Influence of Tracheobronchial Region Expansion and Volume on Reactive Gas Uptake and Interspecies Dose Extrapolations

Abstract

The influence of the value of the tracheobronchial region volume at functional residual capacity (V^FRC_TB) and tracheobronchial (TB) region expansion during breathing on fractional uptake, proximal alveolar region (PAR) dose, and the ratio of rat to human PAR doses was investigated. A dosimetry model was used to simulate the uptake of reactive gases in the respiratory tracts of rats and humans. The PAR dose was chosen because this region is the site of the most severe lesions in laboratory animals exposed to reactive gases, such as O₃ and NO₂. PAR dose ratios can be used to establish exposure concentrations that yield the same PAR dose in different species, thereby facilitating extrapolation of animal toxicological results to humans. The influence of V^FRC_TB and expansion was explored using different breathing frequencies, tidal volumes, and TB region mass transfer coefficients. For TB region expansion, results for uniform expansion of all lower respiratory tract airways and airspaces were compared to results obtained when the TB region did not expand. TB region expansion decreased both predicted fractional uptake and PAR dose, with the decreases being greater for the rat than the human. For example, reductions in predicted fractional uptake due to TB region expansion ranged from 7% to 43% for the rat, but were less than 8% in humans; PAR doses in the rat were reduced by 23% to 67% and in the human by 0.5% to 24%, but generally by less than 8%. The effect of uniform expansion relative to no expansion was to reduce the predicted PAR dose ratio by up to 67%. For the effect of V^FRC_TB, results for V^FRC_TB that were two standard deviations (2SD) less than or greater than mean V^FRC_TB were compared to dosimetry predictions for the mean. Doses were predicted to be up to 57% smaller and up to 197% larger than doses associated with the mean V^FRC_TB. Accounting for uncertainty in both rat and human V^FRC_TB, PAR dose ratios were predicted to be as small as 74% less than or as large as 307% more than the dose ratio estimated for the mean V^FRC_TB depending on the expansion mode and other parameters. Our analyses yield the following general conclusions: (1) A better understanding and characterization of the role of TB region expansion (particularly for the rat) and volume is critically important for an improved understanding of respiratory-tract dosimetry of reactive gases and for decreasing uncertainties in inter- and intraspecies extrapolations of dose associated with toxicological effects. (2) Extrapolations based on dose at toxicologically relevant sites (the PAR in this investigation) can differ significantly from those based on exposure concentration or total uptake. (3) Human subjects who appear similar outwardly may have very different PAR doses and consequently potentially different responses to the same exposure. (4) Controlling for dead-space volume may become important in clinical studies using extended exposure periods (6–8 h/day) with levels of exercise considerably lower than those used in past 2-h exposure studies.