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Page 80 4 Silicone Toxicology Scope and Criteria for the Toxicology Review This chapter reviews studies of the toxicology of silicone compounds carried out over the past 50 years. It does not review immunological studies, except occasionally when immune system toxicology is part of a report covering other toxicology. Otherwise, immunological studies are discussed in Chapter 6. Silicone compounds include a great many chemical entities; a recent compilation lists toxicological data on 56 different siloxanes (Silicones Environmental Health and Safety Council, 1995). This chapter identifies silicone compounds as they are listed in individual reports, but it is organized by route of exposure not by type of compound. Silicone fluids, gels, and elastomers are covered since they are components of silicone breast implants. Although the most relevant exposures are reviewed, that is, tissue injections and subcutaneous implants, the committee, unlike other recent reviews (Kerkvliet, 1998) also decided to include other (nonimplantation) exposure routes, such as dermal, oral, and inhalation, since data from such studies may provide some insights into systemic silicone toxicology. The committee included citations on the toxicology of silica in the reference list of this report, because there has been considerable mention of silica as a component of breast implant elastomers. However, the toxicology of silica is not reviewed here because the committee found no valid scientific evidence for the presence of or exposure to silica in tissues of women with breast implants. Some compounds not found in breast im-
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Page 81 plants (and identified as such) are included briefly, sometimes to complete a survey of silicone species and other times because they have been mentioned in the current debate on the toxic effects of implants. It is important to note that toxicology studies often report silicone dose levels substantially in excess of any doses that could be achieved on a relative weight basis in women with silicone breast implants. Earlier in this report, the committee emphasizes the relevance of published, peer-reviewed scientific reports and assigns secondary importance to technical reports from industry. In this chapter, however, studies done in-house by industry or by commercial testing laboratories have been analyzed. Such reports are often reviewed first in-house, then by the sponsor and panels of outside experts, and eventually by a regulatory agency, which also looks at original data. The conflict of interest inherent in experimentation by an organization with an economic interest in the outcome is recognized. Nevertheless, the committee found many of industry's technical studies informative, useful, and consistent with sound science. The studies cited here consisted of about 50 individual articles from the open scientific literature between 1948 and 1999 and about the same number of industry technical reports. Reviews available to the committee summarized data from some reports not reviewed by or not available to the committee. For example, the Silicones Environmental Health and Safety Council (1995) examined may reports on various organic silicon compounds that are not found in breast implants and reviewed some reports not accessible to the committee. This review was useful in presenting an overall picture of the generally low toxicity of silicones and identifying particular compounds that had toxicity. The report of the Independent Review Group (IRG, 1998) (and earlier versions of the Medical Devices Agency's work), and the report of the National Science Panel (Kerkvliet, 1998) which are described in Appendix C looked at essentially the same body of toxicology information as the committee. The IRG report included proprietary data not available to the committee, and as noted, the committee examined routes of exposure and listed silica references neither of which are included in the IRG or National Science Panel reports. Since the IRG, which had some proprietary data, concluded that silicones were bland substances with little toxicity, such data seem unlikely to have changed the committee's findings in any substantial way. Also, the committee believes that the inclusion of dermal, oral and inhalation toxicology studies in this report provided additional security in conclusions about the biological and toxicological behavior of relevant silicones. Kerkvliet lists three major reasons why toxicology studies are helpful in assessing the safety of a drug or consumer product such as silicone breast implants. (1) Toxicology studies in animals may identify a haz-
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Page 82 ardthat is, whether a given product can cause adverse health effects. (2) Studies may also clarify dose responsesthat is, how much of an entity is necessary to produce effects. (3) Studies may provide mechanistic informationthat is, how and under what circumstances an agent produces effects (Kerkvliet, 1998). Such studies, reviewed here, will not ''fulfill the manufacturers' responsibility to demonstrate the safety of... implants" as Kessler urged in 1992 (Angell, 1995), since unanticipated events cannot be predicted or complete safety proven. Accumulating qualitative and quantitative data on the general toxicity of silicones, however, allow a reasonable degree of confidence that silicone compounds in breast implants are not hazardous. Brief History of Silicone Toxicology The principles of safety evaluation have not changed much over the past 50 years. However, analytical tools, the ability to measure chemicals in the body, and the science of molecular biology, which allows association of complex changes in a few cells or molecules with various disease states, have advanced considerably. These advances affect evaluations of the toxicology of silicones over time and are reflected in more recent studies. One of the first (if not the first) systematic evaluations of the toxicology of commercial silicones was conducted during World War II at the Dow Chemical Company. Silicone intermediates (chlorosilanes and ethoxysilanes) and selected commercial silicones were tested in rats, rabbits, and guinea pigs. The chlorosilanes and some ethoxysilanes were found to be highly corrosive; they represented significant industrial handling hazards. Methyl- and mixed methyl- and phenylpolysiloxanes, on the other hand, had very low toxicity. For practical purposes, they were divided into three groups: fluids, compounds, and resins. Five methylpolysiloxane and two methylphenylpolysiloxane fluids were tested (hexamethyldisiloxane, 0.35 centistoke [cS]; dodecamethylpentasiloxane, 2 cS; DC 200 fluid, 50 cS; DC 550 fluid, 550 cS; DC 702 fluid, 35 cS; DC 200 fluid, 350 cS; and DC 200 fluid, 12,500 cS). None of these killed rats or guinea pigs when given orally at doses up to 30 ml/kg. Some of the fluids had laxative effects not unlike mineral oil. DC 200 fluid (50 cS) "seemed literally to flow through the animals." The fluid with the lowest viscosity (hexamethyldisiloxane, 0.65 cS) did not have a laxative effect, but produced some mild inebriation and subsequent central nervous system depression. This suggests that there might be some absorption of this compound from the gastrointestinal tract. Repeated administration of DC 200 oil (350 cS) by stomach tube, up to dose levels of 20 g/kg, did not produce gross
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Page 83 signs of toxicity such as reduced weight gain, changes in organ weight, or organ pathology. Intraperitoneal injection was well tolerated, except for hexamethyldisiloxane, which produced extensive adhesions within the peritoneal cavity. This compound also produced inflammation and necrosis at the sites of subcutaneous and intradermal injections and proved lethal on repeated intraperitoneal injections. Other silicone fluids in the peritoneal cavity elicited only reactions "typical... of an irritating foreign body" with nodules containing the fluid in the omentum and visceral peritoneum. Eye irritation was transitory and no skin irritation was observed with these fluids (Rowe et al., 1948). Shortly after the report by Rowe et al., Kern et al. (1949) reported their results from feeding rats 0.05%-0.2% silicone-containing diets (a poly-dimethylsiloxane [PDMS], G.E. Dri-Film, No. 9977) and injecting silicone suspensions at unknown (but probably low) doses, intraperitoneally and intravenously in mice, and intra- and subcutaneously and in the muscles of rabbits. Hematological and gross and microscopic pathology examinations after 13 weeks were all normal, and the animals had no loss in body weight or other signs of toxicity (Kern et al., 1949). Two silicone compounds (DC 4 Ignition sealing compound and DC Antifoam A) were examined. Both agents caused transient conjunctival irritation, but no corneal damage when introduced directly into the eyes. No skin irritation was seen. Feeding of Antifoam A at concentrations up to 1% to rats did not produce any untoward effects. In a six-month feeding study in dogs, Antifoam A also exhibited no toxicity (Child et al., 1951). Three types of silicone resins (DC 2102, a methylpolysiloxane, DC 993, a methylphenylpolysiloxane; and DC Pan Glaze, which was similar to DC 993) were evaluated. Acute oral administration of up to 3 g/kg in guinea pigs was not toxic (higher doses could not be administered), and intraperitoneal injection in rats or dermal application in rabbits produced no signs of irritation. Rats fed Pan Glaze at concentrations up to 3% for 50 days gained weight normally, and on microscopic examination, their organs did not show any signs of toxicity (Rowe et al., 1948, 1950). The studies described by Rowe et al. (1948) reflect state-of-the-art toxicity testing at that time. They were done in a respected laboratory by competent toxicologists. The untoward effects observed with some compounds did not alarm toxicologists. These effects were found only after exposure to high doses of the test agent. According to an old classification, substances with a probable human lethal dose in excess of 15 g/kg were considered practically nontoxic (Casarett, 1975). These investigators commented that "for the past few years, an attempt has been made to keep pace with the rapid development of these products so that toxicological information would be available upon which the health hazards of
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Page 84 these materials could be evaluated." Only a few selected samples from each class of compounds were studied, but the experimental toxicology of silicone compounds did not yield data that suggested a need for fundamental, mechanistically oriented experimentation. When these and some other early studies were reviewed in 1950, silicone fluids with a viscosity of 350 cS were described as having exceedingly low toxicity. Some animal toxicity tests, such as oral and subcutaneous administration and eye irritation, were even performed on one of the authors of this study (Barondes et al., 1950). By then-current standards of toxicology, silicone fluids had to be considered harmless, devoid of any obvious acute toxic potential, and thus presumably safe. The Current Database A recent review of silicone toxicology summarized a substantial database (Silicones Environmental Health and Safety Council, 1995). This document does not list any references which makes it impossible to determine whether the data were published or to discover when the studies were done. It is not possible, therefore, to evaluate adherence to modern good laboratory practice regulations, protocols, and procedural requirements. Carcinogenesis studies done before the mid-1970s had different protocols and procedural requirements than later studies and, by today's standards, must be considered less reliable. This may apply to other test systems as well. The Silicones Council review analyzed a total of 629 studies (see Table 4-1), more than half of them done with PDMS linears (Chemical Abstracts Service [CAS] No. 63148-62-9). Compounds that are of concern because a large number of people are exposed to them and because they are found in breast implants, that is, D4 and D5 (where D4 and D5 represent cyclic tetramer and pentamer, respectively), comprise 17% of studies. There are few chronic lifetime or carcinogenesis studies (less than 3%) and immunological studies (less than 5%). Acute and sub-acute toxicity and irritation studies are in the majority (57%). Some of the Silicones Council studies summarized briefly in this current database may also be reviewed subsequently in other parts of this chapter. As noted, this material presents an overall picture of silicone toxicity based on a general review of many data sources covering a wide variety of compounds. Specific studies on breast implant compounds are relied on by the committee for conclusions relevant to the safety of silicone breast implants, however.
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Page 85 Results of Studies in Four Main Groups Group I A: Dimethylsiloxanes A total of 123 reports on cyclic polydimethlsiloxanes (D3, D4, D5, and D6) were reviewed. These compounds are volatile and potentially of concern in manufacturing; however, they also are used in consumer products, such as hair sprays, and are found in breast implants, although in very low amounts (see Chapter 3). They are practically nontoxic on ingestion, dermal application, or inhalation, although they are mildly irritating when placed directly on the skin or in the eyes. Subacute gavage studies showed that these compounds had no untoward effect other than a reversible increase in liver weight due to increases in both cell number and cell size at doses ranging up to 2,000 mg/kg. Skin application did not cause toxicity; however, some D5 penetrates the skin. No signs of toxicity were observed in subacute and chronic inhalation studies, except the development of hepatomegaly in some animal species, which was reversible on cessation of exposure. No evidence for carcinogenicity was found. Bacterial and mammalian mutagenicity studies were generally negative. Developmental and reproductive studies failed to show teratogenic effects or effects on fertility, except when exposure conditions were high enough to cause maternal toxicity in a rabbit study with D4. Immunotoxicity was studied following intraperitoneal, intramuscular, subcutaneous, and dermal exposure. D4 had a substantial adjuvant effect for humoral but not cell-mediated immune reactions when injected subcutaneously. Pharmacokinetic studies showed that these compounds are absorbed following oral administration or inhalation, but that skin penetration is very poor. Most of the compounds were excreted in the urine following intravenous administration. B: Linear Dimethylsiloxanes Fifty one reports on L2, L3, and L4 (where L = linear polymer) were reviewed. Linear polymers of this size are unlikely to be found in breast implants (Kala et al., 1998; reference not found in the original but added for this report, see Chapter 2). Systemic toxicity after oral, dermal, or inhalation exposure is low. However, linear siloxanes appear to have significant potential for dermal irritation in animals and humans. An in vitro study with human cells suggested that the materials are biocompatible. Evidence for modulation of immune function was obtained in some tests, although the biological significance of these findings was questioned.
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Page 86 TABLE 4-1 Summary of Toxicity Studies CAS No. Group Acute Subacute or Subchronic Chronic Irritation 541-05-9 D3 IA 3 3 2 556-67-2 D4a IA 8 15 11 541-02-6 D5 1A 9 12 12 541-02-6 1A 1 1 540-97-6 D6 1A 2 1 Mixturea 107-46-0 lB 21 6 107-51-7 lB 1 141-62-8 lB 1 2 2 Mixture 141-63-9 1C 2 3 677-62-90-7 1C 1 69430-24-6 1C 1 68037-74-1 1C 1 1 70131-67-8a 1C 11 1 3 63148-62-9a 1C 52 45 9 88 2554-06-5 II 2 546-56-5 II 1 2374-14-3 II 9 6 68037-59-2 III 2 67762-94-1 III 680-83-14-7 III 3 Mixture 999-97-3 IV 11 2627-95-4 IV 8 1 Others Totalb 149 95 16 116 aDenotes human data are available. bSum of all studies: 629. (Table continued on next page) C: Polydimethylsiloxanes A total of 516 reports on L5, L6, L7, L9, L13, L16, D7, D8, D9, D15, Dx (cyclosiloxanes, dimethyl(cyclopolydimethylsiloxanes), DMPS (dimethylmonomethylpolysiloxanes, dimethylpolysiloxanes), DMSS (dimethylsilicones and siloxanes, reaction products with silica), SSHS (siloxanes and silicones, dimethyl hydroxy-terminated), PDMS, and Lx (linears) were reviewed. The database on the toxicity of these compounds is extensive. Acute exposure by different routes showed only minimal toxicity. The compounds have minimal potential for skin irritation. Subchronic studies involving oral administration of the agents did not reveal any systemic toxicity. On prolonged dermal application, sometimes under occlusion,
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Page 87 (Table continued from previous page) CAS No. Developmental, Reproductive Pharmaco- kinetic Immunological Cytotoxicity, Mutagenicity Biocompatibility 541-05-9 D3 3 556-67-2 D4a 5 12 3 9 541-02-6 D5 2 1 6 1 541-02-6 540-97-6 D6 1 Mixturea 1 1 3 107--46-0 1 8 3 107-51-7 2 1 141-62-8 1 2 Mixture 1 141-63-9 2 1 1 1 677-62-90-7 69430-24-6 68037-74-1 70131-67-8a 2 5 1 63148-62-9a 66 19 19 41 5 2554-06-5 1 1 546-56-5 3 2374-14-3 7 68037-59-2 67762-94-1 1 2 680-83-14-7 1 Mixture 2 999-97-3 1 2627-95-4 1 Others 3 Totalb 75 39 30 93 16 some edema and scarring are observed, but no systemic toxicity. Implants of these materials under the skin usually produce granulomatous inflammatory changes and fibrosis. Subcutaneous implantation of PDMS gels in rats produced local sarcomas, such as are commonly seen in rats implanted with inert foreign bodies (solid-state carcinogenesis). An oral carcinogenicity study failed to produce any positive data. Multiple tests found a lack of genotoxicity. Tests for reproductive toxicity following oral or dermal exposure failed to show any clearly positive results. On occasion a small increase in fetal abnormalities was found, although the agents are not considered teratogenic. In 29 of 35 studies, no effects on the male gonads were found. The summary document, without providing references however, mentions
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Page 88 that some PDMS fluids given by gavage at 3.3 ml/kg for six days were associated with reduced seminal vesicle weights, whereas others, given for up to 20 days at similar doses, had no such effects. Spermatogenic depression was found in two of ten rabbits treated with 2 ml/kg PDMS for 20 days. Dermal application of 2 ml/kg for 28 days decreased testicular weight. In the case of one PDMS fluid (not characterized), a no-observable-adverse-effect level (NOAEL) of 50 mg/kg per day for a 28-day exposure was established. All of these dose levels are orders of magnitude greater that could be achieved in women with breast implants on a milliliter- or milligram-per-kilogram body weight basis. No immunotoxic potential was identified, although in some studies, adjuvant activity was noted with an increase in humoral but not cell-mediated immunity. The results were not seen with any consistency, and studies were often of poor quality. The absence of virtually any toxicity following acute exposure by oral and dermal routes was confirmed in human volunteers. Group IINon-Dimethyl Siloxanes Thirty reports were reviewed. The acute oral LD50 (mean lethal dose) of these compounds is influenced by solvent effects. Reproductive studies indicated some adverse effects on the male reproductive tract. In addition, the agents produced severe ulceration and necrosis of rabbit skin during the 21-day treatment. Significant histopathological changes in rabbit liver and kidney were seen after four days' treatment at 3.3 mg/kg. No genotoxicity was observed. Agents in Group II are polymer precursors, and no exposure is anticipated outside manufacturing sites. The committee found no evidence that these compounds are in breast implants. Group IIIOther Siloxane Polymers and Copolymers, DHPS, DMMVS (Siloxanes and Silicones, Dimethyl, Methylvinyl), and DMDS (Siloxanes and Silicones, Diphenyl) Ten reports were reviewed. The studied compounds are reactive, and they cross-link easily. Use of the toxicity of starting materials is not appropriate in judging the toxicity of cured cross-link products. There appears to be limited industrial exposure and no exposure of the general public. Acute toxicity, irritation, and sensitization are minimal. These compounds are not known to occur in silicone breast implants. Group IVOther Materials Forty-four reports were reviewed. Toxicity following oral exposure is low, and for inhalation a one-hour LC50 (50% lethal concentration) be-
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Page 89 tween 23 and 111 mg/ml was measured. The lowest-observable-adverse-effect level (LOAEL) for lung hemorrhage was 5.6 mg/l. Tetramethyl-divinyldisiloxane was severely irritating to the skin under occlusive conditions. No evidence for genotoxicity or immunotoxicity was reported. These compounds are not known to occur in silicone breast implants. Toxicology of Subcutaneously Implanted or Injected Silicones Acute and Subchronic Studies with Silicone Fluids and Gels Early toxicological experiments were designed to evaluate the effects of silicone liquids and solids implanted under the skin of experimental animals. Such experiments mimic silicone breast implants in many ways, although there are some important differences. Silicone breast implants are more complex. They may have varied surfaces, including coating with polyurethane. They may also contain many different chemical species, including potentially toxic compounds such as platinum. On the other hand, in many of these studies, actual gel and elastomer components of breast implants were tested. In one early study, medical series 360 Dow Corning PDMS fluid, 350 cS, was injected in massive (up to 540 ml over 27 weeks) doses subcutaneously in rats and guinea pigs. There was very little or no local inflammation. The injected fluid became encapsulated by thin, transparent connective tissue in multiloculated cysts. No systemic toxicity was observed. However, it was not clear whether the material was eventually absorbed, redistributed within the body of the animals, or excreted (Ballantyne et al., 1965). To further elucidate this point, mice were injected subcutaneously or intraperitoneally with 1 ml of Dow Corning 360 silicone fluid, 350 cS, followed by intravenous carbon particles to induce reticuloendothelial blockade. Silicone was found in macrophages in regional lymph nodes in all animals and in macrophages in the adrenal in some intraperitoneally injected animals. Unlike the previous high-dose experiment, all other organs were normal (Ben-Hur et al., 1967). A high-dose exposure in man, multiple massive subcutaneous injections of silicone (1 liter at a time), eventually led to diffuse tissue distribution of the material in various organs (primarily the lungs) of this patient who succumbed to adult respiratory distress syndrome (Coulaud et al., 1983). In mice as in rats, subcutaneous injection of 5 ml of Dow Coming 360 medical fluids did not produce any untoward effects (Andrews, 1966). The same author reported the case of an 18-year-old woman injected subcutaneously twice with 20 ml of 360 fluid. In examining a blood smear, neutrophils and mononuclear cells containing clear vacuoles were seen,
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Page 90 which presumably contained silicone. The smear, however, was taken from an incised injection site where leukocytes had direct access to a silicone deposit, and this finding could not be confirmed by Hawthorne et al. (1970), who examined white cells from rats with high silicone exposures (see below). Nedelman (1968) injected various room temperature vulcanized (RTV) medical-grade Silastics mixed with Dow Corning 360 fluid and stannous octoate catalyst subcutaneously in the back of hamsters and supraperiostally in the jaw and palate of rabbits in doses of 0.5-2.0 ml and followed them for one week to three months. He reported that the Silastic was well tolerated and elicited only a mild connective tissue response. In another study in mice, Rees et al. (1967) observed a redistribution of silicone fluid within the body when injected in 1-ml amounts intraperitoneally or in larger amounts subcutaneously (6 ml in a single dose, 1 ml in repeated doses). Deaths occurred when the mice received more than 7 ml of PDMS by subcutaneous injection, an amount corresponding to about 280 ml/kg or about 14 liters in an average woman. Macrophages, presumably containing silicone, accumulated in multiple organs, including adrenal, lymph nodes, liver, kidney, spleen, ovaries, pancreas, and others (Rees et al., 1967). Whether the wider distribution of silicone injected at high doses results from access to, and distribution by, the circulatory system is unknown. The study by Rees et al. prompted Autian (1975a) to warn against the injection of silicone fluid in humans. He was also influenced by the local complications of silicone injection in women, which were well known by that time. Ashley et al. (1971) briefly reported injecting Dow Coming MDX 40411 in amounts ranging from 1 to 500 ml into mice, rats, guinea pigs, rabbits, and monkeys, with the formation of thin capsules, very little tissue reaction, and no systemic effects. This 350-cS fluid was also injected in small (4 ml) amounts into patients for cosmetic effect without complications. Very few data were reported, and the follow-up of the patients was three months on average (Ashley et al., 1971). Cutler et al. (1974) observed no ill effects on mice of PDMS fluid similar to Antifoam A mixed with 6% amorphous silica injected subcutaneously (0.2 ml) or fed at 0.25 and 2.5% from weaning for 76 weeks. Distribution to liver, spleen, kidneys, and perirenal fat was not detected. In a more recent study, Dow Corning silicone 360 fluid and gel (1 ml per mouse), and elastomer and polyurethane (0.6-cm-diameter disks) were placed subcutaneously in B6C3 F1 mice (Bradley et al., 1994a,b). Animals were examined first over a 10-day period, then for 180 days. Silicone implantation did not affect any of the selected toxicological end-points, including survival, weight gain, body and organ weights, hematology, serum chemistry, and bone marrow cytology. No effects on hu-
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Page 103 weaning and terminated 76 weeks later. In the same study, some animals received a single subcutaneous injection of 0.2 ml silicone or 0.2 ml paraffin. All visibly altered tissues as well as lung, heart, stomach, small intestine, spleen. liver, and kidney from about ten male and female mice in each treatment group were examined microscopically. No treatment-related increase in nonneoplastic or neoplastic lesions was found. Cysts and some fibromas were observed at the injection site in mice injected with silicone oil or paraffin, the latter producing fibromas more frequently than the former. Although carcinogenesis was not observed at the dose levels examined, this study performed in 1974 would not fulfill today's criteria for a carcinogenesis bioassay. The study was terminated early, histopathology was incomplete, and no indication was given of how close the higher dose used was to a maximum tolerated dose. Although the studies of polydimethylsilicone reviewed so far offer little evidence of toxicity, this is not true for all silicone compounds. A series of papers, published in the early 1970s, provides experimental evidence that certain organosiloxanes have estrogenic activity. Several agents were evaluated. The most active of them was cis-2,6-diphenylhexamethyl-cyclotetrasiloxane. This and similar chemicals caused an array of effects in the reproductive systems of male animals and on reproduction in female animals (Bennett et al., 1972; Hayden and Barlow, 1972; Hobbs et al., 1972; LeFevre et al., 1972; LeVier and Boley, 1975; LeVier and Jankowiak, 1975; LeVier et al., 1975; Nicander, 1975). Some human data are available from patients with prostate cancer. The biological half-life varied between 14 and 23 hours (Pilbrandt and Strindberg, 1975). As noted earlier in this chapter, women with breast implants and some recent investigators have expressed an interest in these compounds. However, the toxic effects of these compounds have not been observed in experimental silicone gel implant toxicological studies, and there is no evidence that they are present in silicone breast implants. Inhalation Exposure Because silicone compounds are present in hairspray and shampoo, adverse health effects following inhalation of these compounds have been explored. The toxicity of aerosolized D4 was evaluated, first in a dose-setting study of four weeks' duration, then in a three-month study (Kolesar, 1995a,b). Exposures were six hours a day, five days a week at concentrations of D4 ranging from 200 to 1,333 ppm (2.4-15.8 g/m3, grams per cubic meter) eventually reduced in the three-month study to 12 g/m3 (1,000 ppm). The animals were observed for clinical signs of toxicity, and food consumption was monitored. A few animals died during the first week when exposed to 15 g/m3, necessitating reduction of the dose to 12
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Page 104 g/m3. No treatment-related clinical signs were observed at the lower dose levels, but changes in hematology and clinical chemistry were seen. Enlargement of the liver and its cells was dose dependent and more pronounced in females. Changes in the respiratory tract were interpreted as adaptive responses to mild irritation. In females exposed to the highest concentration (12 g/m3), minimal to marked vaginal mucification accompanied by moderate degrees of ovarian atrophy was noted. A separate group of animals was allowed to recover in air for one month following the exposure. Practically all of the abnormalities eventually disappeared, indicating reversibility of the effects of exposure. These exposures are considered quite high. In a later study, Fischer 344 rats were exposed to D4 at concentrations ranging from 7 to 540 ppm (80 mg to 6.4 g/m3) for six hours a day, 5 days a week, for 28 days (Klykken et al., 1997). In addition to the usual end-points measured, immune function was assessed by splenic antibody-forming assay and enzyme-linked immunosorbent assay (ELISA). The only change noted was liver enlargement, which was reversible after a two-week recovery period in male rats exposed to 540 ppm and females exposed to 20-540 ppm (0.24 to 6.4 g/m3). No immune system changes were observed. This protocol was repeated with D5, except that exposures ranged from 0.4 to 3.5 g/m3 (expressed as milligrams per liter in the original, 27-240 ppm) (Kolesar, 1995c,d). At one month, all animals survived and gained weight normally. Upon termination of the study, only slight interstitial inflammation in the lung and some liver cell enlargement were noted in the highest-dose group. In the three-month study, reduced weight gain was observed in the highest-dose group. Hematology, clinical chemistry, and urinalysis were unremarkable. Histopathological changes were observed in the lungs of animals exposed to the higher concentrations of D5, both those killed immediately after exposure and those allowed to recover for an additional month in air. More frequent interstitial ovarian and vaginal lesions were also seen in the highest-dose group. Exposures used in all these studies were quite high, perhaps unrealistically so. The effects of inhaled D4 and D5 were also evaluated in reproductive toxicity tests. Male and female rats were exposed to D4 concentrations ranging from 70 to 700 ppm (0.83-8.3 g/m3) for six hours a day for a minimum of 28 days or for 70 days prior to mating. Exposure continued throughout the gestation and lactation periods (except on day 21 of gestation and days 1-4 of lactation). Offspring were further exposed following weaning on day 21 until day 28. They were thus potentially exposed to the test agent while in utero, throughout suckling, via inhalation or der-mal contact during lactation, and via inhalation after weaning. Maternal
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Page 105 toxicity consisting of slight reduction in body weight gain and hepatomegaly at autopsy was observed at dose levels of 300, 500, and 700 ppm (3.5, 5.9, and 8.3 g/m3). In the highest-dose group, there was a consistent and reproducible reduction in fetal implantation sites and a decrease in mean live litter size. In the offspring, no exposure-related signs of toxicity were observed (Stump, 1996a). No effect on litter size or pup viability and no signs of maternal toxicity were found in a study with D5, when maternal animals were exposed to concentrations of 26 and 132 ppm (0.38-1.9 g/ m3) (Stump, 1996b). Decamethylcyclopentasiloxane (D5) was also evaluated in a different laboratory (Lambing, 1996). Exposures were six hours a day, seven days a week, for a total of 28 exposures, with exposure concentrations ranging from 10 to 160 ppm (0.15-2.4 g/m3). A two-week recovery period was included in the experimental design. There were no test-related effects on survival, clinical condition, body weight gain, food consumption, clinical chemistry, and urinalysis at any exposure level. There were no adverse effects on immunoglobulin M (IgM) antibody response to a T-dependent antigen (sheep red blood cells). Changes noted were a 5% decrease in hematocrit, enlargement of the liver, and increased lung weight, all reversible upon cessation of exposure. Microscopically, increased alveolar macrophage accumulation and some interstitial inflammation in the lungs were observed. Goblet-cell hyperplasia was found in the nasal passages, which was thought to be reversible. If the histopathological changes confined to level one in the nasal passages are taken into account, the no-observed-effect-level (NOEL) would be less than 10 ppm. A NOAEL for systemic toxicity (liver weight increase) was identified at 75 ppm (1.1 g/ m3) and for immunosuppression at 160 ppm (Lambing, 1996). Presumably because some systemic effects such as liver enlargement were observed during inhalation of D4, a series of pharmacokinetic studies has been initiated. Rats were exposed by nose-only inhalation technique to D4 labeled with 14C. Concentrations used ranged from 7.5 to 716 ppm (90 mg to 8.5 g/m3). The animals were killed immediately after exposure and at selected intervals thereafter up to 168 hours. The animals retained approximately 5.5% of the total radioactivity delivered. Radioactivity was found in all tissues and reached maximum levels between zero and three hours after exposures, except in fat, which seemed to serve as a depot for radioactivity. Half-times of retention for combined radioactivity ranged from 68 hours in plasma to 273 hours in various tissues. Radioactivity was mostly excreted by breathing and excretion was most rapid within the first 12 hours. An initial rapid decline followed by a longer terminal elimination phase was also observed in a study where rats were exposed for 14 days, first to unlabeled, and for 1 day to labeled, D4 vapor
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Page 106 (Ferdinandi and Beattie, 1996a,b, 1997). Exposures in these inhalation studies reached very high levels. Studies have been performed to examine the implications of liver enlargement (McKim, 1995, 1996a,b). Male and female rats were exposed for four weeks to D4 at airborne concentrations of 70 and 700 ppm. Animals were killed from 3 to 28 days after exposure and after 7 and 14 days of recovery. In females, liver size increased early during exposure. At the end of the study, liver weights were approximately 110% of controls in females and 117% in males. However, following cessation of exposure, there was a rapid decrease in liver weight. Some liver enzymes and proteins were increased. It was concluded that D4 acted like a ''phenobar-bital-type" inducer in rat liver. Essentially similar observations were made in studies with inhaled and oral Ds (McKim, 1997). A metabolic study in rats showed that 75 to 80% of intravenously administerd 14C labeled D4 appeared in urine as dimethylsilicone diol, methylsiliconetriol and five other minor metabolites within 72 hours (Varaprath et al., 1997). Because D4 is found in personal care products such as hairsprays, shampoos, and deodorants and, together with D5, has been found in indoor atmospheres, a potentially large number of people are exposed daily (Shields et al., 1996). Very small amounts of these compounds are found in breast implants (see Chapter 3), constituting exposures substantially lower than those possible from other, ubiquitous sources. Recent studies have examined the effects of inhaled D4 on humans. At a concentration of 10 ppm, a one-hour inhalation did not alter human lung function. Deposition of D4 was calculated to be around 12%. Measurement of plasma concentrations showed a rapid nonlinear blood clearance. Immune function was evaluated by several parameters, such as measurement of serum acute-phase reactants, interleukin-6 (IL-6) levels, establishment of lymphocyte subsets, blast transformation in isolated peripheral mononuclear cells, natural killer (NK) cell cytotoxicity, and in vitro production of cytokines. No signs of an immunotoxic or systemic inflammatory response were found (Looney et al., 1998; Utell et al., 1998). The authors pointed out that their studies did not preclude possible immunological effects with exposures of longer durations or at higher concentrations. Since the route of exposure was via inhalation, the negative findings should not be relied on when assessing the immunological effects of implanted silicones in humans. Nevertheless, the low order of toxicity observed when D4 is absorbed and distributed systemically after administration by inhalation or oral routes, tends to support the observations of lack of D4 toxicology after systemic exposure by implant or injection. The committee did not find data that would allow comparisons between possible systemic exposure to D4 from common consumer prod-
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Page 107 ucts to large numbers of the general pupulation and estimated exposures from silicone gel-filled breast implants. In Vitro Assays Few in vitro studies on silicone materials have been published in the open literature. The LC50 of D4, decamethyltetrasiloxane (L4), and tetra-methyltetravinylcyclotetrasiloxane (D'4) on B-cell lymphoma, plasmacytoma, and macrophage cell lines ranged from 30 to 50 micromolar (8.6-14.4 mg/l, D4). At lower concentrations, there were biochemical signs of cytotoxicity. Exposed macrophages produced more IL-6 than did untreated cells (Felix et al., 1998). On the other hand, WI-38 human fibroblast, mouse fibroblast, and Chinese hamster ovary cells, when grown in contact with silicone gel used in breast implants, were not adversely affected, even when exposed up to 12 days. Flow cytometry, a sensitive analytical technique, did not reveal any changes in cell-cycle characteristics (Cocke et al., 1987). Results from in vitro mutagenicity assays are not conclusively negative, although they are suggestively so. Poly-sec-butylsilicate ester (Silicate Cluster 102, Olin Corp.) and PDMS (SF-96, G.E. Corp.) were negative in the Ames test (TA-1535, TA-100, TA-1538, and TA-98), with and without metabolic activation (Marshall et al., 1981). In 1988, it was reported that 12 silicone compounds all tested negative for genotoxicity in salmonella (Ames test), Saccharomyces cerevisiae, and Escherichia coli test systems. Hexamethyldisiloxane (L2) and D4 at one dose and several other compounds, among them methyltriethoxysiloxane, produced sister chromatid exchange, although often no dose-response relationship was found, and the results were considered inconsistent. Chromosome aberrations Were also found with some of the compounds (Isquith et al., 1988). In an evaluation of the mutagenicity of Dow Corning 7-9172 Part A (used to make gel) with several tester strains, with and without metabolic activation systems, no positive responses were found (Isquith, 1992). Six siloxanes were recently examined for mutagenic activity in rat fibroblasts (Felix et al., 1998). Only one compound, tetravinyltetramethylcyclotetrasiloxane was found to give a weak positive response. The study was prompted by the observation that silicones could produce plasmacytomas in highly sensitive mouse strains. Since only one compound was found to be mutagenic, it was concluded that possible nonmutagenic mechanisms might also be responsible for plasmacytoma development. Platinum The potential toxicity of several platinum compounds has received
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Page 108 some attention because they have been used as catalysts in the manufacture of silicone gels and solids. Platinum is present in small amounts in implants (see Chapter 3, in which the amount of platinum and the question of its form are discussed). Reports that this platinum is in the form of platinate (Lykissa et al., 1997) are unconfirmed (Lewis and Lewis, 1989; Lewis et al., 1997). Inhalation of platinum compounds is recognized as a problem in the smelting and refining industry. Platinum can produce chemical pneumonitis (Furst and Rading, 1998). Inhalation of complex salts of platinum, but not elemental platinum, can cause progressive allergic and asthmatic reactions. Skin contact with platinum, particularly its chlorides, which are powerful skin sensitizers, can cause contact dermatitis (American Conference of Governmental Industrial Hygienists, 1998). Cisplatin, an agent used in cancer chemotherapy, is highly toxic to the gastrointestinal tract, kidney, bone marrow, and peripheral nervous system. This compound does not occur in silicone breast implants, however. Early toxicity tests, conducted on a minimum number of animals, showed little if any signs of toxicity for two platinum compounds, Dow Corning Platinum Nos. 1 and 2 (Groh, 1973). Acute oral toxicity was greater than 6.8 g/kg, and upon instillation of the liquids into the eyes of rabbits, only a slight and transient irritation was noted. Moderate to marked skin alterations were seen after repeated application of the undiluted substances. Edema and hyperemia were mentioned, but without any quantitative scores. Studies with Dow Corning X-2-7018 gave essentially similar results (Groh, 1972). The platinum catalysts, when compounded into an elastomer, were nontoxic to human embryonic lung cells in tissue culture. However, in liquid form, the catalysts were toxic, although this effect was abolished for Platinum No. 2 by heating. This seems to indicate that compounding might eliminate toxicity by inactivating reactive sites (Jackson, 1972). The oral toxicity of TX-82-4020-02 (H2PtCl6 reacted with tetramethyldivinyldisiloxane and then diluted with Dow Corning SFD-119 fluid) was greater than 20 g/kg, and no signs of toxicity were observed during a two-week observation period or upon autopsy of rats (de Vries and Siddiqui, 1982). BALB/c female mice received injections of ammonium hexachloroplatinate in the left footpad. Comparison of the weight of left popliteal lymph nodes with nodes collected from the right hind leg showed that five, six, and seven days later, the weight of the lymph nodes was increased. This was taken as evidence that platinum in its multi-valent state has immunogenic potential (Galbraith et al., 1993). The skin sensitizing potential of Platinum Nos. 2 and 4 was recently examined in a study with guinea pigs (Findlay and Krueger, 1996a,b). On day 1 of the test, the guinea pigs received six intradermal injections of Dow Corning 2-0707 Intermediate (Platinum No. 4) or Dow Corning 3-8015 (Platinum No. 2)
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Page 109 intradermally into the skin of the back over the shoulder region. Negative (phosphate-buffered saline) and positive (1-chloro-2,4-nitrobenzene) controls were similarly injected. On days 7 and 8, the same agents were reapplied, this time topically and under occlusion. A first challenge was applied on day 22 and a second challenge on day 29; 24 and 48 hours after the challenge doses, the skin was examined and scored for signs of irritation with a quantitative procedure (Draize scale). For this experiment, both agents were found to be moderate skin sensitizers in guinea pigs although previous studies were said to be inconsistent with this result (Lane et al., 1998). Available data provide little evidence that the platinum catalysts would have a particular systemic toxicity. They may have sensitizing potential, but it is not clear whether this is a function of the platinum itself or of the entire molecule. Harbut and Churchill (1999) reported a small case series of eight women with the onset of asthma at varying intervals after placement of silicone breast implants. These authors speculated that the respiratory signs and symptoms were the result of exposure to hexachloroplatinate in their implants. No evidence for this was reported. Conclusions regarding platinum toxicity in women with breast implants should await evaluations that positively relate platinum to the symptomatology; these might include some or all of elevated serum platinum levels, positive skin prick tests for platinate, positive radioallergosorbent (RAST) or other tests for platinum-specific antibodies, remission of allergic symptoms or reduction of serum platinum levels or skin prick or other allergic tests on ex-plantation in women with no other known exposures to platinum (Biagini et al., 1985; Rosner and Merget, 1990). Absent these tests, diagnoses of platinum toxicity in women with implants are speculative only. Since allergies and asthma are extremely common in the general population, they should be common in women with breast implants, yet epidemiological studies do not report this. These complaints are not prominent in lists of problems with breast implant patients (see Appendix B of this report), and one cohort study of 222 women with breast implants and 80 control women without implants found breathing difficulties to be significantly less frequent (p < 0.05) in the women with silicone breast implants (K.E. Wells et al., 1994). It should also be kept in mind that platinum exposure from vehicle exhaust catalysts is increasing and is reflected in serum levels but not in any known health condition (Farago et al., 1998). The committee could not find any such positive platinum-specific evaluations in women with breast implants and thus finds that evidence is lacking for an association between platinum in silicone breast implants and local or systemic health effects in women who have these implants. If the platinum in breast implants is in zero valence form in the final cured state in excess vinyl as reported by Stein et al. (1999), and if it is in micro-
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Page 110 gram quantities as is usually added to gel (Lane et al., 1998), as the current evidence suggests, then a biologically plausible rationale for platinum related health problems in women with silicone breast implants does not presently exist. Many silicone-containing implants other than breast implants (listed in Chapter 2) are found at high frequency in the general population and presumably contain platinum also; the committee is not aware of any evidence that platinum toxicity is present in these persons. Tin The committee reviewed information bearing on the possible effect of tin on the safety of silicone breast implants. Stannous octoate, stannous oleate or dibutyltin dilaurate catalysts are generally involved in formulation of only part of an implant, e.g., the adhesive sealant in the case of Dow Corning and McGhan Medical or the RTV elastomer shells of saline implants in the case of Mentor and McGhan Medical Corporations. HTV gel-filled shells are platinum catalyzed (B. Purkait, personal communication, Mentor Corporation, May 1999; Eschbach and Schulz, 1994). Tin has been added at low concentrations (e.g., 0.038% stannous oleate to formulate adhesives [about 1.4 µg of tin per Dow Corning implant] or targeted at 70-80 parts per million tin from dibutyltin dilaurate in the case of Mentor saline implant shells and about the same in the case of McGhan shells). Tin has been analyzed at non detectable to 0.73 ppm in saline or dichloromethane extracts of Dow Corning implant silicone gel (J. M. Curtis, Dow Corning, personal communication, May 11, 1999, Lane et al., 1998) or non detectable by inductively coupled plasma atomic emission spectroscopy and cold vapor atomic absorption spectroscopy in saline, ethanol, methylene chloride or hexane extracts in the case of Mentor implant shells (B. Purkait, Mentor Corporation, personal communication, May 1999), or measured within a range of 15 to 100 parts per million in saline shells and non detectable in saline extracts of shell elastomer by inductively coupled plasma atomic emission spectroscopy (R. Duhamel, McGhan Medical Corporation, personal communication, 1999). Normal tissue concentrations of tin can be higher than the levels in implants (0.25-130 ppm, Clayton and Clayton, 1994). Total tin in an average implant1, 1 This depends on saline shell weights which are quite variable, ranging it is said, from a lower limit of 5 g (B. Purhait, Mentor Corporation, personal communication, 1999) to 10 to 30 g (J.M. Curtis, Dow Corning Corporation, personal communication, 1999) to a maximum upper limit as high as 100 g (with a lower average value; R. Duhamel, McGhan Medical Corporation, personal communication, 1999). Also, these weights are dependent on implant model and whether the shell is smooth or textured.
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Page 111 therefore, could vary from 1 or 2 µg to 10 mg as an upper limit in Dow Corning, Mentor or McGhan implants. The toxicology of inorganic and organic tin was reviewed extensively for the U.S. Public Health Service (Agency for Toxic Substances and Disease Registry, 1992) and a few studies of particular tin soap catalysts are available from industry. Human data for organotins are sparse to nonexistent as are experimental animal data on parenteral exposures. The human permissible industrial exposure limit for organotin of 0.1 mg/m3 calculates to a maximum exposure of 14.3 mg/kg per day (American Council of Governmental Industrial Hygienists, 1998). In general, animal data indicate oral toxic levels at more than 10 mg (for the most toxic), although absorption of oral doses is poor, and on inhalation no observable adverse effect levels (NOAELs) over 1 mg/m3. RTV elastomer with stannous octoate was implanted under the skin, intraperitoneally and subdurally in rats. Although no toxic or carcinogenic effects were observed over 22 months, this early study was not designed to examine tin toxicity (Agnew et al., 1962). Other similar implant studies of stannous octoate catalyzed elastomers were also negative but were not designed to evaluate tin (Nedelman, 1968). Likewise, Dow Corning elastomers with 1, 3 and 5% stannous octoate were implanted subcutaneously and intramuscularly in rabbits for 10 or 30 days, and no clear dose response was observed, only the usual foreign body reaction. In another Dow Corning study, the oral LD50 was 3.4g/kg (R. Meeks, Dow Corning, personal communication, 1999). Studies of dibutyltin dilaurate found LD50 levels ranging from 85 mg/kg intraperitoneally to between 175 and 1240 mg/kg body weight orally. In general, these substances were not carcinogenic (Agency for Toxic Substances and Disease Registry, 1992; American Conference of Governmental Industrial Hygienists, 1998; Clayton and Clayton, 1994; Hazardous Substances Data Bank; Mellon Institute of Industrial Research, 1994; National Cancer Institute). These data suggest that toxic effects of even the most toxic (triorganotinswhich have not been found in breast implants) tin compounds are seen at doses above those possible from breast implants even in the most unlikely event of complete release of all the tin into the breast. Moreover, the tin in breast implants appears to be of relatively low toxicity among organic tin compounds, and given the difficulty in extracting it, as noted above, and the durability of silicone elastomer, as noted elsewhere in this report, unlikely to be significantly available to surrounding tissues. The committee concluded that there is currently no evidence for toxic effects of retained tin catalysts at the very low exposures likely from silicone breast implants.
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Page 112 Conclusions Historically, silicone toxicology has tended to focus on short-term, acute and subacute studies and has suffered from a proportionate dearth of chronic, lifetime, and immunologic studies, as noted earlier in this chapter. Presumably, this reflects early conclusions that silicones were inert. Some silicones have clear biological effects. None can be said to be inert, if this implies an absence of tissue reaction, but the term has perhaps been a used as a proxy to indicate that the toxicity of many silicones is of such low order that they comprise a useful class of biomaterials for medical implants. Older silicone toxicology studies have deficiencies by current standards, but the body of toxicological information is substantial and improving. More chronic studies are being done, although modem regulatory requirements will undoubtedly generate a closer identification of silicones (and other substances) in implants and more specific toxicological studies of appropriate duration. Nevertheless, no significant toxicity has been uncovered by studies of individual compounds found in breast implants. Toxicology studies have examined carcinogenic, reproductive, mutagenic, teratologic, immunotoxic, and local and general toxic and organ effects by exposure routes that are varied and range to very high dose levels. Even challenges by doses that are many orders of magnitude higher than could be achieved on a relative-weight basis in women with silicone breast implants are reassuring. Toxic effects that have been found occur at very high, even extreme, exposure levels (e.g., D4, D5). The fact that some organic silicon compounds may have, as one would expect with any large family of chemical compounds, biologic or toxicologic effects is not relevant to women with breast implants since these compounds are not found in breast implants, as noted here and in Chapter 2. Studies using whole fluids, gels, elastomers, or experimental implant models injected or implanted in ways that are directly relevant to the human experience with implants are also reassuring. These studies show that depots of gel, whether free or in implants, remain almost entirely where injected or implanted. Even low molecular weight cyclic and linear silicone fluids appear to have low mobility. Half-lives of low molecular weight silicones in body fluids and tissues have been measured infrequently, but known values appear to be on the order of 1 to 10 days. In general, there do not appear to be long-term systemic toxic effects from silicone gel implants or from unsuspected compounds in these gels or elastomers detected by these animal experiments. Some have speculated that platinum found in silicone gel and elastomer may be responsible for allergic disease in women with silicone breast implants. Very little platinum, microgram quantities, is present in
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Page 113 implants, most investigators believe it to be in the zero valence state, and it likely diffuses through the shell at least over a considerable period of time. Evidence for resulting systemic disease at such exposures is lacking. Toxicological studies of tin compounds used in silicone breast implants are scarce, and generally not of parenterally administered tin. The data on organotins indicate that tin catalysts are among the less toxic, and they have not been extractable from implants shells by saline and some organic solvents. Based on the data available, the committee concluded that evidence is also lacking for tin toxicity at the very low amounts present in saline implants and at the virtually absent levels in gel filled implants.
Representative terms from entire chapter: