Impact of Thermal Stress on Pulmonary Absorption and Toxicokinetics of 3 Organic Solvents

Study Overview
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Brief Summary
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In Quebec, thousands of workers are concomitantly exposed to heat and chemical compounds. Exposure to heat induces physiological responses that help maintaining a stable body temperature. Those changes can affect organ functions implicated in absorption and metabolism. According to literature, those changes could lead to increased concentrations of chemical compounds in the body and their toxicity. Therefore, the aim of this study is to evaluate the pulmonary absorption and toxicokinetics of 3 organic solvents in heat stress conditions in volunteers exposed in a inhalation chamber. Results will then be used to develop PBPK models that will allow to predict organic solvent kinetics when coexposed with heat.

Official Title
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Studying the Impact of Thermal Stress (Heat) Representative of Occupational Settings on Pulmonary Absorption and Toxicokinetics of 3 Organic Solvents

Conditions
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Heat

Intervention / Treatment
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* Other: Heat stress (21)
* Other: Heat stress (25)
* Other: Heat stress (30)
* Other: Heat Stress (21) +TOL
* Other: Heat stress (25) + TOL
* Other: Heat stress (21) + TOL
* Other: Heat stress (21) + ACE
* Other: Heat stress (25) + ACE
* Other: Heat stress (30) + ACE
* Other: Heat stress (21) + DCM
* Other: Heat stress (25) + DCM
* Other: Heat stress (30) + DCM
* Other: Heat stress (21) + TOL (dermal)
* Other: Heat stress (25) + TOL (dermal)
* Other: Heat stress (30) + TOL (dermal)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body mass index between 18,5 et 25 kg/m3 Exclusion Criteria: Smoking Respiratory, cardiovascular and neurological problems History of exposure to solvents Chronic medication Abusive and/or chronic alcohol consumption Alcohol consumption 24h before or 18h following exposure

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Heat stress<br>4h exposure to heat stress alone or in combination with different solvents. Solvent concentrations are equal to their TLV. Heat conditions are 21, 25 and 30°C (WBGT). Inhalation exposure for all solvents and demal exposure for toluene. | Other: Heat stress (21)<br>* 4h exposure to heat (WBGT of 21°C), no solvent<br>Other: Heat stress (25)<br>* 4h exposure to heat (WBGT of 25°C), no solvent<br>Other: Heat stress (30)<br>* 4h exposure to heat (WBGT of 30°C), no solvent<br>Other: Heat Stress (21) +TOL<br>* 4h exposure to heat (WBGT of 21°C) + Toluene (concentration = TLV)<br>Other: Heat stress (25) + TOL<br>* 4h exposure to heat (WBGT of 25°C) + Toluene (concentration = TLV)<br>Other: Heat stress (21) + TOL<br>* 4h exposure to heat (WBGT of 30°C) + Toluene (concentration = TLV)<br>Other: Heat stress (21) + ACE<br>* 4h exposure to heat (WBGT of 21°C) + Acetone (concentration = TLV)<br>Other: Heat stress (25) + ACE<br>* 4h exposure to heat (WBGT of 25°C) + Acetone (concentration = TLV)<br>Other: Heat stress (30) + ACE<br>* 4h exposure to heat (WBGT of 30°C) + Acetone (concentration = TLV)<br>Other: Heat stress (21) + DCM<br>* 4h exposure to heat (WBGT of 21°C) + Dichloromethane (concentration = TLV)<br>Other: Heat stress (25) + DCM<br>* 4h exposure to heat (WBGT of 25°C) + Dichloromethane (concentration = TLV)<br>Other: Heat stress (30) + DCM<br>* 4h exposure to heat (WBGT of 30°C) + Dichloromethane (concentration = TLV)<br>Other: Heat stress (21) + TOL (dermal)<br>* 4h exposure to heat (WBGT of 21°C) + Toluene (concentration = TLV), participants breath normal air through a mask for evaluation of dermal absorption.<br>Other: Heat stress (25) + TOL (dermal)<br>* 4h exposure to heat (WBGT of 25°C) + Toluene (concentration = TLV), participants breath normal air through a mask for evaluation of dermal absorption.<br>Other: Heat stress (30) + TOL (dermal)<br>* 4h exposure to heat (WBGT of 30°C) + Toluene (concentration = TLV), participants breath normal air through a mask for evaluation of dermal absorption.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Respiratory rate | Respiratory rate will be monitored continuously for 4hour with a respirometer | 4hour | 
| Cardiac frequency | Cardiac frequency will be monitored continuously for 4hour with a respirometer | 4hour | 
| Minute ventilation | Minute ventilation will be monitored continuously for 4hour with a respirometer | 4hour | 
| Tidal volume | Tidal volume will be monitored continuously for 4hour with a respirometer | 4hour | 
| Solvent in blood | Solvents concentrations will be measured in blood samples collected at different times (t=0, 2, 4 and 4.5hour). | 4,5hour | 
| Solvent or metabolite in urine | Solvent or metabolite concentrations (o-cresol for toluene exposures) will be measured for urine samples collected at different times (t=0, 4, 10 and 18hour). | 18hour | 
| Solvent in exhaled air | Solvents concentrations will be measured in exhaled air samples collected at different times (t=0, 1.5, 3, 4.5 and 6hour). | 6hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxygen consumption | oxygen consumption will be monitored continuously for 4hour with a respirometer | 4hour | 
| Carbonic dioxide production | carbonic dioxide production will be monitored continuously for 4hour with a respirometer | 4hour | 
| Body temperature | Body temperature is monitored continuously by telemetry | 4hour | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Physiologically based pharmacokinetic modeling, Organic solvents