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health surveillance data
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
not specified
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference Type:

Materials and methods

Study type:
other: experimental study controlled exposure of human subjects
Endpoint addressed:
acute toxicity: inhalation
Test guideline
no guideline followed
Principles of method if other than guideline:
Research study with controlled exposure to human subjects
GLP compliance:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Test material form:
Specific details on test material used for the study:
Ozone was generated by a silent electric discharge method (model 502; Meckenheim, Bonn, Germany) and introduced into a chamber that was maintained at 22.61.0°C and 406.5% relative humidity.


Type of population:
other: Healthy subjects
Ethical approval:
confirmed and informed consent free of coercion received
Details on study design:
Randomized single-blind crossover study in which each subject was exposed twice for 2 hours: once to clean air and once to 0.3-ppm ozone.

Results and discussion

None of the participants reported any complaints or symptoms after exposure to air or ozone.

Immediately after ozone exposure, we observed statistically significant postexposure/preexposure increases in blood levels of interleukin (IL)-1β and nearly significant increases in IL-8 and tumor necrosis factor- compared with postexposure/pre-exposure changes after air exposure.
"Comment: Pre-exposure value for (IL)=1β for the air exposed group was relative high, probably causing the statistical significance"
24 hours after exposure there was a trend towards an increase in blood levels of IL-1β and C-reactive protein of ozone exposed subjects.

Vascular Markers of Thrombosis
There was a 32.8% decrease in postexposure/pre-exposure PAI-1 concentration which persisted for 24 hours, at which point there was a 42.7% decrease in follow-up/preexposure values. There was also a 41.5% decrease in follow-up/pre-exposure plasminogen levels. Finally, there was a trend for a 44.2% increase in tPA postexposure/pre-exposure levels.
"Comment: Statistical analysis on postexposure/pre-exposure and follow-up/pre-exposure ratio overestimates the effect of ozone exposure, masking the analytical variation in measurements. At best there is a trend to lower PAI-1 levels at 4 and 24 hours post ozone exposure. The changes are within normal physiological reponse and albeit not an indication of an advers effect."

HRV and Repolarization
The authors reported statistically significant ozone-induced changes. There was a 51.2% reduction in the postexposure/preexposure
HF component of HRV immediately after ozone exposure compared with postexposure/pre-exposure values after air exposure. There was a trend for decreased HF 24 hours after exposure, at which time there was a 32.8% decrease in HF. There was a small but significant ozone induced 1.2% increase in the duration of the QT interval immediately after exposure when corrected for heart rate by the use of a subject-specific QT/RR slope. We also observed an ozone-induced 5.8% decrease in the complexity of the QRS wave immediately after exposure. The QRS complexity, defined as the ratio of the second eigenvalue to the first, represents the spread of depolarization through the ventricular muscle. Exposure to ozone did not cause changes in other measures of HRV or repolarization.
"Comment: Data treatment masks the normal variation (biological and analytical) in the measurements resulting is statistically significance without biologically relevancy."

Lung Function and Pulmonary Inflammation
Ozone-induced changes in FEV1 and bronchoalveolar lavage neutrophils. Immediately after exposure to ozone, postexposure/pre-exposure FEV1 values after ozone exposure were decreased relative to postexposure/pre-exposure air exposure values by 10.9%. The difference between neutrophils found in bronchoalveolar lavage fluid 24 hours after ozone exposure relative to air exposure was 7.5%
"Comment: These findings are consistent with what others have reported previously in participants exposed to ozone"

Applicant's summary and conclusion

This is an experimental study in healthy subjects published in a peer-reviewed journal. It provides supportive information that exposure for 2 hour to 0.3 ppm ozone causes airway inflammation and injury as manifested by changes cellular markers of inflammation and changes in lung function in healthy subjects. Further, the study suggests that exposure of healthy young adults to 300 ppb ozone causes an increase in vascular markers of inflammation, changes in fibrinolytic markers that could potentially impair fibrinolysis, and changes in autonomic control of heart rate. However, although some of these changes appeared to be statistically significant with the data analysis performed, the magnitude of the changes were small and the clinical significance was not discussed. The biomarkers measured may be on the causal pathway to cardiovascular effects, the changes are of such a small enough magnitude that they are more likely indicative of homeostatic processes and thus do not provide sufficient information on the potential for adverse effects of ozone.
Executive summary:

In this epidemiological research study, twenty-three young healthy individuals were exposed in a randomized crossover fashion to clean air and to 0.3-ppm ozone for 2 hours while intermittently exercising. Blood was obtained immediately before exposure, immediately afterward, and the next morning. Continuous Holter monitoring began immediately before exposure and continued for 24 hours. Lung function was performed immediately before and immediately after exposure, and bronchoalveolar lavage was performed 24 hours after exposure. Immediately after ozone exposure, we observed a 98.9% increase in interleukin-8, a 21.4% decrease in plasminogen activator inhibitor-1, a 51.3% decrease in the high-frequency component of heart rate variability, and a 1.2% increase in QT duration. Changes in interleukin-1B and plasminogen activator inhibitor-1 were apparent 24 hours after exposure. In agreement with previous studies, we also observed ozone-induced drops in lung function and an increase in pulmonary inflammation. This controlled-human-exposure study shows that ozone can cause an increase in vascular markers of inflammation and changes in markers of fibrinolysis and markers that affect autonomic control of heart rate and repolarization. We believe that these findings provide biological plausibility for the epidemiology studies that associate ozone exposure with mortality.