Physiological modeling reveals novel pharmacokinetic behavior for inhaled octamethylcyclotetrasiloxane in rats

Octamethylcyclotetrasiloxane (D4) is an ingredient in selected consumer and precision cleaning products. Workplace inhalation exposures may occur in s ome D4 production operations. In this study, we analyzed tissue, plasma, an d excreta time-course data following D4 inhalation in Fischer 344 rats (K. Plotzke et al., 2000, Drug Metab. Dispos. 28, 192-204) to assess the degree to which the disposition of D4 is similar to or different from that of vol atile hydrocarbons that lack silicone substitution. We first applied a basi c physiologically based pharmacokinetic (PBPK) model (J. C. Ramsey and M. E . Andersen, 1984, Toxicol. Appl. Pharmacol. 73, 159-175) to characterize th e biological determinants of D4 kinetics. Parameter estimation techniques i ndicated an unusual set of characteristics, i.e., a low blood:air (Pb:a con gruent to 0.9) and a high fat:blood partition coefficient (P, congruent to 550). These parameters were then determined experimentally by equilibrating tissue or liquid samples with saturated atmospheres of D4. Consistent with the estimates from the time-course data, blood:air partition coefficients were small, ranging from 1.9 to 6.9 in six samples. Perirenal fat:air parti tion coefficients were large, from 1400 to 2500. The average P,, was determ ined to be 485. This combination of partitioning characteristics leads to r apid exhalation of free D4 at the cessation of the inhalation exposure foll owed by a much slower redistribution of D4 from fat and tissue storage comp artments. The basic PK model failed to describe D4 tissue kinetics in the p ostexposure period and had to be expanded by adding deep-tissue compartment s in liver and lung, a mobile chylomicron-like lipid transport pool in bloo d, and a second fat compartment. Model parameters for the refined model wer e optimized using single-exposure data in male and female rats exposed at t hree concentrations: 7, 70, and 700 ppm. With inclusion of induction of D4 metabolism at 700 ppm (3-fold in males, 1-fold in females), the parameter s et from the single exposures successfully predicted PK results from 14-day multiple exposures at 7 and 700 ppm. A common parameter set worked for both genders. Despite its very high lipophilicity, D4 does not show prolonged r etention because of high hepatic and exhalation clearance. The high lipid s olubility, low blood:air partition coefficient, and plasma lipid storage wi th D4 led to novel distributional characteristics not previously noted for inhaled organic hydrocarbons. These novel characteristics were only made ap parent by analysis of the time-course data with PBPK modeling techniques.