Bioavailability of [D.sub.4] after inhalation and implantation exposure to silicones. (Correspondence).

In the November 2001 issue of EHP, Luu and Hutter (1) described a physiologically based pharmacokinetic (PBPK) model for the bioavailability of octamethylcyclotetrasiloxane ([D.sub.4]) following exposure to [D.sub.4] 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 [D.sub.4] 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 [D.sub.4] and determined total radioactivity in these samples, but did not attempt to distinguish between parent [D.sub.4] and [D.sub.4] metabolites. Although the data obtained by Kirkpatrick were for iv dosing, Luu and Hurter (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 [D.sub.4], with no contribution from metabolites. Luu and Hurter (1) plan to use their PBPK model to assess risk after exposure to [D.sub.4] 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 [D.sub.4]. These concerns relate to a) the assumptions of the level of [D.sub.4] in a silicone gel breast implant, b) the actual level of exposure to [D.sub.4] arising from a silicone gel breast implant, c) the limited understanding of the metabolism of [D.sub.4] reported by Luu and Hurter (1), and d) the prediction from their PBPK model that [D.sub.4] 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 [less than or equal to] 0.1%. In a recent comprehensive pharmacokinetic study on PDMS, Jovanovic (4) measured the actual concentration of [D.sub.4] to be 0.03% of the PDMS by weight. Our own analysis of [D.sub.4] in silicone gel breast implants shows that [D.sub.4] levels rarely exceed 700-1,000 ppm (0.07-0.1%) (5). This higher level of [D.sub.4] 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% [D.sub.4] and that the average size of a breast implant is 250 g, then the total [D.sub.4] content in two breast implants is 500 mg, or 8.7 mg [D.sub.4]/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 [micro]g/day (7), with the migration of [D.sub.4] occurring at a rate of about 0.58 [micro]g/day (5). For a woman who weighs 57 kg, this migration equates to a relatively small exposure of 0.01 [micro]g/kg/day. Luu and Hutter (1) estimated that the extra dose of [D.sub.4] received from a silicone gel breast implant is 5.7 [micro]g/kg/day, an overestimate by over 500-fold. The estimate of daily intake reported by Shipp et al. (8) resulting from exposure to [D.sub.4] in a wide variety of personal care products was 158 [micro]g/kg/day. If we assume the value reported by Luu and Hurter (5.7 [micro]g/kg/day) is correct, then the exposure to [D.sub.4] resulting from migration from a gel-filled implant would account for a proportionately small increase in total exposure to [D.sub.4] (from 158 [micro]g/kg/day to 164 [micro]g/kg/day). This small increase has little effect on the initial risk assessment for [D.sub.4] (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

   the inadequacies, omissions, inconsistencies, and unresolved questions that
   are apparent in the work of Garrido et al. allow only one possible
   conclusion: there is no convincing and reproducible evidence of millimolar
   concentrations of silicon in tissue or blood.

The work of Garrido and colleagues (9,10) certainly does not support the contention of Luu and Hutter (1) in the introduction of their paper that

   the migration of significant amounts of LMWS from silicone gel breast
   implants ... would add to the dermal or inhalation exposures from personal
   care products in a typical woman.

Luu and Hutter (1) postulated that [D.sub.4] saturates the elimination process, thereby potentially increasing the delivered dose to the target tissue and causing accumulation of [D.sub.4] in fat, liver, and kidneys. This conclusion is based on their analysis of the iv data (but they actually used intra-arterial administration). Several studies show that [D.sub.4] induces cytochrome P450 2B1/2B2 in a time, dose-dependent, and Phenobarbital-like manner (13,14). Studies conducted by Plotzke and colleagues (3,15,16) and Varaprath et al. (17,18) provide evidence that rats extensively metabolize [D.sub.4]. Metabolism and subsequent elimination of hydrophilic metabolites in urine and feces are important elimination mechanisms for [D.sub.4] in mammalian species. In addition, the elimination of [D.sub.4] occurs not only by this high metabolic clearance from liver but also by exhalation of parent [D.sub.4] via the lung. If Luu and Hutter (1) were correct and [D.sub.4] did saturate the enzymes responsible for metabolism, proportionately more [D.sub.4] would be eliminated through exhalation. As shown by Plotzke et al. (3,15,16), in fact, the rates of metabolism and clearance of [D.sub.4] and its metabolites support the conclusions reached with a more comprehensive PBPK model developed by Andersen et al. (19); that is, [D.sub.4] will not be unusually persistent in mammalian species.

In their discussion, Luu and Hutter (1) focused much of their attention on the potential bioaccumulation of [D.sub.4]. The PBPK model developed by Andersen et al. (19) was based on an extremely robust inhalation pharmacokinetic data set for [D.sub.4] developed by Plotzke et al. (3) that included exposure to three concentrations, single and repeated exposures, and separate measurement of parent [D.sub.4] and metabolites (15-18). This model showed that [D.sub.4] is not expected to accumulate with repeated exposures. This lack of accumulation, despite high fat:blood partitioning, is due to rapid metabolism and the low blood:air partition coefficient that allows for ready exhalation of [D.sub.4]. Metabolism does not saturate until the inhalation exposure concentration exceeds 500 ppm (v/v). To assess the validity of the prediction that [D.sub.4] would not accumulate, we recently collected blood and fat samples from female rats after 6 months of exposure to [D.sub.4]. As part of a 2-year bioassay, these female rats were exposed by inhalation for 6 hr/day, 5 days/week to 700 ppm (v/v) [D.sub.4]. We measured parent [D.sub.4] concentrations in both the blood and fat and compared the concentrations at 6 months of exposure with those obtained at 15 days in the inhalation pharmacokinetic study by Plotzke et al. (3). The concentrations in blood and fat, respectively, at 15 days were 7.2 [micro]g/g and 1,079 [micro]g/g tissue. At 6 months, the [D.sub.4] concentrations in blood and fat, respectively, were 13 [micro]g/g and 1,200 [micro]g/g tissue. These results confirm that [D.sub.4] does not accumulate in the body.

As with any risk assessment, it is essential to understand both the exposure to target populations and the dose response for toxicity in experimental animals. The development of a PBPK model plays an important role in calculating the dose delivered to target tissue from specific exposure conditions. These PBPK models also can play a role in understanding the dynamic processes that occur while the [D.sub.4] is in the organism. Recently, [D.sub.4] was shown to have an effect on the reproductive system of female rats following inhalation exposure to 500 and 700 ppm (v/v) (20). This effect consisted of a reduction in mean live litter size and implantation sites. In the [F.sub.1] generation, there also was a reduction in mating at 500 and 700 ppm (20). The mode-of-action for these reproductive effects is the ability of [D.sub.4] to block or shift the preovulatory surge of luteinizing hormone (21). The highest exposure concentration that does not cause a significant reproductive effect [i.e., the no-observed-adverse-effect level (NOAEL)] appears to be around 300 ppm. The estimate of daily intake reported by Shipp et al. (8) for [D.sub.4] exposure from a variety of sources including personal care products is influenced by two characteristics or assumptions. First, at the time we completed our initial exposure assessment, roll-on antiperspirants (AP) contained up to 60% [D.sub.4] and accounted for about 50% (70 [micro]g/kg/day) of the estimated daily intake. In the last few years, there has been a shift away from [D.sub.4] in roll-on APs such that the estimate of daily intake today should be about 40-50% lower than the original value. Second, the primary exposure to [D.sub.4] in personal care products is dermal application. After absorption into the venous blood, [D.sub.4] goes to the lung before reaching other tissues. As [D.sub.4] passes through the lung, some is eliminated in the expired air before entering the arterial circulation. Based on its partition coefficient, one-half of the free [D.sub.4] in the venous blood will be exhaled during passage through the lung. This first pass effect, predicted by the PBPK model developed by Andersen et al. (19) is consistent with the physical properties of [D.sub.4] and therefore further lowers the estimated daily intake. Luu and Hutton (1) estimated a daily intake or exposure resulting from migration of [D.sub.4] from a silicone gel breast implant to be 5.7 [micro]g/kg/day, which is likely to significantly overestimate the actual daily intake. However, if we conservatively estimate the daily intake from personal care products to be 78 [micro]g/kg/day (based on the reduced use of [D.sub.4] in roll-on APs as discussed above) and add the estimated daily intake or exposure by Luu and Hutter, then the estimated total daily intake for [D.sub.4] becomes 85 [micro]g/kg/day. Exposure of rats to 300 ppm (v/v) of [D.sub.4] for 6 hr/day equates to an inhaled dose of 45,000 [micro]g/kg/day using an absorption value of 5%, as determined in our inhalation pharmacokinetic studies (3). These values give a margin of safety (or exposure), as determined by dividing the NOAEL by the estimated daily intake, of over 500. A margin of exposure (MOE) of a specified magnitude indicates that exposure at or below the corresponding estimated intake level is not expected to result in adverse effects in the exposed populations. An MOE of 100 is typically considered large enough to be health protective when the NOAEL is based on animal data. The components of the MOE can be thought of as the typical factors of 10 for interspecies extrapolation (from animals to humans) and a factor of 10 for intrahuman variability, resulting in an MOE of 100.

In summary, Luu and Hutter (1) reported that they have developed a PBPK model for exposure to [D.sub.4] via two routes: a) inhalation in association with daily use of multiple personal care products, and b) migration of small amounts of silicone fluid from silicone gel breast implants. Their PBPK model is built from data generated by intravenous administration of [D.sub.4] as a microemulsion (2) and then modeled for intra-arterial dosing. They assumed that all radioactivity was parent [D.sub.4], even though there is significant conversion of [D.sub.4] to hydrophilic metabolites. A more complete PBPK model (3) was developed from an extensive inhalation data set on [D.sub.4], including evaluation of metabolism of [D.sub.4]. This more comprehensive model and the actual data from our 6-month inhalation study show that there are only modest increases of [D.sub.4] concentration in fat on repeated exposures to [D.sub.4] compared to concentrations achieved after single exposures. Luu and Hutter (1) also overestimated the contributions to the daily intake resulting from the migration of [D.sub.4] from a breast implant. However, this overestimation of the daily intake by Luu and Hutter does not significantly change the MOE for [D.sub.4]. The conservative MOE of > 500 indicates that current use practices with [D.sub.4] have adequate safety margins

REFERENCES AND NOTES

(1.) Luu H-MD, Hutter JC. Bioavailability of octamethylcyclotetrasiloxane ([D.sub.4]) after exposure to silicones by inhalation and implantation. Environ Health Perspect 109:1095-1101 (2001).

(2.) Kirkpatrick D. [sup.14]C-[D.sub.4] Pharmacokinetics in the Rat Following Intravenous Administration. Huntingdon Research Center Ltd. Sponsored by the Silicone Environment Health and Safety Council. Midland MI:Dow Corning Corporation, 1995.

(3.) Plotzke K, Crofoot S, Ferdinandi E, Beattie J, Reitz R, McNett D, Meeks R. Disposition of radioactivity in Fischer 344 rats after single and multiple inhalation exposure to [sup.14]C-octamethylcyclotetrasiloxane-[D.sub.4]. Drug Metab Dispos 28:192-204 (2000).

(4.) Jovanovic M. Disposition of Polydimethylsiloxane, 10 cst in Fischer 344 rats Following a Single Exposure by Oral Gavage. Dow Corning Internal Report 2000-10000-49106. Midland, MI:Dow Corning, 2000.

(5.) Meeks RG. Overview of the safety of the components used for the manufacturing of silicone breast implants. Presented at the Safety of Silicone Breat Implants Meeting of the Institute of Medicine, 2 July 1998, Washington, DC.

(6.) U.S. EPA. Exposure Factors Handbook. EPA/600/P-95/002Fa, August 1997. Washington, DC: U.S. Environmental Protection Agency, 1997.

(7.) Yu L, LaTorre G, Marotta, J, Batich C, Hardt N. In vitro measurement of silicone bleed from breast implants. Plast Reconstr Surg 97:756-764 (1996).

(8.) Shipp AM, Van Landingham CV, Meeks RG. Estimation of margins of exposure: a preliminary risk assessment for octamethylcyclotetrasiloxane ([D.sub.4]) based on reproductive toxicity studies in Sprague-Dawley rats [Abstract] Toxicologist 54(1):108 (2000).

(9.) Garrido L, Pfleiderer B, Jenkins BG, Hulka CA, Kopans DB. Migration and chemical modification of silicone in women with breast prostheses. Magn Resort Mad 31:328-330 (1994).

(10.) Pfleiderer B, Garrido L. Migration and accumulation of silicone in the liver of women with silicone gel-filled breast implants. Magn Reson Med 33:8-17 (1995).

(11.) Garrido L, Pfleiderer B, Jenkins BC, Hulka CA, Kopans DB. Erratum. Magn Reson Mad 40:689 (1998).

(12.) Hull WE. A critical review of MR studies concerning silicone breast implants. Magn Reson Mad 42:984-995 (1999)

(13.) McKim JM Jr, Wilga PC, Kolesar GB, Choudhuri S, Madan A, Dochterman LW, Breen JG, Parkinson A, Mast RW, Meeks RG. Evaluation of octamethylcyclotetrasiloxane ([D.sub.4]) as an inducer of rat hepatic microsomal cytochrome P450, UDP-glucuronyl transferase, and epoxide hydrolase: a 28-day inhalation study. Toxicol Sci 41(1):29-41 (1998).

(14.) McKim JM Jr, Kolesar GB, Jean PA, Meeker LS, Wilga PC, Schoonhoven R, Swenberg JA, Goodman JI, Gallavan RH, Meeks RG. Repeated inhalation exposure to octamethylcyclotetrasiloxane ([D.sub.4]) produces hepatomegaly, transient hepatic hyperplasia, and sustained hypertrophy in female Fischer 344 rats in a manner similar to phenobarbital. Toxicol Appl Pharmacol 172:83-92 (2001).

(15.) Salyers KL, Varaprath S, McKim JM, Mast RW, Plotzke KP. Disposition and metabolism of octamethylcyclotetrasiloxane ([D.sub.4]) in F-344 rats: effect of classical inducing agents. Toxicologist 30(1):15 (1996).

(16.) Crofoot SD, McMahon JM, Hubbel BG, Seaton MJ, Plotzke KP. Absorption and disposition of octamethylcyclotetrasiloxane in female Fischer 344 rats following delivery in two carriers via gavage. Toxicologist 36(1):143 (1997).

(17.) Varaprath S, Salyers KL, PIotzke KP, Nanavati S. Identification of metabolites of octamethylcyclotetrasiloxane ([D.sub.4]) in rat urine. Drug Metab Dispos 27(11):1267-1273 (1999).

(18.) Varaprath S, Seaton M, McNett D, Cao L, Plotzke KP. Quantitative determination of octamethylcyclotetrasiloxane ([D.sub.4]) in extracts of biological matrices by gas chromatography-mass spectrometry. J Environ Anal Chem 77(3):203-219 (2000).

(19.) Andersen ME, Sarangapani R, Reitz RH, Dobrev ID, Gallavan RH, Plotzke KP. Physiological modeling reveals novel pharmacokinetic behavior of inhaled octamethylcyclotetrasiloxane. Toxicol Sci 60:214-231 (2001).

(20.) Stump DG, Holson JF, Kirkpatrick DT, Reynolds VL, Siddiqui WH, Meeks RG. Evaluation of octamethylcyclotetrasiloxane ([D.sub.4]) in a 2-generation reproductive toxicity study in rats. Toxicologist 54(1):370 (2000).

(21.) Dalu A, Gallavan RH, Meeker LS, Quinn AL, Jean PA, Crissman JW, Meeks RG, Plotzke KP. Effects of octamethylcyclotetrasiloxane ([D.sub.4]) and phenobarbital (PB) on LH surge and ovulation in Sprague-Dawley (SD) rats. Toxicologist (in press).

Robert G. Meeks
Dow Corning
Midland, Michigan
E-mail: [e-mail]