normalized low-frequency HRV and prolongation of the QT interval corrected for heart rate (QTc). Very low-density lipoprotein and triglyceride concentrations increased significantly immediately after exposure to CAP in participants supplemented with olive oil, but not in those supplemented with fish oil. Conclusions: Exposure of healthy middle-aged adults to CAP for 2 hr induced acute cardiac and lipid changes after supplementation with olive oil, but not fish oil. Our findings suggest that omega-3 fatty acid supplements offer protection against the adverse cardiac and lipid effects associated with air pollution exposure.

Real-Time Characterization of the Composition of Individual Particles Emitted From Ultrafine Particle Concentrators

Particle concentrators are commonly used for controlling exposure levels to ambient ultrafine, fine, and coarse aerosols over a broad range of concentrations. For ultrafine aerosols, these concentrators require water condensation technology to grow and enrich these smaller sized particles (D a < 100 nm). Because the chemistry of the particles is directly related to their toxicity, any changes induced by ultrafine concentrators on ambient particles need to be better characterized in order to fully understand the results obtained in health exposure studies. Using aerosol time-of-flight mass spectrometry (ATOFMS), the size-resolved chemistry was measured of concentrated ultrafine and accumulation mode (50–300 nm) particles from several particle concentrators with different designs. This is the first report detailing the size-resolved distributions of elemental carbon (EC) and organic carbon (OC) particles sampled from concentrators. Experimental measurements of the single particle mixing state of particles in concentrated versus non-concentrated ambient air show transformations of ultrafine EC particles occur as they become coated with organic carbon (OC) species during the concentration process. Based on relative ion intensities, concentrated ultrafine particles showed a 30% increase in the amount of OC on the EC particles for the same aerodynamic size. An increase in the number fraction of aromatic- and polycyclic aromatic hydrocarbon-containing particles was also observed in both the ultrafine and fine size modes. The most likely explanation for such changes is gas-to-particle partitioning of organic components (e.g., water-soluble organic compounds) from the high volume of air used in the concentrator into aqueous phase ultrafine and fine aqueous particles created during the particle enrichment process.

Characterization of an Ambient Coarse Particle Concentrator Used for Human Exposure Studies: Aerosol Size Distributions, Chemical Composition, and Concentration Enrichment

The goals of the experiments described herein involve determining in real time the size, concentration enrichment, and chemical composition of coarse-mode (<2.5 μm) and fine-mode (>2.5 μm) particles within the nonconcentrated and concentrated flows of a coarse particle concentrator used for human exposure studies. The coarse particle concentrator was intended to concentrate ambient particles in the PM10–2.5 size range before sending them into a human exposure chamber. The aerodynamic size and chemical composition of particles in the upstream and downstream flows of the concentrator were monitored with an aerosol time-of-f1ight mass spectrometer (ATOFMS) for fixed time intervals over the course of three days. Based on the ATOFMS results, it was found that there was no change in the composition of the ten major particle types observed in the upstream and downstream flows of the concentrator under normal operating conditions. Furthermore, no new particle types were detected downstream that were not detected upstream of the concentrator. A characterization of the aerosol chemical composition and its dependence on sampling conditions is also discussed. Aerosol size distributions were measured with three aerodynamic particle-sizing (APS) instruments sampling simultaneously from different regions of the concentrator. The APS size distributions were used to scale ATOFMS data and measure the ambient concentration factors for the coarse particle concentrator and the exposure chamber. The average concentration factor (ratio of inlet number concentration to the outlet number concentration) for the particle concentrator was 60 + 17 for the 2.5–7.2 μm size range before dilution and transport to the exposure chamber. It was observed that not only were coarse particles being concentrated but fine (<2.5 μm) particles were being concentrated as well, with concentration factors ranging from 2–46 for aerodynamic particle sizes from 0.54–2.5 μm.

Dietary Supplementation with Olive Oil or Fish Oil and Vascular Effects of Concentrated Ambient Particulate Matter Exposure in Human Volunteers.

Background Exposure to ambient particulate matter (PM) induces endothelial dysfunction, a risk factor for cardiovascular disease. Olive oil (OO) and fish oil (FO) supplements have beneficial effects on endothelial function. Objective In this study we evaluated the potential efficacy of OO and FO in mitigating endothelial dysfunction and disruption of hemostasis caused by exposure to particulate matter (PM). Methods and Results Forty-two participants (58 ± 1 years of age) received either 3 g/day of OO or FO, or no supplements (naive) for 4 weeks prior to undergoing 2-hr exposures to filtered air and concentrated ambient particulate matter (CAP; mean, 253 ± 16 μg/m3). Endothelial function was assessed by flow-mediated dilation (FMD) of the brachial artery preexposure, immediately postexposure, and 20 hr postexposure. Levels of endothelin-1 and markers of fibrinolysis and inflammation were also measured. The FMD was significantly lower after CAP exposure in the naive (–19.4%; 95% CI: –36.4, –2.3 per 100 μg/m3 CAP relative to baseline; p = 0.03) and FO groups (–13.7%; 95% CI: –24.5, –2.9; p = 0.01), but not in the OO group (–7.6%; 95% CI: –21.5, 6.3; p = 0.27). Tissue plasminogen activator levels were significantly increased immediately after (11.6%; 95% CI: 0.8, 22.2; p = 0.04) and 20 hr after CAP exposure in the OO group. Endothelin-1 levels were significantly increased 20 hr after CAP exposure in the naive group only (17.1%; 95% CI: 2.2, 32.0; p = 0.03). Conclusions Short-term exposure to CAP induced vascular endothelial dysfunction. OO supplementation attenuated CAP-induced reduction of FMD and changes in blood markers associated with vasoconstriction and fibrinolysis, suggesting that OO supplementation may be an efficacious intervention to protect against vascular effects of exposure to PM. Citation Tong H, Rappold AG, Caughey M, Hinderliter AL, Bassett M, Montilla T, Case MW, Berntsen J, Bromberg PA, Cascio WE, Diaz-Sanchez D, Devlin RB, Samet JM. 2015. Dietary supplementation with olive oil or fish oil and vascular effects of concentrated ambient particulate matter exposure in human volunteers. Environ Health Perspect 123:1173–1179; http://dx.doi.org/10.1289/ehp.1408988

Cardiovascular effects caused by increasing concentrations of diesel exhaust in middle-aged healthy GSTM1 null human volunteers

Abstract Context: Epidemiological studies have shown an association between the incidence of adverse cardiovascular effects and exposure to ambient particulate matter (PM). Diesel exhaust (DE) is a major contributor to ambient PM and gaseous emissions in urban areas. Objective: This was a pilot study designed to evaluate concentration-dependent effects of short-term exposure to whole DE on the cardiovascular system in order to identify a threshold concentration that can elicit biological responses in healthy human volunteers. Materials and methods: Six healthy middle-aged participants with glutathione-S-transferase-Mu 1 (GSTM1) null genotype underwent sequential exposures to 100 µg/m3, 200 µg/m3, and 300 µg/m3 whole DE generated in real time using an idling diesel truck engine. Exposures were separated by 14 d and each was 2 h in duration. Results: We report concentration-dependent effects of exposure to DE, with 100 µg/m3 concentration causing minimal cardiovascular effects, while exposure to 300 µg/m3 DE for 2 h resulted in a borderline significant reduction of baseline brachial artery diameter (3.34 ± 0.27 mm pre- versus 3.23 ± 0.25 mm post-exposure; p = 0.08). Exposure to the highest concentration of DE also resulted in increases of 5 mmHg in diastolic blood pressure as well as a decrease in indices of the frequency domain of heart rate variability (HRV). Discussion and conclusions: These findings demonstrate that acute exposure to relatively high concentrations of DE produces cardiovascular changes in middle-aged GSTM1 null individuals. This study therefore suggests that arterial vasoconstriction and changes in HRV are responses through which traffic-related air pollution increases the risk of adverse cardiovascular outcomes.

Progress in Assessing Air Pollutant Risks from In Vitro Exposures: Matching Ozone Dose and Effect in Human Airway Cells

In vitro exposures to air pollutants could, in theory, facilitate a rapid and detailed assessment of molecular mechanisms of toxicity. However, it is difficult to ensure that the dose of a gaseous pollutant to cells in tissue culture is similar to that of the same cells during in vivo exposure of a living person. The goal of the present study was to compare the dose and effect of O3 in airway cells of humans exposed in vivo to that of human cells exposed in vitro. Ten subjects breathed labeled O3 ((18)O3, 0.3 ppm, 2 h) while exercising intermittently. Bronchial brush biopsies and lung lavage fluids were collected 1 h post exposure for in vivo data whereas in vitro data were obtained from primary cultures of human bronchial epithelial cells exposed to 0.25-1.0 ppm (18)O3 for 2 h. The O3 dose to the cells was defined as the level of (18)O incorporation and the O3 effect as the fold increase in expression of inflammatory marker genes (IL-8 and COX-2). Dose and effect in cells removed from in vivo exposed subjects were lower than in cells exposed to the same (18)O3 concentration in vitro suggesting upper airway O3 scrubbing in vivo. Cells collected by lavage as well as previous studies in monkeys show that cells deeper in the lung receive a higher O3 dose than cells in the bronchus. We conclude that the methods used herein show promise for replicating and comparing the in vivo dose and effect of O3 in an in vitro system.

Submicrometer Aerosol Generator Development for the U.S. Environmental Protection Agency's Human Exposure Laboratory

A submicrometer aerosol generation unit was developed for use in the U.S. Environmental Protection Agencys new air pollution exposure chambers located on the campus of the University of North Carolina at Chapel Hill. The aerosol mass median aerodynamic diameter and mass concentration are operator-selected, ranging from 0.1 to 1.0 μm and from 0 to 2 mg/m3, respectively. The aerosol was to have a geometric standard deviation (GSD) of < 1.5. Two-fluid nebulization was selected to generate water-soluble aerosols. Multiple Collison-type nozzles are used to create a polydisperse droplet cloud. Aerosol uniformity is improved by removing the large droplets from the original distribution by passing the aerosol through an external impaction device. Variations in the solvent-solute ratio, nebulizer driving pressure, impactor cut-point size, and number of nozzles are used to control the final aerosol size and mass concentration. Aerosol size distributions were determined with an electrical aerosol analyzer and a low...