PBPK MODELING OF SHORT-TERM (0 TO 5 MIN) HUMAN INHALATION EXPOSURES TO HALOGENATED HYDROCARBONS

Abstract

Allowable human exposure to Halons and Halon replacement chemicals is often regulated on the basis of cardiac sensitization potential. Exposure guidelines are established using dose-response data obtained from animal testing. Results from animal tests are often summarized by no-observable-adverse-effect level and lowest-observable-adverseeffect level values. This threshold approach alone does not provide the information necessary to evaluate the cardiac sensitization potential for the chemical of interest under a variety of exposure concentrations and durations. In order to provide a tool for decision makers and regulators tasked with setting exposure guidelines for Halon replacement chem icals, a quantitative approach was established that allows exposures to be assessed in terms of the chemical concentrations in blood during the exposure. A physiologically based pharmacokinetic model was modified to include a respiratory-tract compartment containing a dead-space region and a pulmonary exchange area. The pulmonary exchange area had its own air space, tissue, and capillary subregions. Refinement of the model to include a breath-by-breath description of respiratory-tract uptake allowed successful simulation of exhaled breath concentrations during the first minute of exposure to the anesthetics halothane, isoflurane, and desflurane. The model has been applied successfully to an actual case of accidental exposure to Halon 1211 during extinguishment of a fire in a military armored vehicle. This model ultimately will be useful in simulating various short-term exposure scenarios for better evaluation of safe use of Halon replacement chemicals.