Évaluation des niveaux d’éthanolémie résultant de l’exposition à l’éthanol par inhalation : études chez des volontaires et modélisation toxicocinétique
A physiologically based pharmacokinetic model (PBPK) on inhalation exposure to ethanol has previously been developed based on data from an inhalation study in volunteers exposed to more than 5000 ppm. However, there remains uncertainty about the ability of the PBPK model to predict the blood levels of ethanol (BLE) for exposure to low concentrations. These levels are frequently encountered by a large part of the population and workers by using products such as varnishes and alcoholic solutions (HAS). It is therefore necessary to verify the validity of the existing model and determine the internal exposure to ethanol in such conditions. The objectives of this master’s thesis are 1) to document the BLE resulting from inhalation exposure to low concentrations of ethanol (i.e., ≤ 1000 ppm) and validate/refine the existing PBPK model for these concentrations, and 2) to determine the atmospheric concentrations of ethanol following the use of alcoholic solutions (HAS) and varnish as well as to predict the BLE resulting from their use. Toxicokinetic data collected from volunteers suggest that it is insufficient to limit metabolic clearance of ethanol to the liver during exposures to low levels of ethanol, unlike exposures to stronger levels. In addition, it was clearly demonstrated that light exercise (50W) increased (2-3 fold) the BLE in volunteers exposed to 750 ppm. An addition to the PBPK model of a metabolic clearance of high affinity and low capacity associated with richly perfused tissue was performed to simulate more accurately the toxicokinetic data from low and high ethanol exposure levels. Measurements of ethanol concentrations in inhaled air generated during the use of HAS and varnishes were used to simulate the exposure during the use of these products. The simulation for HAS, for 1.5 g and 3 g, gave a maximum blood concentration (Cmax) of 0.383 and 0.366 mg.L-1 respectively in a poorly ventilated room. In a well-ventilated room, the simulated Cmax for 1.5 g and 3 g of HAS were 0.264 and 0.414 mg.L-1, respectively. The simulation results from the use of ethanol-based varnish yielded a Cmax for men and women of 0.719 and 0.729 mg.L-1 respectively. The blood Cmax of ethanol previously listed for the various simulations are well below the toxic dose for humans (50 mg.L-1). Thus, such exposures do not seem to be a health hazard. The results of this study helped to better describe and understand the elimination of ethanol at low doses and refine the evaluation process associated with chronic inhalation of low levels of ethanol to the population risk, particularly in workers.
Inhalation Solution hydro-alcoolique Blood levels of ethanol PBPK modeling Human exposure Occupational population General population Hydro-alcoholic solution Ethanol-based varnish