Citation:

JARABEK, A. M., J. SCHROETER, M. E. ANDERSEN, AND J. S. KIMBELL. MODULAR APPLICATION OF COMPUTATIONAL MODELS OF INHALED REACTIVE GAS DOSIMETRY FOR RISK ASSESSMENT OF RESPIRATORY TRACT TOXICITY: CHLORINE . Presented at 2007 EPA International Science Forum on Computational Toxicology, Research Triangle Park, NC, May 21 - 23, 2007.

Description:

Inhaled reactive gases typically cause respiratory tract toxicity with a prominent proximal to distal lesion pattern. This pattern is largely driven by airflow and interspecies differences between rodents and humans result from factors such as airway architecture, ventilation rate, breathing mode, and the metabolic capacity of different tissue types. Accurate extrapolation of the dose-response for respiratory toxicity observed in rodents to predict human health risk requires description of these factors at a level of detail commensurate with the experimental data and understanding of the mode of action (MOA) for the inhaled gas. A suite of models can be employed in a modular fashion to address the need for different descriptions that depend on the species and level of detail in the data. Hybrid computational fluid dynamics- physiologically-based pharmacokinetic (CFD-PBPK) models afford the flexibility to predict different dose metrics in the upper respiratory tract (URT) that range from average flux in the entire region to localized estimates. The dose description can be extended into the tissues with PBPK compartments for metabolism and other reactions. A modular application is provided by a CFD-PBPK model for inhaled chlorine. The hypothesized MOA for chlorine is that its irritant effects are due to oxidative stress mediated by hypochlorous acid (HOCl). HOCl forms in epithelial tissues by hydrolysis and downstream biological responses. A CFD-PBPK model was developed using experimental data on chlorine uptake delivered in situ to the isolated URT of F344 rats. Tissue chlorotyrosine (3-chloro- and 3,5-dichlorotyrosine), measured in samples from 4 different regions representing respiratory and olfactory tissues in both septal and lateral airstreams, was used as an internal dosimeter. The CFD mesh was segmented to provide estimates of chlorine flux in each region. The PBPK model of the tissue describes rates for chlorine hydrolysis, reaction of HOCl with proteins, and scavenging of reactive species by soluble anti-oxidants. Human dose estimates, which require consideration of delivery to the lower respiratory tract (LRT) due to mouth breathing, are calculated by calibration of the CFD-PBPK model structures of the human URT to typical-path descriptions of the entire respiratory tract. (This abstract does not reflect Agency policy.)

Record Details: