Letter by Goodman and Sax Regarding Article, “Controlled Exposure of Healthy Young Volunteers to Ozone Causes Cardiovascular Effects”
We read with interest the study by Devlin et al.1 In this study, 23 healthy individuals were exposed once to clean air or to 300 ppb ozone for 2 hours while exercising intermittently. Several biomarkers of inflammation, thrombosis, and heart rate variability were evaluated before exposure, immediately after exposure, for 24 hours, or at 24 hours. Measurements of some of these biomarkers were statistically significantly different after ozone exposure, and the authors observed a decrease in lung function.
Devlin et al evaluated statistical significance, but they did not evaluate the clinical significance of the results. Although the biomarkers they measured may be on the causal pathway to cardiovascular effects, it is our opinion that they are of small enough magnitude that they are more likely indicative of homeostatic processes and thus do not provide information on the potential for adverse effects.2 For example, small changes in heart rate variability can occur as a result of lifestyle factors and should not be considered adverse.3
In addition, not all of the biomarkers changed after ozone exposure. If ozone causes cardiovascular effects, coherent changes in biomarkers should occur, rather than changes in certain biomarkers at certain times. Although it is possible that the mode of action of ozone acts only through a subset of biomarkers at certain time points, there is insufficient evidence to date to support this hypothesis.
There was only 1 exposure level in this study, which was 4 times higher than the ozone National Ambient Air Quality Standard (75 ppb). Thus, it is unknown whether these effects occur at the lower concentrations to which the general population is exposed. In addition, exposure-response, which is critical for addressing causation, cannot be evaluated on the basis of only 1 exposure level.
It is notable that study subjects were exercising at high multiples of normal breathing levels, resulting in a significant group decrease in pulmonary function (as expected on the basis of previous studies). This may be associated with the biomarker changes observed by the authors, because other studies using ozone exposure regimens that likely produced a lower pulmonary response have not reported changes in heart rate variability.4
Finally, Devlin et al suggest that their findings provide support for cardiovascular effects reported in some epidemiology studies. Exposures in epidemiology studies are generally an order of magnitude lower and the effects far more extreme (eg, death). In addition, results among epidemiology studies are inconsistent; most find no association between ozone and cardiovascular mortality.5
Devlin et al demonstrated that high levels of ozone are associated with small changes in biomarkers. Their work adds to the body of knowledge on this topic, which is currently limited. Still, there is no known biologically plausible mechanism by which ambient ozone could cause cardiovascular effects. In fact, because ozone is so reactive, effects tend to be restricted to the point of exposure (ie, the lungs). Future studies should assess whether these same biomarkers are affected in a consistent manner over a range of ozone concentrations, including current ambient levels, and whether they are more likely indicative of adverse effects or homeostatic effects.
Source of Funding
This correspondence was prepared with financial support from the American Petroleum Institute (API). The views expressed are not necessarily those of API.
Julie E. Goodman, PhD, DABT
Sonja Sax, ScD
- © 2013 American Heart Association, Inc.
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- 5.↵US Environmental Protection Agency, National Center for Environmental Assessment (NCEA). Integrated Science Assessment for Ozone and Related Photochemical Oxidants (Third External Review Draft). EPA/600/R–10/076C. Available at: http://cfpub.epa.gov/ncea/isa/recordisplay.cfm?deid=242490. Accessed December 19, 2012.