ToxSci Advance Access published online on June 26, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn125
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Inhalation Dosimetry Modeling with Inhaled Decamethylcyclopentasiloxane in Rats and Humans
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* Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado 80503
Dow Corning Corporation, Midland, Michigan 48686
University of Rochester Medical Center, Rochester, New York 14642
The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709
2 Micaela B. Reddy, is currently employed by Roche Palo Alto (Palo Alto, CA 94304)
3 Ivan D. Dobrev is currently employed at the Fraunhofer Institute of Toxicology and Experimental Medicine, Chemical Risk Assessment Group (30625 Hannover Germany)
1 Address correspondence to: Melvin E. Andersen, Ph.D., Director, Computational Biology Division, The Hamner Institutes for Health Sciences, Six Davis Drive PO Box 12137, Research Triangle Park, NC 27709-2137, Tel: 919-558-1205 Fax: 919-558-1300, MAndersen{at}thehamner.org
Received March 5, 2008; revision received June 9, 2008; accepted June 20, 2008
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Abstract |
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Decamethylcyclopentasiloxane (D5), a volatile cyclic methyl siloxane (VCMS), is used in industrial and consumer products. Inhalation pharmacokinetics of another VCMS, octamethylcyclotetrasiloxane (D4), have been extensively investigated and successfully modeled with a multi-species physiologically based pharmacokinetic (PBPK) model. Here, we develop an inhalation PBPK description for D5, using the D4 model structure as a starting point, with the objective of understanding factors that regulate free blood and tissue concentrations of this highly lipophilic vapor after inhalation in rats and humans. Compared to D4, the more lipophilic D5 required deep compartments in lung, liver and plasma to account for slow release from tissues after cessation of exposures. Simulations of the kinetics of a stable D5 metabolite, HO-D5, required diffusion-limited uptake in fat, a deep tissue store in lung, and its elimination by fecal excretion and metabolism to linear silanols. The combined D5/HO-D5 model described blood and tissue concentrations of parent D5 and elimination of total radioactivity in single and repeat exposures in male and female rats at 7 and 160 ppm. In humans, D5 kinetic data are more sparse and the model structure though much simplified, still required free and bound blood D5 to simulate exhaled air and blood time courses from 1 h inhalation exposures at 10 ppm in five human volunteers. This multi-species PBPK model for D5 highlights complications in interpreting kinetic studies where chemical in blood and tissues represents various pools with only a portion free. The ability to simulate free concentrations is essential for dosimetry based risk assessments for these VCMS.
Key Words: decamethylcyclopentasiloxane; D5; inhalation pharmacokinetics; PBPK modeling; dose metrics; lipophilic volatiles; free concentrations in blood.