Effects of Sequential Exposure to Nitrogen Dioxide and Ozone in Healthy Adult Human Volunteers.
Condition: Respiratory Depression
MeSH terms: Respiratory Insufficiency
Study type: Interventional

Summary: 
      The U.S. Environmental Protection Agency has traditionally examined the effects of single
      pollutant exposure on human health outcomes; however, to provide a better assessment of
      pollutant exposure-associated effect on human health the Agency is moving toward a
      multi-pollutant approach. Ozone (O3) and nitrogen dioxide (NO2) are national ambient air
      quality standards (NAAQS) criteria pollutants that are major constituents of ambient air
      pollution. This study will address the Agency's goals by investigating the cardiopulmonary
      health effects of sequential exposure to O3 and NO2 in healthy adult human volunteers. The
      findings of this study will provide data that will inform risk assessment models for O3 and
      NO2 exposures. Additionally, the findings will provide insight into how the human health
      effects of multi-pollutant exposures differ from those of single pollutant exposures.
    

Detailed description: 
      Despite improvements in air quality over the past several decades, over 100 million people in
      the U.S. still live in counties that do not meet the National Ambient Air Quality Standards
      (NAAQS) for one or more pollutants. During the course of daily living individuals are exposed
      to multiple pollutants from various sources of both natural and anthropogenic origin. It has
      become increasingly clear that air pollutant exposure is a risk factor for exacerbation and
      perhaps even progression of pulmonary and cardiovascular disease. The majority of controlled
      human exposure studies have examined individual pollutants; however, real-world exposures
      occur in the context of a complex mixture of pollutants. Different pollutants reach peak
      levels at different times during the day, which raises the concern that exposure to one
      pollutant may sensitize an individual so that their response to a subsequent exposure may be
      enhanced. Thus the sequence of exposure to these agents may affect their relative health
      effects and result in certain exposure scenarios being more deleterious than others.

      To define multi-pollutant exposures that are relevant to real world scenarios we consulted
      experts in the EPA Office of Air and Radiation (OAR), who advised us to study the effects of
      sequential exposure to NO2 and O3, two ubiquitous NAAQS criteria pollutants. Ambient diurnal
      profiles of these two pollutants indicate that levels of NO2 often peak in the evening and
      morning hours, which are followed by peak ambient O3 concentrations during mid-day. Using
      this information we designed the study described here to determine whether sequential
      exposure to NO2 and O3, or O3 and NO2, will result in greater pulmonary and cardiovascular
      effects than exposure to either pollutant alone. Ozone is a major component of photochemical
      smog and is one of the most thoroughly studied gaseous pollutants. Controlled human exposure
      studies have been critical in demonstrating that it can cause airway inflammation, including
      increases in neutrophil infiltration into the lung and the production of pro-inflammatory
      mediators, and ultimately decrements in lung function. More recent studies have shown that
      ozone can also increase vascular inflammation, as well as alter autonomic nervous system
      control of heart rate. Nitrogen dioxide is an oxidant that is produced by natural and
      anthropogenic processes. The majority of man-made NO2 results from large-scale
      combustion-related processes, such as automobile emissions and the generation of electricity.
      Although traffic-related exposures account for the majority of NO2 emissions. Emissions from
      natural gas cooking appliances and kerosene-fueled space heaters with inadequate ventilation
      can serve as a significant source of human exposure to NO2 indoors. Previous studies have
      shown that NO2 concentrations can reach 600ppb in the area surrounding an operating gas
      stove, and peak levels may exceed 2000ppb. Controlled human exposure studies have indicated
      that exposure to NO2 alone (ranging from 110-2000ppb) results in little to no observable
      decrement in lung function; however, NO2 exposure has been associated with increases in
      airway hyper-responsiveness, susceptibility to pulmonary infection, and increased pulmonary
      inflammation. More recently, exposure to 500ppb NO2 has been associated with changes in
      cardiac electrophysiology. Recent epidemiological data indicate that exposure to NO2 from
      vehicle emissions were associated with both respiratory and cardiovascular-related mortality.
      Previous studies have shown that sequential exposure to NO2 and O3 (at concentrations similar
      to those proposed in this study) results in greater lung function decrements and increased
      non-specific airway responsiveness compared to O3 exposure preceded by clean air exposure in
      young women. Additional studies have demonstrated that sequential exposure to ozone,
      separated by 24 hours, resulted in greater lung function decrements, assessed as forced
      expiratory volume in the first second of exhalation (FEV1), following the second exposure
      than was observed after the first. Ozone exposure has also been shown to have a priming
      effect for subsequent exposure to sulfur dioxide (SO2) in adolescent asthmatics and
      allergen-induced responses of perennially allergic asthmatics. Additionally, ongoing research
      at the EPA Human Studies Facility has demonstrated that sequential exposure of humans to
      diesel exhaust and ozone can result in greater lung function decrement than exposure to
      either pollutant alone. Given the complex nature of pollutant exposure, we are interested in
      determining if exposure to one pollutant can sensitize a person so that subsequent exposure
      to a second pollutant would cause a more pronounced response than would be expected based on
      exposure to just the second pollutant alone. Thus, in this study we will examine two exposure
      scenarios involving sequential exposures of NO2 and O3. The first involves determining
      whether an initial exposure to NO2 will "prime" an individual to a subsequent O3 exposure.
      The second involves determining whether an initial exposure to O3, at a concentration that
      results in small cardiopulmonary changes that resolve within 24 hours, will augment a
      subsequent exposure to NO2. Generally speaking, exposure to NO2 alone is not associated with
      robust changes in metrics of cardiopulmonary function; however, we believe that it can
      modify, and be modified by, ozone exposure. Specifically, this study will test two general
      hypotheses. First, we hypothesize that pre-exposure to a relatively low concentration of NO2
      will "sensitize" individuals to a subsequent O3 exposure and lead to greater changes in
      cardiopulmonary function compared to O3 exposure preceded by clean air exposure. Second, we
      hypothesize that pre-exposure to O3, at a concentration that has been previously associated
      with small changes in cardiopulmonary function, will prime individuals to have a greater
      response to NO2 compared to pre-exposure to clean air. The information obtained during the
      course of this study will enable the EPA to better evaluate the risks associated with
      sequential multi-pollutant exposure and potentially provide advice on activities to mitigate
      the effects.
    

Intervention name(s): Ozone; Nitrogen dioxide
Intervention type(s): Other; Other
Intervention description(s): Exposure to 300ppb ozone with intermittent exercise as either the first exposure in a two-exposure series or as the second exposure approximately 22 hours after the first exposure (either clean air or nitrogen dioxide) in a two-exposure series.; Exposure to 500ppb nitrogen dioxide with intermittent exercise as either the first exposure in a two-exposure series or as the second exposure approximately 22 hours after the first exposure (either clean air or ozone) in a two-exposure series.
Other intervention name(s): Trioxygen; CAS #10028-15-6; Nitrogen peroxide; CAS 310102-44-0
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: Air pollution; Ozone; Nitrogen dioxide; Lung function; Cytokines