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ToxSci Advance Access originally published online on September 19, 2006
Toxicological Sciences 2006 94(2):359-367; doi:10.1093/toxsci/kfl112
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Use of a Pharmacokinetic-Driven Computational Fluid Dynamics Model to Predict Nasal Extraction of Hydrogen Sulfide in Rats and Humans

Jeffry D. Schroeter1, Julia S. Kimbell, Melvin E. Andersen and David C. Dorman

CIIT Centers for Health Research, Research Triangle Park, North Carolina 27709-2137

Received July 18, 2006; accepted September 17, 2006

Hydrogen sulfide (H2S) is a naturally occurring and industrially generated gas. Human exposure to H2S results in dose-related neurological, respiratory, and cardiovascular effects. Subchronic exposure of rats to 30 or 80 ppm H2S results in olfactory neuron loss and basal cell hyperplasia. Olfactory lesions commonly border main airflow streams in the rat, indicating an influence of airflow on H2S-induced lesion locations. In this study, anatomically accurate computational fluid dynamics (CFD) models were used to quantitatively predict H2S tissue dose in rat and human nasal passages. Air-tissue flux was defined in terms of H2S solubility, diffusivity, and reaction kinetics in nasal tissue. Kinetic parameters for the rat were estimated from an air-tissue pharmacokinetic (PK) model that was fit to experimental nasal extraction (NE) data. Using this PK-driven CFD model, predicted flux at the mid-dorsomedial meatus and the middle portion of the ethmoid recess showed a good correlation with olfactory lesion incidence. Scaled kinetic parameters were incorporated into a human CFD model to predict H2S flux in human nasal passages. Assuming that equivalent H2S flux values will induce similar responses in the olfactory regions of rats and humans, a no-observed-adverse-effect–level human-equivalent concentration was estimated to be 5 ppm. This estimate was based on quantitative tissue dose estimates extrapolated from both lesion and NE data in rats and represents a risk estimate that is science based and does not rely on simplified dosimetric assumptions for interspecies extrapolation.

Key Words: hydrogen sulfide; computational fluid dynamics; pharmacokinetics; olfactory; nasal passages; interspecies extrapolation.


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