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

[Guest guest]

Thanks Lea -

(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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