Improved Predictive Model for n-Decane Kinetics Across Species, as a Component of Hydrocarbon Mixtures
Authors: Merrill, E. A.; Gearhart, J. M.; Sterner, T. R.; Robinson, P. J.
Source: Inhalation Toxicology, Volume 20, Number 9, July 2008 , pp. 851-863(13)
Publisher: Informa Healthcare
Abstract:n-Decane is considered a major component of various fuels and industrial solvents. These hydrocarbon products are complex mixtures of hundreds of components, including straight-chain alkanes, branched chain alkanes, cycloalkanes, diaromatics, and naphthalenes. Human exposures to the jet fuel, JP-8, or to industrial solvents in vapor, aerosol, and liquid forms all have the potential to produce health effects, including immune suppression and/or neurological deficits. A physiologically based pharmacokinetic (PBPK) model has previously been developed for n-decane, in which partition coefficients (PC), fitted to 4-h exposure kinetic data, were used in preference to measured values. The greatest discrepancy between fitted and measured values was for fat, where PC values were changed from 250-328 (measured) to 25 (fitted). Such a large change in a critical parameter, without any physiological basis, greatly impedes the model's extrapolative abilities, as well as its applicability for assessing the interactions of n-decane or similar alkanes with other compounds in a mixture model. Due to these limitations, the model was revised. Our approach emphasized the use of experimentally determined PCs because many tissues had not approached steady-state concentrations by the end of the 4-h exposures. Diffusion limitation was used to describe n-decane kinetics for the brain, perirenal fat, skin, and liver. Flow limitation was used to describe the remaining rapidly and slowly perfused tissues. As expected from the high lipophilicity of this semivolatile compound (log Kow = 5.25), sensitivity analyses showed that parameters describing fat uptake were next to blood:air partitioning and pulmonary ventilation as critical in determining overall systemic circulation and uptake in other tissues. In our revised model, partitioning into fat took multiple days to reach steady state, which differed considerably from the previous model that assumed steady-state conditions in fat at 4 h post dosing with 1200 ppm. Due to these improvements, and particularly the reconciliation between measured and fitted partition coefficients, especially fat, we have greater confidence in using the proposed model for dose, species, and route of exposure extrapolations and as a harmonized model approach for other hydrocarbon components of mixtures.
Document Type: Research Article
Affiliations: Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Wright-Patterson Air Force Base, Ohio, USA
Publication date: July 2008