INFLUENCE OF TRACHEOBRONCHIAL REGION EXPANSION AND VOLUME ON REACTIVEGAS UPTAKE AND INTERSPECIES DOSE EXTRAPOLATIONS

The influence of the value of the tracheobronchial region volume at fu nctional residual capacity (V-TB(FRC)) and tracheobronchial (TB) regio n expansion during breathing on fractional uptake, proximal alveolar r egion (PAR) dose, and the ratio of rat to human PAR doses was investig ated. A dosimetry model was used to simulate the uptake of reactive ga ses in the respiratory tracts of rats and humans. The PAR dose was cho sen because this region is the site of the most severe lesions in labo ratory animals exposed to reactive gases, such as O-3 and NO2. PAR dos e ratios can be used to establish exposure concentrations that yield t he same PAR dose in different species, thereby facilitating extrapolat ion of animal toxicological results to humans. The influence of V-TB(F RC) 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 tra ct airways and airspaces were compared to results obtained when the TB region did not expand. TB region expansion decreased both predicted f ractional uptake and PAR dose, with the decreases being greater for th e rat than the human. For example, reductions in predicted fractional uptake due to TB region expansion ranged from 7% to 43% for the rat, b ut were less than 8% in humans; PAR doses in the rat were reduced by 2 3% 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 re duce the predicted PAR dose ratio by up to 67%. For the effect of V-TB (FRC), results for V-TB(FRC) that were two standard deviations (25D) l ess than or greater than mean V-TB(FRC) were compared to dosimetry pre dictions for the mean. Doses were predicted to be up to 57%, smaller a nd up to 197% larger than doses associated with the mean V-TB(FRC). Ac counting for uncertainty in both rat and human V-TB(FRC), PAR dose rat ios 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-TB(FRC), depending on the expansion mode and other parameters. Our analyses yield the fol lowing general conclusions: (1) A better understanding and characteriz ation of the role of TB region expansion (particularly for the rat) an d volume is critically important for an improved understanding of resp iratory-tract dosimetry of reactive gases and for decreasing uncertain ties in inter- and intraspecies extrapolations of dose associated with toxicological effects. (2) Extrapolations based on dose at toxicologi cally relevant sites (the PAR in this investigation) can differ signif icantly 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 l evels of exercise considerably lower than those used in past 2-h expos ure studies.