Critical review of the human data on short-term nitrogen dioxide (NO₂) exposures: Evidence for NO₂ no-effect levels

Abstract

Nitrogen dioxide (NO₂) is a ubiquitous atmospheric pollutant due to the widespread prevalence of both natural and anthropogenic sources, and it can be a respiratory irritant when inhaled at elevated concentrations. Evidence for health effects of ambient NO₂ derives from three types of studies: observational epidemiology, human clinical exposures, and animal toxicology. Our review focuses on the human clinical studies of adverse health effects of short-term NO₂ exposures, given the substantial uncertainties and limitations in interpretation of the other lines of evidence. We examined more than 50 experimental studies of humans inhaling NO₂, finding notably that the reporting of statistically significant changes in lung function and bronchial sensitivity did not show a consistent trend with increasing NO₂ concentrations. Functional changes were generally mild and transient, the reported effects were not uniformly adverse, and they were not usually accompanied by NO₂-dependent increases in symptoms. The available human clinical results do not establish a mechanistic pathway leading to adverse health impacts for short-term NO₂ exposures at levels typical of maximum 1-h concentrations in the present-day ambient environment (i.e., below 0.2 ppm). Our review of these data indicates that a health-protective, short-term NO₂ guideline level for susceptible (and healthy) populations would reflect a policy choice between 0.2 and 0.6 ppm.

Extended abstract

Nitrogen dioxide (NO₂) is a ubiquitous atmospheric pollutant due to the widespread prevalence of both natural and anthropogenic sources, and it can be a respiratory irritant when inhaled at elevated concentrations. Natural NO₂ sources include volcanic action, forest fires, lightning, and the stratosphere; man-made NO₂ emissions derive from fossil fuel combustion and incineration.

The current National Ambient Air Quality Standard (NAAQS) for NO₂, initially established in 1971, is 0.053 ppm (annual average). Ambient concentrations monitored in urban areas in the United States are ~0.015 ppm, as an annual mean, i.e., below the current NAAQS. Short-term (1-h peak) NO₂ concentrations outdoors are not likely to exceed 0.2 ppm, and even 1-h periods exceeding 0.1 ppm are infrequent. Inside homes, 1-h NO₂ peaks, typically arising from gas cooking, can range between 0.4 and 1.5 ppm.

The health effects evidence of relevance to ambient NO₂ derives from three lines of investigation: epidemiology studies, human clinical studies, and animal toxicology studies. The NO₂ epidemiology remains inconsistent and uncertain due to the potential for exposure misclassification, residual confounding, and co-pollutant effects, whereas animal toxicology findings using high levels of NO₂ exposure require extrapolation to humans exposed at low ambient NO₂ levels. Given the limitations and uncertainties in the other lines of health effects evidence, our review thus focused on clinical studies where human volunteers (including asthmatics, children, and elderly) inhaled NO₂ at levels from 0.1 to 3.5 ppm during short-term (½–6-h) exposures, often combined with exercise, and occasionally combined with co-pollutants. We examined the reported biological effects and classified them into (a) lung immune responses and inflammation, (b) lung function changes and airway hyperresponsiveness (AHR), and (c) health effects outside the lungs (extrapulmonary).

We examined more than 50 experimental studies of humans inhaling NO₂, finding that such clinical data on short-term exposure allowed discrimination of NO₂ no-effect levels versus lowest-adverse-effects levels. Our conclusions are summarized by these six points: For lung immune responses and inflammation: (1) healthy subjects exposed to NO₂ below 1 ppm do not show pulmonary inflammation; (2) at 2 ppm for 4 h, neutrophils and cytokines in lung-lavage fluid can increase, but these changes do not necessarily correlate with significant or sustained changes in lung function; (3) there is no consistent evidence that NO₂ concentrations below 2 ppm increase susceptibility to viral infection; (4) for asthmatics and individuals having chronic obstructive pulmonary disease (COPD), NO₂-induced lung inflammation is not expected below 0.6 ppm, although one research group reported enhancement of proinflammatory processes at 0.26 ppm. With regard to NO₂-induced AHR: (5) studies of responses to specific or nonspecific airway challenges (e.g., ragweed, methacholine) suggest that asthmatic individuals were not affected by NO₂ up to about 0.6 ppm, although some sensitive subsets may respond to levels as low as 0.2 ppm. And finally, for extra-pulmonary effects: (6) such effects (e.g., changes in blood chemistry) generally required NO₂ concentrations above 1–2 ppm.

Overall, our review of data from experiments with humans indicates that a health-protective, short-term-average NO₂ guideline level for susceptible populations (and healthy populations) would reflect a policy choice between 0.2 and 0.6 ppm. The available human clinical results do not establish a mechanistic pathway leading to adverse health impacts for short-term NO₂ exposures at levels typical of maximum 1-h concentrations in the present-day ambient environment (i.e., below 0.2 ppm).

Keywords::

• Air pollution
• airway challenge
• airway hyperresponsiveness
• controlled human exposure study; epidemiology
• inflammation
• lung function
• nitrogen dioxide (NO2)
• air quality standard

Acknowledgments

Many thanks to Dr. Sonja Sax of Gradient for her editorial review of the manuscript during its preparation.

Declaration of interest: This review was prepared by T. W. Hesterberg and W. B. Bunn in the course of their employment with Navistar, Inc., and by R. O. McClellan, Advisor in Toxicology and Risk Analysis, and A. K. Hamade, C. M. Long, and P. A. Valberg of Gradient Corporation, as consultants to Navistar, Inc. Gradient provides consulting services to a variety of parties, including industry (e.g., utilities, engine manufacturers), governmental agencies, regulators, and law firms. R.O. McClellan has also served as a consultant to the American Petroleum Institute on matters related to the setting of National Ambient Air Quality Standards. The scientific analyses, content, and writing of this paper are the sole responsibility of the authors.