Fw: Dr. Brawer's Full Article on Mechanisms of BI Toxicity

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Subject: Dr. Brawer's Full Article on Mechanisms of BI Toxicity

> ~~~ many thanx to Dan Buck for getting this for us all ~~~

>

> (Published in Medical Hypotheses, July 1998, ppg 27-35)

>

> SILICON AND MATRIX MACROMOLECULES:

>

> NEW RESEARCH OPPORTUNITIES FOR OLD

>

> DISEASES FROM ANALYSIS OF POTENTIAL

>

> MECHANISMS OF BREAST IMPLANT TOXICITY

>

> ARTHUR E. BRAWER, M.D.

> DEPARTMENT OF MEDICINE

> DIVISION OF RHEUMATOLOGY

> MONMOUTH MEDICAL CENTER

> THIRD AND PAVILION AVENUES

> LONG BRANCH, NEW JERSEY 07740

> U.S.A.

>

>

>

>

>

> Corresponding author: Address for reprints:

> Arthur E. Brawer, M.D. Arthur E. Brawer, M.D.

> 170 Avenue 170 Avenue

> Long Branch, New Jersey 07740 Long Branch, New Jersey

> U.S.A. 07740 U.S.A.

> (908) 870-3133

> FAX: (908) 222-0824

>

> KEY WORDS: SILICON; MATRIX MACROMOLECULES; BREAST IMPLANTS;

> SILICONE

>

>

> ABSTRACT

>

> An understanding of the normal and essential integration of the element

> silicon in biosystems, as well as knowledge of its fundamental chemistry,

> are crucial to understanding its role in health and disease. Modern

> organosilicon chemistry, based in part on the artificial silicon-ca-rbon

> bond, coincided with the emergence of biomaterials and bioengineering

> fields fifty years ago, and was thought to be a fortunate coincidence due

> to conventional wisdom that high molecular weight polymeric siloxanes were

> chemically and biologically inert. These concepts have been shattered by

> the emergence of a novel systemic illness in many breast implant

> recipients, which in turn has spurred an avalanche of investigations

> implicating varied and permeating immunotoxic mechanisms of disease

> causation. The present study develops additional potential pathogenetic

> ideas based on alterations of cell biochemistry by silicon-containing

> compounds, and offers correlation of the patients' diverse clinical

> features with plausable disruption of basic biological processes. This in

> turn raises new questions concerning everyday environmental exposure, has

> broad implications for multiple other diseases, can provide alternative

> directions for future investigative research, and may contribute to the

> ongoing redefinition of immune dysfunction and inflammation.

>

> TEXT

>

> Silicon (Si) is the second most abundant element in the earth's upper

> crust, second only to oxygen (0), to which it is usually bound in nature

> rather than existing free in its elemental form. Under ordinary

> circumstances silicon, like carbon, is capable of forming four bonds, and

> both are known for their ability to polymerize and form network covalent

> structures(1,2). However, unlike carbon, silicon does not usually form

> stable bonds to itself(1,2). Silica (silicon dioxide, or SiO,) consists of

> two double bonded oxygens to silicon, and is found in amorphous and

> crystalline forms. The amorphous forms include natural and synthetic

> glasses and fumed fillers in many consumer products(10).

>

> Crystalline silica in the form of quartz is the most abundant mineral in

> the earth's crust, and is essentially a dehydrated hard igneous rock

formed

> by high temperature and pressure processes(1). Other forms of crystalline

> silica include cristobalite and tridymite(10). Silicates are minerals

> composed of silicon, oxygen and other ions (K, Na, Ca, Mg, Fe, Al, P,

> etc.), and are also part of most rocks on the earth's surface(1,10). Some

> nonfibrous (crystalline) forms of silicates include feldspar, talc, mica,

> vermiculite, and bentonite, while fibrous forms include all the asbestos

> compounds(1,10).

>

> The upper crust layer above the mantle of the earth consists of igneous

> rocks, sedimentary rocks, hydrosphere (oceans, ice,rivers, lakes, water

> vapor), and atmosphere (air)(1). Igneous rocks are rocks which have been

> formed by a melting process caused by high temperature and pressure.

> Silicon content in igneous rocks is very high(1). The most silicon rich

> rocks are designated as acidic (e.g., granite, quartz), while those poorer

> in silicon, which also contain much magnesium and calcium oxide, are

> designated as basic (e.g., diorite, gabbro). Sedementary rocks consist of

> three main types: limestone, shale, and sandstone. These contain the

common

> minerals like feldspar and quartz, and also contain dolomite, calcite, and

> hemotite. The silicon content of sedimentary rocks is also high(1).

>

> The hydrosphere acts as a link and balance between the igneous rocks and

> the sedimentary rocks by the natural process of chemical weathering. In

> this process, silicon in various forms is leached out and transported via

> rivers and streams from the igneous rocks of the continents to the oceans,

> where water, carbon dioxide, and hydrochloric acid are added along the

> way(1). As the sediments grow in thickness, they sink deeper and deeper

> into the sea bottom where temperatures increase, mixing with magma occurs,

> and eventually rise up to the surface forming new mountains and

continents.

> The entire weathering process releases free solid silica which, in the

> presence of water, produces monosilicic acid:

>

> Sio2 + 2H20 ----> SI(OH )4

>

> This is true for any of the forms of silica, amorphous or crystalline. The

> rate of reaction depends only on the temperature, pressure, and the nature

> of the solid silica phase. The -OH group attached to silicon is called a

> silanol. Silicon in natural waters exists mainly as monosilicic acid(1).

> Despite varying concentrations in drinking waters in different

> municipalities and countries, human serum concentrations of silicon remain

> the same in the presence of normal renal function(1,10).

>

> The emergence of silicon metabolizing biological systems 500-600 million

> years ago, especially in diatoms (unicellular algae), resulted in a

drastic

> alteration of the concentration of dissolved silica in the oceans, which

> eventually reached a balance(1). For these organisms silicon was and still

> is essential for virtually any and all cellular functions, including DNA

> synthesis, energy production, and cell wall structure(1). During the

> subsequent complex and long evolutionary process a choice was made between

> phosphorus and silicon, and the original primative formation of organic

> silicate esters gave way to present day sulfate and phosphorate esters(1).

> The net result was that the older pathways have long since been abandoned

> by the higher organisms. Thus, part of the intracellular capability to

> recycle silicon in this globally crucial and integrated biochemical manner

> appears to have been lost.

>

> This is not inconsistent with current knowledge that silicon is essential

> to normal growth and development. It should be noted, however, that the

> organic derivatives of silicates that have functional significance in man

> contain silicon bonds linked to oxygen, not carbon(1). There is a

> biological need for silicon beginning with embryologic development of

> connective tissues and subsequently encompassing maintenance of the

> same(1). It has

> been known for over two decades that silicon, calcium, phosphorus, and

> magnesium accumulate in the mitochondria of osteoblasts before any

evidence

> of extracellular ossification occurs(1). Silicon deficiency in animals

> causes reduced mineralization of bone, reduced callagen content of bone,

> reduced skeletal growth, bone deformities, thinner articular cartilage,

> smaller and less well formed joints, and adverse effects on skin, hair,

> nails, and mucous membranes(1). Under normal conditions silicon is found

in

> highest concentration in the aorta, trachea, tendons, ligaments, bone,

> cartilage, skin, dental enamel, cornea, and sclera(1,10). For these areas

> and all other connective tissue sites throughout the body, the proteins in

> the solid phase extracellular matrix containing covalently bound

> carbohydrates are classified into three categories: glycoporteins,

> collagens, and proteoglycans. For proteoglycans, the major carbohydrate

> component is a glycosaminoglycan, which is an unbranched long chain that

is

> highly sulfated and has a motif of a disaccharide repeat(11). Examples are

> keratan sulfate, chondroitin sulfate, hyaluronan, dermatan sulfate,

> heparin, and heparan sulfate. Silicon provides links within and between

> polysaccharide chains of glycosaminoglycans, and helps link the

> glycosaminoglycans to their respective proteins(1). Type IX collagen is

> also known to contain bound glycosaminaglycan chains. Glycoproteins are

> formed when sugars such as mannose, fucose, galactose, sialic acid, and

> N-acetylglucosamineare linked to proteins in oligosaccharide units(23).

All

> of these matrix components are adhesives, acting as glues by binding to

> each other. Thus, in an extracellular locale, silicon contributes to the

> architecture, form, strength, and resilience of connective tissues.

>

> The solid phase extracellular matrix is also involved in storing, binding,

> protecting, and releasing many regulatory agents. All hormones, growth

> factors, gases, waste disposal, and nutrients must penetrate or pass

> through the matrix in moving from one tissue or compartment to another.

> Matrix components can select, inhibit, facilitate, and remove molecules

> with which they come in contact. For intercellular exchanges of

information

> (e.g., neural transmission), the role of the matrix must be considered.

>

> The classic extracellular matrix macromolecules are chemically similar to

> macromolecules found on cell surfaces, and as such are integral membrane

> components as well(11). The cell membrane bilayer of phospholipids acts as

> a solvent for integral membrane proteins which can diffuse laterally in

> this milieu. The attached sugar residues on these proteins are always

> located on the extracellular side of the plasma membrane(23). These

> carbohydrates are information rich molecules, and their diversity and

> complexity confers a variety of important functional characteristics.

> Examples in the proteoglycan category include syndecan, aggrecan, decorin,

> versican, biglycan, and glypican, with known functions as receptors,

> adhesion molecules, signal transducers, inhibitors, regulators, and

> epithelial cell layer stabilizers(11).

>

> Other cell surface proteins are intermittently linked to

glycosaminoglycans

> and are termed part-time proteoglycans. Examples include thrombomodulin

(an

> endothelial cell membrane proteoglycan that interacts with protein C and

> thrombin to influence coagulation), betaglycan (receptor for transforming

> growth factor , and CD44 (hyaluronan receptor, lymphocyte homing

> receptor)(11). The CD44 receptor mediates specific adhesion of lymphocytes

> to high endothelial venules in lymph nodes. it has a wide distribution,

and

> is expressed in brain, medullary thymocytes, B cells, monocytes, mature T

> cells, fibroblasts, granulocytes, erythrocytes, keratinocytes, and

> carcinoma cell lines. Some of the solid phase and cell surface

> proteoglycans are also known to be soluble in the body (i.e., exist in

> blood or tissue fluids), such as aggrecan, decorin, glypican, hyaluronan,

> betaglycan, and syndecan. Hyaluronan is involved in varied biologic

> processes ranging from embryonic development to wound healing. On the cell

> surface betaglycan enhances signal responsiveness to TGF-B, but in the

> soluble matrix phase it is an antagonist.

>

> By inference, silicon can be expected to be present in all of the

> proteoglycan macromolecules discussed so far. Even the basement membrane

> (cell lamina) is likely to incorporate silicon in its structure. This

> matrix, which is noncovalently linked to the plasma membrane of most

animal

> cells, is present over most of the surface of muscle cells (smooth,

> cardiac, and skeletal), fat cells,Schwann cells, and the basal surface of

> most epithelial cells(11). The basement membrane contains at least one

> proteoglycan, perlecan, which contains the glycosaminoglycan heparan

> sulfate. The cell lamina is intimately involved with active exchange in

and

> out of the cell, filters and protects the surface of the cell, and

provides

> temporary binding and/or storage of a variety of regulators and growth

> factors. Signals from the synaptic cell lamina of muscle cause

> acetylcholine receptor genes to transcribe agrin (which contains three

> laminin modules). Secretion of agrin results in interaction with

> proteoglycans, inducing aggregation of the acetylcholine receptors at the

> neuromuscular junction. Perlecan also interacts with platelet derived

> growth factor and dampens its stimulation of smooth muscle replication. In

> the fluid phase heparan sulfate can inhibit fibroblast growth factor

> binding to fibroblast receptors.

>

> Glycosaminoglycans are also present in secretary granules inside mast

> cells, the latter of which are found in or around alveoli, bowel mucosa,

> dermis, nasal and conjunctival mucosa, synovium, blood vessels, and

> bronchioles(11). Preformed mediators such as tryptase are stored inside

> secretary granules bound to heparin, in close proximity to chondroitin

> sulfate E. Mast cells secrete serglycin, a proteoglycan also made by all

> other types of hematopoetic cells (including natural killer cells), which

> stores and protects a variety of agonists with which it is copackaged. For

> the mast cell this includes histamine, and when taken in its entirety

> serglycin clearly in involved in regulating the release and rates of

> degradation of all sorts of bioactive reagents responsible for

> inflammation, immune responses, and

> coagulation. In this regard it is interesting to note that suppression of

> natural killer cell activity has been reported in patients with silicone

> gel breast implant toxicity, with reversal of this dysfunction following

> explantation(25).

>

> Glycoproteins are equally pervasive in their functional importance, and

> mediate many biological recognition processes(11). Glycoprotein receptors

> in the cell membrane of platelets are intimately involved in adhesion and

> activation. Thrombospondin (a glycoprotein found in platelets and other

> cells) influences fibrin formation and lysis by inhibiting plasmin.

Laminin

> bound to adhesion molecules of endothelial cells is in turn bound to type

> IV collagen by entactin (a glycoprotein that is a major constituent of

> basement membranes). Proteolytic fragments of the laminin alpha chain are

> chemotactic for mast cells. The majority of cell surface receptors

> mediating endocytosis are transmembrane glycoproteins(23). Apolipoproteins

> are glycoproteins that not only solublize lipoprotein constituents but

also

> hold the key function for their metabolic fate by interacting with enzymes

> and cell membrane receptors. Endothelial cell surface receptors for

> oxidized LDL are complemented by lipoprotein lipase bound to heparan

> sulfates. Indeed, the comingling of numerous glycoprotein and proteoglycan

> molecules on the surface of endothelial cells enables these cells to

> perform a wide variety of critical physiologic functions by interacting

> with (1)cellular and soluble blood components, (2)other cells in the

> vascular wall, (3)solid phase matrix components, and (4)multiple

cytokines,

> the latter of which can up regulate other adhesion molecules (selecting,

> integrins, etc.). The carbohydrate binding adhesion molecules known as

> selecting are similar to the carbohydrate binding proteins of E. coli

> called lectins, which enable the bacteria to adhere to epithelial cells of

> the GI tract. This highly preserved evolutionary mechanism forms the basis

> for some viruses to gain entry into host cells, and for the CD44 ligand.

> Adhesins are surface molecules expressed by other microorganisms that use

> the matrix as a substrate to establish infection. As an example, both

> pneumocystis and aspergillus bind to fibronectin, a glycoprotein that has

> affinities for collagen, fibrin, heparin, thrombospondin, integrins, and

> components of bacterial cell walls, and which forms a substrate for repair

> cells to adhere to in wound healing. During angiogenesis

> (neovascularization) if anchorage dependent endothelial cell spreading and

> migration is inhibited, apoptosis is triggered. Apoptosis has recently

been

> reported to occur when anti-cardiolipin antibodies bind to membrane

> complexes of phosphatidylserine and B29lycoprotein(44).

>

> >From the preceding discussion it can be appreciated that despite losing

> >its role in energy production and DNA synthesis, silicon biointegration

> >remains quite extensive in that it is intimately involved with

> >macromolecules displaying endless variations of complex overlapping

> >interactions. It also seems logical that silicon (like growth factors,

> >cytokines, hormones, and vitamins) should impact on matrix regulation,

> >contributing to the circuitous observation that the matrix itself is

> >directly and indirectly involved in feedback on its own production,

> >polymerization, degradation and recycling.

>

> Perhaps one of the most striking facts regarding the biochemistry of

> silicon is that virtually no silicon-carbon,silicon-hydrogen, or

> silicon-silicon bonds have been detected in nature(1,2). But over 50,000

> such compounds were synthesized during the last century in many

> laboratories, and form the basis of modern organosilicon chemistry. These

> molecules essentially contain organic substituents bound to silicon

through

> the siliconcarbon bond. Common silicon containing products include fluids,

> oils, rubbers, plastics, resins for impregnation of paper and fabrics,

> glass, cosmetics, lacquer, paint, varnish, adhesives, sealers, anti-stick

> agents, anti-foam agents, water repellents, insulation materials,

household

> abrasives, beer, insect repellents, pesticides, insectisides, and other

> poisons. These latter three items are comparable to strychnine and can

> cause muscle twitching, convulsions, fever, tremors, respiratory

> depression, paralysis, and altered coagulation(1). Other products increase

> the yield and quality of crops, increase the weight of fowl, increase egg

> production, serve as food additives (e.g., spices, powdered sugar, dried

> eggs), coat fruits to prevent bruising, and aid in food processing.

> Biologically active organosilicon compounds with everyday medical uses are

> myriad, and include antomicrobials, psychotropic drugs, anticonvulsants,

> anti-tumor agents, wound and burn ointments, skin coverings to promote

> faster healing, antiflatulants, anti-ulcer agents, and allopecia

> preparations(1). Some of these products contain silicones and have the

> ability to

> modulate hormonal, endocrinologic, and neurotransmitter functions. Other

> widespread applications of this technology include intravenous tubing,

> cardiac pacemaker lead tips, heart valves, cerebrospinal fluid shunt

> tubing, digital joint arthroplasty prostheses, vitreous replacements, lens

> implants, contact lenses, syringe lubrication, nasal and mandibular

> reconstruction devices, dental impression materials, and breast implants.

> All of the products in this last category are composed of silicones.

> The obvious question to be asked, then, as more and more of these products

> proliferate for routine commercial use is: in which way will living

> organisms react if they are confronted with artificial organosilicon

> compounds? The in vivo chemistry evolved by biological systems is

different

> from the chemistry of man's ingenuity. Although chemists have collected a

> great deal of physical data on the strength, energy, polarization,

> rearragement, and stability of the various bonds of these artificial

> molecules, anticipated or unanticipated biodegradation may subsequently be

> followed by novel and unanticipated biointegration. Thus, an advantageous

> quality in theory may turn out to be disadvantageous in reality. As an

> example, by 1977 several artificial organosilicon compounds were already

> known to be capable of serving as the sole energy source for many

> bacteria(1). These substrates, when broken down, do not necessarily result

> in the release of free silicon as an end product. Because such compounds

> are a carbon source for growth, smaller residual silicon containing

> molecules may be rearranged and/or redirected for anabolic utilization,

> with subsequent adverse physiological implications. During the degradation

> of these compounds, intermediates can be formed with one or more free Si-O

> groups, which inherently have a tendancy to react with each other(1). This

> chemical reconstitution is not simply the reverse direction of the

original

> degradation. Biological systems are far from homogeneous, and locally

> concentrated silicon can form polymerized species of unknown crystal forms

> (i.e., silicates) by interacting with calcium, magnesium, and

> phosphorus(1). In this regard, the reported presence of magnesium silicate

> (talc) in periprosthetic breast tissues may have profound importance, and

> is worthy of additional study(3). Talc is a known sclerosing agent, is

> associated with granuloma formation and chronic inflammation, and may also

> have adjuvant properties in animal models. Biology can also energize

> systems, and silicates bound to sugars can become catalytically active,

> taking on the properties of enzymes(1). This phenomenon has direct

> relevance to the reported observation that the sequential evolution of the

> systemic illness caused by silicone gel-filled breast implants precedes in

> an exponential manner analogous to a reactor catalysis mechanism(7).

> Alternatively, binding of silicates to the sugars of matrix macromolecules

> could have multiple other profound consequences.

>

> All of the biochemical data discussed thus far have distinct practical

> significance in light of observations dealing with silicone gel-filled

> breast implants, including: (1) the documented occurrence of gel bleed

> through an intact elastomer envelope; (2) the uptake of silicone gel by

> macrophages and other cells; (3) the dispersion of silicone gel to

multiple

> distant body sites; and (4) the in vivo breakdown of silicone gel to

> smaller molecules(37-43). But these reports also raise more ominous and

> fundamental considerations, since from the discussion on matrix

> macromolecules it would appear that there is a finite limit of adaptive

> mechanisms by which normal cells and tissues can dispose of excess

silicon.

> After that, biochemical chaos affecting synthesis, polymerization,

> degradation, and recycling of connective tissue components could ensue,

> with multiple physiological effects. In multiple cohorts of symptomatic

> breast implant recipients the skin displays a myriad of prominent

> findings(6,7,26-35), implying global connective tissue dysfunction of

cells

> and matrix. What is noted on the outside of the body is likely to be

> diffusely occurring on the inside. Many of these patients' systemic

> symptoms and signs include (but are not limited to) fatigue, joint pain,

> bone pain, dry eyes, dry mouth, dry skin, cognitive dysfunction, myalgia,

> weakness, hair loss, nail changes, skin rashes, paresthesia, dysesthesia,

> freckling, pigment change, headache, dizziness, nausea, foul taste, w & fght

> gain, weight loss, bruising, photosensitivity, fever, chills, infections

in

> various tissues and organs, loose stools, constipation, periodontal

> disease, skin papules, muscle twitching, urinary symptoms, dysphagia,

> menstrual irregularity, blurry vision, tinnitus, drug reactions, emotional

> lability, insomnia, Raynaud's, edema, hemangiomas, poor wound healing,

> venous and capillary dilatation and neovascularization (telangiectasias),

> reduced hearing, reduced smell, tremor, mouth sores, tight skin, dyspnea,

> wheezing,

> palpitations, seizures, parotid swelling, heat intolerance, and

> cancer(6,7,26-36). As a logical extension of global matrix dysfunction,

and

> considering the diverse constitutional (genetic) make-up of these

patients,

> such a generalized disease process would be expected to exhibit

> considerable and variable latency, as well as considerable heterogeneity,

> two of the hallmarks repeatedly emphasized by multiple investigators

> reporting on the clinical symptomatology of breast implant recipients. It

> would also explain the general futility noted in treating patients

> suffering from silicone toxicity with anit-inflammatory medication, since

> such a mismatch should come as no surprise, and ought to be expected.

> Indeed, such patients often exhibit marked intolerance to

anti-inflammatory

> and other medications, probably reflecting metabolic imbalance that leaves

> little room for normal drug utilization(6).

>

>

>

> The question then arises, is silicone gel-induced disease an extreme form

> of a more generalized and slower-paced process occurring in the general

> population? The proliferation of man made silicon containing compounds has

> raised the exposure level in everyday life considerably. In addition,

prior

> absorption studies of high molecular weight polymeric siloxanes have dealt

> with urinary excretion studies over days to weeks(1), and may be

> fundamentally flawed by not taking into account: (1) the latency of

diverse

> biological processes; (2) the extraction and identification of

> organosilicon molecules and/or metabolites from biological material is

very

> complicated; (3) the possible degradation of dietary organosilicon

> compounds by gut bacteria, which may enhance absorption and long

> term biointegration; and (4) symbiosis disruption, i.e. the possible

> interference with the conversion (by gut bacteria) of numerous endogenous

> and exogenous substrates into a wide spectrum of metabolites (e.g.,

> glycosidases that act on excreted liver products to produce B complex

> vitamins). Applying the knowledge from the rapidly expanding field of

> geomicrobiology to medicine could have important implications for a whole

> host of medical phenomena and conditions including asthma, colitis,

> atherogenesis, senile dementia, aging, thrombosis, osteoarthritis,

allergy,

> neuropathy, lupus, myositis, multiple slcerosis, ovarian cysts,

> fibromyalgia, chronic fatigue syndrome, Sjogren's syndrome, apoptosis,

> migraines, Alzheimer's, and cancer. One's scientific curiosity can be

> enhanced by considering four pieces of knowledge readily available in 1977

> encompassing the interface and interaction of silicon containing compounds

> with organic components of biological systems(1). One such reaction was

the

> reasonable expectation that acqueous monosilicic acid, SI(OH) 4, like the

> related compounds boric acid, B(OH)3, and germanic acid, Ge(OH)4, would

> form strong complexes with organic hydroxy compounds such as polyols,

> saccharides, and hydroxycarboxylic acid. Indeed, the formation of such

> SI-O-C bonds had been demonstrated to result from the esterification of

> organic hydroxylgroups with SIOH groups. A second known fact was that in

> water solution, labile bonds are formed between the neutral oxygen or

> nitrogen atoms of alcohols, ketones, ethers, amides, and amines and the

> hydrogen atoms of silanol groups, SIOH. The resulting Si-O-H--C hydrogen

> bonds

> occur with silica particles as well as polysilicic acid, and can result in

> denaturation of adsorbed proteins due to distortion of the natural

> molecular conformation. This change in configuration renders the protein

> unable to fulfill its biological role. Phosphate esters are powerful

> hydrogen bonding agents, and account for the significant bonding of

> phospholipids to silica and silicic acid. These observations have direct

> implications for the interactions of proteins with the fatty acid

> composition of cell membrane lipid bilayers, thereby potentially adversely

> affecting membrane permeability, receptors, signal transduction, or other

> matrix functions. Cell membrane fatty acids exert an antibacterial effect,

> and are important in maintaining symbiosis between hundreds of bacteria

and

> the epithelium of the oropharynx, vagina, and intestinal tract. Trapping

of

> bacteria in the mucous secretions of the nasopharynx, trachea, and bronchi

> usually renders the sinuses and lower respiratory tract sterile.

> Interference with these functions may have significance for the recurrent

> sinusitis and other infections experienced by implant patients. Thirdly,

> the chemistry of silicon is much more flexible than that of carbon, as the

> former behaves at times like a metal and can participate in chelation

> reactions. An example is the chelation of silicic acid with catecholamines

> (e.g., dopamine), thereby affecting neurotransmitters. Fourth,

> polyphosphates (ATP, etc.) are metal ion bound in biological systems, and

> competition of silicon for phosphorus can occur with resultant

> silicate-phosphate compounds. The implications for energy production in

> mitochondria are obvious.

>

> In light of all that has been presented, it is thus hard to understand the

> resistance encountered to date in accepting silicone gel-filled breast

> implant induced disease as a novel entity. With the exception of

> scleroderma, there does not appear to be any rationale for expecting

> silicone toxicity to translate into welldefined " textbook " medical

> conditions such as lupus, etc. The tightening and thickening of the skin

in

> idiopathic systemic sclerosis are due to the accumulation of excess

> collagen and other extracellular matrix constituents, including

> glycosaminoglycans(11). Considering that the receptors for fibroblast

> growth factor and vascular endothelial growth factor are proteoglycans,

and

> considering that one of many sources of growth factors is the mast

> cell(11), the circuitous pathogenetic mechanisms of silicone toxicity

> proposed in this report could easily result in unrestrained fibroblast

> activation. Resultant features of scleroderma need not necessarily

resemble

> classical subtypes. The controversy over the published studies to date

that

> purport to show no association between silicone breast implants and

> classical connective tissue diseases should not just focus on the analysis

> of multiple flaws, such as study design, data gathering, exclusions,

> latency, statistical power,disease misclassification, bias, follow-up,

> control groups, and mortality contribution(4,21,22). The first pressing

> notion should be to dispense with preconceived ideas of how patients

should

> get ill. In this regard it is not surprising that many of the immunotoxic

> mechanisms reported and/or proposed to be operative in symptomatic breast

> implant recipients have been subjected to a critical and scathing

> review(24). Even in classical diseases such as lupus, where immune

> dysfunction has clearly been demonstrated, novel studies of biochemical

and

> functional abnormalities of lupus T cells have led to the hypothesis that

> symptoms and signs of lupus are preceded by an early antigen-nonspecific

> immune response(9).

>

> The diversity of silicon-based products on today's international market is

> the result of over 100 years of cumulative experience in the synthesis of

> innumerable organosilicon compounds. Fifty years ago this proliferation

> coincided with the emergence of biomaterials and bioengineering fields,

and

> was thought to be a fortunate coincidence due to conventional wisdom that

> polymeric organosilicon compounds (i.e., siloxanes) in the form of high

> molecular weight silicones were biologically and chemically inert. This

> " wisdom " was based on observations of the reported chemical resistance of

> silicones to be degraded by acids and bases as well as resistance to

> hydrolysis, the small variation in physical properties as a function of

> temperature, the very low surface tension, the apparent lack of oral

> absorption of high molecular weight polymeric species, and the relatively

> mild inflammatory and humoral responses seen with low molecular weight

> fluids. Indeed, in a published Nobel Symposium held in 1977, researchers

> from the Dow Corning Corporation were noted to state that " such

> considerations are among those which have influenced the success of

> silicones as biomaterials where inertness is absolutely required(1).

> However, prior experiments by Dow Corning and others in animals tested

with

> orally administered or injected smaller linear siloxanes, cyclic

siloxanes,

> or polydimethylsiloxane fluids or gel, revealed pharmacologic and/or

> toxicologic effects such as estrogenicity, analgesia, hyperalgesia, weight

> loss, hepatomegaly, decreased release of hypothalamic catecholamines, male

> gonadal shrinkage, vacuolization of peripheral blood neutrophils and

> monocytes, chronic organ inflammation (liver, kidneys, pancreas), and

> systemic migration to lymph nodes, liver, spleen,lung, kidneys, adrenal

> glands, pituitary, hypothalamus, and ovaries(1-4, 13-17). In addition, an

> internal Dow Corning report in 1975 examined endotoxin induced interferon

> type I production in mice after pretreatment with various silicones,

> including octamethylcyclotetrasiloxane (D4). D4 was shown to have adjuvant

> activity when mixed with Dow Corning 360 fluid (medical grade silicone

> fluid, or DC-360, used in humans) in that it substantially augmented the

> interferon production to endotoxin over that in the controls(3). This was

> complemented by another Dow Corning unpublished report in 1974, whereby it

> was shown that DC-360 had adjuvant effects on humoral immune responses in

> animals(3). Yet any mention of these observations by the Dow Corning

> chemists in the 1977 Nobel Symposium was conspicuously absent, despite

> discussion of D4 in another experiment detailing its augmentation of

> catalepsy and ptosis in reserpinized mice(1). In other words there was the

> potential for D4 to possibly interfere with monoamine synthesis. A close

> analogue of D4, Cisobitan, was without significant effect in this same

> experiment, but two of its isomers were antagonistic to reserpine

(possibly

> by stimulating monoamine synthesis). These experiments highlighted the

> unexpected activities of cyclosiloxanes, and demonstrated " pharmacologic

> actions not predicted from the activity of known pharmacons(1).

>

> Unfortunately, in the 1970's these early warning signs did not lead to any

> large scale studies of the fate of high molecular weight polymeric

> siloxanes in biological systems, and their half life still remains

unknown.

> Substances were categorized on the basis of intended use, with less

> consideration for bioavailability, biodegradation, biotransformation,

> biointegration, or adverse biological activities. It is now clear that

high

> molecular weight silicones (along with the multiple other components,

> contaminants,and impurities found in breast implant devices) are neither

> chemically nor biologically inert. In addition to examples already cited

> throughout this paper, there are reports on (1) local tissue inflammatory

> and fibrotic reactions to a host of implant materials, including foreign

> body giant cell granulomas and the presence of numerous cytokines, (2)

> antibodies to collagen in implant recipients that recognize different

> epitopes from those seen in patients with SLE or RA, (3) anti-silicone

> antibodies, (4) T lymphocyte hyperresponsiveness to silica in implant

> recipients, (5) a higher than expected incidence of antinuclear antibodies

> in women with breast implants, which increases with duration of

> implantation and the appearance of systemic symptoms, (6) induction of

> plasmacytomas by silicone gel in BALB/C mice, (7) diffusion into intact

> implants of hydrophobic human constituents, such as triglycerides and

other

> lipids, with the potential for immunomodulating liposome-like structures

to

> be formed, (8)the unexpectedly high presence of subclinical device

> infections, and their relationship to capsular contracture and clinical

> complaints, (9) theoretical increased risk of breast cancer in gel implant

> recipients (with and without polyurethane foam additive), (10) abnormal

> esophageal motility, and rheumatic complaints with positive ANA tests, in

> children breast fed by women with implants, (11) morphological and

> behavioral alterations of fibroblasts by silicone polymers, (12) the

> demonstration that anti-DNA antibodies from some SLE patients bind to

> phosphorylated polystyrene, raising theoretical implications for silicone

> behaving as a specific immunogen leading to cross-reacting immune

responses

> to matrix macromolecules, (13) the association of cancer with silicate

> fibers (e.g., asbestos), (14) the linkage of silica exposure to systemic

> lupus and rheumatoid arthritis, (15) other disease entities known to be

> caused by exposure to crystalline silica dust (e.g., pulmonary fibrosis,

> nephrotoxicity, scleroderma, macrophage cytotoxicity), (16) the similar

> reduction of mean plasma serotonin levels in both fibromyalgia patients

and

> symptomatic breast implant recipients compared to normal controls, (17)

the

> increased presence of HLA-DRw53 in both fibromyalgia patients and

> symptomatic breast implant recipients compared to normal controls and

> breast implant recipients without symptoms, and (18) the presence of

> anti-polymer antibodies in both fibromyalgia patients and symptomatic

> breast implant recipients compared to normal controls(2-8,10-12,18-20).

>

> But there has been a far too narrow focus of investigative direction for

> both classical and non classical disease states. The evidence put forth

> thus far by researchers representing numerous disciplines needs to be

> sorted out, reassessed, and reanalyzed in light of current knowledge of

the

> fundamental molecular basis of life. Silicase, an enzyme that liberates

> silicic acid from an artificial organic silicic acid compound,is a

membrane

> bound enzyme found in mitochondria and microsomes of pancreas, stomach,

and

> kidney(1). Its natural substrate is unknown, but it may have a role in

> transport function. The silicon content of brain, liver, spleen, lung, and

> lymph nodes increases with age, and high silicon levels are found in the

> senile plaques of Alzheimer's dementia (in conjunction with amyloid)(1).

> The silicon content of aorta, skin, thymus, and hair decreases with

age(1).

> In other parts of the universe a very different type of silicon chemistry

> could have occurred if water solutions were replaced with something else.

> In another world, silicon might still be a requirement for the structural

> stability of plants, and the fiber contents of grains might still be found

> to be proportional to their silicon contents. Diseases in that world,

> however, might have nothing to do with cell-cell and cell-matrix adhesion

> phenomena. Here on earth these are basic and highly regulated biological

> processes that permeate every aspect of life. The molecular determinants

> for these processes are likely to be profoundy affected by excess silicon

> occurring from the in vivo degradation of breast implant components. This

> in turn could provide the rationale for predicting the potential toxicity

> of other organosilicon compounds and simultaneously elicit alternative

> research endeavors for multiple other disease entities.

>

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>

>