Inhalation Dosimetry Modeling with Inhaled Decamethylcyclopentasiloxane in Rats and Humans.
June 29th, 2008 | by admin |Inhalation Dosimetry Modeling with Inhaled Decamethylcyclopentasiloxane in Rats and Humans.
Decamethylcyclopentasiloxane (D(5)), a volatile cyclic methyl siloxane (VCMS), is used in industrial and consumer products. Inhalation pharmacokinetics of another VCMS, octamethylcyclotetrasiloxane (D(4)), have been extensively investigated and successfully modeled with a multi-species physiologically based pharmacokinetic (PBPK) model. Here, we develop an inhalation PBPK description for D(5), using the D(4) 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 D(4), the more lipophilic D(5) 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 D(5) metabolite, HO-D(5), 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 D(5)/HO-D(5) model described blood and tissue concentrations of parent D(5) and elimination of total radioactivity in single and repeat exposures in male and female rats at 7 and 160 ppm. In humans, D(5) kinetic data are more sparse and the model structure though much simplified, still required free and bound blood D(5) 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 D(5) 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.
Reddy MB, Dobrev ID, McNett DA, Tobin JM, Utell MJ, Morrow PE, Domoradzki JY, Plotzke KP, Andersen ME.
Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado 80503.