The Phthalate-Allergen Immune Response Study (PAIR)

July 31, 2019 updated by: Christopher Carlsten, University of British Columbia

Effects of Phthalate Inhalation on Airway Immunology: A Controlled Human Exposure Study

Phthalates are commonly used plasticizers that have been linked to asthma in epidemiological studies. The investigators are researching effects of phthalates on airway immunology and lung function, and on allergic responses by doing an inhaled allergen challenge. After exposing participants to either filtered air or carefully controlled levels of phthalate in our exposure chamber we will collect samples from the nose and the upper airways, by rinsing the nose with saltwater or performing small brushings. The investigators will also collect a bronchial samples by bronchoscopy after each exposure. After 2 weeks, the entire procedure will be repeated with the alternate exposure.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

  1. Purpose:

    To study the effects of phthalates on airway immunology, lung function and nasal allergic responses.

  2. Hypotheses:

    Phthalate inhalation increases recruitment of immune cells to the upper airways and affects the functionality of immune and epithelial cells.

    Hypothesis 2: Phthalate inhalation alters the cellular response to an inhalation allergen challenge.

  3. Justification:

    Phthalates are plasticizers or softeners, used in PVC and other plastics and a range of consumer products. Since phthalates are not chemically bound to the plastic they leak out from these products, causing routine human exposure through air, dust and food. Exposure to phthalates has been linked to worsening or development of airway diseases in epidemiological studies, but the effects of phthalates on our airways and immune responses are largely unknown. In this study we would like to investigate how one particular phthalate, dibutyl phthalate (DBP), can affect the human respiratory and immune systems. The investigators are not expecting that the responses will be noticeable to the subjects; they are expecting that any responses that may occur will only be detectable through careful examination of cells and tissues (e.g. nasal lavage and brushes (fluid from the nose), bronchial samples, blood, urine). Nasal samples will be used for measurement of nasal inflammatory responses in terms of cell recruitment and levels of inflammatory mediators. Bronchial samples will allow for a refined examination of an inflammatory responses in the lung and thus provide a much more detailed information concerning the phthalate-induced responses due to allergen challenge. Understanding these subtle changes will help us prevent health problems associated with phthalate exposure in the future.

  4. Objectives:

    To establish that phthalates alter the cellular immune response in the upper airways.

  5. Research Method:

    This is a blinded crossover experiment between two conditions (dibutyl phthalate, DBP, or filtered air, FA), randomized and counter-balanced to order.

    After each exposure of DBP or FA, we will deliver an inhaled allergen challenge. Data collection for each condition will be separated by a 2-week washout period.

    To evaluate the effects of the exposure on the immune response and lung function, the investigators will collect and perform the following on the day of the exposure or the following day:

    • Before each exposure, 3h and 24h post-exposure, we will collect urine and blood samples, perform NAL, and measure forced expiratory volume (FEV1) by spirometry and FeNO.
    • Methacholine challenge will be performed 24h after exposure.
    • Nasal brushing (NAB) will be performed at 3h pre-exposure on the left nostril and 3h post-exposure in the right nostril.
    • A fraction of the subjects enrolled will have a bronchoscopy performed 24h post-exposure, where bronchoalveolar samples and endobronchial biopsies will be collected.

    The literature provides conflicting data for phthalates with regard to some of the analytical endpoints. Therefore, to facilitate the choice of endpoints for the principal study, as well as to validate some study procedures, a 'Method optimization sub-study' will be performed prior to the start of the principal study. A maximum of 25 healthy subjects will be recruited for this sub-study, who will sign a modified consent that reflects their limited participation. These subjects will not be exposed to DBP or CA, but will only be recruited for collection of blood, nasal lavage, and nasal brushing, or a subset of these samples. They will only attend one visit to the Vancouver General Hospital, dedicating 1 - 3 hours of their time when participating in the sub-study. Moreover, prior starting the principal study (above), up to four healthy subjects may be recruited for a 'Pilot study' to optimize the logistics of the exposures and the experimental procedures of the principal study. These subjects will be subjected to CA exposure only and have all procedures and samples collected as described for the actual study with the exception of the bronchoscopy.

    Samples collected during the Method optimization sub-study and the Pilot study, will be used to establish analytical methods to measure immune cellular responses such as white blood or nasal epithelial cell responses to bacterial components (Toll Like Receptor (TLR) agonists) and phagocytosis assays after in vitro phthalate exposure (as described under study procedures).

  6. Statistical Analysis:

A mixed effects model will be used to estimate all effects and pertinent contrasts will be used to test the hypotheses. Specifically, models will include exposure (CA or DBP), order (CA before DBP or DBP before CA) and gene variant status (e.g., GSTM1 present or GSTM1 null) as fixed effects and subject identifying number as a random effect. The inhalation allergen challenge is given during both DBP and CA exposures and will therefore not be included in the statistical analyses.

The influence of the general phthalate exposure level for 6 commonly measured phthalates, assessed in urine samples Day 1 and 2 on FeNO/blood/lung function will be analyzed by mixed effects model including exposure (DBP, CA), sampling period (Day 1, Day 2) and phthalate level (Day 1, Day 2). A one-way ANOVA will be used to compare pre- and post-exposure urinary MnBP levels for various time-points to verify phthalate exposure.

Study Type

Interventional

Enrollment (Anticipated)

20

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • British Columbia
      • Vancouver, British Columbia, Canada, V5Z 1M9
        • University of British Columbia

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

19 years to 49 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Age between 19 and 49 years.
  2. Non-smoking.
  3. Proficient in English
  4. Positive skin prick test for at least one of: birch, grass, or dust.
  5. Healthy, or diagnosed with mild asthma

Exclusion Criteria

  1. pregnancy/breastfeeding
  2. unstable asthma symptoms (eg: exacerbations in previous 2 weeks)
  3. use of inhaled corticosteroids or bronchodilator medication more than 3 times a week
  4. presence of co-existing medical conditions i.e. arrythmia (as assessed by the primary investigator)
  5. participation in another study that involves taking medications
  6. regular use of antihistamines, non-steroidal anti-inflammatories, anticoagulants, acetylsalicylic acid (ASA) or decongestants
  7. allergy to salbutamol or lidocaine.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Filtered air
Exposure for 3 hours to filtered air followed by subject specific inhaled allergen challenge
Other: Filtered Air
Delivered by inhalation on day 1 of the triad
Other: Allergen
Subject specific allergen is delivered by inhalation on day 1 of the triad
Experimental: Phthalate
Exposure for 3 hours to dibutyl phthalate followed by subject specific inhaled allergen challenge
Other: Allergen
Subject specific allergen is delivered by inhalation on day 1 of the triad
Other: Phthalate
Delivered by inhalation on day 1 of the triad
Other Names:
  • DBP

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Recruitment of immune cells in airways
Time Frame: 3-24 hours
Recruitment will be identified by performing differential cell counts
3-24 hours
Activation of immune cells in airways
Time Frame: 3-24 hours
Cellular activation will be measured by cytokine expression in airway samples.
3-24 hours
Airway responsiveness
Time Frame: 3-24 hours
Airway responsiveness will be measured by spirometry.
3-24 hours
Airway Inflammation
Time Frame: 3-24 hours
Airway Inflammation will be measured by Fractional exhaled NO.
3-24 hours

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Allergen specific IgE
Time Frame: 24 hours
Allergen specific IgE will be measured in airway and blood samples.
24 hours
Inflammatory markers in plasma and cell function after in vitro stimulation with inflammatory ligands (LPS & R848)
Time Frame: 3-24h
whole blood In vitro stimulation using inflammatory ligands will be analyzed for inflammatory markers, same as in plasma.
3-24h
Response of immune cells in blood
Time Frame: 3-24 hours
Immune cell responses will be identified by analyzing changes in cellular activation
3-24 hours
Response of immune cells in airways
Time Frame: 3-24 hours
Cellular activation will be measured after in-vitro stimulation with inflammatory ligands like Lipopolysaccharide.
3-24 hours

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of British Columbia

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 2, 2017

Primary Completion (Anticipated)

May 7, 2020

Study Completion (Anticipated)

May 7, 2021

Study Registration Dates

First Submitted

January 6, 2016

First Submitted That Met QC Criteria

February 17, 2016

First Posted (Estimate)

February 23, 2016

Study Record Updates

Last Update Posted (Actual)

August 2, 2019

Last Update Submitted That Met QC Criteria

July 31, 2019

Last Verified

July 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • H14-01119

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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