Bioavailability of D4 after inhalation and implantation exposure to silicones.

In the November 2001 issue of EHP, Luu and Hutter (1) described a physiologically based pharmacokinetic (PBPK) model for the bioavailability of octamethylcyclotetrasiloxane (D4) following exposure to D4 by inhalation and implantation. In this paper the authors developed a PBPK model that used a very limited data set obtained after either single or repeated intravenous (iv) administration of D4 as a microemulsion (2). The intravenous pharmacokinetic data reported by Kirkpatrick (2) were obtained from a study I helped design and conduct; I am familiar with the data and with the limitations of the study design for this type of assessment. Kirkpatrick (2) obtained blood and tissue samples at various time intervals after administration of radiolabeled D4 and determined total radioactivity in these samples, but did not attempt to distinguish between parent D4 and D4 metabolites. Although the data obtained by Kirkpatrick were for iv dosing, Luu and Hutter (1) actually used intra-arterial dosing in their PBPK model. They validated their model by predicting inhalation kinetics in rats and comparing their prediction with a data set published by Plotzke et al. (3); they assumed that the radioactivity measured by Plotzke et al. (3) was parent D4, with no contribution from metabolites. Luu and Hutter (1) plan to use their PBPK model to assess risk after exposure to D4 resulting from migration from silicone gel breast implants. In addition to specific issues about their PBPK model, I also have several concerns about the manner in which this model will ultimately influence any risk assessment performed for D4. These concerns relate to a) the assumptions of the level of D4 in a silicone gel breast implant, b) the actual level of exposure to D4 arising from a silicone gel breast implant, c) the limited understanding of the metabolism of D4 reported by Luu and Hutter (1), and d) the prediction from their PBPK model that D4 will bioaccumulate with repeated exposures. The level of low molecular weight siloxanes (LMWS), both cyclic and linear, that persist in the polydimethylsiloxane (PDMS) used to make the silicone gel and elastomer shell of a breast implant is in the range of ≤ 0.1%. In a recent comprehensive pharmacokinetic study on PDMS, Jovanovic (4) measured the actual concentration of D4 to be 0.03% of the PDMS by weight. Our own analysis of D4 in silicone gel breast implants shows that D4 levels rarely exceed 700–1,000 ppm (0.07–0.1%) (5). This higher level of D4 in the silicone gel could result during the manufacturing process. If one conservatively assumes that a silicone gel breast implant could contain up to 0.1% D4 and that the average size of a breast implant is 250 g, then the total D4 content in two breast implants is 500 mg, or 8.7 mg D4/kg body weight based on the U.S. Environmental Protection Agency’s default body weight of 57 kg for a woman (6). The migration of silicone from a silicone gel breast implant ranges up to 820 μg/day (7), with the migration of D4 occurring at a rate of about 0.58 μg/day (5). For a woman who weighs 57 kg, this migration equates to a relatively small exposure of 0.01 μg/kg/day. Luu and Hutter (1) estimated that the extra dose of D4 received from a silicone gel breast implant is 5.7 μg/kg/day, an overestimate by over 500-fold. The estimate of daily intake reported by Shipp et al. (8) resulting from exposure to D4 in a wide variety of personal care products was 158 μg/kg/day. If we assume the value reported by Luu and Hutter (5.7 μg/kg/day) is correct, then the exposure to D4 resulting from migration from a gelfilled implant would account for a proportionately small increase in total exposure to D4 (from 158 μg/kg/day to 164 μg/kg/day). This small increase has little effect on the initial risk assessment for D4 (8). Two of the references (9,10) cited by Luu and Hutter (1) to support “migration of significant amounts of silicone out of gel implants into surrounding tissue and to the liver” have been retracted by the authors (11). Further, Hull (12), a member of the Magnetic Resonance in Medicine’s Editorial board, wrote that “as a referee, none of Garrido’s papers should have been published in their current form,” and in a summary statement concluded that