Epigenetic Effects of Diesel Exhaust and Ozone Exposure (Lamarck)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
David Diaz-Sanchez, Environmental Protection Agency (EPA)
ClinicalTrials.gov Identifier:
NCT01492517
First received: December 13, 2011
Last updated: February 1, 2013
Last verified: February 2013
  Purpose

Purpose: The purpose of this protocol is to compare the genetic and epigenetic effects between diesel exhaust and ozone exposure in healthy individuals and in mild/moderate asthmatics.

Participants: The investigators will recruit up to 30 mild to moderate asthmatics and up to 50 healthy adults to participate in this study.

Procedures (methods): Subjects will be exposed to clean air, to 300 µg/m3 of diesel exhaust for 2 hours and to 0.3 ppm of ozone for 2 hours with intermittent exercise in a controlled environment chamber. Primary endpoints will include spirometry and lung cell changes post-exposure. Secondary endpoints will include analysis of blood clotting/coagulation factors, Holter monitoring of cardiac parameters, analysis of soluble factors present in plasma and bronchial lavage and analysis of intracellular factors present in lung tissue obtained from a brush biopsy.


Condition Intervention
Exposure to Pollution
Inhalation of Ozone
Other: Ozone exposure
Other: Diesel exhaust
Other: Ozone18
Other: Clean Air

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Official Title: Epigenetic Effects of Diesel Exhaust and Ozone Exposure

Resource links provided by NLM:


Further study details as provided by Environmental Protection Agency (EPA):

Primary Outcome Measures:
  • Airway responses [ Time Frame: Pre exposure to 24hours post exposure ] [ Designated as safety issue: No ]
    Airway responses include spirometry and lung cell changes following exposure to either clean air, ozone or diesel exhaust Lung cell changes include change in number and type of cells, changes in genetic (gene expression) and epigenetic responses (primarily changes in DNA methylation, microRNA expression and chromatin modification.


Secondary Outcome Measures:
  • Cardiovascular responses [ Time Frame: Pre exposure to 24hours post exposure ] [ Designated as safety issue: No ]
    Cardiovascular responses are analysis of blood clotting/coagulation factors and Holter monitoring of cardiac parameters following exposure to clean air, ozone or diesel exhaust

  • Soluble factors [ Time Frame: Pre exposure to 24hours post exposure ] [ Designated as safety issue: No ]
    Analysis of soluble factors present in plasma and bronchial lavage and analysis of intracellular factors present in lung tissue obtained from a brush biopsy following exposure to clean air ozone or diesel exhaust


Estimated Enrollment: 80
Study Start Date: May 2010
Estimated Study Completion Date: May 2014
Estimated Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Sham Comparator: Clean air exposure
Exposure to clean air will be conducted in an exposure chamber at the EPA Human Studies Facility on the UNC campus. Each subject will be exposed to clean air for 2 hours. Subjects will begin exercising on an exercise bike. Each exercise session will consist of a 15 minute exercise interval at a level of up to 25 L/m2/BSA followed by a 15 minute rest period. The exposure atmosphere will be at approximately 40 + 10% RH and approximately 22 + 2 oC.
Other: Clean Air
Exposure to air which has been scrubbed to remove air pollutants including ozone and particles.
Other Name: CA
Ozone exposure
Exposure to 0.3ppm ozone will be conducted in an exposure chamber at the EPA Human Studies Facility on the UNC campus. Each subject will be exposed for 2 hours. Subjects will begin exercising on an exercise bike. Each exercise session will consist of a 15 minute exercise interval at a level of up to 25 L/m2/BSA followed by a 15 minute rest period. The exposure atmosphere will be at approximately 40 + 10% RH and approximately 22 + 2 oC. Ozone exposures will be conducted in a (6 ft x 6 ft x 8 ft) stainless steel chamber with a continuous supply of exposure medium. Ozone will be monitored continuously.
Other: Ozone exposure
Exposure to 0.3ppm ozone for 2 hours
Other Name: O3
Diesel exhaust exposure
Exposure to diesel exhaust will be conducted in an exposure chamber at the EPA Human Studies Facility on the UNC campus. Each subject will be exposed to diesel exhaust (up to 300 ug/m3). Subjects will begin exercising on an exercise bike. Each exercise session will consist of a 15 minute exercise interval at a level of up to 25 L/m2/BSA followed by a 15 minute rest period. The exposure atmosphere will be at approximately 40 + 10% RH and approximately 22 + 2 oC. The DE will be generated from a diesel generator used to power a load bank that is located outside the Human Studies Facility, and subsequently introduced into the exposure chamber after different dilutions with clean HEPA and charcoal filtered and humidified air to give a chamber concentration of up to 300 μg/m3.
Other: Diesel exhaust
Diesel exhaust generated from a diesel generator delivered to the exposure at a target concentration of 300 μg/m3
Other Names:
  • DE
  • DEP
18Ozone
Exposure to ozone generated using the heavy non-radioactive isotope of oxygen (18O). Exposure to 0.3ppm 18O will be conducted in an exposure chamber at the EPA Human Studies Facility on the UNC campus. Each subject will be exposed for 2 hours. Subjects will begin exercising on an exercise bike. Each exercise session will consist of a 15 minute exercise interval at a level of up to 25 L/m2/BSA followed by a 15 minute rest period. The exposure atmosphere will be at approximately 40 + 10% RH and approximately 22 + 2 oC. Ozone exposures will be conducted in a (6 ft x 6 ft x 8 ft) stainless steel chamber with a continuous supply of exposure medium. Ozone will be monitored continuously.
Other: Ozone18
Exposure to ozone generated using the heavy non-radioactive isotope of oxygen (18O).
Other Name: O18

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Healthy Individuals Specific Inclusion Criteria

  1. Physical exams will be performed by study physicians during the screening visit (IRB approved EPA protocol 95-EPA-66).
  2. Normal lung function (pre or post albuterol), defined by Knudson 1976/1984 as:

    - FVC of > 75 % of that predicted for gender, ethnicity, age and height.

    - FEV1 of > 75 % of that predicted for gender, ethnicity, age and height.

    - FEV1/FVC ratio of > 75 % of predicted values.

  3. Oxygen saturation of > 96 %.
  4. Ability to tolerate intervals of moderate exercise

Mild to Moderate Asthmatics

Inclusion Criteria:

  1. Physical exams will be performed by study physicians during the screening visit (IRB approved EPA protocol 95-EPA-66) where diagnosis will be judged by EPA physicians.
  2. Mild/Moderate asthmatics as defined by NHLBI guidelines.
  3. Positive history of asthma (wheezing, chest tightness, and reversible airway obstruction);
  4. Baseline FEV1/FVC ≥ 60%;
  5. Oxygen saturation of ≥ 94%
  6. Ability to tolerate moderate exercise

Exclusion Criteria:

  • Healthy Individuals

    1. A history of chronic illnesses such as diabetes, rheumatological diseases, immunodeficiency state, known clinically significant cardiac disease (including myocardial infarction, congestive heart failure and angina), chronic respiratory diseases such as chronic obstructive pulmonary disease, and lung cancer.
    2. If the subject is pregnant, attempting to become pregnant or breastfeeding.
    3. Allergy to any medications which may be used or prescribed in the course of this study.
    4. Subjects currently taking mega doses of vitamins and supplements, homeopathic/naturopathic medicines or medications which may impact the results of the PM and/or ozone challenge or interfere with any other medications potentially used in the study (to include systemic steroids and beta blockers). Subjects must refrain from all over the counter anti-inflammatory agents including those for allergies, and naproxen, and anti-oxidants for a period of one week prior to exposure. Medications not specifically mentioned here may be reviewed by the investigators prior to a subject's inclusion in the study.
    5. Smoking history within 2 years of the study.
    6. Use of inhaled steroids, cromolyn, or leukotriene inhibitors (Montelukast, Zafirkulast, etc) initiated within the past month (except for use of cromolyn exclusively prior to exercise). Patients must be on a stable regimen of therapy.
    7. Untreated hypertension (> 150 systolic, > 90 diastolic)
    8. Dementia.
    9. Unspecified illnesses, which in the judgment of the investigator might increase the risk associated with PM inhalation challenge or exercise, will be a basis for exclusion.
    10. History of skin allergy to tape or electrodes.
    11. Subjects who do not understand or speak English
    12. Subjects who are unable to perform moderate exercise

      Exclusion criteria for bronchoscopy:

    1. Any food or fluids after midnight prior to bronchoscopy
    2. FEV1/FVC ratio less than 60% predicted on AM of bronchoscopy.
    3. Regular use of aspirin or other nonsteroidal anti-inflammatory drugs (which inhibit platelet function).

      Mild to Moderate Asthmatics

      Use of oral steroid therapy within the past month

    2. Physician directed emergency treatment for asthma exacerbation within the preceding 6 months.

    3. Abnormal EKG that precludes evaluating heart rate variability. 4. Aside from mild/moderate asthma, a history of chronic illnesses such as diabetes, rheumatological diseases, immunodeficiency state, known clinically significant cardiac disease (including myocardial infarction, congestive heart failure and angina), chronic respiratory diseases such as chronic obstructive pulmonary disease or severe asthma, and cancer (possible exception for history of nonmelanoma skin cancer).

    5. If the subject is pregnant, attempting to become pregnant or breastfeeding. 6. Allergy to any medications which may be used or prescribed in the course of this study 7. Subjects currently taking mega doses of vitamins and supplements, homeopathic/naturopathic medicines or medications which may impact the results of the PM challenge or interfere with any other medications potentially used in the study (to include systemic steroids and beta blockers). Subjects must refrain from all over the counter anti-inflammatory agents including those for allergies, and naproxen, and anti-oxidants for a period of one week prior to exposure. Medications not specifically mentioned here may be reviewed by the investigators prior to a subject's inclusion in the study.

    8. Dosing level of an inhaled steroid must be consistent with mild asthma as outlined by the NHLBI NAEPP guidelines. Regular use of oral corticosteroids, or use of inhaled steroid at doses typically used for severe asthma, will result in exclusion of that individual from the protocol.

    9. Severe asthmatics as defined by: nighttime symptoms of cough or wheeze greater than 1 time per week at baseline, daily exacerbation of asthma or requirement for albuterol due to asthma symptoms (cough, wheeze, chest tightness, but not to include prophylactic use of albuterol prior to exercise), more than mild interference with normal activity, any episode of physician directed emergency treatment for asthma requiring oral corticosteroid therapy within the past twelve months.

    10. Smoking history within 2 years of study. 11. Use of inhaled steroids, cromolyn, or leukotriene inhibitors (Montelukast, Zafirkulast, etc) initiated within the past month (except for use of cromolyn exclusively prior to exercise). Patients must be on a stable regimen of therapy.

    12. History of skin allergy to tape or electrodes. 13. History of respiratory diseases other than allergic rhinitis and asthma 14. Untreated hypertension (> 150 systolic, > 90 diastolic) 15. Dementia. 16. Unspecified illnesses, which in the judgment of the investigator might increase the risk associated with PM inhalation challenge or exercise, will be a basis for exclusion.

    17. Subjects who do not understand or speak English 18. Subjects who are unable to perform moderate exercise

Exclusion criteria for bronchoscopy:

  1. Any food or fluids after midnight prior to bronchoscopy
  2. FEV1/FVC ratio less than 60% predicted on AM of bronchoscopy.
  3. Regular use of aspirin or other nonsteroidal anti-inflammatory drugs (which inhibit platelet function).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01492517

Locations
United States, North Carolina
U.S. EPA Human Studies Facility
Chapel Hill, North Carolina, United States, 27514
Sponsors and Collaborators
Investigators
Study Director: David Diaz-Sanchez, Ph.D. U.S. Environmental Protection Agency
Principal Investigator: Kelly Duncan, PhD University of North Carolina, Chapel Hill
  More Information

No publications provided by Environmental Protection Agency (EPA)

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: David Diaz-Sanchez, Chief, Clinical Research Branch, Environmental Protection Agency (EPA)
ClinicalTrials.gov Identifier: NCT01492517     History of Changes
Other Study ID Numbers: E10-025CS
Study First Received: December 13, 2011
Last Updated: February 1, 2013
Health Authority: United States: Federal Government

Keywords provided by Environmental Protection Agency (EPA):
Controlled Human exposure study
Air Pollution
Gene expression
Epigenetic
Cardiovascular

Additional relevant MeSH terms:
Respiratory Aspiration
Respiration Disorders
Respiratory Tract Diseases
Signs and Symptoms, Respiratory
Signs and Symptoms

ClinicalTrials.gov processed this record on July 26, 2014