Frances Silverman

Effect of low concentrations of ozone on inhaled allergen responses in asthmatic subjects

The relation between inhalation of ambient concentrations of ozone and airway reactivity to inhaled allergens may be important in asthma, since both agents can produce inflammatory changes in the airways. Seven asthmatic patients (mean age 40 [SD 13] years), with seasonal symptoms of asthma and positive skin tests for ragweed or grass, took part in a study to investigate whether exposure to low concentrations of ozone potentiates the airway allergic response. The patients were studied during 4 separate weeks in the winter. In each week there were 3 study days: on days 1 and 3 methacholine challenges were carried out; and on day 2 the subject received one of four combined challenges in a single-blind design--air breathing followed by inhalation of allergen diluent (placebo); ozone followed by inhalation of allergen diluent; air followed by allergen; or ozone followed by allergen. The ozone concentration was 0.12 ppm during 1 h of tidal breathing at rest, and allergens were inhaled until the forced expiratory volume in 1 s (FEV1) had fallen by 15% (PC15). There were no significant differences in baseline FEV1 after exposure to ozone but PC15 was significantly reduced when allergen was preceded by ozone inhalation: the mean PC15 after air was 0.013 (SD 0.017) mg/ml compared with 0.0056 (0.0062) mg/ml after ozone (p = 0.042). Thus, low ozone concentrations, similar to those commonly occurring in urban areas, can increase the bronchial responsiveness to allergen in atopic asthmatic subjects. This effect does not seem to be the result of changes in baseline airway function.

Insights Into the Mechanisms and Mediators of the Effects of Air Pollution Exposure on Blood Pressure and Vascular Function in Healthy Humans

Fine particulate matter air pollution plus ozone impairs vascular function and raises diastolic blood pressure. We aimed to determine the mechanism and air pollutant responsible. The effects of pollution on heart rate variability, blood pressure, biomarkers, and brachial flow-mediated dilatation were determined in 2 randomized, double-blind, crossover studies. In Ann Arbor, 50 subjects were exposed to fine particles (150 &mgr;g/m3) plus ozone (120 parts per billion) for 2 hours on 3 occasions with pretreatments of an endothelin antagonist (Bosentan, 250 mg), antioxidant (Vitamin C, 2 g), or placebo. In Toronto, 31 subjects were exposed to 4 different conditions (particles plus ozone, particles, ozone, and filtered air). In Toronto, diastolic blood pressure significantly increased (2.9 and 3.6 mm Hg) only during particle-containing exposures in association with particulate matter concentration and reductions in heart rate variability. Flow-mediated dilatation significantly decreased (2.0% and 2.9%) only 24 hours after particle-containing exposures in association with particulate matter concentration and increases in blood tumor necrosis factor &agr;. In Ann Arbor, diastolic blood pressure significantly similarly increased during all of the exposures (2.5 to 4.0 mm Hg), a response not mitigated by pretreatments. Flow-mediated dilatation remained unaltered. Particulate matter, not ozone, was responsible for increasing diastolic blood pressure during air pollution inhalation, most plausibly by instigating acute autonomic imbalance. Only particles from urban Toronto additionally impaired endothelial function, likely via slower proinflammatory pathways. Our findings demonstrate credible mechanisms whereby fine particulate matter could trigger acute cardiovascular events and that aspects of exposure location may be an important determinant of the health consequences.

Acute blood pressure responses in healthy adults during controlled air pollution exposures

Exposure to air pollution has been shown to cause arterial vasoconstriction and alter autonomic balance. Because these biologic responses may influence systemic hemodynamics, we investigated the effect of air pollution on blood pressure (BP). Responses during 2-hr exposures to concentrated ambient fine particles (particulate matter < 2.5 μm in aerodynamic diameter; PM2.5) plus ozone (CAP+O3) were compared with those of particle-free air (PFA) in 23 normotensive, non-smoking healthy adults. Mean concentrations of PM2.5 were 147 ± 27 versus 2 ± 2 μg/m3, respectively, and those of O3 were 121 ± 3 versus 8 ± 5 ppb, respectively (p < 0.0001 for both). A significant increase in diastolic BP (DBP) was observed at 2 hr of CAP+O3 [median change, 6 mm Hg (9.3%); binomial 95% confidence interval (CI), 0 to 11; p = 0.013, Wilcoxon signed rank test] above the 0-hr value. This increase was significantly different (p = 0.017, unadjusted for basal BP) from the small 2-hr change during PFA (median change, 1 mm Hg; 95% CI, −2 to 4; p = 0.24). This prompted further investigation of the CAP+O3 response, which showed a strong association between the 2-hr change in DBP (and mean arterial pressure) and the concentration of the organic carbon fraction of PM2.5 (r = 0.53, p < 0.01; r = 0.56, p < 0.01, respectively) but not with total PM2.5 mass (r ≤ 0.25, p ≥ 0.27). These findings suggest that exposure to environmentally relevant concentrations of PM2.5 and O3 rapidly increases DBP. The magnitude of BP change is associated with the PM2.5 carbon content. Exposure to vehicular traffic may provide a common link between our observations and previous studies in which traffic exposure was identified as a potential risk factor for cardiovascular disease.

DNA Hypomethylation, Ambient Particulate Matter, and Increased Blood Pressure: Findings From Controlled Human Exposure Experiments

Background Short‐term exposures to fine (<2.5 μm aerodynamic diameter) ambient particulate‐matter (PM) have been related with increased blood pressure (BP) in controlled‐human exposure and community‐based studies. However, whether coarse (2.5 to 10 μm) PM exposure increases BP is uncertain. Recent observational studies have linked PM exposures with blood DNA hypomethylation, an epigenetic alteration that activates inflammatory and vascular responses. No experimental evidence is available to confirm those observational data and demonstrate the relations between PM, hypomethylation, and BP. Methods and Results We conducted a cross‐over trial of controlled‐human exposure to concentrated ambient particles (CAPs). Fifteen healthy adult participants were exposed for 130 minutes to fine CAPs, coarse CAPs, or HEPA‐filtered medical air (control) in randomized order with ≥2‐week washout. Repetitive‐element (Alu, long interspersed nuclear element‐1 [LINE‐1]) and candidate‐gene (TLR4, IL‐12, IL‐6, iNOS) blood methylation, systolic and diastolic BP were measured pre‐ and postexposure. After adjustment for multiple comparisons, fine CAPs exposure lowered Alu methylation (β‐standardized=−0.74, adjusted‐P=0.03); coarse CAPs exposure lowered TLR4 methylation (β‐standardized=−0.27, adjusted‐P=0.04). Both fine and coarse CAPs determined significantly increased systolic BP (β=2.53 mm Hg, P=0.001; β=1.56 mm Hg, P=0.03, respectively) and nonsignificantly increased diastolic BP (β=0.98 mm Hg, P=0.12; β=0.82 mm Hg, P=0.11, respectively). Decreased Alu and TLR4 methylation was associated with higher postexposure DBP (β‐standardized=0.41, P=0.04; and β‐standardized=0.84, P=0.02; respectively). Decreased TLR4 methylation was associated with higher postexposure SBP (β‐standardized=1.45, P=0.01). Conclusions Our findings provide novel evidence of effects of coarse PM on BP and confirm effects of fine PM. Our results provide the first experimental evidence of PM‐induced DNA hypomethylation and its correlation to BP.

Relative Contributions of PM2.5 Chemical Constituents to Acute Arterial Vasoconstriction in Humans

Studies have shown associations between acute ambient particulate matter (PM) levels and increases in morbidity and mortality from cardiovascular diseases. We have previously reported in 24 healthy adults that exposure to concentrated ambient particles plus ozone (CAP + O3) caused a mean decrease of 0.09 mm in brachial artery diameter (BAD), which was significantly larger than a mean increase of 0.01 mm among the same individuals exposed to filtered air (FA). Our current objective is to examine the relationship between total and constituent PM2.5 mass concentrations and the acute vascular response. We have analyzed both ambient and exposure filters from the brachial artery study for major chemical constituents, allowing us to compare the strength of the associations between each constituent and an individuals arterial response. We determined gravimetric PM2.5 mass concentration and inorganic ion content from exposure filters. Twenty-three-hour ambient PM2.5 filters collected from the same site and on the same day were used to estimate exposure concentrations of trace elements and organic and elemental carbon. We performed linear regression analyses on the levels of measured or estimated PM constituents using each subjects FA exposure as a control. We found, from our regression analyses, a significant negative association between both the organic and elemental carbon concentrations and the difference in the postexposure change in the BAD (Δ BAD) between and CAP + O3 and FA exposure days. An understanding of the PM constituents most responsible for adverse health outcomes is critical for efforts to develop pollution abatement strategies that maximize benefits to public health.

Baseline repeated measures from controlled human exposure studies: associations between ambient air pollution exposure and the systemic inflammatory biomarkers IL-6 and fibrinogen.

Introduction 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. Objective We investigated the association between ambient air pollution and systemic inflammation using baseline measurements of IL-6 and fibrinogen from controlled human exposure studies. Methods 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. Results 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. Conclusions 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.

“Passive” exposure of asthmatic subjects to cigarette smoke

Fourteen asthmatic subjects volunteered for a controlled trial of 2-hr passive exposure to cigarette smoke. Seven cigarettes were burnt in a closed room of 14.6-m3 capacity, producing a carbon monoxide concentration 24 ppm above ambient and a suspended particulate concentration of 2–4 mg·m−3. Most symptomatic responses were as in normal individuals, but there were more complaints of wheezing (36%) and tightness in the chest (43%). Changes of pulmonary function were slight. Relative to the corresponding control exposure, there was a small decrease of total lung capacity as assessed by helium mixing (P < 0.02), possibly indicating an effect of the smoke on small airways. There was also some evidence of arousal and/or emotional excitement, including a slight tachycardia (at 80-min exposure, P < 0.05) and a slight increase of forced vital capacity (P < 0.05 at 90-min exposure). However, dynamic lung volumes (FEV 1.0, V˙max 50%vc, V˙max 25%vc) were unaltered. Examining separately the four subjects who claimed sensitivity to cigarette smoke, the only significant difference from the remaining asthmatic individuals was agreater FEV1.0 relative to the corresponding time in the control exposure. Our data thus do not suggest that asthmatic subjects have an unusual sensitivity to cigarette smoke.

Autonomic Effects of Controlled Fine Particulate Exposure in Young Healthy Adults: Effect Modification by Ozone

Background Human controlled-exposure studies have assessed the impact of ambient fine particulate matter on cardiac autonomic function measured by heart rate variability (HRV), but whether these effects are modified by concomitant ozone exposure remains unknown. Objective In this study we assessed the impact of O3 and particulate matter exposure on HRV in humans. Methods In a crossover design, 50 subjects (19–48 years of age) were randomized to 2-hr controlled exposures to filtered air (FA), concentrated ambient particles (CAPs), O3, or combined CAPs and ozone (CAPs + O3). The primary end point was change in HRV between the start and end of exposure. Secondary analyses included blood pressure (BP) responses, and effect modification by asthmatic status. Results Achieved mean CAPs and O3 exposure concentrations were 121.6 ± 48.0 μg/m3 and 113.9 ± 6.6 ppb, respectively. In a categorical analysis, exposure had no consistent effect on HRV indices. However, the dose–response relationship between CAPs mass concentration and HRV indices seemed to vary depending on the presence of O3. This heterogeneity was statistically significant for the low-frequency component of HRV (p = 0.02) and approached significance for the high-frequency component and time-domain measures of HRV. Exposure to CAPs + O3 increased diastolic BP by 2.0 mmHg (SE, 1.2; p = 0.02). No other statistically significant changes in BP were observed. Asthmatic status did not modify these effects. Conclusion The potentiation by O3 of CAPs effects on diastolic BP and possibly HRV is of small magnitude in young adults. Further studies are needed to assess potential effects in more vulnerable populations.

Carbon dioxide inhalation challenges in idiopathic environmental intolerance.

BACKGROUND Idiopathic environmental intolerance (IEI) is associated with unexplained physical symptoms, which overlap considerably with those of panic disorder (PD). OBJECTIVE This study tested the hypothesis that patients with symptoms to suggest IEI exhibit features of PD in response to nonnoxious environmental stimuli. METHODS A single-blind, case-control 35% carbon dioxide inhalation challenge was conducted at a university-based occupational health unit with the use of standardized psychologic questionnaires involving 36 patients with IEI and 37 healthy control subjects. The main outcome measures included panic attack symptoms and scores on the Anxiety Sensitivity Index, a measure of panic-related anxiety. RESULTS Patients with IEI scored significantly higher on the Anxiety Sensitivity Index than control subjects did (P <.05). Significantly more patients with IEI (71%) than control subjects (26%) fulfilled panic attack criteria after carbon dioxide (P <.001). Physiologic responses to the challenge were not significantly different between groups. CONCLUSIONS Results suggest that, similar to patients with PD, patients with IEI display high anxiety sensitivity and in response to carbon dioxide inhalation tend to experience heightened anxiety and panic attacks.

Profile of eicosanoids in breath condensate in asthma and COPD

The collection of exhaled breath condensates (EBC) is a noninvasive method for obtaining samples from the lungs. Eicosanoids are lipid mediators implicated in the asthmatic inflammatory response. The objective of our study was to investigate whether the profile of eicosanoid lipid mediators in EBC can characterize the inflammation in asthma and chronic obstructive pulmonary disease (COPD). EBC samples were collected from 22 healthy controls (C), 25 mild intermittent asthmatics (MIA), 20 with moderate to severe asthma (MSA) and 20 with moderate to severe COPD. EBC samples were analyzed by unique tandem mass spectrometry that allows the quantification of up to 25 eicosanoid mediators simultaneously. No differences were found between MIA and C. Subjects with MSA and COPD had higher levels of 6-keto, PGE2, LTB4, 11-12 EET and AA, while lower levels of LXA4, 11DHyTxB2, 11HETE and 8,9EET, when compared to MSA and C (p < 0.05). Our study shows that the analysis of EBC through mass spectrometry is mixed and has a similar response in MSA and COPD when compared to MIA and controls.