Human Study to Develop a Signature of Occupational Diesel Exhaust Exposure

NCT ID: NCT03234790

Last Updated: 2021-11-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-09-27
• Study Completion Date: 2021-07-16

Brief Summary

Strong scientific understanding of how emissions from diesel engines impact the lungs could improve policies and regulations protecting workers exposed to diesel exhaust. Accordingly, we are recruiting healthy volunteers who are non-smokers to participate in our study. Volunteers sit in a room for four hours and breathe either clean filtered air or air that contains pollution at various concentrations similar to occupational settings such as bus and ferry terminals where diesel engines are used. A respirologist assesses the volunteer's lung health and clinical samples are taken. We are equipped with advanced molecular biology tools to measure different molecules and compare samples from our volunteer subjects following exposure to clean air or diesel exhaust. Our research aim is to find a simple, clinically relevant strategy that can be used to measure the impact of diesel exhaust on workers' lung health. This knowledge will empower regulators, companies, and ultimately workers to better manage their health risks. Our research aims to provide specific data to help regulators to make informed decisions about the risks of diesel exhaust exposure.

Detailed Description

1. Purpose: Over 100,000 employees in Alberta are inadvertently exposed to diesel exhaust at work because of wide use of diesel engines in vehicles and machines used in road construction, trucking, forestry, oil extraction and mineral mining. Although ambient air monitoring of DE exposure exists in some occupational settings, ambient air monitoring depends heavily on surrogate models and may yield a distorted picture of past exhaust exposure. Thus, a clear exposure limit based on bio-monitoring is needed to adequately protect the workers.

2. Objective: Our research aims to establish the relationship between exposure concentration and biological effect as an aid to determination of reference ranges for acceptable exposure.

3. Hypotheses and Aims:

Hypothesis 1: Diesel exhaust (DE) inhalation elicits a characteristic protein output, in a dose-dependent manner.

Aim 1. Demonstrate, using a proteomic analysis of serum and urine, a signature that acutely increases in response to a range of occupationally relevant DE concentrations.

Hypothesis 2: DE inhalation increases concentrations of metabolites of polyaromatic hydrocarbons (PAH) in urine, in a dose-dependent manner.

Aim 2. Ascertain the range of PAH metabolites accumulation in urine following acute exposure to a range of occupationally relevant DE concentrations.

Hypothesis 3: DE inhalation alters the airway responsiveness to a contractile stimulus, in a dose-dependent manner, and that alteration is associated with changes in a combined proteomic/PAH-metabolomic signature.

Aim 3: Determine the dose-response slope to methacholine, in response to a range of occupationally relevant DE concentrations, and correlate changes in this slope to changes in proteins and metabolites.

Additionally, we aim to establish the relationship between a range of controlled DE exposure concentrations and sleep quality and breathing in sleep through the sub-study component.

4. Justification:

Our work will inform decision makers and stakeholders in creating evidence-based policies to limit occupational diesel exhaust exposure based on relevant biology.

5. Research Method:

This is an order-randomized, double-blinded, crossover human exposure study.

This project aims to determine markers of DE exposure that can be used in an occupational setting. Therefore, we will use a range of occupational exposure levels to appropriately contextualize our results. For this, 20 healthy participants will be exposed to a control condition and 3 different levels of DE concentration, each for a period of 4 hours, in a randomized order. Each exposure will be separated by a washout period of two weeks. The levels will be DE titrated to 20, 50 and 150 ug/m3 PM2.5, and the control exposure will be filtered air (FA).

Participants will undergo a methacholine challenge and will provide urine and blood samples before and after exposures to analyze lung function and biological responses.

If participants consent to participation in the sleep sub-study, they will be provided with additional questionnaires throughout their visits pertaining to their sleep quality. The participants will be provided with an Alice NightOne sleep monitor and instructions on how to operate the equipment. The sleep monitor will be hooked up by the participant at home when they are about to sleep, following an exposure, and will monitor their sleep patterns for that night.

6. Statistical Analysis:

First, the changes in clinical parameters (methacholine PC20 and dose response slope) and serum blood protein abundance between pre- and post-exposure will be determined. These 'delta' values will be statistically compared across exposures using linear mixed effects models using R program, as outlined in our previous publications from similarly-designed protocols from our group. Values of p<0.05 will be considered significant throughout, with adjustments for multiple comparisons. Although the 2-week washout period is intended to minimize the likelihood of carryover effects, we will formally assess for this by including a term for order of exposures in the models.

Analyses for the sleep component will be performed at the Hospital of Ottawa and will be completed through a linear or logistic mixed effects model, as applicable using the R program. Similar methods to data collected from the main study. Data interpretation will be completed through a software algorithm on the local server.

Conditions

Experimental

Keywords

Diesel Exhaust; Air Pollution; Airway Responsiveness; Proteomics; Urine PAH Metabolites

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: SCREENING
• Blinding Strategy: TRIPLE

Study Groups

Filtered Air Exposure

Exposure for 4 hours to filtered air

Group Type: ACTIVE_COMPARATOR

Filtered Air Exposure

Intervention Type: OTHER

Exposure to Filtered air

Diesel Exhaust Exposure

Volunteers exposed to different concentrations of diesel exhaust

Group Type: EXPERIMENTAL

Diesel Exhaust Exposure

Intervention Type: OTHER

Diesel exposure to different concentrations at different times: 20, 50 and 150ug/m3

Interventions

Filtered Air Exposure

Exposure to Filtered air

Intervention Type: OTHER

Diesel Exhaust Exposure

Diesel exposure to different concentrations at different times: 20, 50 and 150ug/m3

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

1. 19-49 years

2. Non-smokers

3. No physician diagnosed asthma

Exclusion Criteria

1. Pregnant/breastfeeding

2. Using inhaled corticosteroids

3. Co-existing medical conditions (as assessed by the primary investigator)

4. Taking part in another study that involves taking medications.

5. Abnormal lung function based on screening spirometry

6. Cardiac diagnosis or arrhythmia is discovered during the screening process

• Minimum Eligible Age: 19 Years
• Maximum Eligible Age: 49 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Government of Alberta

OTHER_GOV

Sponsor Role: collaborator

Ottawa Hospital Research Institute

OTHER

Sponsor Role: collaborator

University of British Columbia

OTHER

Sponsor Role: lead

Responsible Party

Christopher Carlsten

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Christopher Carlsten, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

University of British Columbia

Locations

University of British Columbia - VGH site

Vancouver, British Columbia, Canada

Countries

Canada

References

Guest PC, Gottschalk MG, Bahn S. Proteomics: improving biomarker translation to modern medicine? Genome Med. 2013 Feb 27;5(2):17. doi: 10.1186/gm421. eCollection 2013. No abstract available.

Reference Type: BACKGROUND

PMID: 23445684 (View on PubMed)

Huang W, Smith TJ, Ngo L, Wang T, Chen H, Wu F, Herrick RF, Christiani DC, Ding H. Characterizing and biological monitoring of polycyclic aromatic hydrocarbons in exposures to diesel exhaust. Environ Sci Technol. 2007 Apr 15;41(8):2711-6. doi: 10.1021/es062863j.

Reference Type: BACKGROUND

PMID: 17533828 (View on PubMed)

Morgott DA. Factors and Trends Affecting the Identification of a Reliable Biomarker for Diesel Exhaust Exposure. Crit Rev Environ Sci Technol. 2014 Aug;44(16):1795-1864. doi: 10.1080/10643389.2013.790748.

Reference Type: BACKGROUND

PMID: 25170242 (View on PubMed)

Orach J, Rider CF, Yuen ACY, Schwartz C, Mookherjee N, Carlsten C. Controlled Diesel Exhaust Exposure Induces a Concentration-dependent Increase in Airway Inflammation: A Clinical Trial. Ann Am Thorac Soc. 2023 Jun;20(6):834-842. doi: 10.1513/AnnalsATS.202209-762OC.

Reference Type: DERIVED

PMID: 36930796 (View on PubMed)

Other Identifiers

H16-03053

Identifier Type: -

Identifier Source: org_study_id