A real-time methodology to evaluate the nasal absorption of volatile compounds in anesthetized animals

Nasal dosimetry models that combine computational fluid dynamics and physiologically based pharmacokinetic modeling incorporate information on species-specific anatomical differences, including nasal airflow, mucosal diffusion, clearance-extraction, and metabolism specific to different epithelial layers. As such, these hybrid models have the potential to improve interspecies dosimetric comparisons, and may ultimately reduce uncertainty associated with calculation of reference concentrations. Validation of these models, however, will require unique experimental data. To this end, a method for evaluating the uptake of a prototypical compound, methyl iodide (MeI), in the nasal cavity of the intact animal was developed. The procedure involved insertion of a small-diameter air-sampling probe in the depth of the nasal cavity to the nasopharynx region in anesthetized animals. The exterior portion of the probe was connected directly to a mass spectrometer to provide a continual real-time analysis of concentrations of MeI in the nasal cavity. A plethysmography system was used to monitor breathing parameters, including frequency and tidal volume for each animal. Animals were placed in a sealed glass chamber and exposed to MeI at initial chamber concentrations ranging from 1 to 50 ppm. Studies were conducted on n = 3 rabbits per exposure concentration for a total of nine animals and n = 6 rats at a single exposure concentration of 1 ppm. In the rabbit, the percent of MeI absorbed in the nasal cavity ranged from 57 to 92% (average 72 +/- 11) regardless of exposure concentration. Similarly, the percent of MeI absorbed in the nasal cavity of the rat ranged from 51 to 71% (average 63 +/- 8).