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Comments on Total Platinum Concentration and Platinum Oxidation States in Body Fluids, Tissue, and Explants from Women Exposed to Silicone and Saline Breast Implants by IC-ICPMS Michael A. Brook*,†
Department of Chemistry, McMaster University, 1280 Main Street W., Hamilton, ON, Canada
The paper by Lykissa and Maharaj (Lykissa, E. D.; Maharaj, S. V. M. Anal. Chem. 2006, 78, 2925-2933) comes to two main conclusions: platinum is found at elevated levels in women who have received breast implants, and the platinum is present in unusual oxidation states. The authors make clear their view that these are very surprising and disturbing results, both because of the quantity of platinum found and the association between higher oxidation states of platinum and toxicity of various types (sensitization-contact dermatitis, carcinogencity, among others). However, the conclusions arrived at by the authors are unsupported by the Experimental Section of the paper and the data that are reported there, and contravene the well-established chemistry of platinum. Silicone breast implants (SBI) have been used since the 1960s for cosmetic augmentation and breast reconstruction after mastectomy. Two classes of silicone devices exist: “saline” and “silicone”. Both devices have a cross-linked silicone elastomer as an external shell, which is filled with saline and silicone gel, respectively.2 These devices have been the subject of intense scrutiny since the early 1990s, when a series of tort cases were mounted against the implant manufacturers because of putative associations between implants and disease.3 In recent years, specific allegations have been made about the platinum species present in silicone implants (see below). It has been inferred that women have experienced allergic responses due to exposure to platinum in SBIs,4 a claim not found to be * Fax: +1 (905) 522 2509; Tel: +1 (905) 525 9140 ext. 23483; E-mail:
[email protected]. † The author provided information on the chemical nature of the platinum in silicone breast implants at the FDA panel hearing on breast implants April 2005 on behalf of Inamed Corporation. He was also a member of Health Canada regulatory advisory panels considering applications by Mentor Corporation and Inamed Corporation for new breast implant models in March and September 2005. (1) Lykissa, E. D.; Maharaj, S. V. M. Anal. Chem. 2006, 78, 2925-2933. (2) Bondurant, S.; Ernster, V. L.; Herdman, R. Safety of silicone breast implants. Washington, DC: Institute of Medicine, IOM (US). Committee on the safety of silicone breast implants; 2000. (3) Mayesh, J.; Scranton, M. F. Legal Aspects of Biomaterials. In Biomaterials Science, 2nd ed.; Ratner, B. D., Hoffman, A. S., Schoen, F. J., Lemons, J. E., Eds.; Elsevier: San Diego, 2004; Chapter, 10.5, pp 797-804. (4) Harbut, M. R.; Churchill, B. C. Isr. J. Occup. Health 1999, 3, 73-82. 10.1021/ac060779g CCC: $33.50 Published on Web 07/31/2006
© 2006 American Chemical Society
credible by regulatory agencies.5 More recent studies have shown the release of platinum in vitro from SBIs6 and found platinum in tissues adjacent to breast implants.7,8 It has been suggested that the platinum released may be biotoxic because it is in a very high oxidation state,8 although such proposals are inconsistent with known platinum chemistry.9 Traditionally two different platinum catalysts have been used to cure silicones in breast implants: H2PtCl6 (Speier’s catalyst10) and a platinum(0) compound formed by reduction of Speier’s catalyst with vinylsilicones (Ptn(H2CdCHMe2SiOSiMe2CHd CH2)m, Karstedt’s catalyst11). The latter catalyst has been used exclusively by manufacturers for decades,2 not ionic platinum as asserted by Lykissa and Maharaj. Many different platinum species may exist during the conversion of chloroplatinic acid to the active platinum hydrosilylation catalyst, particularly at oxidation states IV, II, and 0. When starting from Pt(0) Karstedt’s catalysts, the external ligands are removed by reaction with hydrosilanes to generate a series of complexes that lead to active catalytic species. Thus, both chloroplatinic acid and Karstedt’s catalysts are catalyst precursors. Either compound is reduced to form the active hydrosilylation catalyst by various reducing agents including Si-vinyl,10,11 and Si-H.12 Ultimately, (5) Sturrock, R. D., Chief editor. Silicone Gel Breast Implants, Report of the Independent Review Group, UK Crown: London, 1998. (6) Lykissa, E. D.; Kala, S. V.; Hurley, J. B.; Lebovitz, R. M. Anal. Chem. 1997, 69, 4912-4916. (7) Flassbeck, D.; Pfleiderer, B.; Klemens, P.; Heumann, K. G.; Eltze, E.; Hirner, A. V. Anal. Bioanal. Chem. 2003, 75, 56-362. (8) Maharaj, S. V. M. Anal. Bioanal. Chem. 2004, 80, 4-89. (9) Brook, M. A. Biomaterials, 2006, 27, 3274-86. (10) Speier, J. L. Adv. Organomet. Chem. 1979, 17, 407-47. (11) (a) Karstedt, B. D. (General Electric) Platinum complexes of unsaturated siloxanes and platinum containing organopolysiloxanes, U.S. Patent 3775452, 1974. (b) Chandra, G,; Lo, P. Y.; Hitchcock, P. B.; Lappert, M. F. Organometallics 1987, 6, 191-192. (12) Stein, J.; Lewis, L. N.; Gao, Y.; Scott, R. A. J. Am. Chem. Soc. 1999, 121, 3693. (13) (a) Lewis, L. N.; Stein, J.; Gao, Y.; Colborn, R. E. Platinum Metals Rev. 1997, 41, 66. (b) Lewis, L. N.; Uriarte, R. J.; Lewis, N. J. Catal. 1991, 127, 67. (c) Stein, J.; Lewis, L. N.; Smith, K. A.; Lettko, K. X. J. Inorg. Organomet. Polymers 1991, 1, 325. (d) Lewis, L. N.; Uriarte, R. J. Organometallics 1990, 9, 621. (e) Lewis, L. N.; Lewis, N.; Uriarte, R. J. J. Am. Chem. Soc. 1992, 114, 541. (f) Lewis, L. N.; Lewis, N. J. Am. Chem. Soc. 1986, 108, 7228. (g) Lewis, L. N.; Lewis, N.; Uriarte, R. J. Hydrosilylation. A “Homogeneous” Reaction Really Catalyzed by Colloids In Homogeneous Transition Metal Catalyzed Reactions; ACS Advances in Chemistry Series 230; American Chemical Society: Washington, DC, 1992; Chapter 37, p 541.
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platinum catalysts of either origin are converted primarily to Pt(0), primarily metal colloids, in silicone elastomers12-16 long before implantation in the body. Preparation of the samples for ion chromatography. The hallmark of any scientific paper, particularly a paper appearing in Analytical Chemistry, is the Experimental Section. Sufficient experimental detail needs to be provided both to support the conclusions made by the authors and to permit other scientists to try and reproduce the work. The Experimental Section requires particular attention when conclusions are drawn from the data that go against the previous body of knowledge. Insufficient detail is provided in this article. Various samples examined by Lykissa and Maharaj,1 both biological and derived from silicone elastomer explants, were dissolved/digested prior to separation in an ion chromatograph. The method used for digestion of silicone elastomers is supposedly taken from a previous Lykissa paper.6 However, the Experimental Section of that paper comments only on the dissolution of the silicone gel in ethyl acetate. No protocol is provided for the degradation of the silicone shell into an aqueous medium suitable for ion chromatography. While one might imagine that acid digestion was used, having a description of the protocol actually used is important for understanding the experimental results reported: with the wrong acid, no degradation of the implant would take place and soluble platinum will not form; with strong acids such as aqua regia, platinum zero is solubilized only during its oxidation to Pt(IV) species.17 The authors use cisplatin, transplatin diamine dichloride, platinum oxide, and hexachloroplatinate (counterion not specified) as ion chromatography standards. In addition, they used “platinum” in an unspecified form as a standard for the zero oxidation state. Platinum metal does not dissolve in any single mineral acid:18 its stability to solublization and oxidation is one of the reasons this metal is used in sensitive biomedical devices such as pacemaker leads.19 The authors claim to dissolve the platinum in 5% HNO3sconditions under which platinum metal dissolution does not take placesand then run the separation on an ion chromatograph in basic buffers. The dissolution of platinum is commonly performed using aqua regia,17 but in this case, dissolution only follows the oxidation of Pt(0) to Pt(II) and Pt(IV); the latter two species do dissolve in water, unlike platinum metal. If a peak was obtained in the ion chromatograph from the Pt(0) standard, it should be due to some other species of platinum than platinum zero. This calls into question the identity of the other peaks the authors ascribe to Pt(0) in their biological and explanted silicone samples. No retention times are provided for any of the compounds or standards used. (14) Lewis, L. N.; Colborn, R. E.; Grande, H.; Bryant, G. L., Jr.; Sumpter, C. A.; Scott, R. A. Organometallics 1995, 14, 2202. (15) Marceniec, B.; Gulinski, J.; Urbaniak, W.; Kornetka, Z. W. Comprehensive Handbook on Hydrosilylation Chemistry; Pergamon: Oxford, 1992 (experimental details of several thousand reactions are included here). (16) Brook, M. A.; Ketelson, H. A. M.; Pelton, R. H.; Heng, Y. M. Chem. Mater. 1996, 8, 2195. (17) El-Jammal, A.; Templeton, D. M. Anal. Proc. 1995, 32, 293-295 (incl. Anal. Commun.). (18) Cotton, F. A.; Wilkinson, G.; Murrilo, C. A.; Bochmann, M. Inorganic Chemistry, 6th ed.; Wiley: New York, 1999; p 1002. (19) Robblee, L. S.; Cogan, S. F. Metals for Medical Electrodes. In Concise encyclopedia of medical and dental materials; Williams, D., Ed.; Pergamon: Oxford, 1990; p 245.
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Oxidation states. The injection into an ion chromatograph of extracts of explanted silicones implants (formed by an unreported method, although Dr. Maharaj has previously used microwave digestion and aqua regia8) led to up to seven different peaks, of unreported retention times. The authors infer these are Pt(0) and ions Pt(1) f Pt(6). What is the basis of these assignations? No standards are available for Pt(I) and Pt(III), oxidation states that are exceptionally unusual for platinum.20 The authors infer, without any justification for this assignation, that two of the peaks observed, of unspecified retention times, must be Pt(I) and Pt(III), respectively. Other possibilities were not considered. According to Cotton and Wilkinson,18 the inorganic text book for decades, only with the strongly electron-withdrawing ligands such as fluoride is it possible to form platinum V or VI species.20 Platinum(VI) fluorides are of historical interest. It has been shown that PtF6 is such a strong oxidant that it can oxidize oxygen.21 Such compounds cannot, of course, be manipulated outside of an inert atmospheresand even the noble gas xenon is insufficiently inert to resist reaction with PtFt6;22 Pt(VI) undergoes reduction to other oxidation states, principally II and IV. Lykissa and Maharaj note in the Experimental Section that there are no standards for Pt(VI) and Pt(V) compounds; no wonder, based on the reactivity just noted. However, they assign the identities of two peaks on the chromatogram (not shown) to these species which, based on extensive precedent, cannot exist in water. There is no discussion of this point, and no independent experiment to substantiate these assignments. The inference that platinum species at up to seven different oxidation states are present in some of the explants is unsupported because there were no standards for four of the observed peaks, is confounded by solubility issues for platinum metal noted above, and, with respect to Pt(V) and Pt(VI), completely contravenes the well-known chemistry of platinum. Alternative explanations exist. The putative presence of Pt(I) and Pt(III) was only observed with explanted silicones. However, we do not know how the explant samples were chosen (shell, gel, presence of tissue on the device surface, etc.) or digested. Since there was no independent characterization of these or other peaks, particularly of peaks assigned to Pt(I), Pt(III), Pt(V), and Pt(VI), they could be anything (except Pt(V) and Pt(VI)). The burden of proof for the identity of chemical species reported in a paper lies with the author. That burden is heavier when the claim contravenes known chemistry. This paper does not provide data that substantiates the conclusions drawn. Statistics. The authors’ statistical analysis shows that the mean concentration of platinum in urine in women exposed to breast implants and the control population are not statistically different. Either this should have been the main focus of the paper or a statistically larger number of implanted women and members of the control group should have been recruited such that statistically different results could be demonstrated. Instead, the authors then state that the former group had 60-1700 times higher platinum concentrations than individuals with no known exposure. If there (20) Ibid. ref 18, p 1063. (21) Bartlett, N.; Lohmann, D. H. J. Chem. Soc. 1962, 5253-61. (22) Graham, L.; Graudejus, O.; Jha N. K.; Bartlett, N. Coord. Chem. Rev. 2000, 197, 321-334.
is no statistical difference, then there can be no assignation of a higher concentration to one group. The results are more striking when blood samples were examined: again the platinum concentrations in the control and implanted groups were not statistically different. Now, however, the observed platinum concentrations for implanted women (and for their statistically related control group) are claimed to be comparable to occupationally exposed individuals, who are exposed to orders of magnitude higher platinum concentrations (based on the known concentrations of platinum in the shells and gels of silicone breast implants,2 and depending on manufacturer and size of implants, the total platinum bolus contained in two implants will range from about 0.1 to 10 mg). It should be noted that everyone in developed and undeveloped societies is exposed to platinum, primarily as a consequence of the use of this metal in pollution control devices for automobiles.23 While the authors might wish to infer that women who have had breast implants have higher platinum levels than control groups, perhaps even as high as workers who work daily with platinum salts, statistically their data does not support this inference by their own admission. Either their control group was well chosen, and implanted women had similarly low levels of platinum in their biological samples, or their control group was poorly chosen, such (23) Ek, K. H.; Morrison, G. M.; Rauch, S. Sci. Total Environ. 2004, 334-335, 21-38.
that they had higher than normal platinum concentrations. Before the authors make allegations about implanted women having, “Pt levels that exceed that of the general population”, the experimental issues noted in the previous section need to be dealt with, and larger control and implanted groups will have to be examined that provide a statistically significant support to this contention. Conclusion. The Lykissa and Maharaj paper notes that there is no statistical difference between the control and the implanted groups with respect to platinum concentration in blood and urine. They are careful to note that the observed platinum concentrations in implanted women, and by extension the nonimplanted control group, are comparable to that found in workers in the platinum industry. This is a paradox not addressed by the authors. The control group cannot be held up as a “low value” comparator and then found to have concentrations similar to that of the implanted population. The authors do not provide sufficient experimental detail to permit their experiments to be reproduced and do not provide convincing data to support their speciation. In particular, they do not address their apparent ability to measure Pt(V) and Pt(VI) in water, conditions under which a large body of research has shown such oxidation states do not exist. Received for review April 26, 2006. Accepted June 2, 2006. AC060779G
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