Human Study to Develop a Signature of Occupational Diesel Exhaust Exposure
Condition: Experimental
Study type: Interventional

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.
    

Intervention name(s): Filtered Air Exposure; Diesel Exhaust Exposure
Intervention type(s): Other; Other
Intervention description(s): Exposure to Filtered air; Diesel exposure to different concentrations at different times: 20, 50 and 150ug/m3
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Screening
Keywords: Diesel Exhaust; Air Pollution; Airway Responsiveness; Proteomics; Urine PAH Metabolites