Toxicological Sciences 71, 41-52 (2003)
Copyright © 2003 by the Society of Toxicology
BIOTRANSFORMATION AND TOXICOKINETICS |
Route-Specific Differences in Distribution Characteristics of Octamethylcyclotetrasiloxane in Rats: Analysis Using PBPK Models
* ICF Consulting, P.O. Box 14348, Research Triangle Park, North Carolina 27709;
Environ Corporation, 933 Mesa Lane, Collegeville, Pennsylvania 19426;
Department of Environmental Health, CETT/Foothills Campus, Colorado State University, Ft. Collins, Colorado 80523;
RHR Toxicology Consulting Services, Midland, Michigan 48640; and
¶ Toxicology, Health and Environmental Sciences, Dow Corning Corporation, Mail CO3101, Midland, Michigan 48686
Octamethylcyclotetrasiloxane (D4) is used in selected consumer products and has a potential for human exposure from multiple routes. Here we develop a physiologically based pharmacokinetic (PBPK) model to describe the tissue dosimetry, plasma concentration, and clearance in the rat following inhalation and dermal, oral, and iv exposure. An initial multiroute PBPK model, based on a previously published inhalation PBPK model for D4, provided excellent fits to the observed concentration time course of D4 metabolites in urine and D4 exhalation rate following dermal exposures. However, the pharmacokinetics of D4, following oral and iv exposure, were sensitive to the mode of entry into the blood compartment. A refined model, describing delivery of D4 from the GI tract to the nonexchangeable/deep blood compartment, provided the best fits to observed plasma D4, exhaled D4, and D4 metabolites excreted in the urine following oral exposure. Pharmacokinetics following iv administration was best described by delivery of D4 directly into the deep blood compartment, possibly reflecting a kinetically identifiable characteristic of the administration of D4 as an emulsion for the intravenous route of exposure. This model-based analysis indicates that the pharmacokinetics of D4 delivered by the inhalation or dermal routes is similar, and is different from the iv or oral delivery routes.
Key Words: inhalation, oral; dermal; iv; multiroute; pharmacokinetics; PBPK model; siloxane.
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