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Hoan-My Do Luu and Joseph C. Hutter

Center for Devices and Radiological Health, U.S. Food and Drug Administration, Rockville, Maryland, USA

Abstract

We developed a physiologically based pharmacokinetic (PBPK) model to predict the target organ doses of octamethylcyclotetrasiloxane (D₄) after intravenous (IV) , inhalation, or implantation exposures. The model used ¹⁴C-D₄ 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 D₄ after inhalation to experimental results in both rats and humans. We then used the model to simulate D₄ kinetics after single and/or repeated D₄ exposures in rats and humans. The model predicted bioaccumulation of D₄ in fatty tissues (e.g., breast) , especially in women. Because of its high lipid solubility (Log P_oct/water = 5.1) , D₄ 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 D₄ in fatty tissues should play an important role in the risk assessment of D₄ especially in women exposed daily to multiple personal care products and silicone breast implants. Key words: bioavailability, breast implant, D₄, implantation, inhalation, octamethylcyclotetrasiloxane, PBPK, physiologically based pharmacokinetic model, risk assessment, silicone. Environ Health Perspect 109:1095-1101 (2001) . [Online 11 October 2001]

http://ehpnet1.niehs.nih.gov/docs/2001/109p1095-1101luu/ abstract.html

Address correspondence to H-M. D. Luu, U.S. FDA, Center for Devices and Radiological Health, 12725 Twinbrook Parkway HFZ-150, Rockville, MD 20852 USA. Telephone: (301) 827-4711. Fax: (301) 827-4853. E-mail: hml@cdrh.fda.gov

We thank R. Kammula, M. Myers, C.S. Kim, and L. Schroeder for helpful suggestions in this investigation. Without their help, this study would not have been possible.

This work was presented in part at the 219th Annual Meeting of the American Chemical Society, April 2000, Anaheim, CA.

The opinions or assertions about specific products identified by brand name herein are the private views of the authors and are not to be construed as conveying either an official endorsement or criticism by the U.S. Department of Health and Human Services or the Food and Drug Administration.

Received 23 March 2001 ; accepted 5 April 2001.