Ozone

Sensitisation data (human)

Administrative data

Endpoint:

sensitisation data (humans)

Type of information:

other: observation study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2009

Materials and methods

Type of sensitisation studied:

respiratory

Study type:

other: observational study in asthmatic and non-asthmatic people

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

This a so called observation study in asthmatics and healthy control subject. Assessment of associations of summertime ozone levels on airway inflammation

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ozone

EC Number:

233-069-2

EC Name:

Ozone

Cas Number:

10028-15-6

Molecular formula:

O3

IUPAC Name:

trioxygen

Test material form:

gas

Specific details on test material used for the study:

Peak 1-hour ozone levels, peak 8-hour averaged ozone levels, peak Air Quality Index (AQI) measurements, as well as temperature and relative humidity of the previous 48-hour and 24-hour time period, were abstracted from regional air monitoring data. A map of metropolitan Atlanta was used to visually determine the closest monitoring station to individuals’ reported locations during each hour of the previous 2 days. Air quality data from that particular station were then abstracted from the Georgia Department of Natural Resources monitoring website (http://www.air.dnr.state.ga.us/amp/).

Method

Type of population:

general

Ethical approval:

other: Participants were asked to review and sign an informed consent that was approved by the Emory University Institutional Review Board.

Subjects:

Asthmatics included were at least 18 years of age, nonsmokers (less than 5 pack-year smoking history more than 5 years ago), and lived in metropolitan Atlanta. Individuals who were acutely ill or had received systemic corticosteroids within the last 2 weeks were excluded from participation. The definition and severity of asthma was based on clinical history and presence of airflow obstruction and/or documentation of a significant bronchodilator response

Clinical history:

A brief medical and medication history was obtained, including questions about subjective exposures to pollution and allergies. “(Have you been exposed to pollution in the last 24 or 48 hours? If yes, was the level of exposure low, medium, or high?)”. Similar questions were asked about exposures to common allergens such as pets, pollen, mold, and dust.

Controls:

Healthy control subjects were non-smokers with no history of pulmonary disease or allergic rhinitis and normal spirometry.

Route of administration:

inhalation

Details on study design:

At the day of investigation, participants were asked to provide hourly information about their location by zip codes and level of physical activity for the previous 2 days, subjectively qualifying their levels of activity as low (no exertion), medium, and high exertion. Spirometry was performed according to American Thoracic Society (ATS) standards (24). A peripheral blood sample was sent to a certified clinical laboratory for leukocyte, eosinophil, and immunoglobulin E (IgE) levels. The Juniper asthma quality of life questionnaire (QOLQ) was orally administered to all asthmatic participants

Results and discussion

Results of examinations:

The study provides supportive information that peak ambient ozone concentrations in the summer seasons are associated with more frequent upper airway symptotics, worse airflow obstruction, lower quality of life scores, greater eosinophilia, and higher exhaled NO levels in asthmatic. These associations were enhanced in atopic participants, both with and without asthma. Importantly, the study findings were noted while atmospheric ozone levels were predominantly within the current and revised national air quality standards.

Any other information on results incl. tables

Patient Characteristics

The study sample included 38 asthmatic patients and 13 healthy control subjects between May and September. Twelve asthmatic patients and 5 control subjects were studied during the 2003 season (during which 13 days exceeded air quality standards); 20 asthmatic patients and 6 control subjects were studied in 2005 (during which 17 days exceeded air quality standards), and 6 asthmatics and 2 healthy control subjects were studied in 2006 (during which 30 days exceeded air quality standards). One asthmatic individual was not able to reliably perform spirometry but did provide all other biosamples and clinical information and was therefore included in the analyses.

Since a significant number of men screened for enrolment were smokers, a higher number of women participated in the study. As expected, participants with asthma demonstrated worse airflow obstruction. Markers of allergy and inflammation were more prevalent in the asthmatics. Over half of asthmatics had confirmed allergies by skin testing. However, three control subjects had skin tests positive as well. Fifty percent of the asthmatic group had mild disease, and the rest had moderate or severe asthma based on Global Initiative for Asthma-GINA criteria. Medication history demonstrated that frequency of controller therapy increased with severity. A small number of individuals with moderate or severe asthma (8%) were not on any controller therapy at the time of evaluation.

Ambient Ozone and Activity Levels

Peak 1-hour and peak 8-hour averaged levels recorded by ambient posted monitors nearest to enrolled individuals in the 24 and 48 hours before study visits were similar in the asthmatic and non-asthmatic groups (Appendix Table A1). Subjective estimation of high pollution exposures (“medium” or “high” over prior 48 hours) also did not significantly differ between the asthma and healthy control group. In any given time period (day of visit, 1 day before, or 2 days before participant evaluation), 8-hour averaged atmospheric ozone levels were inversely related to relative humidity (R < −0.60,p < 0.001) and correlated with temperature (R>0.45,p < 0.01). Reported levels of activity and exertion were also similar between groups over the previous 2 days

Table:—Peak levels of ozone (ppm) days prior to evaluation.

                                                                                        Asthmatics                    Controls                           p value*

8-hour averaged ozone levels 2 days prior               0.061      (.032–.074)     0.056     (.037–.064)       0.97

1-hour ozone levels 2 days prior                                   0.072       (.045–.087)    0.066      (.050–.082)      0.99

8-hour averaged ozone levels 1 day prior                   0.059       (.044–.073)    0.065      (.057–.083)      0.35

1-hour ozone levels 1 day prior                                   0.070        (.049–.080)   0.077      (.070–.094)      0.28

Air Quality index†

2 days prior                                                                      75            (53–101)         76           (61–111)         0.53

1 day prior                                                                           75            (55–103)         97            (70–121)        0.18

Subjective exposure to high pollution‡                            26              (68%)              6                 (46%)        0.17

Data presented as median (IQR); *p-value based on wilcoxon rank sum testing.  † AQI defined as the index of air quality as determined by the highest level of criteria pollutants: PM, Ozone, sulfur dioxide, nitrogen dioxide, and carbon monoxide.

‡Those reporting exposure to medium to high levels of pollution during prior 2 days..

Symptoms

Frequency of upper airway symptoms such as itchy eyes, asthmatic group, and headaches also tended to be higher. Stepwise logistic regression analyses with symptoms as the outcome variables were performed. Independent variables included in the model were presence of asthma, use of nasal steroids, measured ozone levels, and subjective levels of exposure to allergen and pollution. Presence of asthma and high pollution exposures were significantly associated with itchy eyes (asthma OR=12.62 [1.14–139.99], allergen exposure OR=10.18 [2.12–48.88]). High allergen exposures was the only independent variable significantly associated with headaches, sneezing, and congestion (OR 1.67 [1.06–2.61], 1.72 [1.09–2.72], and 2.05 [1.26–3.33], respectively).

Quality of Life

Of a best possible score of seven, the median total quality of-life score in our panel of asthmatics was 5.22, with a range from 2.16 to 7.00. The forced expiratory volume in 1 second (FEV1) percent predicted was associated with the overall score (R = 0.35, p = 0.04), and the emotional domain score was especially related (R = 0.50, p < 0.01). Linear regression models controlling for recent high allergen exposures, activity levels, and atmospheric ozone levels in the previous 2 days estimated that a 50% increase in baseline %FEV1 would be associated with an average increase of the quality-of-life score by 1. In contrast, increases in atmospheric peak ozone levels by only 0.020 ppm (a plausible difference from high to low ozone days) was associated with an average decrease in the quality of life score by a half a point.

Markers of Allergic Inflammation: Eosinophils, (IgE), and Exhaled NO

Peripheral eosinophilia in asthmatics was higher in association with peak ozone levels the day before evaluation, whereas no such association was seen in the healthy control group. Linear regression modelling of peripheral eosinophilia and ozone levels, controlling for FEV1 % predicted tended to demonstrate a lag effect for ozone levels. Increases in peak 8-hour averaged ozone levels every 0.020 ppm was associated with a 1.6 percent higher number of eosinophils. A similar tendency for a 2-day lag effect was also noted, such that a 0.020 ppm increase in 8-hour averaged ozone levels was associated with an average 1% higher peripheral eosinophilia (p ≤ 0.10 for model and ozone variable coefficient).

Exhaled NO values were higher in the asthmatics (n=29) than healthy control subjects (n = 11) in whom off-line samples were collected. Exhaled NO was inversely related to airflow (FEV1/forced vital capacity [FVC] ratio % predicted, and FEV1 and peak flow % predicted) and directly correlated with post-bronchodilator changes in FEV1 and FVC. Interestingly, in asthmatics, exhaled NO also correlated with peak ozone levels 1 to 2 days before evaluation and tended to correlate with subjective exposures to pollution. Adding allergen exposures did not contribute to the significance of the model. Correlation between ozone and exhaled NO levels was particularly strong among the known atopic asthmatics. Linear regressions of exhaled NO and ozone levels, controlling for FEV1 % predicted, demonstrated that for every 0.020 ppm increase in 8-hour averaged ozone levels, exhaled NO levels would be higher by nearly 3 ppb (model p = 0.07, coefficient for zone = 2.78 [C.I. 0.09–5.47], p = 0.05). Introducing peripheral eosinophils into the model predicted similar increases in exhaled NO with ozone levels. Adding variables for subjective exposure to high pollution and eosinophils to the model estimated that a positive response to “high pollution” was associated with  7 ppb higher levels of exhaled NO, thereby supporting the premise that individual estimations of pollutant exposures are likely to be accurate.

Associations of Ozone Exposure with Lung Function and Inflammation

Percent predicted FEV1/FVC ratio was inversely related to peak 8-hour ozone levels 2 days before testing evaluation (R = 0.34, p = 0.04). When controlling for IgE, peripheral eosinophilia, subjective level of recent allergen and pollution exposures, and 8-hour averaged ozone levels, eosinophilia and pollution exposures were related to reduced airflow. Subjective exposures to high levels of air pollution, controlling for allergen exposures, was associated with, on average, a 14-point lower (95% C.I. 3, 25) predicted FEV1/ FVC ratio. Similar associations were seen in the group of all enrolled (asthma and non-asthma), especially in those with allergies where subjective exposures to pollution was associated with an average 16-point lower predicted ratio. In addition, increases in peak 8-hour averaged levels of ozone by 0.020 were associated with an average 8-point lower % FEV1/FVC ratio (95% C.I. 3,14). Linear regression modelling demonstrated a trend of reduced FEV1 percent predicted with subjective reporting of high exposures to air pollution. Adding temperature and relative humidity variables into models predicting FEV1/FVC or FEV1 % predicted did not demonstrate significant associations or alter the relationships of the original model. Only in the group of all atopic individuals, it was estimated that every 5% higher level of relative humidity was associated with a 4-point higher % FEV1/FVC ratio.

Applicant's summary and conclusion

Conclusions:

This is an observational study on the association between higher ambient ozone levels and lung effects in asthmatics as compared to non-asthmatic individuals. The study provides supportive information that peak ambient ozone concentrations in the summer seasons are associated with more frequent upper airway symptotics, worse airflow obstruction, lower quality of life scores, greater eosinophilia, and higher exhaled NO levels in asthmatic. These associations were enhanced in atopic participants, both with and without asthma. Importantly, the study findings were noted while atmospheric ozone levels were predominantly within the current and revised national air quality standards.

Executive summary:

In an observational study during the summer months, it was hypothesized that higher ambient ozone levels are associated with more frequent symptoms, higher airway and systemic inflammation, as well as worse lung function in asthmatics as compared with non-asthmatic individuals. Thirty-eight asthmatics and thirteen healthy control subjects residing in metropolitan Atlanta were enrolled during peak ozone season. Medical histories, quality-of-life questionnaires, spirometry, serum immunoglobulin (IgE), peripheral eosinophil counts, and exhaled nitric oxide (NO) were obtained during study visits. Personal ozone exposures over the 2 days before presentation were estimated based on location and activity surveys. Upper airway symptoms were more frequent in asthmatics. Higher levels of ozone were associated with worse airflow obstruction, lower quality of life scores, greater eosinophilia, and higher exhaled NO levels in asthmatics. Finally, both asthmatics and non-asthmatics with allergies showed associations between air quality and airway inflammation.

In conclusions, in adults with asthma but not controls studied during peak ozone season, increasing ozone exposure predicted lower lung function and increased biomarkers of respiratory and systemic inflammation.

These associations were enhanced in atopic participants, both with and without asthma. Importantly, the study findings were noted while atmospheric ozone levels were predominantly within the current and revised national air quality standards.