Effects of Sequential Exposure to Nitrogen Dioxide and Ozone in Healthy Adult Human Volunteers.
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Depression, Depression, Pulmonary |
| Therapuetic Areas: | Psychiatry / Psychology, Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 18 - 40 |
| Updated: | 2/10/2019 |
| Start Date: | January 2014 |
| End Date: | May 2020 |
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.
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.
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.
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.
Inclusion Criteria:
1. Healthy men and women between 18 and 40 years of age.
2. Physical conditioning allowing intermittent, moderate exercise for two hours.
3. Ability to complete the exposure exercise regimen without reaching 80% of predicted
maximal heart rate.
4. Normal baseline 12-lead baseline EKG or if not normal the EKG must be approved by a
study cardiologist.
5. Normal lung function
1. Forced vital capacity (FVC) >75% of that predicted for gender, ethnicity, age,
and height (according to National Health and Nutrition Examination Survey
[NHANESIII] guidelines).
2. Forced expiratory volume in one second (FEV1) > 75% of that predicted for gender,
ethnicity, age, and height (according to NHANESIII guidelines).
3. FEV1/FVC ration >75% of predicted values (according to NHANESIII guidelines).
6. Oxygen saturation >96% on room air.
Exclusion Criteria:
1. Individuals with a history of acute or chronic cardiovascular disease, chronic
respiratory disease, diabetes, rheumatologic disease, or immunodeficiency state.
2. Individuals with a Framingham risk score (Hard Coronary Heard Disease [HCHD] 10-year
risk) ≥10.
3. Individuals with asthma or a history of asthma.
4. Individuals who are allergic to chemical vapors or gases.
5. Females who are pregnant, attempting to become pregnant, or breastfeeding.
6. Individuals that are unwilling or unable to stop taking vitamin C or E, or medications
that may impact the results of ozone challenge such at least two weeks prior to the
study and for the duration of the study. Medications not specifically mentioned here
may be reviewed by the investigators prior to an individual's inclusion in the study.
7. Individuals who have smoked tobacco during the last five years or those with a history
of >5 pack years.
8. Individuals living with a smoker who smokes inside the house.
9. Individuals with a body mass index (BMI) >30 or <18. Body mass index is calculated by
dividing the weight in kilograms by the square of the height in meters.
10. Individuals with occupational exposures to high levels of vapors, dust, gases, or
fumes on an on-going basis.
11. Individuals with uncontrolled hypertension (≥150 systolic or ≥90 diastolic).
12. Individuals that do not understand or speak English.
13. Individuals that are unable to perform the exercise required for the study.
14. Individuals that are taking beta blocker medications.
15. Individuals with a history of skin allergies to adhesives used in securing EKG
electrodes.
16. Individuals with unspecified diseases, conditions, or medications that might influence
the responses to the exposures, as judged by the medical staff.
17. Individuals that are unwilling or unable to stop taking over-the-counter pain
medications such as aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), or other
non-steroidal anti-inflammatory ("NSAID") medications for 48 hours prior to the
exposures and post-exposure visits.
18. Individuals that are taking systemic steroids or beta-blocker medications.
19. Individuals with a hemoglobin A1c (HbA1c) level > 6.4%.
Temporary Exclusion Criteria
1. Individuals with active seasonal allergies during the time of participation in the
study.
2. Individuals suffering from acute respiratory illness within four weeks prior to any of
the study exposure series.
3. Individuals that have been exposed to smoke and fumes within 24 hours of any study
visit.
4. Individuals that have consumed alcohol within 24 hours of any study visit.
5. Individuals that have engaged in strenuous exercise within 24 hours of any study
visit.
6. Individuals that have been exposed to ozone-based home air purifiers within 24 hours
of any study visit.
7. Individuals that have been exposed to unvented household combustion sources (gas
stoves, lit fireplaces, oil/kerosene heaters) within 48 hours of any study visit.
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