Grantee Research Project Results
Final Report: Acute Exposure to Particulate Air Pollution in Childhood Asthma
EPA Grant Number: R825702C013Subproject: this is subproject number 013 , established and managed by the Center Director under grant R825702
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Denver Children’s Environmental Health Center - Environmental Determinants of Airway Disease in Children
Center Director: Schwartz, David A.
Title: Acute Exposure to Particulate Air Pollution in Childhood Asthma
Investigators: Rabinovitch, Nathan , Gelfand, Erwin
Institution: National Jewish Medical and Research Center
EPA Project Officer: Chung, Serena
Project Period: February 16, 1998 through February 28, 2003 (Extended to February 28, 2004)
RFA: Environmental Lung Disease Center (National Jewish Medical and Research Center) (1998) RFA Text | Recipients Lists
Research Category: Targeted Research
Objective:
The objectives of this research project were to: (1) quantify the effect of misclassification of exposure to particulate air pollution by determining the relationships among data collected from an outdoor community monitor, an indoor monitor, and personal air sampling monitors; (2) determine if there is an association of daily asthma symptoms, inhaled bronchodilator use, and lung function with particulate air pollution in schoolchildren with moderate to severe asthma; and (3) evaluate the mechanisms by which air pollutants induce and exacerbate respiratory symptomatology in asthmatic children: we will define a group of biomarkers associated with this process to determine if known clinical parameters predict susceptibility to pollutant-induced asthma exacerbations.
Summary/Accomplishments (Outputs/Outcomes):
Objective 1
To quantify the effect of misclassification of exposure to particulate air pollution by determining the relationships among data collected from an outdoor community monitor, an indoor monitor, and personal air sampling monitors.
Fine particulate matter (PM2.5) measurements from central monitors are well correlated with local concentrations and personal exposures. The strength of associations obtained from these monitors is a valid reflection of actual exposures. Underestimation of the magnitude of health effects can occur if one does not correct for measurement error that occurs with use of outdoor stationary monitors.
To explore this potential for misclassification bias in wintertime studies of fine particulate, we have performed personal air sampling of PM2.5 using personal monitors obtained from Research Triangle Institute, Inc. (Research Triangle Park, NC). These studies have determined consistent patterns of exposure as summarized below: (1) There is a high correlation between ambient fine particulate measured by a central monitor, local monitor, and personal monitors, suggesting a high degree of spatial homogeneity for ambient PM2.5. (2) Despite these high correlations there exists concentration-dependent measure error in that the central monitor consistently overestimates local concentrations and personal exposures.
Zeger, et al., discuss the issue of bias in health effect estimates and point out that bias likely is to occur when measurement errors are correlated with pollutant levels. As this appears to be a common trend across subjects in this study, there would be expected bias in the associated health effect estimates. To quantify this bias due, we have developed a modeling technique based on regression calibration. Using sulfate levels as a marker of personal exposure to ambient particulate, this allows for a determination of bias using the smaller amounts of data available from personal monitoring and its application to the larger database available using a stationary monitor. Using this approach, we estimated that estimates using a stationary central monitor underestimate percent predicted declines in forced expiratory volume (FEV1) per unit increase in PM2.5 by approximately 70 percent. A local stationary outdoor monitor underestimates effect sizes by approximately 50 percent. Specifically, we observed a 1 percent decrease in FEV1 per 10 μg/m3 increase in total ambient PM2.5 using a local stationary monitor. Using the estimated slope for personal exposures, the adjusted estimate based on average decrease in FEV1 of 2.2% per 10 μg/m3 increase in ambient PM2.5 exposure.
Objective 2
To determine if there is an association of daily asthma symptoms, inhaled bronchodilator use, and lung function with particulate air pollution in schoolchildren with moderate to severe asthma.
Findings
- Consistent associations occur between particulate concentrations and immediate medication use in children with moderate to severe asthma.
- These associations only are observed utilizing hourly measurements reflecting immediate exposures and responses.
In our initial approaches to this Specific Aim, we relied on 24-hour averaged concentrations and health effects to assess the association between particulate air pollution and asthma as this was consistent with U.S. Environmental Protection Agency (EPA) methodology and previous publications. Using this approach, we found no clearly consistent associations across outcomes and across years between particulate (or gaseous) concentrations and any of the asthma severity indices (Rabinovitch, et al., 2004). We subsequently used a more defined approach utilizing hourly concentrations instead of 24-hour averages to determine the timing and magnitude of the exposure-response relationship. Specifically, peak morning PM2.5 associations with morning medication use clearly were apparent across years with almost identical estimates of effect. Figure 1 illustrates the estimates and two standard error bars for the association between morning (midnight–11 a.m.) mean PM2.5 or peak PM2.5 and school medication use measured by the electronic doser.
As illustrated below, these effects were not apparent utilizing 24-hour averaged concentrations.
Figure 1. Morning PM2.5 Concentrations are Associated with Increased Medication Use
Figure 2 illustrates the change in bronchodilator use per interquartile range (IQR) change in PM2.5 in 73 schoolchildren followed over 1 or 2 years (339 total days). Illustrated are the 95 percent confidence intervals based on Poisson regression fits with adjustment for meteorology (temperature, barometric pressure, humidity) and time trend. Estimates are provided for peak and mean morning (midnight–11 a.m.) PM2.5 concentrations measured by the tapered element oscillating microbalance (TEOM) and 24-hour and lagged measurements measured by the TEOM or Federal Reference Monitor (FRM).
Figure 2. Change in Bronchodilator Use Per IQR Change in PM2.5
Objective 3
To evaluate the mechanisms by which air pollutants induce and exacerbate respiratory symptomatology in asthmatic children, we will define a group of biomarkers associated with this process to determine if known clinical parameters predict susceptibility to pollutant-induced asthma exacerbations.
Findings
- Increased levels of fine particulate are associated with urinary leukotriene E4 (LTE4) a mediator of early asthma worsening.
- Children with severe asthma are more susceptible to the effects of ambient fine particulate.
Identifying the latency between pollutant exposure and acute asthma worsening in Specific Aim 2 was a crucial element in the identification of the pathogenesis by which pollutants induce airway reactivity. We hypothesized that one of two primary mechanisms likely was responsible for this clinical phenomenon: One is via nonspecific irritation of the airways without underlying inflammation (similar to exercise-induced bronchospasm), which may be caused by release of mediators from cells that reside in the airways such as mast cells and epithelial cells. The second is an inflammatory response (similar to allergen-induced airway inflammation), causing influx of eosinophils and other nonresident cells into the airways. The short and limited interval between exposure and symptoms (i.e., hours) argues for a noninflammatory mechanism involving resident mast cells or epithelial cells within the airway. Elevations in urinary LTE4 levels occur during early allergen-induced bronchoconstriction. Studies also report increases in LTE4 levels in association with other stimuli, such as exercise, that are associated primarily with an immediate bronchospastic response. LTE4 levels are increased in the sputum 30 minutes after exercising and urinary LTE4 levels are elevated within 4 hours, returning to baseline within 24 hours after exercise.
We were able to identify urinary LTE4 as a biomarker of exposure to peak PM2.5. After control for days with upper respiratory infection (URI) symptoms, urinary LTE4 levels were increased by 6.2 percent for each IQR increment in morning maximum PM2.5 (95% CI = 1.9 to 10.5%; p = 0.006) based on 388 records. Estimates based on morning mean PM2.5 were similar. No significant effects were observed either on the same day or up to 3 days later, based on 24-hour averaged concentrations from TEOM or FRM monitors (Table 1). This response was related to height, possibly indicating a dose response effect as smaller children with higher ventilation rates inhaled more particulate.
Table 1. Estimates of Percentage LTE4 Increase Per IQR Increase in Pollutant, Based on Linear Mixed Model Fits, for TEOM Monitor by Height and TEOM and FRM Monitors, 24-hour Averaged Concentrations. 95 percent confidence intervals are given in parentheses. Associated analyses used n = 51 subjects. Model predictors included: URI, subject height, pollutant, and height*pollutant (Interaction term only in Table a models.)
PM2.5 pollutant statistic, monitor |
Height=25th percentile |
Median height |
Height=75th percentile |
Model without height*pollutant |
Morning mean, |
8.9 (3.0, 14.7) |
5.9 (1.4, 10.4) |
1.9 (-3.4, 7.3) |
5.6 (1.0, 10.2) |
Morning maximum, TEOM |
8.3 (3.4, 13.2) |
6.1 (2.1, 10.2) |
3.2 (-2.0, 8.4) |
6.2 (1.9, 10.5) |
We also explored clinical markers of susceptibility to air pollution. We observed a significant interaction between asthma severity (as measured by National Asthma Education and Prevention Program criteria) and susceptibility to air pollution. This interaction is summarized in Table 2.
Table 2. Estimates of Percentage Doser Medication Use Increase Per IQR Increase in Pollutant Based on Poisson Regression Fits, for the TEOM Monitor, Combined Year, by Severity, With and Without URI Adjustment. 95 percent confidence intervals are given in parentheses.
PM2.5 pollutant statistic |
URI adjusted? |
Effect for mild/moderates |
Effect for severes |
P-value for severity group difference |
Aggregate effect |
Morning |
No |
1.5 (-0.5, 3.4) |
3.7 (1.6, 5.8) |
0.12 |
2.2 (0.7, 3.6) |
Yes |
1.0 (-1.9, 3.9) |
6.0 (1.8, 10.1) |
0.08 |
2.7 (-0.1, 5.4) |
|
Morning maximum |
No |
1.9 (-0.2, 4.1) |
3.9 (1.1, 6.8) |
0.29 |
2.6 (0.9, 4.2) |
Yes |
1.6 (-2.2, 5.4) |
8.1 (2.9, 13.4) |
0.03 |
3.8 (0.2, 7.4) |
Significance
We believe that the results of this research are highly significant to EPA, to the scientific community at large, and to asthma clinicians. We have addressed a number of issues regarding measurement error, an issue that has been a priority for EPA. We have assessed in detail two types of measurement error. One is spatial measurement error with use of a surrogate monitor instead of personal exposures. The second is temporal measurement error using 24-hour averaged concentrations instead of temporally more precise measurements. These findings, if replicated across other locations, would argue for a reassessment of the metrics by which EPA regulates fine particulate to protect against early cardiorespiratory effects.
Earlier studies primarily assessing patients with mild intermittent asthma requiring no medications had reported associations between increased particulate and acute disease severity indices such as pulmonary function and symptoms. Surprisingly, individuals with persistent asthma requiring the chronic use of beta-2 agonists or daily-inhaled corticosteroids appeared not to be obviously susceptible to the effects of air pollution exposure. Therefore, there was some ambiguity about the potential for particulate air pollution to trigger asthma worsening in patients taking controller medications as recommended by national asthma guidelines for all but the mildest asthmatics. In observing associations in moderate to severe asthmatics, we have demonstrated that children with severe asthma continue to be affected by air pollution despite use of controller medications.
An important limitation in the clinical literature was that there was no previous assessment of the relationship between particulate air pollution and biological mediators related to asthma. It therefore, was unclear, how increases in particulate air pollution could lead to increased cardiopulmonary morbidity. Recognition that increases in biologic mediators associated with particulate levels support a causal rather than an associative relationship between ambient particulate and health outcomes may shed light on potential mechanisms of effect.
For the clinician, it is important to note that air pollution levels may lead to early asthma effects. If patients are complaining of increased use of medication on high air pollution days, it may be a sign of poor overall asthma control.
Journal Articles on this Report : 5 Displayed | Download in RIS Format
Other subproject views: | All 20 publications | 5 publications in selected types | All 5 journal articles |
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Other center views: | All 132 publications | 111 publications in selected types | All 110 journal articles |
Type | Citation | ||
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Rabinovitch N, Zhang L, Murphy JR, Vedal S, Dutton SJ, Gelfand EW. Effects of wintertime ambient air pollutants on asthma exacerbations in urban minority children with moderate to severe disease. The Journal of Allergy and Clinical Immunology 2004;114(5):1131-1137. |
R825702 (Final) R825702C013 (Final) |
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Rabinovitch N, Liu AH, Zhang L, Rodes CE, Foarde K, Dutton SJ, Murphy JR, Gelfand EW. Importance of the personal endotoxin cloud in school-age children with asthma. The Journal of Allergy and Clinical Immunology 2005;116(5):1053-1057. |
R825702 (Final) R825702C013 (Final) |
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Rabinovitch N, Strand M, Gelfand EW. Particulate levels are associated with early asthma worsening in children with persistent disease. American Journal of Respiratory and Critical Care Medicine 2006;173(10):1098-1105. |
R825702 (Final) R825702C013 (Final) |
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Rabinovitch N, Liu AH, Zhang L, Foarde K, Rodes CE, Gelfand EW. Increased personal respirable endotoxin exposure with furry pets. Allergy 2006;61(5):650-651. |
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Strand M, Vedal S, Rodes C, Dutton SJ, Gelfand EW, Rabinovitch N. Estimating effects of ambient PM2.5 exposure on health using PM2.5 component measurements and regression calibration. Journal of Exposure Science and Environmental Epidemiology 2006;16(1):30-38. |
R825702 (Final) R825702C013 (Final) |
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Supplemental Keywords:
air toxics, acute lung injury, air pollutants, airway disease, animal studies, environmental toxicant, exposure, genetic susceptibility, health effects, human exposure, human health risk, lung disease, lung epithelial cells, occupational disease, occupational exposure,, Health, Scientific Discipline, PHYSICAL ASPECTS, Risk Assessments, Microbiology, Disease & Cumulative Effects, Physical Processes, Molecular Biology/Genetics, Biology, Histology, Electron Microscopy, Immunology, health effects, electron microscope, lung disease, immune system effects, pathology, airway disease, exposure, immunocytochemistry, human exposure, cell injury, histopathology, animal studies, immune response, exposure assessment, protein expression, tissue studiesRelevant Websites:
http://www.nationaljewish.org/patient-info/progs/med/environmental/index.aspx Exit
Progress and Final Reports:
Original AbstractMain Center Abstract and Reports:
R825702 Denver Children’s Environmental Health Center - Environmental Determinants of Airway Disease in Children Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R825702C001 SP-A and SP-D in Environmental Lung Disease
R825702C003 Adaptation to Nitrogen Dioxide: Role of Altered Glycolytic Pathway Enzyme Expression and NF-κB-Dependent Cellular Defenses Against Apoptosis
R825702C005 Inhalation of Particulate Matter Alters the Allergic Airway Response to Inhaled Allergen
R825702C006 Particle-Induced Lung Inflammation and Extracellular EC-SOD
R825702C007 Indoor-Outdoor Relationships of Airborne Particle Count and Endotoxin Concentrations
R825702C008 The Role of Mitochondrial DNA Mutations in Oxidant-Mediated Lung Injury
R825702C009 Immunopathogenesis of Hypersensitivity Pneumonitis in the Mouse
R825702C010 Activation of Natural T Lymphocytes by Diesel Exhaust Particulates Leads to Their Production of Interleukin-4 and TH2 Lymphocyte Differentiation to Allergen
R825702C011 Latex Antigen Levels During Powdered and Powderless Glove Use
R825702C012 Adjuvant Effects of Ozone in a Model of Allergen-Induced Airway Inflammation and Hyperresponsiveness
R825702C013 Acute Exposure to Particulate Air Pollution in Childhood Asthma
R825702C014 Mechanisms of Ozone Toxicity to the Lung
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
5 journal articles for this subproject
Main Center: R825702
132 publications for this center
110 journal articles for this center