Meta-analysis of nitrogen dioxide exposure and airway hyper-responsiveness in asthmatics

Abstract

The effects of 0.1 to 0.6 ppm nitrogen dioxide (NO₂) on airway hyper-responsiveness (AHR) to airway challenges in asthmatics have been evaluated in several controlled exposure studies. The authors conducted meta-analyses and meta-regressions of these studies using several effect measures for AHR: a change (in NO₂ versus air) in (1) the provocative dose of a challenge agent necessary to cause a specified change in lung function (PD), (2) the change in FEV₁ after an airway challenge, and (3) the fraction of subjects with increased AHR. Although several effect estimates from the meta-analyses are statistically significant, they are all so small that they are not likely to be clinically relevant. More importantly, there are no exposure-response associations for any effect estimates based on linear meta-regressions or analyses of effect estimates for exposure groups (0.1 to <0.2 ppm, 0.2 to <0.3 ppm, etc.). This is also generally the case for analyses stratified by airway challenge (specific/nonspecific), exposure method (mouthpiece/whole chamber), and activity during exposure (rest/exercise). The results of these analyses indicate that, to the extent the effects observed are associated with NO₂ exposure, they are sufficiently small such that they do not provide evidence that NO₂ has a significant adverse effect on AHR at concentrations up to 0.6 ppm.

Keywords::

• Airway hyper-responsiveness
• asthmatic
• controlled exposure
• meta-analysis
• meta-regression
• nitrogen dioxide

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Erratum

Acknowledgments

We thank Ruth L. Lyddy, MS, for conducting the literature searches, Carla A. Walker for contributing to the data extraction and quality control, and Brian Wiessmeyer and Leslie Beyer for translating studies into English.

Declaration of interest: The authors are all employees of Gradient, a private environmental and risk science consulting firm. This paper was prepared with financial support to Gradient from the American Petroleum Institute (API), a trade association representing producers, refiners, and distribution of petroleum products, and the Utility Air Regulations Group (UARG), a voluntary, not-for-profit association of individual electric generating companies and national trade associations that participate collectively in administrative proceedings under the Clean Air Act, and in litigation arising from those proceedings, that affect electric generators. The work reported in the paper was conducted during the normal course of employment by Gradient. The authors have the sole responsibility for the writing and contents of this paper. The views and opinions expressed in this paper may not necessarily be those of API or UARG.

Notes

¹Individual subjects’ provocative dose data from Bylin et al. (1985) and Witten et al. (2005) were excluded because complete data were not provided (only the lower limit of provocative dose values were reported).

²Individual subjects’ ΔFEV₁ data for 0.40 ppm NO₂ exposures from the Witten et al. (2005) study were excluded because this was the only instance of a negative correlation.

³Frampton et al. (1991) and Utell et al. (1991) describe the same study.

⁴Rudolf A. Jorres clarified that the Jorres et al. (1990) study was a summary of the Jorres and Magnussen (1991) study.

⁵Cheryl Salome was unable to retrieve individual subject data associated with the Salome et al. (1996) study. Torben Riis Rasmussen could not be contacted to obtain data from the Rasmussen et al. (1990) study.

⁶Utell et al. (1991) reported the effective level as ≥15% decrease in FEV₁ or ≥40% decrease in sGaw, whereas Morrow and Utell (1989) did not report what effective level they used.

⁷Nonasthmatic subjects were exposed to NO₂ concentrations up to 2 ppm.