Journal of Nutritional & Environmental Medicine; Abingdon; Mar 1998;
Arthur Dale Ericsson;
Silicone breast implants have been associated with a variety of medical conditions. This article is the first in an analysis of the data that have been accumulated in over 500 patients with medical conditions that appear coincident with implantation with several different silicone breast prosthetic devices.
Silicone breast implants have been associated with a variety of medical conditions. This article is the first in an analysis of the data that have been accumulated in over 500 patients with medical conditions that appear coincident with implantation with several different silicone breast prosthetic devices. The vast majority, over 87% of symptomatic patients, appear to have a neuropathy (demyelinating and axonal diagnosis made on nerve and muscle biopsy and ELISA analysis), while approximately 22-25% of symptomatic patients have evidence of autoimmune thyroid disease. A small percentage of patients (10-12%) have evidence of central demyelination (brain and spinal cord-diagnosis made by magnetic resonance imaging and ELISA testing). Silicone breast implant adjuvant syndrome is proposed as a diagnosis for these symptomatic patients. The significance of these findings is discussed in considerable detail and extensive references are offered for the reader. Keywords: silicone, silica, polyurethane, silicone breast implants, chronic inflammatory demyelinating polyneuropathy, fibromyalgia, Hashimoto's thyroiditis, multiple sclerosis-central demyelination, autoantibodies, polymyositis, dermatomyositis, lupus erythematosis, rheumatoid arthritis, scleroderma.
Silicone breast implants have been associated with a number of local complications as well as a diffuse systemic inflammatory disease. It has been suggested that the systemic syndrome should be called `adjuvant breast disease'  although the name 'silicone breast implant adjuvant syndrome' is more precise and appropriate and will be used throughout this article. The silicone gel used in the silicone implants for the purpose of mammary prosthesis has been found to be an adjuvant to the immune system in experimental animals. After an overview of the chemistry of the various types of silicone breast implant, this article will present the clinical and laboratory features of 138 patients with the uniquely neuroimmunological 'silicone breast implant adjuvant syndrome'.
CHEMISTRY AND TYPES OF BREAST IMPLANT
Silicon is the basic element of all silicones which represent a family of synthetic polymers that all have a 'backbone' of repeated Si-O units. Silicon has the same electronic configuration as the carbon atom which presents four binding sites . Silicones vary in their composition and this is dependent upon the length of the polymers as well as the organic grouping in the side chains. The longer the side chain and the more cross-links (usually vinyl groups) between the side chain groups the more solid is the resulting silicone. Therefore, silicone can have the consistency of fluid, oil, gel or rubber . Polydimethylsiloxane is the pre-eminent medical grade silicone polymer used for mammary prosthetic devices [4, 5]. To make this compound,quartz is purified to silica (silicon dioxide: SiO2), which is then reduced to silicon, reacted with methylene chloride and hydrated to form a polydimethylsiloxane:
Since the polymer itself is never thick enough for the envelope, silica (SiO2), itself is added to the polymer to make up 30% of the envelope . Moreover, platinum is used as the catalyst for the manufacturing process of silicone breast implants and this elemental metal is bound and remains behind in the prosthesis. On the other hand, the gel inside the silicone-gel implant can contain anywhere between 50 and 95% of the silicone fluids, which are low molecular weight silicones [7, 8]. Since the silicone envelope is a semi-permeable membrane, every commercially available silicone breast implant leaks and this phenomenon is called `gel bleeding' of the low molecular weight silicones in the case of silicone-gelfilled breast implants. Incidentally, since the capsule of a breast implant is a semi-permeable membrane, the lighter molecular weight saline of the saline-filled implants is particularly susceptible to inducing body fluids to leak into, rather than out of, the silicone-saline breast implant .
CLINICAL HISTORY OF SILICONE BREAST IMPLANTS
In 1962, Dr Thomas Cronin and Dr Frank Gerow, two plastic surgeons from Houston, Texas, were the first physicians to insert a silicone-gel breast implant in a patient . Although breast implants have been on the market since the mid-1960s, most silicone breast prostheses were implanted in the 1980s and it is now estimated that between 304 000 and 815 700 women have received breast implants in the US [10, 11]. While approximately 20% of those implanted were for reconstruction of the breast(s) after mastectomy for either fibrocystic disease or cancer, approximately 80% have been implanted for cosmetic breast enlargement in otherwise healthy women.Until 1991, there were four types of implant available in the US .
(1) The silicone-gel-filled silicone elastomer envelope breast implant (the implant most commonly used and the one placed in the Federal Drug Administration (FDA) moratorium on 4 January 1992) [13-15].
(2) The saline-filled silicone elastomer envelope breast implant.
(3) The double lumen breast implant with silicone gel in the inner elastomer envelope and saline in the outer elastomer envelope.
(4) The silicone-gel-filled (with or without the silicone elastomer envelope) breast implant coated with polyurethane and withdrawn from the market by the manufacturer on 10 April 1991 . Polyurethanes Polyurethanes are polymers that contain the urethane linkage:
The urethane linkage is formed from isocyanates and alcohols without the inclusion of any volatile by-product. The remainder of the polymer may contain a variety of other functional groups such as polyether, polyesters, ureas, epoxies, silicones, aromatic or aliphatic hydrocarbon groups and polyolefins .
Biological Potentials of Silicone, Silica and Polyurethane
It has become clear from the experimental evidence that silicone is neither biologically nor chemically inert. It has been demonstrated that silicone as well as silica is cytotoxic [4, 14, 18] and that they are active immunostimulatory agents when given in vivo [8, 13, 19-32]. Furthermore, they are efficiently taken up by macrophages from the implant surface and react with the membranes surrounding the implant containing secondary lysosomes.Lytic enzymes are released into the cytoplasm, causing death of the macrophage and damage to the surrounding tissue environment. Moreover, silicone has been found phagocytized in macrophages and lymphocytes in tissue and in monocytes and polymorphonuclear leukocytes in peripheral blood of implanted patients [33-35].
It has been demonstrated experimentally by Pfleiderer et al.  that implanted silicone in rats will degrade and migrate to the liver, spleen and pericapsular tissue and, furthermore, that silicone is not biologically inert. In fact, silicone biodegradation in tissue may be monitored within 9-12 months following experimental implantation in animals. These changes were observed by (Si, C and H) magnetic resonance spectroscopy and confirmed by atomic absorption spectroscopy. The implication of this research is that with time (12 months) the chemical composition of the silicone gel changes and there appears to be a rupture of the polymer chain which increases the molecular mobility of the silicone polymer. Moreover, the degradation provides valuable information about the metabolic intermediate products of silicone which include substitution of the methyl and vinyl groups of the silicone-gel backbone by hydroxyl groups which leads to hydrolyzed silica and silica. In this model, silicone has been shown to migrate from the implants to adjacent tissues as well as to remote sites.
In addition to the cytotoxic effects, both silicone and silica elicit a cellular immune and a humoral response, acting as hapten-like incomplete antigens. Thus, antigen trapping by macrophages has been demonstrated by investigators who have identified silicone in the antigen-processing rough endoplasmic reticulum of the macrophages . In 1993, Heggers et aL  identified silicon at both ends of plasma bridges from macrophages to lymphocytes with silicone deposits in up to 30% of the Golgi apparatus, endoplasmic reticulum and exocytic vesicles.
Anti-silicone antibodies in symptomatic patients with silicone breast implants have been measured [33, 34]. Moreover, Goldblum et al.  demonstrated specific antibody production to elastomers of polydimethylsiloxane in two children with ventriculo-peritoneal shunts. Furthermore, in two animal studies by Nain et al.  and Black , Dow Coming inbred rats were injected with a homogenized gel form of silicone in the presence of bovine serum albumin (BSA). In this model, it was demonstrated that the silicone gel has a similar adjuvant activity compared to that of complete Freund's adjuvant in amplifying the anti-BSA antibody response. These studies, therefore, have demonstrated that silicone acts as an adjuvant, enhancing the ability of the immune system to produce antibodies to a foreign antigen.
In 1975 an experiment was conducted at Dow Coming on D4 (cyclotetradimethylsiloxane), a low molecular weight silicone compound used in breast implants, and it was found that there was a significant gel bleed through the elastomer envelope. Furthermore, this study demonstrated that D4 had both a very strong immunostimulatory and cytotoxic action.
Biochemically, the interaction of native macromolecules with silicone leads to conformational changes and denaturation [33, 37] and the denatured macromolecules may then present as an antigenic target to the immune system. Kossovsky et al.  found that antibodies were present against macromolecules, in particular fibronectin and laminin, which were denaturated by silicone in patients with silicone breast implants. The denatured macromolecules, moreover, present as an antigenic target to the immune system. A cross-reaction of antibodies to still intact macromolecules may then explain the subsequent often-delayed autoimmune response.
Many of the complexes of silicone, including pentamethylsiloxane, hexamethyldisiloxane,decamethyltetrasiloxane,pentamethylvinylsiloxane,tetravinyltetramethylsiloxane, trivinylmethyltrisiloxane,heptamethylvinyltrisiloxane and octapentamethyltrisiloxane, have been studied extensively for their ability to evoke a cytotoxic reaction. Many of these siloxane derivatives readily produce lethal effects on cells in very low concentrations of the 25-80 uM range. Furthermore, it has been demonstrated that each may penetrate the plasma membrane at a sublethal concentration in the 15 MM range or less. Once the cellular membranes have been bridged by these molecules, the various cellular interactions and degradation reactions of these cells are possible. Macrophages have demonstrated that three primary cellular reactions to silicone may take place. These are as follows [22, 23,38, 39].
(1) Hydrolysis: the polar siloxane bond is subject to hydrolysis by the addition of water molecules under a variety of conditions. In the conditions of the human body temperature, hydrolysis occurs in S8 years (37oC) and at this temperature approximately half of the surface silonals are converted by the addition of water.
(2) Oxidation: in the presence of water the alkyl group on siloxane is subject to hydrogen abstraction and this process has been shown to occur in the macrophage when exposed to siloxane.
(3) Conjugation: conjugates are formed by vinyl siloxanes in the presence of other silicone gels, in vitro and in vivo. By a process of silicone degradation, new species of silicone(s) may be introduced into the body and, thus, cause a variety of tissue reactions. The capsule of the periprosthetic tissue is organized and it is usually a multi-layered tissue in which the inner surface is composed of an amorphous proteinaceous material with an adjacent layer of vacuolated palisading pseudo-synovium containing a variable number of inflammatory cells, including lymphocytes, plasma cells and macrophages. On the other hand collagen and fibroblasts comprise the outermost surface of the capsular membrane. Later, multi-nucleated giant cells predominate the cell type of the capsule. Experimentally, the inflammatory silicone granuloma persists for many months and, at about the tenth month of the inflammatory process, the character changes, in which the granuloma is gradually replaced by a foamy conglomeration of silicone-like material with less inflammatory components. Later in this stage of inflammation, this mass breaks up into tiny shreds of stringy silicone material and remains in the localized tissue. In the experimental model, the genetically predisposed animals, these masses of inflammatory cells differentiate into plasma cells which persist and then proliferate, forming plasmacytomas and, possibly, through cytokine interaction, monoclonal gammopathy of undetermined significance. In certain animal models, in the presence of specific cytokines, normal B-cells and plasma cells may be transformed into myeloma cells.
Clinically, systemic scleroderma, systemic lupus erythematosis (SLE) and silicosis of the lungs have been reported in individuals with occupational silica exposure, as found in coal miners [35, 40, 45]. The development of rheumatological-type illness in coal miners has also been described as Caplan's Syndrome [42, 43]. Injections of silica into the body may cause a florid inflammatory reaction. Therefore, many laboratories use silica as a booster or adjuvant to provoke the most significant immunological response possible in animals and to enhance antibody production in order to manufacture sera for vaccinations . Moreover, macrophages exposed to silica in vivo elaborate factors that cause increased fibroblast proliferation and stimulate collagen production [45, 46] and might even produce silica from phagocytized silicone , an important concept because silica itself is mutagenic. Furthermore, Garrido et al. [23, 24] showed that silicone migrates from the implant to the liver in an animal model and they further found that new silicon-containing compounds are formed after silicones are injected into rats. The interaction of silica and macrophages resulted in a derangement of the immune system and, irrespective of the anatomic source, silica was found to be equally lethal for macrophages from the blood, peritoneal cavity, liver and lung .
The polyurethane foam that has been used on the surface of some breast implants was found to be a polyester polyurethane which could be expected to be susceptible to hydrolysis and, furthermore, the diisocyanate was used for the manufacture of polyurethane; this was toluene diisocyanate (TDI) which upon hydrolysis releases toluenediamine (TDA) . In 1991, the manufacturer withdrew polyurethane-covered breast implants from the market because of the degradation of polyurethane to 2,4 diaminotoluene (TDA) and 2,4 dinitrotoluene, both of which are known carcinogens [13, 25]. The FDA, the National Toxicology Program and the International Agency for Research on Cancer have all categorized TDA as an animal carcinogen and a potential human carcinogen . Furthermore, the polyurethane of these silicone breast implants was manufactured and sold as Scott Industrial Foam, a product made for automobile air filters and carpet cleaning equipment, which was never tested for human implantation . David Black, the Director of Aegis Analytical Laboratories, conducted studies on polyurethane for the breast implant manufacturer, Surgitek. Not surprisingly, he found the carcinogen (TDA) in the breast milk of women with polyurethane-coated silicone breast implants [12, 36] and Chan et al.  isolated toluenediamines in the urine of a woman with polyurethane-coated breast implants. Moreover, Picha et al.  showed that the foreign body reaction led to the degradation of polyurethane in long-term animal studies. Finally, by 1986, there appeared two reports of women whose polyurethane-coated breast implants had totally 'dissolved' on explantation .