Metabolism and disposition of [14C]-methylcyclosiloxanes in rats.

Octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) are low molecular weight cyclic volatile methyl siloxanes (cVMSs) primarily used as intermediates or monomers in the production of high molecular weight silicone polymers. The use of D4 as a direct ingredient in personal care products has declined significantly over the past 20 years, although it may be present as a residual impurity in a variety of consumer products. D5 is still used as an intentional ingredient in cosmetics, consumer products and in dry cleaning. Persons who may be exposed include occupational exposure for workers, and potential inhalation or dermal exposure for consumers and the general public. Because of the diverse use, especially of D5, and the potential for human exposure, a comprehensive program was undertaken to understand the kinetics, metabolism, enzyme induction and toxicity of D4 and D5 in rats following relevant routes of exposure. Physiologically based pharmacokinetic (PBPK) models utilizing these studies have been reported for D4 and D5 in the rat and human following dermal and inhalation exposures, with the oral uptake component of the model being limited in its description. Data from high dose oral studies in corn oil and simethicone vehicles and neat were used in the D4/D5 harmonized PBPK model development. It was uncertain if the inability to adequately describe the oral uptake was due to unrealistic high doses or unique aspects of the chemistry of D4/D5. Low dose studies were used to provide data to refine the description of oral uptake in the model by exploring the dose dependency and the impact of a more realistic food-like vehicle. Absorption, distribution, metabolism and elimination (ADME) of D4 and D5 was determined following a single low oral gavage dose of 14C-D4 and 14C-D5 at 30 and 100mg/kg body weight (bw), respectively, in a rodent liquid diet. Comparison of the low vs. high dose oral gavage administration of D4 and D5 demonstrated dose-dependent kinetic behavior. Data and modeling results suggest differences in metabolism between low and high dose administration indicating high dose administration results in or approaches non-linear saturated metabolism. These low dose data sets were used to refine the D4/D5 multi-route harmonized PBPK model to allow for a better description of the disposition and toxicokinetics of D4/D5 following oral exposure. With a refined oral uptake description, the model could be used in risk assessment to better define the internal dose of D4 and D5 following exposure to D4 and D5 via multiple routes.

Physiologically based pharmacokinetic modeling of the disposition of octamethylcyclotetrasiloxane (D4) migration from implants in humans.

A physiologically based pharmacokinetic model was developed to describe the silicone constituent octamethylcyclotetrasiloxane (D4) and its migration from intact or ruptured silicone gel-filled breast implants into surrounding tissues. D4 is a representative low-molecular weight constituent of silicone gel that is soluble enough in biological fluids to migrate from the implant and into surrounding tissues. The simulations were based on a representative young adult (premenopausal) woman and a mature (postmenopausal) woman using worst-case exposure conditions (i.e., complete rupture of the largest implant available, maximum levels of D4 in silicone, equal solubility of D4 in breast tissue and gel, and a range of breast tissue fat contents). The results indicate that D4 is cleared primarily by exhalation with highest concentrations achieved briefly in breast tissues of a representative postmenopausal woman. Maximum D4 levels in breast tissues for this scenario were estimated to be approximately 750 ppb with over 90% cleared in about 20 days. Thus, it is unlikely that D4 would be detected in any tissue within a few weeks of receiving an implant, even if immediately ruptured, under the assumptions used in this model.

Bioavailability of octamethylcyclotetrasiloxane (D(4)) after exposure to silicones by inhalation and implantation.

We developed a physiologically based pharmacokinetic (PBPK) model to predict the target organ doses of octamethylcyclotetrasiloxane (D(4)) after intravenous (IV), inhalation, or implantation exposures. The model used (14)C-D(4) IV disposition data in rats to estimate tissue distribution coefficients, metabolism, and excretion parameters. We validated the model by comparing the predicted blood and tissues concentrations of D(4) after inhalation to experimental results in both rats and humans. We then used the model to simulate D(4) kinetics after single and/or repeated D(4) exposures in rats and humans. The model predicted bioaccumulation of D(4) in fatty tissues (e.g., breast), especially in women. Because of its high lipid solubility (Log P(oct/water) = 5.1), D(4) persisted in fat with a half life of 11.1 days after inhalation and 18.2 days after breast implant exposure. Metabolism and excretion remained constant with repeated exposures, larger doses, and/or different routes of exposure. The accumulation of D(4) in fatty tissues should play an important role in the risk assessment of D(4) especially in women exposed daily to multiple personal care products and silicone breast implants.

Acute respiratory exposure of human volunteers to octamethylcyclotetrasiloxane (D4): absence of immunological effects.

Humans are exposed to silicones in a number of commercial and consumer products. Some of these silicones, including octamethylcyclotetrasiloxane (D4), are volatile. Therefore, there is a potential for respiratory exposure. A pharmacokinetic analysis of respiratory exposure to D4 is presented in the accompanying paper (M. J. Utell et al., 1998, Toxicol. Sci. 44, 206-213). Possible immune effects of respiratory exposure to D4 are investigated in this paper. Normal volunteers were exposed to 10 ppm D4 or air for 1 h via a mouthpiece using a double-blind, crossover study design. Assays were chosen to screen for immunotoxicity or a systemic inflammatory response. Assessment of immunotoxicity included enumeration of peripheral lymphocyte subsets and functional assays using peripheral blood mononuclear cells. Because in humans there is no direct test for adjuvant effect of respiratory exposure, we analyzed proinflammatory cytokines and acute-phase reactants in peripheral blood, markers for a systemic inflammatory response, as surrogate markers for adjuvancy. These tests were repeated when the volunteers were reexposed to D4 approximately 3 months after this initial exposure. Blood was obtained prior to exposure, immediately postexposure, and 6 and 24 h postexposure. In these short-term, controlled human exposures, no immunotoxic or proinflammatory effects of respiratory exposure to D4 were found.