Dynamic Inhalation System for Individual Whole-Body Exposure of Mice to Volatile Organic Chemicals

Abstract

The in vivo rate of metabolism of gases and vapors can be quantitated from the uptake of a chemical by animals exposed in either a closed inhalation system or a dynamic inhalation system. Chemicals that are highly extracted by the animal due to solubility are best studied in a dynamic inhalation system, where the rate of metabolism is quantitated from the steady-state uptake of the chemical. A physiologically based pharmacokinetic model was used to design a dynamic inhalation system for exposing individual male B6C3F1 mice to butadiene and styrene. The system volume and flow rate were identified as important system parameters for using the dynamic system to quantitate the rate of metabolism. The constructed system had a total volume of 0.324 L and was operated at an overall flow rate of 0.97 L/h. The small volume and low flow rate maximized the difference between the inlet and outlet concentration of the chemicals when a mouse was present in the inhalation system. Because of the low overall flow rate through the system, a recirculating line was added to the chamber to ensure the atmosphere in the chamber was well mixed and to remove CO₂ from the chamber. Use of the recirculation line is analogous to placing a fan in the chamber. The recirculating flow was 5 L/h. Estimates of intraspecies variability in the rate of metabolism were made from repetition of individual exposures. The mice were unrestrained in the exposure system to prevent restraint stress from affecting their metabolism or physiology. The dynamic inhalation system can be adapted to expose larger rodents or converted to a closed system for uptake studies with appropriate gases and vapors.