Ozone Exposure for Acute Lung Injury

(LOCONOZ2 Trial)

Overseen By Andrea Davis, R.N.

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Martin W. Case

Must not be taking: Systemic steroids, Beta blockers

Disqualifiers: COVID-19, Cardiovascular disease, Asthma, Diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how a small amount of ozone in the air affects lung function and symptoms in healthy young adults. Participants will breathe either clean air or air with a low concentration of ozone while engaging in moderate exercise. The researchers aim to observe any changes in breathing and lung inflammation. The trial seeks healthy individuals who can exercise moderately for several hours and have no history of asthma or recent respiratory illnesses. As a Phase 1 trial, this research focuses on how ozone exposure affects lung function, offering participants the chance to contribute to foundational scientific knowledge.

Do I need to stop taking my current medications to join the trial?

Yes, you may need to stop taking certain medications. The trial excludes participants taking mega doses of vitamins, supplements, homeopathic/naturopathic medicines, or medications that may impact the ozone challenge results, including systemic steroids and beta blockers. Other medications not mentioned may be reviewed by investigators before inclusion.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that ozone levels of 0.070 ppm can affect breathing. Studies have found that short-term exposure to high ozone levels might lead to increased breathing problems. Even lower levels, such as 60 parts per billion (ppb), can impact lung function.

Evidence also indicates that long-term ozone exposure can affect lung growth, particularly in children. Short-term exposure, as tested in this trial, might cause some breathing issues, though this is less certain.

Overall, while this study is in its early stages, it is important to recognize that ozone exposure can pose risks to lung health. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this trial because it explores the impact of ozone exposure combined with moderate intermittent exercise on acute lung injury. Unlike current treatments that focus on medications or ventilatory support to manage symptoms, this approach investigates a potential environmental and physical intervention. By understanding how different ozone levels influence lung health during exercise, scientists aim to uncover new insights that could lead to novel preventive strategies or therapeutic methods for lung injury.

What evidence suggests that this trial's treatments could be effective for acute lung injury?

This trial will compare the effects of exposure to 0.070 ppm ozone concentration with exposure to clean air (0.0 ppm ozone) during moderate intermittent exercise. Research has shown that even low levels of ozone, like 0.070 ppm, can affect lung function and cause inflammation. One study found that ozone exposure led to small changes in lung function, such as a slight decrease in the amount of air exhaled quickly and the total air exhaled after a deep breath. However, these changes are usually minor and reversible. Other studies have shown that ozone exposure can cause breathing issues, including coughing and shortness of breath. While these effects are documented, the impact can vary from person to person. ^{1 2 3 6 7}

Who Is on the Research Team?

Andy Ghio, M.D.

Principal Investigator

EPA/ORD/CPHEA/PHITD/CRB

Are You a Good Fit for This Trial?

Healthy adults aged 18-35 with normal lung function and the ability to do moderate exercise for 6.6 hours can join this trial. Pregnant women, smokers, those with asthma or recent respiratory illness, uncontrolled hypertension, or not up-to-date on COVID vaccines are excluded.

Inclusion Criteria

My symptoms are mild, with none too severe.

You are physically able to do moderate exercise for about 6.6 hours.

My lung function is within normal range.

Exclusion Criteria

Temporary exclusion criteria: acute respiratory illness within 4 weeks, active allergies, engaged in strenuous exercise within 24 hours of any study visit, unable to avoid drinking alcohol for 24 hours prior to all study visits, exposed to smoke and fumes for 24 hours before all visits, used an ozone-based home air purifier for 24 hours before all visits, eaten or drank anything for 2 hours prior to the sputum training/screening day visit, refrain from caffeine for 12 hours prior to all study visits, refrain from all over the counter anti-inflammatory agents including those for allergies, and anti-inflammatory drugs or antioxidants for a period of one week prior to the train and to the exposure, exposed to or have consumed any agent or have undertaken any activity within 24 hours of any study visit that may compromise the results of the study

I am not taking large doses of vitamins, natural medicines, or other drugs that could affect the study.

I have been diagnosed with or hospitalized for COVID-19.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Exposure

Participants are exposed to either clean air or 0.070 ppm ozone for 6.6 hours while performing moderate intermittent exercise

1 day

1 visit (in-person)

Immediate Post-Exposure Assessment

Pulmonary function and inflammatory responses are measured immediately after exposure

1 day

1 visit (in-person)

Follow-up

Participants are monitored for changes in neutrophil levels and lung function 18 hours post-exposure

1 day

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Exposure to 0.070 ppm Ozone Concentration
• Exposure to Clean Air (0.0 ppm Ozone)
• Moderate Intermittent Exercise

Trial Overview The study is testing how breathing in a low concentration of ozone (0.070 ppm) compared to clean air affects lung function and inflammation during/after exercising for 6.6 hours in healthy young adults.

How Is the Trial Designed?

Group I: Clean air (0.0 ppm ozone) Experimental Treatment 1 Intervention

Exposure to clean air (0.0 ppm ozone) for 6.6 hours while performing moderate intermittent exercise.

Group II: 0.070 ppm ozone concentration Experimental Treatment 1 Intervention

Exposure to 0.070 ppm ozone for 6.6 hours while performing moderate intermittent exercise.

Who Is Running the Clinical Trial?

Martin W. Case

Lead Sponsor

Trials

1

Recruited

60+

University of North Carolina

Collaborator

Trials

174

Recruited

1,457,000+

Published Research Related to This Trial

In a study of 30 healthy adult nonsmokers exercising outdoors, exposure to ozone (O3) significantly decreased respiratory function, with specific reductions in lung capacity and airflow measurements per increase in ozone concentration.

Subjects with higher minute ventilation (over 100 L) experienced smaller functional decrements compared to those with lower ventilation rates, suggesting that exercise intensity may influence the impact of ozone on respiratory health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of ambient ozone on respiratory function in healthy adults exercising outdoors. Spektor, DM., Lippmann, M., Thurston, GD., et al.[2013]

In a study of male amateur cyclists, it was found that higher ozone concentrations during exercise negatively affected lung function, with significant changes observed even at low exposure levels (average 87 micrograms/m3).

The study also revealed that acute respiratory symptoms, such as shortness of breath and chest tightness, increased with ozone exposure, particularly in midsummer, indicating a potential risk for healthy individuals exercising outdoors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Respiratory effects of low-level photochemical air pollution in amateur cyclists. Brunekreef, B., Hoek, G., Breugelmans, O., et al.[2013]

In a study involving rats exposed to ozone (O3) for up to 3.75 hours, it was found that both the concentration of ozone and the duration of exposure contributed to lung tissue injury, but exercise had the most significant impact on the severity of lung lesions.

The findings suggest that physical activity amplifies the harmful effects of ozone exposure on lung health, highlighting the need to consider exercise when evaluating the health risks associated with air pollution.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhancement of ozone-induced lung injury by exercise. Mautz, WJ., McClure, TR., Reischl, P., et al.[2013]

In a study involving 40 young women (20 obese and 20 non-obese), exposure to ozone resulted in significantly greater lung function decrements in obese individuals, with a decrease in forced vital capacity of 12.5% compared to 8.0% in non-obese individuals after exposure.

Despite the greater lung function decline in obese women, both groups exhibited similar levels of airway reactivity and inflammation in response to ozone, indicating that while obesity affects lung function, it does not necessarily increase airway hyperresponsiveness to ozone exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Obesity on Acute Ozone-Induced Changes in Airway Function, Reactivity, and Inflammation in Adult Females. Bennett, WD., Ivins, S., Alexis, NE., et al.[2018]

In a study of 64 healthy young men exposed to ozone, significant variability was observed in lung function changes, particularly in FVC and FEV1, indicating that individual sensitivity to ozone can differ widely.

The research suggests that intrinsic narrowing of small airways may play a crucial role in how individuals respond to ozone exposure, as changes in FEF25-75 were not fully explained by changes in FVC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response to acute ozone exposure in healthy men. Results of a screening procedure. Weinmann, GG., Bowes, SM., Gerbase, MW., et al.[2013]

In a study involving 17 elite endurance cyclists, exposure to 0.20 ppm ozone significantly impaired exercise performance, reducing peak ventilation, oxygen consumption, and overall ride time compared to filtered air, indicating that higher ozone levels can negatively affect athletic performance.

While exposure to 0.12 ppm ozone resulted in mild symptoms and no significant performance decline, the 0.20 ppm level led to more severe symptoms and a notable decrease in lung function, suggesting that even low concentrations of ozone can have detrimental effects on respiratory health during intense exercise.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impaired exercise performance and pulmonary function in elite cyclists during low-level ozone exposure in a hot environment. Gong, H., Bradley, PW., Simmons, MS., et al.[2013]

Exercise significantly increases the pulmonary dose of inhaled ozone (O3) in humans, as evidenced by higher concentrations of labeled O3 in the bronchoalveolar lavage fluid (BALF) of exercising subjects compared to resting subjects.

The study found that resting humans had only one-fifth the O3 concentration in BALF compared to exercising individuals, indicating that exercise enhances the inhalation and potential toxicity of pollutants like ozone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarkers of Dose and Effect of Inhaled Ozone in Resting versus Exercising Human Subjects: Comparison with Resting Rats. Hatch, GE., McKee, J., Brown, J., et al.[2021]

In a study involving 12 trained men, inhaling 0.30 ppm ozone during both continuous and intermittent exercise led to significant decrements in pulmonary function, with forced expiratory volume decreasing by about 17% across all exercise types.

While both exercise types resulted in similar pulmonary function responses, subjective symptoms were more pronounced after continuous exercise, suggesting that the type of exercise may influence the perception of discomfort during ozone exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pulmonary function response to equivalent doses of ozone consequent to intermittent and continuous exercise. McKittrick, T., Adams, WC.[2016]

Ozone exposure, especially during exercise, can significantly impair pulmonary function and exercise performance, with effects observed at concentrations as low as 0.18 ppm, which is common in areas like the Los Angeles basin.

The 'ozone effective dose,' which considers ozone concentration, minute ventilation, and exposure time, provides a better prediction of respiratory effects than ozone concentration alone, highlighting the increased risk for highly trained athletes due to their higher ventilation rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of ozone exposure at ambient air pollution episode levels on exercise performance. Adams, WC.[2018]

In a study involving 21 asthmatic subjects aged 19 to 40, exposure to 0.10 and 0.25 ppm ozone did not significantly affect lung function (FEV1 or FVC) after exercise, regardless of whether the subjects had exercise-induced asthma (EIA).

However, exposure to 0.40 ppm ozone resulted in a significant reduction in FEV1 (-9.6%), indicating that higher levels of ozone can exacerbate asthma symptoms, although lung function returned to baseline within an hour.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pre-exposure to ozone does not enhance or produce exercise-induced asthma. Weymer, AR., Gong, H., Lyness, A., et al.[2015]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8783034/

Systematic Review of Ozone Effects on Human Lung ... Twelve-month ozone exposure was associated with an increased FEV1 of 3.95% predicted and FVC of 2.15% predicted in lung transplant recipients, which may be ...

2. withpower.com withpower.com/trial/phase-1-lung-injury-9-2022-ea198

Ozone Exposure for Acute Lung Injury (LOCONOZ2 Trial) The treatment of moderate intermittent exercise with exposure to 0.070 ppm ozone concentration is not promising for acute lung injury. Research shows that ozone ...

3. atsjournals.org atsjournals.org/doi/10.1164/rccm.201708-1613OC

Respiratory Responses to Ozone Exposure. MOSES (The ... Exposure to ozone reduced these increases in a concentration-dependent manner. After 120-ppb exposure, FEV1 and FVC decreased by 1.7% (1.1–2.3) ...

4. epa.gov epa.gov/system/files/documents/2024-12/o3_irp-vol-1_final_1.pdf

Integrated Review Plan for the National Ambient Air Quality ... The respiratory effects associated with O3 exposure range from small, reversible changes in lung function and pulmonary inflammation (documented ...

5. lung.org lung.org/getmedia/0ef2e27c-a9be-4905-a00e-53735244f676/groups-support-ozone-standard.pdf.pdf

Groups Support Ozone Standard further agree that exposure to ozone at 60 ppb causes respiratory effects, including lung function decrements that equal or exceed these 10 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7837374/

Health Effects of Ozone on Respiratory Diseases - PMC Short-term exposure to high concentrations of ozone has been associated with increased mortality and cardiovascular and respiratory morbidity in many regions ...

7. ahajournals.org ahajournals.org/doi/10.1161/CIRCOUTCOMES.119.005598

Association of Long-Term Exposure to Particulate Matter ... In our study, greater exposure to PM 2.5 and ozone was associated with poorer 1-year health status following an MI, and PM 2.5 was associated with increased ...