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A HYBRID CFD-PBPK MODEL OF INHALED CHLORINE GAS UPTAKE AND TISSUE DOSIMETRY IN THE ISOLATED UPPER RESPIRATORY TRACT (URT) OF F344 RATS
Citation:
JARABEK, A. M., J. D. SCHROETER, M. E. ANDERSEN, AND J. S. KIMBELL. A HYBRID CFD-PBPK MODEL OF INHALED CHLORINE GAS UPTAKE AND TISSUE DOSIMETRY IN THE ISOLATED UPPER RESPIRATORY TRACT (URT) OF F344 RATS. Presented at Society of Toxicology Annual Meeting, Charlotte, NC, March 25 - 29, 2007.
Description:
Chlorine (Cl2), an important commercial gas, is highly reactive in water, causing irritant effects in the respiratory tract on inhalation. Nasal extraction of Cl2 is high and resultant lesions in the respiratory tract show a proximal to distal distribution indicating that airflow patterns and exposure concentration play a key role in pathogenesis. Our hypothesis for the mode of action (MOA) for Cl2 is that its irritant responses are caused by oxidative stress mediated by hypochlorous acid (HOCl). HOCl would be formed in epithelial tissues by hydrolysis of Cl2, and to a lesser extent, by downstream biological responses including neurogenic inflammation. In order to describe tissue dose metrics associated with different endpoints of this proposed MOA for use in dose response analysis, a recent computational fluid dynamics-physiologically based pharmacokinetic (CFD-PBPK) model of inhaled hydrogen sulfide (Schroeter et al., Toxicol. Sci.,2006, 90(1), 198) was modified to address experimental dosimetry data on Cl2. These data included gas uptake of Cl2 delivered unidirectionally at three different flow rates and concentrations and measured in situ in the isolated URT of both sexes of F344 rats, and tissue chlorotyrosines (Cl-Tyr) (3-chloro- and 3,5-dichlorotyrosine) in samples obtained from four different regions representing respiratory and olfactory tissues in both the septal and lateral airstreams. Cl-Tyr are proven useful as biomarkers for production of HOCl in vivo (Hazen et al., 1997, Free Radic. Biol. Med. 23, 909.). Cl-Tyr were used here as an internal dosimeter. The CFD mesh was segmented to provide estimates of Cl2 flux in each of the four regions. The PBPK model of the tissue in each region describes rates for Cl2 hydrolysis, reaction of HOCl with proteins, and scavenging of reactive species by soluble anti-oxidants, including glutathione, obtained by both evaluation of the literature and fitting to the uptake and Cl-Tyr data. This model can be used to estimate flux to the URT and internal tissue HOCl as improved dose metrics for risk assessment. Correlation of these dose metrics with lesion incidence and location will provide insights on their utility in characterizing oxidative stress as the MOA for inhaled Cl2 in the respiratory tract. (This abstract does not reflect Agency policy.)