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Epithelial perturbation by inhaled chlorine: Multi-scale mechanistic modeling in rats and humans
Citation:
JARABEK, A. M. AND H. R. KEHRL. Epithelial perturbation by inhaled chlorine: Multi-scale mechanistic modeling in rats and humans. Presented at American Association for Aerosol Research 2010 International Conference, San Diego, CA, March 22 - 26, 2010.
Impact/Purpose:
Description of lab animal and human studies input to computational modeling effort for chlorine.
Description:
Chlorine is a high-production volume, hazardous air pollutant and irritant gas of interest to homeland security. Thus, scenarios of interest for risk characterization range from acute high-level exposures to lower-level chronic exposures. Risk assessment approaches to estimate emergency egress or reentry levels and lifetime risk use an assumption based on "Haber's Rule", applying a concentration times duration ("C x t") adjustment to extrapolate across exposure scenarios. As a prototype for an important class of gases, chlorine provides a unique opportunity to target a testing strategy and computationally describe critical determinants of interspecies and dose-duration extrapolations. The existing database can be enhanced with contemporary endpoints to facilitate integrated, mechanistically-motivated analyses. As with other reactive gases, inhaled chlorine induces irritant and corrosive damage in the respiratory tract of all species. Lesions show a proximal to distal distribution pattern, indicating that airflow patterns and exposure concentration influence their pathogenesis. Due to differences in airway architecture, ventilation rate, and breathing mode across species, characterization of gas uptake and epithelial responses using anatomically accurate computational models is necessary for accurate dose, duration, and interspecies extrapolation. We developed a hybrid computational fluid dynamics-physiologically-based pharmacokinetic (CFDPBPK) model to allow flexibility to predict different internal dose metrics. Because recent studies suggest that the mode of action for chlorine is oxidative stress mediated by hypochlorous acid which forms in epithelial tissues by hydrolysis and downstream responses such as inflammation, the PBPK portion of the CFD/PBPK model extends the dose description into the tissue phaseto address epithelial reactions. A response model structure that specifies different tissue states of oxidative stress (normal, adaptive, inflammatory and toxic) will refine the description into a biologically-based dose response (BBDR) model to both predict different dose metrics and integrate various endpoints at different levels of observation (e.g., subcellular to tissue), providing a more comprehensive description of pathogenesis better suited to predicting different risk levels than default algorithms. To provide data input, our testing strategy performed "C x t" experiments in rats with homologous testing in clinical human studies to serve as target context verification. Laboratory animal studies evaluated a comprehensive set of endpoints established to correspond with epithelial damage in a matrix of studies ranging from 1 hr to 90 days, including stop-exposure studies. Endpoints included evaluation of nasal and broncheoalveolar lavage (NAL and BAL) for markers of cellular viability and response, and antioxidant status and inflammatory cytokines in NALIBAL and tissues. Tissue samples from four locations in the upper respiratory tract, the trachea, and lung lobes are being analyzed for oxidized amino acids to track tissue delivery and inflammatory reactions. Changes in expression of oxidative stress responsive genes in selected tissue will also be evaluated. Histopathology is included for "phenotypic anchoring" of more "novel" mechanistic endpoints as an apical endpoint established in regulatory risk assessment. Prognostic significance of these endpoints will be compared in this context. Measurements in the human studies include: symptom questionnaire, spirometry, methacholine challenge, nasal resistance, NAL, BAL, exhaled breath condensate and nasal and lung nitric oxide production.