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ToxSci Advance Access originally published online on December 12, 2005
Toxicological Sciences 2006 90(1):198-207; doi:10.1093/toxsci/kfj072
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Incorporation of Tissue Reaction Kinetics in a Computational Fluid Dynamics Model for Nasal Extraction of Inhaled Hydrogen Sulfide in Rats

Jeffry D. Schroeter1, Julia S. Kimbell, Anna M. Bonner, Kay C. Roberts, Melvin E. Andersen and David C. Dorman

CIIT Centers for Health Research, 6 Davis Drive, P.O. Box 12137, Research Triangle Park, North Carolina 27709-2137

Received August 16, 2005; accepted December 3, 2005

Rodents exposed to hydrogen sulfide (H2S) develop olfactory neuronal loss. This lesion has been used by the risk assessment community to develop occupational and environmental exposure standards. A correlation between lesion locations and areas of high H2S flux to airway walls has been previously demonstrated, but a quantitative dose assessment is needed to extrapolate dose at lesion sites to humans. In this study, nasal extraction (NE) of 10, 80, and 200 ppm H2S was measured in the isolated upper respiratory tract of anesthetized rats under constant unidirectional inspiratory flow rates of 75, 150, and 300 ml/min. NE was dependent on inspired H2S concentration and air flow rate: increased NE was observed when H2S exposure concentrations or inspiratory air flow rates were low. An anatomically accurate, three-dimensional computational fluid dynamics (CFD) model of rat nasal passages was used to predict NE of inhaled H2S. To account for the observed dependence of NE on H2S exposure concentration, the boundary condition used at airway walls incorporated first-order and saturable kinetics in nasal tissue to govern mass flux at the air:tissue interface. Since the kinetic parameters cannot be obtained using the CFD model, they were estimated independently by fitting a well-mixed, two-compartment pharmacokinetic (PK) model to the NE data. Predicted extraction values using this PK-motivated CFD approach were in good agreement with the experimental measurements. The CFD model provides estimates of localized H2S flux to airway walls and can be used to calibrate lesion sites by dose.

Key Words: hydrogen sulfide; rat; inhalation; pharmacokinetics; computational fluid dynamics; olfactory toxicity; nasal passages.


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