Reddy Micaela B, Dobrev Ivan D, McNett Debra A, Tobin Joseph M, Utell Mark J, Morrow Paul E, Domoradzki Jeanne Y, Plotzke Kathleen P, Andersen Melvin E
Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado 80503, USA.
Toxicol Sci. 2008 Oct;105(2):275-85. doi: 10.1093/toxsci/kfn125. Epub 2008 Jun 26.
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 multispecies 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 with 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 multispecies 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.
十甲基环五硅氧烷（D(5)）是一种挥发性环状甲基硅氧烷（VCMS），用于工业和消费品中。另一种VCMS八甲基环四硅氧烷（D(4)）的吸入药代动力学已得到广泛研究，并成功地用多物种生理药代动力学（PBPK）模型进行了模拟。在此，我们以D(4)模型结构为起点，开发了一种D(5)的吸入PBPK描述，目的是了解在大鼠和人类吸入后调节这种高度亲脂性蒸气的游离血液和组织浓度的因素。与D(4)相比，亲脂性更强的D(5)在肺、肝和血浆中需要更深的隔室来解释暴露停止后从组织中的缓慢释放。对稳定的D(5)代谢物HO-D(5)的动力学模拟需要脂肪中的扩散限制摄取、肺中的深部组织储存以及通过粪便排泄和代谢为线性硅烷醇来消除。组合的D(5)/HO-D(5)模型描述了雄性和雌性大鼠在7和160 ppm的单次和重复暴露中母体D(5)的血液和组织浓度以及总放射性的消除。在人类中，D(5)的动力学数据更为稀少，模型结构虽然大大简化，但仍需要游离和结合的血液D(5)来模拟五名人类志愿者在10 ppm下1小时吸入暴露后的呼出空气和血液时间进程。这种D(5)的多物种PBPK模型突出了在解释动力学研究时的复杂性，其中血液和组织中的化学物质代表了各种池，只有一部分是游离的。模拟游离浓度的能力对于这些VCMS基于剂量学的风险评估至关重要。
