Human Study to Develop a Signature of Occupational Diesel Exhaust Exposure (DICE)

A Controlled Dose-Response Human Study to Develop a Signature of Occupational Diesel Exhaust Exposure

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.

Study Overview

• Status: Completed
• Conditions: Experimental
• Intervention / Treatment: Other: Filtered Air Exposure; Other: 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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • University of British Columbia - VGH site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 49 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Screening
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Filtered Air Exposure; Exposure for 4 hours to filtered air	Other: Filtered Air Exposure; Exposure to Filtered air
Experimental: Diesel Exhaust Exposure; Volunteers exposed to different concentrations of diesel exhaust	Other: Diesel Exhaust Exposure; Diesel exposure to different concentrations at different times: 20, 50 and 150ug/m3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum proteome in response to DE exposure	Serum from each experimental condition will be analyzed by liquid chromatography-mass spectrometry (LC-MS/MS) to observe any changes between the baseline and listed time points	4 hours & 24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urine proteins in response to DE exposure	Urine from each experimental condition will be analyzed by liquid mass chromatography to observe any changes between the baseline and listed time points.	4 hours & 24 hours
Polycyclic Aromatic Hydrocarbons (PAH) metabolites in response to DE exposure	PAH metabolites in urine samples will be analyzed by HPLC to observe any changes between the baseline and listed time points.	4 hours & 24 hours
Sleep quality	Sleep quality will be assessed by level 3 overnight monitor and questionnaires	baseline versus 24 hours post-exposure

Collaborators and Investigators

• Sponsor: University of British Columbia
• Collaborators: Ottawa Hospital Research Institute; Government of Alberta

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 27, 2017
• Primary Completion (Actual): July 16, 2021
• Study Completion (Actual): July 16, 2021

Study Registration Dates

• First Submitted: July 25, 2017
• First Submitted That Met QC Criteria: July 26, 2017
• First Posted (Actual): July 31, 2017

Study Record Updates

• Last Update Posted (Actual): November 2, 2021
• Last Update Submitted That Met QC Criteria: October 29, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Air Pollution; Proteomics; Diesel Exhaust; Airway Responsiveness; Urine PAH Metabolites
• Other Study ID Numbers: H16-03053

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No