Pathology (Plaintiffs' Science SubmissiontoNational Science Panel)

[Guest guest]

This is very long, but very interesting - Something to

take to your doctor to explain what happens to

silicone in ones body!

Rogene

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http://womnhlth.home.mindspring.com/PSC/PATH.HTM

III. PATHOLOGY

A. INTRODUCTION

Dr. Sergent, who made a presentation to this

Panel on behalf of the manufacturers, wrote in the

Textbook of Rheumatology that:

An ideally biocompatible material should not lead to

any of the following: (1) immunologic, inflammatory,

toxic, or thrombogenic reactions; (2) deterioration of

the biomaterial or adjacent tissues; (3) alteration in

host plasma proteins or enzymes; and (4) carcinogenic

effects.(106)

As documented in this section on pathology, silicone

breast implants fail Dr. Sergent's widely-accepted

standard for biocompatibility. Numerous reports

spanning over thirty years have consistently

documented:

1. extensive angiofibroplasia and chronic,

granulomatous inflammation in silicone-exposed tissue;

2. the development of granulomas whose cellular

structure is identical to delayed hypersensitivity or

immunogenic granulomas;

3, fat and tissue necrosis with atrophy and ulcerated

skin following exposure to silicone;

4. deterioration and failure of the elastomer envelope

resulting in excessively high rates of rupture which

releases large quantities of silicone into the breast

(an area of the body banned for silicone injections);

and

5. as will be set forth in the immunopathology and

immunology sections, alteration in host plasma

proteins and enzymes, suppression of natural killer

cell activity, activation of macrophages with

secretory production of cytokines Interleukin-1

(IL-1), Tumor Necrosis Factor-, and Interleukin-6

(IL-6), and production of antibodies to silicone-bound

proteins.

As Dr. Louise Brinton, NIH, recently wrote " there is

now recognition that silicone is immunogenic. " (107)

Plaintiffs submit that the evidence from the

specialized disciplines of pathology and

immunopathology is compelling and demonstrates that

silicone gel breast implants are notbiocompatible.

This evidence also provides a reliable and scientific

basis for one to conclude that silicone gel breast

implants can cause one or more symptoms of diseases or

immune system dysfunction.

B. DOCUMENTED COMPLICATIONS FROM SILICONE GEL BREAST

IMPLANTS

The pathology and histology of silicone breast

implants and tissue exposed to silicone has been

extensively reported on in the published,

peer-reviewed medical literature since the 1960s.

There is, in fact, a wealth of information and

research that has consistently shown that silicone,

when exposed to tissue in animals and humans, reacts

in an easily identifiable manner(108), i.e., the

initial acute inflammation progresses to chronic

inflammation and granulomatous inflammation,(109)

extensive fibrosis occurs with granuloma formations

throughout the breast and in other areas of the body

where silicone has migrated, followed by systemic

symptoms of the long-term inflammation.

The published literature contains numerous reports

from animal models of various strains of rats and

mice, rabbits, guinea pigs, dogs, and primates in

which systemic distribution of silicone to distant

areas and organs is well-documented. As demonstrated

below, silicone has been found in virtually every

major organ including the brain, liver, spleen,

kidneys, pancreas, ovaries, breast milk in lactating

dogs, bone marrow, blood, adrenals, lymph nodes,

stomach, bladder and urine, thyroid and lung. Reports

of systemic silicone migration in women implanted with

silicone breast implants have also been published. In

addition, extensive research exists in published

articles and unpublished internal studies from the

manufacturers concerning liquid silicone and its

adverse consequences, including chronic and

granulomatous inflammation and cell-mediated immune

responses. Each of these issues well as discussed in

greater detail below as will the implications of these

findings.

One example of an unpublished study was a " highly

confidential " review by Dow Corning of its internal

studies on silicone termed the " Medtox Project. " (110)

Dow Corning's " principal conclusion " was that, " [t]he

reaction at the implantation site is an acute

inflammation progressing to chronic inflammation

characteristic of a mild foreign body response. " Dow

Corning also noted " substantive deficiencies [in their

studies which are] specifically relevant to current

claims and suspicions of autoimmune-like disorders

linked to silicone fluid and gel and to synovitis and

lymphadenopathy associated with elastomer abrasion

particles. " These deficiencies, Dow Corning wrote,

limited the value of relying on their internal studies

on the systemic effects of silicone in the body. The

deficiencies that Dow noted were:

1. The histopathology of the reticuloendothelial

system has not been adequately assessed in any

long-term study including determination of the organ

distribution of silicone materials.

2. None of the existing studies critically assess

possible systemic effects arising from the local

inflammatory reaction or from material transport.

The following section on pathology and histopathology

of silicone gel breast implants will follow the

chronology in Dow Corning's Medtox Project, and

specifically Figure 5 of that report, reproduced on

the next page, which shows the progression of events

and reactions within the body following implantation:

1) gel bleed, leakage or rupture; 2) silicone

phagocytosis; 3) acute inflammation; and 4) chronic

and granulomatous inflammation and formation of

silicone granulomas.

1. The Fda Has Long-Prohibited the Use of Silicone for

Injections into the Breast

As noted in the historical section above, the FDA has

strictly forbidden the use of injected silicone in the

mammary area. In fact, such a use was listed as

contraindicated in Dow Corning's New Drug Application

on medical grade silicone fluid.(111) This followed

adverse reactions from injections of both pure

silicone fluid (Dow Corning 360 fluid) and adulterated

silicone fluid in the early 1960s. The FDA made it

clear in 1965 that it " regarded silicone fluid for

injection as a new drug since it is not generally

recognized, among experts qualified by scientific

training and experience to evaluate its safety and

effectiveness, as safe and effective for injection

purposes. " (112) While drugs such as silicone were

regulated by the FDA in the 1960s, medical devices

were not. As a result, Dow Corning and plastic

surgeons Drs. Cronin and Gerow designed a thin,

fragile silicone elastomer likened to " Saran Wrap " to

hold the silicone fluid which was then implanted

directly in the area forbidden for silicone

injections, i.e., in the female breast.(113)

2. Dr. Feng Described Breast Implant Surgery to the

Panel

Dr. Lu-Feng's presentation before this Panel

discussed the placement of the silicone gel breast

implant through an inframammary, axillary or a

periareolar incision.(114) The implant is then placed

in a retroglandular (subglandular) or submuscular

position. When it is positioned behind the pectoralis

major, only the medial portion of the implant is

covered by muscle. Dr. Feng's data indicates that the

retroglandular placement is the most frequent

placement with silicone gel breast implants, and that

the retropectoral placement is typically used with

mastectomy patients.(115)

The surgical procedure itself can cause hematoma,

fluid accumulation around the implant, infection,

sensory changes in the breast and nipple, and local

tissue damage.(116) This is followed by the body's

normal healing process in which the body reacts to the

silicone gel implant as a foreign material and begins

to mount a typical foreign body reaction with acute

inflammation. If the body is successful, the acute

reaction subsides into a quiescent scar enumerated by

an orderly deposit of fibrous tissue. The result is

the fibrous capsule surrounding the implant which is a

normal host response to a foreign body.(117) However,

the reaction in many women does not stop at that

point. Instead, as silicone continuously bleeds into

the capsule, the acute inflammatory reaction persists

and produces the chronic inflammatory response seen so

frequently in tissue biopsies of implanted women. In

this regard, the capsule differs markedly from normal

fibrous capsules with other non-silicone implanted

devices and presents unique histologic features and

adverse results. As described by Dr. Shanklin,

a pathologist at the University of Tennessee:

[t]he capsule is the active field of pathologic and

immunopathic response to the silicone device. A

surgical plane is created in the anterior thoracic

wall . . . whose very presence changes the details of

wound healing at that site. As the source of and, at

least initially, the location of the highest

concentrations of foreign or alien material, the

device capsule interface is the contact front for this

immunopathic response. As elastomeric shards or

gel/oil droplets migrate through tissue fluids

(including lymph channels) or are carried away (by

macrophages), the reaction spreads.(118)

3. The Capsule Surrounding Silicone Breast Implants Is

Not a Typical Foreign Body Response

In the 1970s, frequent reports began to appear in the

medical literature about a painful complication of

silicone breast implantation involving the contracture

of the breast implant capsule, termed capsular

contracture. Contracture causes significant chest wall

pain and discomfort, a feeling of hardness of the

breasts, disfigurement, and tenderness. Clinically,

the contracture often can be seen by the appearance of

distorted and disfigured breasts, such as in the

photographs which were presented to the Panel by Dr.

Feng and Dr. Hardt. (See, e.g., following

photographs [Photo 1] [Photo 2].) A widely used system

for describing capsular contracture is the Baker

classification which has four grades, Grade IV being

the most severe(119):

Grade I The augmented breast feels as soft as an

unoperated breast

Grade II The breast is less soft and the implant can

be palpated but is not visible

Grade III The breast is firmer and the implant is

visible or causing distortion of the breast and can

easily be palpated

Grade IV The breast is hard, tender, painful, and

cold. Distortion of the breast is present.

Reports of the incidence of Grade III and IV capsular

contracture range up to 95% in patient populations

reported by s,(120) with lower rates of

contracture reported with saline breast implants and

" low-bleed " breast implants.(121) Dr. Feng presented

recent data to this Panel on the distribution of

contracture grade for the 842 women she had explanted.

Of these women, 67% had Baker Grade III or IV

contracture. She also reported that contracture grade

III or IV was a risk factor for rupture of the implant

Silicone gel bleed has been implicated in numerous

studies in the literature as a basis for contracture

since the 1970s, particularly since the presence of

silicone has been identified in the implant

capsule.(122) Studies have shown that an immune

response to silicone is responsible for the thickening

of the capsule,(123)and, agains, that so-called

" low-bleed " implants have a statistically lower

incidence of capsular contracture.(124)

a) Calcification and Capsular Contracture

Calcification of the fibrous capsule, which is often

seen in severely contracted breasts, has also been

detected in many explanted breast implant

capsules.(125) The calcification is often extensive

and is usually seen in retroglandular-placed implants,

particularly those implanted for many years.(126)

Rolland reported in 1989 that he detected

histologically mineralization of the capsule in 15 of

the 46 (32.6%) capsules he examined.(127) The deposits

were generally found on the internal face of the

capsules at the capsule-prosthesis interface. However,

two of the capsules exhibited mineralization within

the fibrous tissue. Minerals found in the fibrous

capsule are salts of calcium, phosphorus, and zinc and

include carbonate-hydroxylapatite, a hydrated

zinc-calcium phosphate (parascholzite), and hydrated

zinc phosphate (hopeite). tis and Wlodarczyk

also documented the presence of calcium phosphate in

the capsules.(128)

Extensive Fibrosis in Silicone-Exposed Tissue and

Cellular Components of Capsular Contracture

With both injected silicone and silicone breast

implants, the fibrotic reaction in exposed tissue is

remarkably consistent.(129) Many reports in animals

and women show extensive fibrosis in the implant

capsule and in areas of the body where silicone has

migrated or was transported via cellular mechanisms.

This is similar to that seen in silicosis and

scleroderma patients,(130)Histology of the fibrotic

tissue reveals macrophages, fibroblasts, and giant

cells with the presence of silicon and/or silicone

documented by various accepted methods.(131)

The extent of the angiofibroplasia is of particular

importance and distinguishes the manifestations of the

fibrotic capsule - painful contracture and muscle pain

in the exposed tissue - from normal tissue capsules

with other implanted materials. Clinically, the

fibrosis has caused a number of problems including

nerve damage, neuromas, upper chest, shoulder and

extremity regional musculoskeletal pain,(132), (133)

chest pain which may mimic a heart attack and has been

referred to as " pseudo-heart attack syndrome. " (134),

(135), (136)

The mechanism of the fibrotic reaction in capsular

contracture has also been extensively studied and

reported. Thomsen found a positive correlation between

the amount of silicone in the surrounding tissue and

the extent of the inflammatory reaction.(137) The

reaction consisted of fibroblasts, lymphocytes and

plasma cells with droplets of silicone. He stated,

" [t]he positive relation between the number of

fibroblasts and the silicone concentrations indicates

this material is a fibrogenic agent. " McCauley

demonstrated a significant change in cellular

configuration and a progressive reduction in cell

proliferation. Transmission electron microscopy

demonstrated a twofold increase in the rough

endoplasmic reticulum after human fibroblasts were

exposed to silicone polymers.(138) He noted that the

growth rate of fibroblasts actually decreased but

pointed out that the increase in the rough endoplasmic

reticulum of the surviving cells suggested a

subpopulation of cells with altered metabolism: " These

findings suggest significant alterations in the

behavior of human fibroblast subpopulations in

response to silicone polymers. " Lossing reported in

1993 that the inflammatory cells in contracted

silicone gel breast implant capsules including

fibroblasts expressed IGF-1, TGF-, PDGF, NGF and TNF-

immunoreactivity.(139)Modified fibroblasts having

smooth muscle properties, called myofibroblasts, have

also been identified in the capsule surrounding

implants. Myofibroblasts have been reported in

relation to capsular contracture.(140)

Kossovsky also analyzed the surface of silicone

implants from women and experimental animals.(141)

Using scanning electron microscopy and dispersive

x-ray energy spectrography, they found small (2 to 5

m) spheres in a film surrounding the prostheses. These

were not uniform, but aggregated in patches up to 200

m wide. Kossovsky discovered that the silicone

droplets also contained high levels of sodium and

potassium and suggested that the phagocytic cells were

migrating into the envelope wall as a consequence of

gel bleed.

Additional reports by Chase, Hameed, Raso, Emery

(Hardt), O'Hanlon and others describe a variation in

the capsule cellularity observed in silicone breast

implant capsules including reports of

pseudo-epithelialization, synovial metaplasia, and

dynamic cytological changes as a result of the

presence of silicone. Wickman was one of the first to

report on the pseudo-epithelialization of breast

implant capsules around textured breast implants.(142)

He found that capsules of smooth wall silicone

prostheses formed a single collagenous layer and had

sparse fibroblasts whereas the capsules around

textured prostheses had an inner smooth surface

containing epithelial-like cells.

Hameed also reported on capsular synovial-like

hyperplasia which she observed in seven explanted

silicone breast implant capsules.(143) The capsules

were characterized by:

.. . . an exuberant form of papillary villous

hyperplasia (capsular synovial-like hyperplasia, CSH).

Microscopically, the process featured formation of

villous-like folds of capsular membrane with

infiltration of the subcapsular space by histiocytes,

multinucleated giant cells, and chronic inflammatory

cells. The histological appearance bore a striking

resemblance to proliferative synovitis of the joints

associated with orthopedic joint devices.

One of the seven capsules examined by Hameed had an

associated infiltrating duct carcinoma underlying the

capsular synovial-like hyperplasia. Two specimens had

contracture response with infiltration of foamy

macrophages in the scar tissue. The remaining samples

had fat necrosis and foreign body giant cell reaction

with occasional foreign material including silicone

granulomas. Immunohistochemical studies showed a

" striking similarity of the staining patterns of the

synovial membrane of Detritic synovitis and four cases

of CSH . . . . " (144) Hameed concluded that the

histological appearance of the breast tissue

recapitulated detritic synovitis.

Dr. Hardt, who presented her findings to this

Panel, reported in her 1996 article published in

Immunology of Silicones that the anatomy of the

implant capsule resembled that of synovial lined joint

or bursal spaces.(145) Dr. Hardt found that:

.. . . the most superficial layer of cells were

vacuolated mononuclear cells resembling those observed

free in the capsular space. Often, amorphous

proteinaceous material formed the surface of the

capsule, and extracellular droplets of refractile

foreign material were noted to be embedded there.

The amount of cells or nuclei varied depending on the

age of the capsule and how much foreign material there

was from the implant.(146) Early bursa is very

cellular and vascular, and its structure has

perpendicular orientation of the cells to the implant

surface, a pattern recognized as synovial

metaplasia.(147) Ultrastructurally, the implant bursae

are identical to synovium, regardless of the degree of

cellularity. Implants implanted from 1-18 years showed

a great variation in cellularity which did not

diminish with time. The most cellular bursae are those

with macrophages containing multiple small vacuoles of

silicone (oil). The less cellular bursae are those

without foreign material or those with large vacuoles

of silicone gel. Hardt also reached similar

conclusions based on a rabbit implant study which

found that, " reast implant capsules engulf and

transport foreign particulate matter identical to the

mechanism employed by synovial membranes. Therefore,

the capsule is not a static barrier, but a

physiologically active transport system. " (148) These

findings were also made by Chase who reported

" profound pseudo-epithelialization " around implants

similar to the short-term changes seen in tissue

around implanted orthopedic devices.(149)Chase noted,

like Hardt, that the degree of cellularity and

synovial metaplasia related to the type of implant and

its integrity, and that the cytological changes around

the implants appear to be dynamic in nature.

In 1996, O'Hanlon reported in Immunology of Silicones

that he observed epithelioid cells in the

pseudo-synovial layer of the capsules which showed

strong OPD4 and HLA-DR staining indicating activation

of cells with phagocytic characteristics.(150)

Similarly, Helbich in 1997 reported that a woman who

had received silicone injections developed multiple

silicone granulomas in her breasts. Histology revealed

that the granuloma had a pseudo synovial layer inside

the fibrous capsule, chronic granulomatous

inflammation which did not disappear with time, and

foreign body giant cells within the granulomatous

cyst.(151)

Stark's research in 1990 provides confirmatory support

that the capsule surrounding silicone gel breast

implants is immune-mediated.(152) He reported that

intraluminal cyclosporine A reduced capsular thickness

around silicone implants in female Sprague-Dawley

rats. Cyclosporin A, which is a highly potent

T-lymphocyte-specific immunosuppressive agent used in

organ transplant surgeries, was placed inside the

implant where it diffused slowly through the outer

shell of a standard double-lumen silicone breast

implant. Ten controls were implanted with round tissue

expanders containing only 50 mg of cyclosporine A.

After three months, there was a significant decrease

in collagen capsular thickness of 21.6 + 5.69 m (mean

_standard deviation was measured histomorphometrically

in the treated group) versus 39.06 m _8.63 standard

deviation in the controls (p < 0.001, t - 4.933).

Stark suggested that:

Cyclosporine A interferes with the induction of

T-helper cells and cytotoxic T cells. This leads to an

inhibition of the release of interleukin-1 as well as

interleukin-2. Interleukin-1, a fibroblast

proliferation factor, can be responsible for an

excessive collagen deposition. In vitro T-lymphocyte

lymphokines stimulate fibroblast migration and

replication as well as collagen synthesis. The

reduction in capsular thickness in the experiments

could be due to the immunosuppressive effect of

cyclosporine A by blocking the release of these

trophic factors. This would support the immune theory

of capsule formation.(153)

This body of work confirms the scientific opinions

given during plaintiffs' presentation offered to this

Panel.

Progressive degenerative changes and chronic

inflammation in breast implant capsules have also been

reported extensively, as discussed below. The

uniformity of observations seen histologically by Dow

Corning consultant, Dr. Kaminski, led him to

report in 1977 that this was not a " typical foreign

body reaction, " but that it was a " specific type of

reaction [he had not] seen so far with implant

materials. " (154) Thus, the scientific evidence

convincingly demonstrates that the fibrous capsule

surrounding the silicone breast implant is not a

normal foreign body response as suggested by the

manufacturers. Rather, it is a unique, atypical

reaction with immunological significance.

4. Gel Bleed and Rupture

a) Gel Bleed Is Undisputed

Noted in Figure 5 of Dow Corning's Medtox report, the

first step in the inflammatory process in breast

implant capsules is the bleeding or leaching of

silicone gel and low molecular weight cyclics

contained within the thin silicone elastomer into

surrounding tissue immediately after implantation. The

silicone is phagocytized and can be seen in vacuoles

as a refractile, non-birefringent material by electron

microscopy, infrared spectroscopy, atomic absorption

spectrophotometry and other procedures.(155)

Histologically, the tissue is characterized by an

infiltration of mononuclear cells which include

macrophages, fibroblasts, lymphocytes, eosinophils,

mast cells, foreign body and multinucleated giant

cells and plasma cells.(156) Dow Corning summarized

the role of gel bleed in the inflammatory process in

the Medtox report in 1987, likening it to an " infinite

sink " or reservoir of gel which is slowly and

continuously released into the body:

[t]he greater incidence of macrophages and giant cells

is more characteristic of a chronic inflammatory state

than usually seen around elastomer implants in the

absence of abrasion particles . . .. The resinous

component of the gel may tend to retard the rate at

which fluid polymer can become available for

phagocytosis. As a consequence, the inflammatory

reaction is of a persistent chronic type with clearly

evident connective tissue encapsulation. In the case

of free gel, progressive gel subdivision by connective

tissue septa is superimposed on encapsulation of the

entire gel mass.

Silicone gel contained within a silicone elastomer

shell induces a chronic inflammatory reaction with the

same characteristics as noted for free gel. It is

probable, however, that resolution is never entirely

achieved because the permeation of fluid through the

shell is very slow and constitutes a rate-limiting

process. That is, the contained gel functions as an

infinite sink.(157)

Surgitek, another manufacturer, also acknowledged the

risks associated with gel bleed in an internal report

on the " Risks And Benefits Of Silicone Gel-Filled

Breast Implants: A Summary Of Findings In The

Literature. " (158) The Surgitek report stated:

ilicone gel bleed through the intact envelope of

breast implants is a serious risk associated with

implantation of all silicone gel-filled breast

implants, regardless of design. Gel bleed may result

in deposition and migration of free silicone in the

body leading to capsular contracture, silicone

granuloma, lymphadenopathy and other unknown systemic

toxic effects.(159)

Thus, the manufacturers' internal -- and undisclosed

-- data on gel bleed and its significance is

confirmatory of what scientists noted during

Plaintiffs' presentation.

Rupture Rates Of Silicone Breast Implants

Silicone gel is also dispersed throughout the body

when the breast implant ruptures, spilling large

quantities of silicone. The most recently published

data on silicone breast implant rupture rates

summarizes prior rupture articles and concludes that

the failure rate " raises very serious questions about

the safety of silicone gel implants. " (160)

The data, depicted on the graph above, consists of a

failure rate master curve constructed from the

reported data on 1,652 explanted prostheses

cumulatively reported in some of the literature. The

curve demonstrates a " significant direct correlation

of failure rate with implant time and a failure rate

that is so high that one must seriously question the

safety of this device for general clinical use due to

biomechanical failure problems alone . . . . "

The data, presented by biomaterials specialist, Dr.

Eugene Goldberg, Biomedical Engineering Center,

University of Florida, had been accepted for

publication and was in process when another article by

Cohen was published in May 1997.(161) Cohen examined

350 implants from 159 women and found that 63% of

implants in place for 12 or more years were not

intact. Additional evidence of the extremely high rate

of failure with silicone breast implants was presented

to the Panel by Dr. Lu-Feng, who discussed her

data from the explantation of 1,619 implants.(162)Her

data revealed a rupture rate in excess of 67% for

implants that had been in place for more than 10

years.

That breast implants have a high failure rate is not

surprising since studies have found that exposure in

vivo weakens silicone gel breast implant shells over

time. A 1996 study by Greenwald demonstrated that the

elastomer shells weakened over time through host

responses which altered the physical properties of the

shell material.(163) He stated, the data

" demonstrate that the human body is able to alter

the material properties of silicone shells to the

point that they become weaker and more compliant over

time. " Further, he confirmed that shell elasticity

also decreased over time, a finding which has been

widely reported in the literature.

Other data also demonstrates that the elastomer shells

weaken ex vivo. For example, in 1981 Dow Corning

tested the physical properties of standard breast

implant envelopes after they had been filled with

gel.(164) After only one year, the envelopes showed

marked differences in shell strength:

STANDARD MAMM.

t=0 t=1yr % Decrease

Tear 98 21 78.6

Tensile 808 553 31.6

Elongation 669 513 23.3

The reasons for the acknowledged loss of strength are

two-fold. First, the loss of tensile strength has been

attributed to the swell of the gel.(165) Second, once

in the body there is a further loss of strength due to

the uptake of lipids.(166)

The scientific evidence for the failure of silicone

gel breast implants is well-substantiated and provides

a reliable basis for one to conclude that the implants

rupture at an increasing rate over time, with

resultant spillage of silicone into the breasts.

5. Gel Bleed Has Been Documented in Breast Implant

Capsules

The finding of silicone gel, gel microdroplets,

silicon and microparticles of silicone elastomer

within the breast implant capsule is extensively

documented in the literature(167) and is no longer

disputed by the manufacturers or within the medical

community. While the manufacturers historically

claimed that the fibrous implant capsule contained the

gel bleed and gel from ruptured breast implants, a

number of studies have proven this claim to be

incorrect. For example, a recent article by Beekman

affirmatively demonstrated that the gel bleed of low

molecular weight fluids was not contained by the

fibrous capsule surrounding the implant, but rather

that the low molecular weight cyclics migrated through

the intact capsule wall into the pericapsular

space.(168) In this study of 71 silicone breast

implants and capsules removed from 40 patients, the

authors were able to classify the gel bleed by the

detection of silicone particles in the capsule

confined to the inner half of the capsule thickness

(Stage 2), the outer half of the capsule thickness

(Stage 3), and particles outside the capsule (Stage

4). Gel bleed was detected in 67 of the 71 capsules,

with 26 containing gel in the inner thickness, 24

containing gel in the outer thickness, and 17

containing gel completely outside of the breast

implant capsule. The degree of silicone migration was

significantly more in patients implanted longer than

12 years.

6. Silicone Gel Bleed Contains Low Molecular Weight

Extractables

Researchers have also reported on their analysis of

the molecular components of the gel bleed from breast

implants. It is well-accepted that the gel bleed

consists of the entire range of the various components

contained in the implant, including low molecular

weight cyclics D4 and D5. The FDA's analysis of the

components of the bleed from Dow Corning's implants

showed that it was comprised of 80% compounds of low

molecular weight cyclics with approximately 4%

considered very low molecular weight.(169)

7. Systemic Gel Migration

Systemic migration of silicone has been reported in

virtually every study conducted internally by the

manufacturers since the first study Dow Chemical and

Dow Corning conducted in 1956. In that study,

conducted several years prior to the development of

silicone gel breast implants, C14 labeled

polydimethylsiloxane (PDMS) fluid contained in an

antifoam emulsion was given orally to one albino rat

and two lactating dogs. One rat was given an

intramuscular injection of the pure DC 200 fluid

(fluid which is chemically identical to the DC 360

fluid contained in breast implants).(170) After one

week, the rat injected with DC 200 fluid was

sacrificed and tissue samples were taken. C14 labeled

PDMS was recorded (in order of highest concentrations)

in the intestines, right adrenal, skin and hair,

heart, skull bone, brain, kidney, urine, liver,

muscle, lung, peri-renal fat, blood and spleen.

Similar findings were obtained in the animals given

the DC 200 fluid in the antifoam emulsion. Tissue from

the rat showed the presence of the C14 labeled

material (in the order of highest concentrations) in

the ileum, stomach and content, bladder and urine,

kidney, liver, heart, lung, muscle, spleen, adrenal,

testes, thyroid, brain, skull bone, skin and hair.

Siloxane was found in the two lactating dogs in the

skin and hair, brain, bile, liver, kidney, heart,

milk, urine, skeletal muscle, lung, adrenal, blood,

pancreas and thyroid. In a follow-up study, silicone

was absorbed through the skin of a rabbit within hours

and was found in the adrenals and kidneys.(171)Several

years later, Dow Corning received data showing that

the polymer size may affect transportation of silicone

across the G.I. tract and ultimately to the kidney,

liver, and urine.(172)

Subcutaneous injection of DC 360 fluid in dogs also

showed systemic distribution to the gastrointestinal

tract, in the aorta, to the lymph nodes and salivary

glands, liver, spleen, kidneys, heart, lungs and

brain.(173)

Another joint Dow Chemical - Dow Corning study in 1970

found Dow Corning 360 fluid adhered to the exterior

surface of the cellular elements of the bone marrow in

Sherman rats.(174)Systemic distribution of silicone

was found in the lung, liver, kidney, heart, pancreas,

adrenal and spleen.

While the internal manufacturers' studies remained

" restricted " and were not published or disseminated to

the medical community, other researchers reached

similar conclusions and reported on gel migration and

histologic examination of silicone-exposed tissue in

the published peer-reviewed literature. Further

evidence was presented to the Panel by Dr. Hardt who

found elevated levels of silicone in the brains and

spleens of rabbits implanted with ruptured silicone

implants which was statistically significant when

compared to rabbits implanted with saline implants or

intact silicone implants.(175) Systemic silicone

migration is now so extensively documented that it can

no longer be seriously disputed by the manufacturers.

Silicone migrating from silicone breast implants in

women has been found in the axillary lymph nodes(176),

alveolar lymph nodes(177), brachial plexus, shoulder

joint and base of the neck,(178) the medial nerve at

the elbow resulting in compression neuropathy,(179)

arms, fingers and groin(180), arm resulting in

neuropathy and dysthrophy,(181) lower abdomen and

groin area,(182) and liver(183)of implanted women.

These findings are consistent with reports of solid

silicone and silicone elastomer abrasion or

particulization with migration of the " microshards "

and particles to the regional lymph nodes from other

types of implantable silicone devices,(184) as well as

silicone migration from implants such as buttock

implants.(185) Gel migration in implanted women is

also well-accepted, as evidenced by Brinton's recent

paper in which she noted systemic silicone gel

migration from ruptured breast implants and intact

implants with gel bleed.(186)

As will be discussed in the immunology section, gel

migration raises serious immunologic implications,

particularly since research has uniformly reported

that free silicone in the body is subdivided into

numerous - indeed billions - of microdroplets of gel,

and that these extremely small gel fragments are

intensely inflammatory. The importance of gel

migration is summarized in a 1985 memo by a senior Dow

Corning scientist. He wrote, " The phenomenon of

silicone migration within the body is very central " to

the question of immunomodulation.(187)

8. Silicone Lymphadenopathy

As free silicone escapes the implant and migrates

through the fibrous capsule, it is transported to the

lymph nodes where it accumulates and often results in

silicone lymphadenopathy.(188)Silicone lymphadenopathy

is characterized by enlarged, painful nodes and

tenderness. Dr. Feng's recent presentation before this

Panel reported on 169 silicone-containing nodes in the

axillary, retropectoral, internal mammary chain,

supraclavicular, inframammary, and infraclavicular

areas.(189) Kao also reported in January 1997 on

silicone migration and lymphadenopathy in the internal

mammary nodes that mimicked recurrent breast cancer in

an implanted mastectomy patient.(190)Similarly, other

reports document silicone lymphadenopathy in women

with intact and ruptured silicone implants(191), and

in persons implanted with other types of silicone

devices.(192)

Histologically, the silicone " engorged " lymph nodes

resemble the reaction seen in tissue exposed to

silicone.

9. Silicone Granulomas

Among the three experts on granulomas cited in Dow

Corning's 1987 Medtox report was Dr. Epstein,

who presented his experience of 45 years of research

on granulomas to this Panel. Dr. Epstein defines a

granuloma as, " [a] locally confined persistent

response to the presence of a generally poorly soluble

substance, mediated through the accumulation,

proliferation and differentiation of cells of the

mononuclear phagocytic system. " (193) Other definitions

of a granuloma also recognized by Dow Corning include:

[a] focal chronic inflammatory reaction characterized

by the accumulation and proliferation of leukocytes

principally of the mononuclear type. (194)

and:

[a] granuloma is a compact collection of mature

mononuclear phagocytes which may or may not be

accompanied by accessory features such as necrosis or

the infiltration of other inflammatory leukocytes.

(195)

Silicone granulomas, or siliconomas as they are

sometimes referred to in the literature, have been

reported as early as 1964 (the year silicone breast

implants were first made commercially available). They

have been reported following silicone injections in

animals(196) and humans,(197)silicone gel breast

implantation(198) and implantation of other types of

gel,(199) in solid silicone implants including

orthopedic silicone elastomer implants,(200) silicone

plate,(201)TMJ,(202)and ophthalmology implants,(203)

in genitourinary devices,(204) and in patients exposed

to silicone tubing during hemodialysis.(205)

There are several types of granulomas that are

well-recognized and described with great specificity

in the granuloma literature which are relevant to the

types of granulomas found in women with silicone

breast implants. The first is a histiocytic granuloma,

which is defined as a tissue reaction pattern

characterized by an infiltrate composed predominantly

of histiocytes. Other cells are also present in small

numbers including lymphocytes, multinucleated giant

cells, plasma cells, foci of epithelioid cells and

fibroblasts. Known diseases associated with

histiocytic granulomas include lepromatous leprosy,

histoplasmosis, leishmaniasis, rhinoscleroma,

malakoplakia and Lobo's disease.(206)

Foreign body granulomas are characterized by tissue

reaction in which the giant cell is the most

conspicuous member of the granulomatous infiltrate.

Foreign bodies which elicit the reaction include

various minerals, polyethylene, and steel.

Delayed hypersensitivity (immunogenic) granulomas are

defined by a histologic pattern that may have elements

of an acute, chronic and granulomatous process.(207)

The epidermis may show pseudoepitheliomatous

hyperplasia as well as thinning or atrophy. The dermis

and subcutaneous tissue generally show an infiltrate

composed of neutrophils, eosinophils, lymphocytes,

histiocytes and multinucleated giant cells against a

background of fibrocapillary proliferation and

occasional necrosis. They are also referred to in the

literature as mixed inflammatory

granulomas.(208)Diseases associated with mixed

inflammatory granulomas are well-documented including

chronic granulomatous disease.

Silicone granulomas have been widely reported in the

breast implant literature as well as the silicone

injection and other silicone implant product

literature, as set forth in Tables 1 and 2. Their

immunological significance has often been overlooked

by pathologists examining experimental animals who

developed lesions in silicone-exposed tissue and

organs and in women with silicone breast

implants.(209) This is due in part to the lack of

familiarity with the extensive and specialized field

of granulomas and granulomatous inflammation. As

previously pointed out, Dow Corning could identify

only three recognized experts in the United States in

1987 on this issue.

(210) Also, as set forth by Dr. Hardt:

[p]athologists first look for evidence of cancer, then

in the case of implant related capsule, the foreign

material is the next most important observation. In

few of the original reports were the inflammatory

responses characterized, indeed only 30 of the 56

patients with granulomata had been so identified. This

indicates that literature indicating that inflammation

is rare in implant related tissues is less than

accurate. Surely we see best those things that we look

for.(211)

Dr. Hardt, in fact, after re-reviewing Dr. Epstein's

presentation on granulomas to this Panel, re-reviewed

304 breast implant capsules from 171 patients

explanted between 1979 and 1997.(212)Upon re-review,

Dr. Hardt found granulomata in 33% of the

patients.(213) Her findings, which she described as

" remarkable " match the histologic features of the

delayed hypersensitivity granulomas described by Dr.

Epstein (macrophages, lymphocytes, plasma cells,

eosinophils and giant cells).(214)As discussed below,

she also found consistent histologic features for

chronic inflammation in silicone breast implanted

women.

Dr. Epstein's knowledge and experience with 45 years

of work devoted solely to granulomas remains the best

source for interpreting the immunological significance

of the inflammatory cell infiltrate in silicone

granulomas. In his presentation to the Panel, he

stated that silicone-induced granulomas can be

cytotoxic or immunogenic, and that the entire roster

of inflammatory cells may be drawn into the

lesion.(215)His chart depicting the inflammatory

progression shows that with these types of granulomas

in silicone-implanted women, the mononuclear phagocyte

system is incapable of fully halting the proliferation

of the offending agent - silicone - and additional

inflammatory processes, including humoral and cellular

immunity, are called into play. (See chart on

following page.)

Dr. Epstein further reported that in the beginning of

the granuloma formation, lymphocytes and macrophages

are present. Later, as the macrophages are unable to

phagocytize the silicone particles, giant cells are

formed and plasma cells and eosinophils begin to

appear.

He also observed that the presence of eosinophils in

silicone-exposed tissue and granulomas marks the

progression of the disease process from a T-1 to a T-2

type response.(216)

Dr. Epstein's findings that silicone induces

hypersensitivity granulomas were recently presented at

the International Congress on Sarcoidosis,

Granulomatous and Vasculitic Disorders on September

19, 1997. His poster presentation, which is being

prepared as a full article for publication, states:

[w]e have examined over 30 cases submitted to

litigation because of dire results from the implants,

by light and polarizing microscopy. We found, in

addition to silicone bodies and distinctive

polyurethane crystals in macrophages and giant cells,

that occasionally large amounts of silicon dioxide

could be found in the tissue by polarizing microscopy.

Furthermore, in virtually every case, we have observed

in the perivascular area surrounding the granuloma

clusters and collections of small lymphocytes, plasma

cells and often large numbers of eosinophils and

polymorphonuclear leukocytes. Often these are seen in

nearby breast muscle tissue. The findings indicate

that the tissue reaction to the breast implants is far

more than a simple foreign body granuloma. We propose

that this response is a form of granulomatous

hypersensitivity in which a T-1 microenvironment of

the granulomas has been converted to a T-2

microenvironment, predisposing the patient to an

autoimmune disease as occurs in many parasitic

granulomas including schistosomiasis and lepromatous

leprosy and is also seen in diseases such as atopy and

HIV infection.(217)

Potter, of the National Cancer Institute, and others

reported on the development of inflammatory silicone

granulomas in mice injected with Dow Corning 360 fluid

from breast implants.(218) They reported that:

n the early silicone granulomas, interstitial

tissue between silicone vacuoles contained scattered,

isolated plasma cells and body cells.

Plasmacytosis (i.e., clusters of plasma cells) was

also observed in the silicone granulomas of some of

the mice: these plasma cells had relatively low

nuclear-to-cytoplasmic ratios, and their cytoplasms

stained pink in the hematoxylineosin preparations.

Also,

[t]here was a considerable increase in the deposition

of a highly eosinophilic, collagenous material around

the vacuoles. The most striking difference between the

short silicone exposures ( 200 days) and the long

silicone exposures ( 400 days) was the absence in the

latter of the cellular matrix containing macrophages,

neutrophils, and other connective tissue cells between

the vacuoles that predominates after the shorter

periods of silicone exposure. Perivascular lymphocytes

could be seen frequently in the older silicone

granulomas, and plasma cells were occasionally present

as well.

Based on the histologic observations, Potter suggested

that the inflammatory silicone granulomas " play an

important role in the development of the plasma cell

tumor. " He observed that inflammatory silicone

granulomas seemed to depend on " fresh " or continuing

release of silicone gel to the tissue. This could

explain why multiple injections of silicone gel were

more effective at inducing plasmacytomas compared to a

single injection of gel.

Potter's findings are consistent with the " infinite

sink " of continuous gel bleed from silicone gel breast

implants as described by Dow Corning(219) and as

documented in numerous internal and published studies

on gel bleed.

The immunological implications of these findings for

implanted women and the disease processes known and

accepted in the literature on granulomas and

granulomatous disease are not disputed within the

medical community. There is an extensive body of

published work spanning over 80 years (dating back to

the first reports of silica-induced granulomas in the

early 1910s) which supports the same progression and

mechanism of disease association and immune

dysfunctions reported in silicone implanted women. Dr.

Epstein himself has been a prolific author, having

published over several hundred articles on granulomas

and granulomatous inflammation and disease. Indeed,

much of the published literature and texts on

granulomas refer to his work.(220)

In contrast to Dr. Epstein's presentation, the

manufacturers did not offer any scientific evidence

concerning granulomas to this Panel. There is a

credible and sound scientific basis for one to

conclude that hypersensitivity silicone granulomas,

found in some women with silicone breast implants, can

cause disease symptoms and immune dysfunctions.

10. Chronic and Granulomatous Inflammations

a) Experience with Liquid Silicone Injections

The tissue reaction to silicone from breast implants

" is similar to that produced by a fluid polymer. " (221)

This is demonstrated in the many reports summarized in

Table 1. Thus, the extensive histopathologic

information gathered on tissue exposed to injected

silicone is highly relevant to the present discussion.

While there are undoubtedly some cases of silicone

injection involving adulterated silicone as the

manufacturers point out, the examples cited herein

focus on injections of pure, " medical grade, " all

methyl silicone polymer and principally Dow Corning

360 fluid.

As early as 1967, Rees reported that Dow Corning MDX

4-4011 silicone (which was the designation given in

the clinical trials for the DC 360 silicone fluid used

in breast implants) was deposited in the spleen,

liver, adrenals, pancreas, ovaries, abdominal lymph

nodes and kidneys of female albino mice of CF and

Swiss Webster strains after intraperitoneal

administration.(222) There was considerable alteration

of the tissue structure of the subcutis, varying

degrees of atrophy in the fat cells immediately

adjacent to the encapsulated silicone, and widespread

microscopic lesions in all parts of the hepatic lobule

of the liver and interstitial renal lesions. Histology

showed a finely granular, eosinophilic cytoplasm and,

in many abdominal organs (adrenals, lymph nodes,

liver, kidney, spleen, pancreas and ovary) there were

focal infiltrates of macrophages with abundant clear

cytoplasm containing silicone droplets.

(223) and Ben-Hur(224) reported similar findings

in 1967. Ben-Hur found that liquid silicone injected

peritoneally into female mice migrated into the lymph

nodes of the axilla, groin and mesentery.

Bronchopneumonia of the left lung developed in one

mouse nine weeks after injection; another developed a

fine nodular liver. Histologically, the lymph nodes in

the axilla and groin evinced " focal collections of

histiocytes filled with abundant clear 'cytoplasm' in

the marginal sinus. " Silicone fluid was also

metabolized through other organs including the liver,

spleen, ovary and renal glomeruli. Silicone injections

of DC fluid in primates in 1967 showed foreign body

giant cells in breasts, acute necrotizing pneumonitis

in the lungs; similar changes in the submaxillary

gland, degenerative changes in the kidneys, pleural

fibrosis and edema in the lungs, small and large

cystic spaces in the dermis and subcutaneous tissues,

focal calcification in the adrenal glands, chronic

stomach inflammation, and chronic pyclonophritis in

the kidneys.(225) 's injections of DC silicone

in squirrel monkeys, rats and rabbits from 1967 - 1971

found similar results including inflammatory reaction

with the presence of polymorphonucleated cells,

eosinophils and lymphocytes.(226)

In 1968, a series of articles by Brody(227),

Nosanchuk(228), Minagi(229), and Symmers(230) further

documented the widespread deposition of liquid

silicone systemically in various animal models and in

women who had received injections in their breasts;

the ingestion of the silicone by macrophages; the

formation of silicone granulomas at sites distant to

the site of injection; and acute and chronic

inflammation present in the tissue exposed to

silicone. Nosanchuk, for example, injected Dow Corning

360 fluid and complete Freund's adjuvant in six male

guinea pigs. After three weeks, he observed

microscopically a " granulomatous reaction with focal

necroses and numerous cystic spaces, surrounded in

part by histiocytes. " Scattered lymphocytes, plasma

cells and marked sinus histiocytic proliferation were

also present in the lymph nodes where the silicone was

found. Adhesions were noted on the surfaces of the

liver and spleen. In the women injected with Dow

Corning 360 fluid, Symmers found extensive bilateral

granulomatous mastitis after 18 months. The breasts

were studded with tender, ill-defined nodules ranging

up to 3 cm; had visible nodularity; the breast skin

was blotchy and reddened; the lymph nodes on the

medial wall were large, firm and tender and, biopsy

revealed sclerosing granuloma with associated fat

necrosis. Symmers reported that the lymph node biopsy

showed an unusual reaction of the histiocytes which

was comparable to that seen in histological changes in

lymph nodes in lepromatous leprosy and lipidoses (a T2

cell-mediated immune disease) although he could find

no evidence of lepromatous leprosy or lipidoses in the

injected women.

Numerous similar observations were made throughout the

1970s and 1980s as documented in Table 1. Of interest

is an article by Vinnik and Russel entitled " Silicone

Mastopathy With Complications In Facial

Injections. " (231) Dr. Vinnik, a Nevada plastic surgeon

who treated numerous women injected with silicone in

their breasts, reported on the complications seen in

these patients and in those who received injections in

the face. Complications included marked skin fixation,

erythema, skin edema, ischemic necrosis, mild

inflammatory response characterized by fibrosis and

multinucleated giant cell; marked cellular response

with many lymphocytes, histiocytes, plasma cells and

giant cells; silicone exuding through necrotic skin;

cyanosis; facial muscle fibrosis evidenced by

difficulty opening the mouth; itching; multiple

granulomas; and, giant cells filled with foamy

material. Also, Lavey reported in 1985 that a patient

who had been injected with silicone in her upper and

lower lip, glabella and nose developed pain and

erythema at the injection sites three years

later.(232) Examination of a biopsy specimen

demonstrated a reaction to a foreign material with

inflammation and fibrosis consistent with a

silicone-induced granuloma. The involved skin was

excised. Nine months later, however, she received a

P.P.D. (TB skin test) in her arm which triggered the

previous distant silicone injection site to once again

become erythematous and indurated. Lavey suggested

that the patient had a cellular immune response from

the previously injected silicone. Lavey's report was

strikingly similar to a 1978 by Pearl, who reported on

a woman injected with a dimethyl polysiloxane polymer

in the left eyebrow, glabella, nose and lower

eyelids.(233) Several years after the injections, the

woman had a P.P.D. test in her forearm and experienced

a cellular immune reaction at the site of the

injections. Biopsy revealed a chronic inflammatory

process consistent with a granulomatous response to

silicone.

The effects of silicone injections including severe

necrosis and atrophy of the skin over injected

sites(234) has led to radical mastectomy,(235)

substantial cosmetic revisions in the forehead, cheek,

eyelids, nose and glabella.(236)

The Silicone Breast Implant Experience

Animal models of rats, rabbits, and monkeys implanted

with silicone gel breast implants document silicone

migration through the implant capsule into the

surrounding tissue as well as inflammatory

granulomatous reaction in the capsule tissue and

surrounding area characterized by a significant number

of eosinophils,(237) chronic inflammation with foreign

body giant cells, multinucleated giant cells,

histiocytes, leukocytes, and plasma cells, and

macrocytic activity in the capsules. For example,

Medical Engineering Corporation (Surgitek) conducted a

study on silicone gel breast implants implanted in

rabbits in 1971.(238) At 2, 3 and 5 months,

multinucleated giant cells were found. At nine months,

the brain showed a mild leptomeningitis; the lung had

early interstitial pneumonia; there was considerable

distention of the pulmonary veins as well as pulmonary

artery hypertrophy in certain lung sections which

represented subpleural pulmonary parenchyma, a mild

interstitial inflammatory reaction in one of the

kidneys; pigment laden macrophages in the spleen; and,

a " remarkable centrolobular fatty change " with central

vein distention and enlargement of the central sinuses

in the liver. The heart also showed a variation in the

eosinophilic tone of the myocardial fibers and loss of

individual myocardial fibers with accompanying acute

inflammatory response, granulocytes and histiocytes.

At ten months, the brain " presents a high power field

of relatively acute encephalitis with destruction of

the brain parenchyma and inflammatory reaction in the

perivascular spaces.... Lung tissue reveals

engorgement and hemorrhages and marked post mortem

autolysis. " The lung tissue was " deeply engorged,

hemorrhagic, and shows focal areas of inflammatory

reaction accompanied by mononuclear and

polymorphonuclear aggregations within the distended

bronchioles. " Id.

Likewise, Heyer-Schulte's 90-day animal implant study

in 1978 showed a " chronic inflammatory reaction,

granulomatous in nature; " " fairly extensive

infiltration of mononuclear phagocytes, lymphocytes

and occasional hetrophils; " and, " chronic

granulomatous lesions. " (239) Studies on human data

report identical findings. For example, pathology

reports received by a manufacturer, McGhan Medical,

describe a silicone granuloma, partially necrotic

granulation tissue which was heavily infiltrated by

polymorphonuclear leukocytes, plasma cells and foreign

body giant cells.(240) The pathological reaction to

silicone from a breast implant is illustrated by the

photographs on the following pages.

Dow Corning received similar reports from Dr.

Kaminiski based on his examination of 20 breast

implant capsules.(241) He found extensive chronic

inflammation in all the tissue samples, perivascular

round cell infiltration, and an atypicalforeign body

reaction. The reaction was the same in all the tissue

samples:

[t]he capsule shows degenerative changes of the

connective tissue and a fairly significant degree of

inflammation of the subcapsular tissues - particularly

the residual breast tissues, which show extensive

chronic inflammation and perivascular round cell

infiltration....

To a lesser or greater extent, all tissues are

affected, there are some slight differences here and

there, but these differences are, as I just said, most

significant in that I have difficulty in explaining

this uniform chronic inflammatory reaction of

subcapsular tissue which is not a typical foreign body

reaction.

The similarities between the tissue reaction and

complications seen in breast implanted women and those

who had received silicone injections did not go

unnoticed. Dr. Vinnik repeatedly telephoned the Dow

Corning Center For Aid To Medical Research and wrote

to them reporting that women with silicone breast

implants were experiencing the identical fat necrosis

and the " same typical inflammatory and foreign body

reaction " that he had seen in silicone injection

cases.(242)

--------------------------------------------------------------------------------

Figure 9

" Swiss cheese " pattern by regular light but with

condenser down and slightly off focus, making silicone

much easier to see. Hematoxylin and eosin. Original

magnification 100X.

Figure 12

Clustered granulomas. Dark field illuminated and

showing abundant silicone in lacunae. Hematoxylin and

eosin. Original magnification 100X.

Figure 13

Dense capsular scar formation with silicone deposits

undergoing micronization. In lower right is a piece of

multistrand suture. Normal lighting. Hematoxylin and

eosin. Original magnification 100X.

Figure 15

Bulk silicone deportation. Ruptured gel filled implant

with multiple sites of migratory gel. This large

collect is in the soften tissues of the parametrium,

specifically the broad ligament. Normal lighting.

Hematoxylin and eosin. Original magnification 100X.

Figure 17

Bulk silicone deposits with chronic

inflammation...lymphocytosis. Silicone is refractile

with substage condenser lowered slightly. Normal

lighting. Hematoxylin and eosin. Original

magnification 100X.

Figure 18

Intense lymphocytosis in area with coarse globules of

silicone gel. This patient had little granuloma

formation three to four years after implantation. No.

rupture. Normal lighting. Hematoxylin and eosin.

Original magnification 100X.

--------------------------------------------------------------------------------

Likewise, Smahel reported in 1979 on the histological

observations from 13 fibrous capsules from 10

implanted women.(243) He noted the similar responses

in injected women and tissue exposed to silica. He

concluded that the common occurrence of plasma cells

in the vicinity of the silicone " suggests

immunological activity.... " That same year, 1979,

Gayou reported finding discrete droplets of

silicone gel ranging from 10-75 in the majority of the

capsule specimens, an increase in cellularity

(primarily fibroblast) in the contracted capsules, and

an increase in the number of macrophage cells.(244)

Similarly, an internal document from Surgitek

acknowledged that the histochemical observations

reported in the literature from silicone breast

implants shows that " silicone is capable of eliciting

a cellular immune response that can be demonstrated by

the migration inhibition technique. This response is

comparable to that elicited by purified protein

derivative and suggests that silicone may act as a

hapten-like incomplete antigen . . . . " (245)

In 1985, Dolwick reported on granulomatous

inflammation, multinucleated giant cells associated

with the silicone materials, and telangiectasias in

the areas of reaction to silicone in eight patients

with silicone TMJ implants.(246)He concluded that the

indigestibility of the silicone and the presence of a

cell-mediated immunity to the inciting agent led to

the formation of the granuloma. A similar reaction was

observed in a silicone plombe implanted in the

sclera.(247) Eight years after implantation, the

patient presented with inflammation of the tissue and

partial protrusion of the sclera. Cellularly,

macrophages, giant cells and erythrocytes were

observed indicating a foreign body granuloma. The

author concluded that the presence of lymphocytes in

and on the surface of the pores indicate that silicone

elicits an immunoresponse in the category of chronic

inflammation. Similarly, Dow Corning acknowledged in

an internal document that implanted silicone breast

implants lead to granulomatous and chronic

inflammation, and that the consequence of the specific

immune response to silicone resulted in " severe

disruption of immunoregulatory functions . . . . " (248)

Mitnick reached similar conclusions in 1993 in his

report of six women with silicone breast

implants.(249) All had silicone granulomas related to

silicone gel bleed from implantation ranging from 7-18

years earlier. He stated that the silicone gel

elicited a cellular immune response characterized by

multinucleated macrophages and cyotic spaces with

refractile silicone. Hameed reported in 1995 on the

immunohistochemical analysis of the capsules from

seven women with silicone breast implants. He noted a

" striking similarity of the staining patterns of the

synovial membrane of detritic synovitis and four cases

of capsular synovial-like hyperplasia. "

Immunoreactivity for PNA and Con A, known histiocytic

markers, was established.

Dr. , the pathologist who presented to this

Panel on behalf of the manufacturers, agreed that

silicone granulomas and chronic inflammation were seen

in tissue exposed to silicone, and that the

pseudo-synovial appearance of the capsule or

synovialization was an inflammatory process.(250) On

the surface of the capsule is a proliferation of cells

which have a peculiar and somewhat bizarre epithelial

appearance, thus, the body of literature on the

effects of synovial capsules and synovitis is

particularly relevant to this inquiry. He also agrees

that long-term chronic inflammation can cause systemic

symptoms and immune disease. Other pathologists

concur.(251)

For women with silicone gel breast implants, the

surface area of granulomatous reaction is extremely

large. As Dr. Epstein explained to the Panel, the

combined weight of the implants signifies a relatively

large depot of foreign material slowly released to the

body through the synovial lining of the capsule. If

that lining is disrupted through external or internal

capsulotomy, the release of silicone to the body may

be much more rapid.(252)

Pathologists Hardt and Shanklin, both of whom have

examined hundreds of silicone breast implant capsules,

lymph nodes, and silicone-exposed tissue and who have

conducted research on the immunopathologic

significance of the cellular infiltrate, report

similar observations. Dr. Hardt's re-review of all

silicone implant-related tissue samples from 1971

through 1997 showed that there were two types of

inflammatory responses observed.(253)

She states:

[a] paucity of histiocytes was accompanied by

polymorphonuclear leukocytes and a few lymphocytes and

plasma cells were seen in 22 capsules of 16 different

patients.

The rest of the patients had moderate to large

infiltrates of histiocytes accompanied by lymphoid

aggregates punctuated with plasma cells. In many

cases, the histiocytes were more superficially located

in the capsule, and the plasma cells and lymphocytes

were deeper in the collagen layers or, alternatively,

located in the soft tissue deep to the capsule.

Epithelioid histiocytes and formed granulomas were

identified in 87 capsules of 56 patients. Mast cells

were difficult to identify in the cellular areas, so

their numbers may be slightly underrepresented.

TABLE OF DATA

CAPSULES PATIENTS

Total 304 171

Histiocytes 282 (93%) 155 (91%)

Plasma Cells Present 138 (42%) 104 (61%)

Plasma Cells Prominent 77 (25%) 57 (33%)

Granuloma(ta) 87 (29%) 56 (33%)

Binucleate Plasma Cells 18(06%) 15 (09%)

Eosinophils 30 (10%) 26 (15%)

Mast Cells Present 31 (10%) 26 (15%)

Neutrophil (polys) 22 (07%) 18 (11%)

Dr. Shanklin's quantitative analysis of 100 breast

implant cases (121 tissue samples) " showed a strong

association between the lymphocytic and the

granulomatous features, observations wholly consistent

with the workings of the immunopathic system,

especially as mediated by Interleukin-2. Plasma cells

were observed less often (4.96%). Granulomatosis was

much enhanced by overt rupture of gel-filled

devices. " (254)

Finally, as presented to this Panel by Dr. Epstein,

attached is a representative pathology report on a

patient whose explanted breast implant capsule Dr.

Epstein reviewed.(255) He wrote in the report that:

[v]ery severe granulomatous responses and ultimately,

tissue necrosis with tissue eosinophilia with evidence

that silicone material has persisted in the tissue for

at least three years. The final denouement is that the

patient moved from an immunologic response of T-1 to

T2 type response which represents hypersensitivity and

an inflammatory mode that could trigger almost any

kind of serious autoimmune disease.

Thus, as documented both in humans and animals, the

cellular reaction seen in silicone-exposed tissue,

whether in breast implant capsules, lymph nodes,

granulomas, other tissue exposed to free silicone, or

in joints with silicone implants -- is strikingly

similar and is characterized by adverse clinical and

immunologic manifestations.

c) Silicone Synovitis from Other Silicone Implants

Numerous reports also appeared in the literature over

the past two decades documenting the similar

histologic findings of severe inflammation seen in

some patients with silicone orthopedic devices and

other types of silicone implants. Of particular

significance, certainly from a toxicological and

immunologic standpoint, are the findings with respect

to the importance of silicone particulate size. Many

researchers conclude that gel subdivision into

numerous - indeed billions - of microdroplets causes

the severe inflammatory response characterized by

chronic and granulomatous inflammation. These findings

are consistent with the pathological and histological

findings for silicone breast implants and will be

discussed in detail in the immunopathology section.

Table 2 details some of the more significant papers

that report on the pathologic findings upon

explantation.

C. SUMMARY OF FINDINGS FROM LIQUID SILICONE

INJECTIONS, SILICONE GEL BREAST IMPLANTS AND OTHER

SILICONE PRODUCTS

The consistency of histologic findings documented in

the literature and herein (Tables 1 and 2) provide

credible and solid scientific evidence that the

chronic inflammation seen in women with silicone

breast implants results from contact of the silicone

with the tissue. The evidence on this point is

overwhelming.

While Dr. agreed that chronic inflammation

resulted from silicone exposure,(256) he also

suggested that the chronic inflammation could have

resulted from what he referred to as " fibrocystic

disease. " (257) As the affidavit of Dr. Shanklin,

however, clearly sets out, fibrositis: (1) is not a

disease, and (2) it is not an inflammatory

process.(258) Its cellular characteristics are clearly

distinguishable from silicone-exposed cellular

characteristics. Dr. Shanklin states:

[t]here should be no difficulty in distinguishing the

complex of findings in so-called fibrocystic disease

from silicone mammary disease which includes intrusive

fibrosis from adjacent areas (shown to advantage by

polarization microscopy which demonstrates the pattern

of fibrosis), chronic inflammation including

lymphocytes, plasma cells, macrophage aggregates short

of granuloma formation, granulomas, vasculitis of

either lymphocytic or plasmacytic type, deposits of

silicone gel or oil, fragments of silicone elastomer,

and in the special case of polyurethane device

implantation, shards of polyurethane.(259)

SUMMARY OF SILICONE REACTIONS

Finding Reported in Literature Silicone Injections

Silicone Breast Implants Other Silicone Implantable

Products

Migration of silicone gel or particles locally XXX XXX

XXX

Migration of silicone gel and particles systemically

to distant tissue or organs XXX XXX XXX

Subdivision of gel/ particularization of elastomer XXX

XXX XXX

Silicone Granulomas XXX XXX XXX

Granulomatous reaction XXX XXX XXX

Lymphocytes XXX XXX XXX

Macrophage activation XXX XXX XXX

Fibroblasts XXX XXX XXX

Histiocytes XXX XXX XXX

Eosinophils XXX XXX XXX

Plasma cells XXX XXX XXX

Foreign body giant cells / multinucleated giant cells

XXX XXX XXX

Chronic inflammation years after exposure XXX XXX XXX

Fat or tissue necrosis at exposure site XXX XXX XXX

Vacuoles containing refractile non-birefringent

material positively identified as silicone droplets or

elastomer particles XXX XXX XXX

Synovial metaplasia, synovitis XXX XXX XXX

Silicone lymphadenopathy XXX XXX XXX

Continue to Section IV of Plaintiffs' Submission.

106. Sergent, J. S., Fuchs, H., , J.S.,

" Silicone Implants and Rheumatic Diseases, " Textbook

of Rheumatology, Update 4, pp. 1-13 (1993) [Record No.

1666].

107. Brinton, L.A., Brown, S.L., " Breast Implants and

Cancer, " Journal of the National Cancer Institute

89(18):1341-1349 (9/17/97) [Record No. 7063].

108. Affidavit of Shanklin, M.D. (9/26/97)

[Record No. 7214].

109. The process of inflammation can be classified as

acute, subacute and chronic, as well as a special

category of granulomatous inflammation. Acute

inflammation is the immediate and early response to an

injurious agent. It has three major components: 1)

alterations in vascular caliber that lead to an

increase in blood flow, 2) structural changes in the

microvasculature that permit the plasma proteins and

leukocytes (neutrophils, lymphocytes, macrophages) to

leave the circulation, and 3) emigration of the

leukocytes from the microcirculation and their

accumulation in the focus of injury. It is typically

characterized by venular and capillary dilation,

diapedesis of leukocytes, and formation of an exudate

with a predominance of polymorphonuclear leukocytes in

the early stages, preceded or accompanied by variable

activation of complement cascade, plasminogen

activators, kinins, and prostaglandin synthesis.

Within several days, the foreign material which

incited the reaction is usually neutralized and

inactivated.

Subacute and chronic inflammation follow a similar

progression but the persistence of the foreign

material to incite a reaction or the difficulty in

antigen processing accounts for a large number of the

most persistent inflammations. Local tissue injury,

through subacute or chronic inflammation, constitutes

a threat to host survival and can lead to autoimmune

disease. Chronic inflammation seen with silicone

breast implants will be discussed in greater depth

later in this section. L. Epstein, 7/23/97

Transcript of Panel Hearing, p. 428 and overheads;

Epstein, W.L., Fukuyama, K., " Chemically-Induced

Granuloma Formation, " Immunologic Diseases of the

Skin, Chapter 45, pp. 525-535 (1991) [Record No.

7259]; Epstein, W.L., " Chemical-Induced Granulomas, "

Dermatology in General Medicine, Chapter 135, pp.

1590-1598 (1987) [Record No. 7260]; Epstein, W.L.,

" Cutaneous Granulomas as a Toxicologic Problem, "

Dermatotoxicology and Pharmacology, Chapter 17, pp.

465-472 (1977) [Record No. 7261]; Epstein, W.L.,

" Pathogenesis of Granulomatous Inflammation in Skin, "

Dermatology, 3rd ed., Chapter 16, pp. 378-388 (1992)

[Record No. 7262]; Epstein, W.L., " Cutaneous

Granulomas as a Toxicologic Problem, "

Dermatotoxicology, 2nd ed., Chapter 27, pp. 545-553

(1982) [Record No. 7263]; Epstein, W.L., Fukuyama, K.,

" Mechanisms of Granulomatous Inflammation, " Immune

Mechanisms in Cutaneous Disease, Chapter 29, pp.

687-721 (1989) [Record No. 7264]; also see discussion

later in this section.

Granulomatous inflammation is distinctively

characterized by the accumulation and proliferation of

leukocytes, particularly the mononuclear type. It

results when the offending agent is nondegradable by

both neutrophils and nonactivated macrophages. The

actions of polymorphonuclear leukocytes, nonactivated

macrophages, and chemical mediators associated with

tissue injury are insufficient to digest and eradicate

the offending agent.

110. Medtox [Record No. 0479].

111. Dow Corning's NDA or Investigational New Drug

(IND) Application 2702 was on its MDX 44011 Medical

Grade Silicone Fluid (a dimethylpolysiloxane fluid, 30

cs), which was the clinical designation given to Dow

Corning 360 medical fluid. Radzius, J.R., Dow Corning

NDA No. 2702, M 330071 - 330072; MED 24390 - 24398;

Referenced in M 410001 - 410003. (8/12/75) [Record No.

6311].

112. Saduak, J., FDA, Letter to Dr. P. Schneider re:

silicone fluids, DCCKMM 3804-3805 (6/28/65) [Record

No. 2801].

113. In a memo to its sales representations dated

April 14, 1980, a Surgitek spokesperson stated,

" Regrettably one of the characteristics of silicone

rubber is that it has a very low tear strength. Even

if Dow Corning has made a shell with twice the tear

strength of what they presently have, the new value

will still be low compared to other materials, such as

Saran Wrap. " Lynch, W., Stith, W., Surgitek memo to

field force, MEA 22-25 (4/14/80) [Record No. 7056].

114. Lu-Feng, 7/22/97 Transcript of Panel

Hearing, p. 50.

115. Id.

116. Steinbach, B.G., Hardt, N.S., Abbitt, P. L.,

" Mammography: Breast Implants - Types, Complications,

and Adjacent Breast Pathology, " Current Problems in

Diagnostic Radiology, pp. 39-86 (1993) [Record No.

7057].

117. Id.; Hardt, 7/22/97 Transcript of Panel

Hearing, p. 93.

118. Affidavit of Shanklin (9/26/97) [Record

No. 7214].

119. Steinbach, B.G., Hardt, N.S., Abbitt, P.L.,

" Mammography: Breast Implants - Types, Complications,

and Adjacent Breast Pathology, " Current Problems in

Diagnostic Radiology, pp. 39-86 at p. 62 (1993)

[Record No. 7057].

120. s, W., , D., Lugowski, S., " Failure

Properties of 352 Explanted Silicone-Gel Breast

Implants, " Can. J. Plast. Surg. 4(1):55-58 (1996)

[Record No. 5277] (reporting 95% Grade III and IV

contracture after 12 years in 169 implants removed

from 125 women implanted with second generation Dow

Corning silicone breast implants, and 75% contracture

in 217 implants implanted from 1992 - 1995 in 115

women). Also, Brawer reported in 1996 that 70% of

patients in his study of 300 women reported pain,

tenderness and hardness associated with contracture.

Brawer, A., " Clinical Features Of Local Breast

Phenomena In 300 Symptomatic Recipients Of Silicone

Gel-Filled Breast Implants, " J. Clean Technology,

Environmental Technology, and Occupational Medicine

5(3):235-247 (1996) [Record No. 5049]. See also

Silverman, B., Brown, S., Bright, R., " Reported

Complications of Silicone Gel Breast Implants: An

Epidemiologic Review, " Ann. Intern. Med.124(8):744-56

(1996) [Record No. 0234].

121. Steinbach, B. G., Hardt, N.W., Abbitt, P.L.,

" Mammography: Breast Implants - Types, Complications,

and Adjacent Breast Pathology, " Current Problems in

Diagnostic Radiology, pp. 39-86 (1993) [Record No.

7057].

122. Barker, D. E., Retsky, M.I., Schultz, S.,

" 'Bleeding' of Silicone from Bag-Gel Breast Implants,

and Its Clinical Relation to Fibrous Capsule

Reaction, " Plast. Reconstr. Surg. 61(6): 836-841

(1978) [Record No. 0998]; Vistnes, L.M., Bentley,

J.W., Fogarty, D.C., " Experimental Study of Tissue

Response to Ruptured Gel-Filled Mammary Prostheses, "

Plast. Reconstr. Surg.59(1):31-34 (1977) [Record No.

0969] (In the unruptured specimens a local acute

inflammatory response was noted at ten days, with

polymorphonuclear leukocytes and round cells

incorporated in the fibrous capsule. There was a

significant increase in the thickness of the capsules

around the ruptured implants.).

123. Stark, G.B., Gobel, M., Jaeger, K., " Intraluminal

Cyclosporine A Reduces Capsular Thickness Around

Silicone Implants in Rats, " ls of Plastic Surgery

24:156-161 (1990) [Record No. 1206].

124. Chang, L., Caldwell, E., Reading, G., et. al., " A

Comparison of Convention and Low-Bleed Implants in

Augmentation Mammaplasty, " Plast. Reconstr. Surg.

89(1):79-82 (1992) [Record No. 1595].

125. Young, V.L., Bartell, T., Destouet, J.M., et.

al., " Calcification of Breast Implant Capsule, " South

Med. J. 82:1171-1173 (1989) [Record No. 7200];

, J.L., Guy, C.L, " Calcification on Implant

Capsules Following Augmentation Mammaplasty, " Plast

Reconstr. Surg. 59:432-433 (1977) [Record No. 5027];

Redfern, A.B., , J.J., Su, C.T., " Calcification of

the Fibrous Capsule about Mammary Implants, " Plast.

Reconst. Surg.59:249-254 (1977) [Record No. 7215];

Koide, T, Katayama, H., " Calcification in Augmentation

Mammoplasty, " Radiol130:337-340 (1979) [Record No.

7216]; s, W.F., Pritzker, K.P.H., " Massive

Heterotpic Ossification in Breast Implant Capsules, "

Aesth. Plast. Surg. 9:43-45 (1985) [Record No. 7217];

Cocke, W.M., White, R., Vecchione, T.R., et. al.,

" Calcified Capsule Following Augmentation

Mammoplasty, " Ann Plast Surg 15:61-65 (1985) [Record

No. 7218].

126. Steinbach, B.G., Hardt, N.S., Abbitt, P.L.,

" Mammography: Breast Implants - Types, Complications,

and Adjacent Breast Pathology, " Current Problems in

Diagnostic Radiology, pp. 39-86 (1993) [Record No.

7057].

127. Rolland, C., Guidoin, R., Marceau D., et. al.,

" Nondestructive Investigations on Ninety-Seven

Surgically Excised Mammary Prostheses, " J. Biomed.

Mater. Res.: Applied Biomaterials 23(A3):285-298

(1989) [Record No. 1185].

128. tis, C., Wlodarczyk, B., " Une Complication

Rare Des Protheses Mammaries: La Calcification De La

Coque Retractile Periprothetique, " Ann Chir Plast Esth

28:388-389 (1983) [Record No. 7219].

129. Sergent, J.S., Fuchs, H., , J.S.,

" Silicone Implants And Rheumatic Diseases, " Textbook

of Rheumatology, Update 4, pp. 1-13 (1993) [Record No.

1666].

130. For example, in 1993, Silver attempted to compare

the clinical findings seen in three patients with the

presence of silicone and tissue reaction in the

affected areas. In the scleroderma patient with

silicone breast implants, silicon was detected in the

involved skin, but not in the uninvolved skin. The

involved skin consisted of skin lesions on her arms,

which the biopsy revealed to be consistent with

morphea/scleroderma. The implanted woman diagnosed

with Systemic Lupus Erythematous had silicon within

her alveolar macrophages, which correlated with her

chronic interstitial lung disease. The third implanted

woman was diagnosed with tenosynovitis of the right

third finger. Biopsy revealed silicon in her right

finger; the tissue was characterized by acute and

chronic inflammation involving the synovial lining and

underlying stroma. Silver, R.M., Sahn, E.E., ,

J.A., et al., " Demonstration of Silicon in Site of

Connective-Tissue Disease in Patients with

Silicone-Gel Breast Implants, " Arch. Dermatol.

129:63-68 (1993) [Record No. 1651]; See also Teuber,

S.S., Ito, L.K., , M., et al., " Silicone

Breast Implant-Associated Scarring Dystrophy of the

Arm, " Arch. Dermatol.131:54-56 (1995) [Record No.

2282] (skin changes mimicking linear scleroderma of

the right upper extremity as a result of local tissue

response to silicone gel).

131. Id.

132. Silverman, S.L., Mendoza, M., " Chest Wall

Syndrome in Patients with Silicone Breast Implants, "

Arthritis & Rheumatism 37(9)(Supp):270 (1994) [Record

No. 0750].

133. Huang, T., " Breast and Subscapular Pain Following

Submuscular Placement of Breast Prostheses, " Plastic

and Reconstructive Surgery 86(2):275-280 (1990)

[Record No. 5178].

134. Lu, L., Ostermeyer, Shoaib B., Patten, B.M.,

" Atypical Chest Pain Syndrome in Patients with Breast

Implants, " Southern Medical Journal 87(10): 978-984

(1994) [Record No. 0186].

135. Lu, L, Patten, B., Ostermeyer, Shoaib B.,

" Non-Cardiac Chest Pain in Silicone Breast Implants: A

Pseudo-Heart Attack Syndrome? " Arthritis & Rheumatism

36(9):219 (1993) [Record No. 0731].

136. Cuellar, M., , C., Molivia, J.F.,

" Angina-Like Chest Pain in Women with Silicone Breast

Implants (SBI), " Arthritis & Rheumatism

37(9)(Supp):270 (1994) [Record No. 0714].

137. Thomsen, J.L., Christensen, L., Nielsen, M., et.

al., " Histologic Changes and Silicone Concentrations

in Human Breast Tissue Surrounding Silicone Breast

Prostheses, " Plastic and Reconstructive Surgery

85(1):38-41 (1990) [Record No. 1199].

138. McCauley, R.L., Riley, W.B., no, R.A., et.

al., " In Vitro Alterations in Human Fibroblast

Behavior Secondary to Silicone Polymers, " J. Surg.

Res. 49(1):103-109 (1990) [Record No. 1428].

139. Lossing, C., Hansson, H., " Peptide Growth Factors

and Myofibroblasts in Capsules Around Human Breast

Implants, " Plast. Reconstr. Surg.91(7):1277-1286

(1993) [Record No. 2929].

140. Baker, J.L., Chandler , M.L., LeVier, R.R.,

" Occurrence and Activity of Myofibroblasts in Human

Capsular Tissue Surrounding Mammary Implants, " Plast.

Reconst. Surg. 68(6):905-912 (1981)[Record No. 1185];

Ginsbach, G., Busch, L.C., Kuhnel, W., " The Nature of

the Collagenous Capsules Around Breast Implants: Light

and Electron Microscopic Investigations, " Plast.

Reconstr. Surg. 64:456 (1979) [Record No. 3008];

Lossing, C., Hansson, H., " Peptide Growth Factors and

Myofibroblasts in Capsules Around Human Breast

Implants, " Plast. Reconstr. Surg. 91(7):1277-1286

(1993) [Record No. 2929].

141. Kossovsky, N., Heggers, J.P., Parson, R.W., et.

al., " Analysis of the Surface Morphology of Recovered

Silicone Mammary Prostheses, " Plast. Reconstr. Surg.

71:795-804 (1983) [Record No. 2459]

142. Wickman, M., Johansson, O., Olenius, M., et. al.,

" A Comparison of Capsules Around Smooth and Textured

Silicone Prostheses Used for Breast Reconstruction: A

Light and Electron Microscopic Study, " Scand. J.

Plast. Reconstr. Hand Surg.27:15-22 (1993) [Record No.

7201].

143. Hameed, M., Erlandson, R., Rosen, P.P., " Capsular

Synovial-like Hyperplasia Around Mammary Implants

Similar to Detritic Synovitis: A Morphologic and

Immunohistochemical Study of 15 Cases, " The American

J. of Surgical Pathology 19(4):433-438 (1995) [Record

No. 0645].

144. Detritic synovitis is a reactive process that

results from failed orthopedic devices and is

characterized by villous hyperplasia of the synovium.

The synovial space is infiltrated with histiocytes,

multinucleated giant cells, and chronic inflammatory

cells. Id.

145. Hardt, N.S., Emery, J.A., LaTorre, G., et. al.,

" Macrophage-Silicone Interactions in Women with Breast

Prostheses, " Immunology of Silicones pp. 245-252

(1996) [Record No. 0157]; Presentation of Hardt,

7/22/97, at p. 112 (the capsule is structurally and

functionally identical to bursa or synovium).

146. Presentation of Hardt, 7/22/97, at p. 97.

147. Hardt, N.S., replying to a letter to the Editor

from Chase, et. al., on her 1994 article, Modern

Pathology 9(2):157-158 (2/96) [Record No. 5067].

148. Emery, J.A., Hardt, N.S., Caffee, H., et. al.,

" Breast Implant Capsules Share Synovial Transporting

Capabilities, " Abstract presented at the United States

and Canadian Academy of Pathology Annual Meeting, San

Francisco (3/12/94) [Record No. 5116]; Emery, J.A.,

Spanier, S.S., Kasnic, G., et. al., " The Synovial

Structure of Breast-Implant-Associated Bursae, " Modern

Pathology 7(7):728-733 (1994) [Record No. 0079] ( " The

superficial cell layer of all capsules had cytoplasmic

processes directed toward the surface. These long

cytoplasmic processes contained vacuoles

ultrastructurally, indicating phagocytic and

pinocytotic capability. These cells bore immunological

markers of bone marrow derived macrophage-type cells.

The extracellular matrix of the surface layer

consisted of an amorphous fibrillar protein lacking

the ultrastructural periodicity of mature collagen.. .

.. The structure of breast-implant-related capsules is

identical to the synovial structure of bursae and

joints; therefore, it is likely that the

breast-implant-associated capsule functions like

synovium and participates in the movement of particles

from the capsular surface to deeper structures. " ).

149. Chase, D.R., Mallot, R.L., Weeks, D., et. al.,

Letter to the Editor, Modern Pathology9(2):157-158

(2/96) [Record No. 5067]. See also del rio, Bui X;

Singh, J., Petrocine, S., et. al., " True Synovial

Metaplasia of Breast Implant Capsules: A Light and

Electron Microscopic Study, " Mod. Pathol. 7:14A (1994)

[Record No. 7203].

150. O'Hanlon, T.P., Okada, S., Love, L.A., et. al.,

" Immunohistopathology and T-Cell Receptor Gene

Expression in Capsules Surrounding Silicone Breast

Implants, " Immunology of Siliconespp. 237-242 (1996)

[Record No. 0279] (This article is covered in-depth

later in the discussion of the immunopathology of

silicone breast implants).

151. Helbich, T., Wunderbaldinger, P., Plenk, H., et.

al., " The Value of MRI in Silicone Granuloma of the

Breast, " European J. Radiology 24:155-158 (1997)

[Record No. 7069].

152. " " -

153. Id. at 160.

154. lin, B., Dow Corning Memo to Z. Dennett, M.

Hinsch and R. regarding the " Preliminary Report

- Histology Evaluation of Mammary Capsular Contracture

Tissues, " M 190427 - 190430 (2/24/77) [Record No.

7058].

155. Rosen, Rosen's Breast Pathology 3:42-46 (1997)

[Record No. 7059].

156. According to Rosen, analysis of the tissue from

breast implant capsules reveal increased amounts of

hyaluronic acid when compared to normal breast tissue.

Associated inflammatory cells were predominantly T

cells and macrophages. Large amounts of interleukin-2

(IL-2) have been found in association with

infiltrating lymphocytes. Other studies revealed

similar histological findings. See later discussion on

cytokines.

157. Medtox Report [Record No. 0479]; see also Dumas,

R. Memo to Jakubcczak re: " Project Report -- Complaint

Analysis, Plastic Surgery, " DCC KKA 119771-119774

(8/14/84) [Record No. 7275] ( " The appearance of some

of these antsunits [breast implants] made me

sympathize with one surgeon, stating that he believed

we [Dow Corning] were soaking the units in mazola oil

before shipping. " ).

158. Surgitek, " Risks and Benefits of Silicone

Gel-Filled Breast Implants: A Summary of Findings in

the Literature, " MEX 120859 - 120899 (1989) [Record

No. 7211].

159. Id..

160. Goldberg, E.P., " Silicone Breast Implant Safety:

Physical, Chemical, and Biological Problems, " Plastic

and Reconstructive Surgery 99(1):258-260 (1997)

[Record No. 7061].

161. Cohen, B.E., Biggs, T.M., Cronin, E.D., et al.

, " Assessment and Longevity of the Silicone Gel Breast

Implant, " Plas. & Recon. Surg. 99(6):1597-1601 (1997)

[Record No. 7212].

162. Presentation of Lu-Feng, 7/22/97, at pp.

57-58.

163. Greenwald, D.P., Randolph, M., May, J.W., et.

al., " Mechanical Analysis of Explanted Silicone Breast

Implants, " Plas. & Recon. Surg. 98(2):269-272 (1996)

[Record No. 2648]( " [T]hat silicone implant shells

weaken over time in vivo now seems fairly clear. " ).

164. s, S., Memo to Hinsch, et. al., re: Physical

Properties versus Time for Silastic II and Standard

Prosthesis, M160031-160036 (11/30/81) [Record No.

0036].

165. Id.; Wolf, C.J., , H.J., Young, V.L., et

al., " Chemical Physical and Mechanical Analysis of

Explanted Breast Implants, " Immunology of Silicones,

pp. 25-37 (1996) [Record No. 0295].

166. Uhlmann, 7/24/97 Transcript of Panel

Hearing, p. 921.

167. Vistnes, L.M., Bentley, J.W., Fogarty, D.C.,

" Experimental Study of Tissue Response to Ruptured

Gel-Filled Mammary Prostheses, " Plast. Reconstr. Surg.

59(1):31-34 (1977) [Record No. 0969] (In the

unruptured specimens a local acute inflammatory

response was noted at ten days, with polymorphonuclear

leukocytes and round cells incorporated in the fibrous

capsule. There was a significant increase in the

thickness of the capsules around the ruptured

implants); Baker, J.L., LeVier, R.R., Spielvogel,

D.E., " Positive Identification of Silicone in Human

Mammary Capsular Tissue, " Plast. Reconstr. Surg.

69:56-60 (1982) [Record No. 1063]; Leibman, A.J.,

Kossoff, M.E., Kruse, B.D., " Intraductal Extension Of

Silicone From A Ruptured Breast Implant, " Plast.

Reconstr. Surg. 89(3):10-11 (1991) [Record No. 1231];

s, W., , D., Lugowski, S., et. al.,

" Analysis of Silicon Levels in Capsules of Gel and

Saline Breast Implants and of Penile Prostheses, " Ann.

Plast. Surg.34(6):578-584 (1995) [Record No. 1813];

Hardt, N.S., Emery, J.A., Steinbach, B.G., et. al.,

" Cellular Transport of Silicone from Breast

Prostheses, " Int. J. Occup. Med. Toxicol. 4:127 (1995)

[Record No. 7060]; Greene, W.B., Raso, D.S., Walsh,

L.G., et. al., " Electron Probe Microanalysis of

Silicon and the Role of the Macrophage in Proximal

(Capsule) and Distant Sites in Augmentation

Mammaplasty Patients, " Plast. Reconstr. Surg.

95(3):513-519 (1995) [Record No. 2934]; Pfleiderer,

B., Ackerman, J.L., Garrido, L., " Migration and

Biodegradation of Free Silicone from Silicone

Gel-Filled Implants after Long-Term Implantation, "

Mag. Reson. Med. 30:534-543 (1993) [Record No. 1651];

Goldberg, E.P., " Silicone Breast Implant Safety:

Physical, Chemical, and Biological Problems, " Plast.

Reconstr. Surg. 99(1):258-260 (1997) [Record No. 7061]

( " t is now quite clear that silicone bleed can pass

through and beyond the capsule and throughout the body

by emulsification into droplets and transport by

phagocytic immune cells. " ); Beekman, W., Feitz, R.,

van Diest, P.J., et. al., " Migration of Silicone

Through the Fibrous Capsules of Mammary Prostheses, "

ls of Plastic Surg. 38(5):441-445 (1997) [Record

No. 7062].

168. Beekman, W.H., Feitz, R., van Diest, P.J., et.

al., " Migration of Silicone Through the Fibrous

Capsules of Mammary Prostheses, " ls of Plastic

Surgery 38(5):441-445 (1997) [Record No. 7062].

169. Coyne, L.D., Memo from FDA Materials Research

Engineer, re: " Dow Corning Single and Double Lumen

Silastic II and Silastic MSI Breast Prothesis:

In-Depth Review of Gel Bleed Testing, " DCC 241000088 -

241000101 (10/9/91) [Record No. 2644].

170. Chenoweth, M., Holmes, R., Stark, F., " The

Physiological Assimilation of Dow Corning 200 Fluid,

" Dow Corning Report No. 1377, DCCKMM 25794 - 259803

(1956) [Record No. 0006].

171. Stark, F., " The Physiological Activity of Dow

Corning 200 Fluid, " Dow Corning Report No. 1570,

DCCKMM 259804-259808 (8/57) [Record No. 2697].

172. McHard, J. A., Memo to Hunter re: Notes on Visit

to Battelle Memorial Institute, DCCKMM 299059-299063

(1/13/64) [Record No. 2700].

173. Lacefield, R.M., Vogel, G.E., Stark, F.O., et.

al., " Biological Distribution of

Dimethylpolysiloxane, " Dow Corning Report No. 3323,

DCC 281001381-281001399 (6/3/68) [Record No. 2386].

174. Sparschu, G., Clashman, A., " Pathology Report on

the Effects Dow Corning 360 Fluid - 350 Centistrokes

After Administration to Rats Intraperitoneally or

Subcutaneously, " TDC 8028-8078 (12/70) [Record No.

0018].

175. Presentation of Hardt, 7/22/97, at pp.

118-125.

176. Leibman, A.J., Kossoff, M.B., Kruse, B.D.,

" Intraductal Extension of silicone from a Ruptured

Breast Implant, " Plastic and Reconstructive Surgery

89(3):10-11 (1991) [Record No. 1231].

177. Silver, R.M., Shan, E.E., , J.A., et al.,

" Demonstration of Silicon in Sites of

Connective-Tissue Disease in Patients with

Silicone-Gel Breast Implants, " Archives of Dermatology

129:63-68 (1993) [Record No. 1651] (silicon).

178. Presentation by Lu-Feng, 7/22/97, at p.

56-57 with accompanying slides. The patient

experienced swelling and difficulty moving her arm.

During surgery, it was discovered that silicone had

infiltrated the muscle. Histology showed atrophy in

the muscle. Also, Parsons, R.W, Thering, H.R,

" Management of the Sil-Injected Breast, " Plastic and

Reconstructive Surgery 60(4):534-558 (1977) [Record

No. 1340] (gel migration high in the axilla which

formed a " cement-like " mass around the brachial plexus

and great vessels).

179. Sanger, J., Matloub, H., Yousif, J., " Silicone

Gel Infiltration of a Peripheral Nerve and

Constrictive Neuropathy Following Rupture of a Breast

Prosthesis, Plastic and Reconstructive Surgery

89(5):949-952 (1992) [Record No. 2896].

180. Capozzi, A., Du Bou, R., Pennisi, V.R., " Distant

Migration Of Silicone Gel From A Ruptured Breast

Implant: Case Report, " Plast. Reconstr. Surg.

62(2):302-303 (1978) [Record No. 0983] (gel migration

along the medial aspect of the right arm); Edmond, J.,

" Late Complication of Closed Capsulotomy of the

Breast, " Plastic and Reconstructive

Surgery66(3):478-479 (1980) [Record No. 1036] (gel

mass in the mid-left biceps); Mason, J.,

Apisavnthanarax, P., " Migratory Silicone Granuloma, "

Archives of Dermatology 117:366-367 (1981) [Record No.

1048] (gel migrated to the left upper portion of the

chest and left upper arm); , W., Springfield,

D., Brown, K., " Pseudotumor of the Arm Associated with

Rupture of Silicone-Gel Breast Prostheses: Report of

Two Cases, " J. Bone and Joint Surg. pp. 548-550 (1983)

[Record No. 1089] (gel migrated to medial aspect of

distal end of arm and proximal end of forearm in one

patient and the medial aspect of the right mass in

another patient).

181. Teuber, S., Ito, L.K., , M., et. al.,

" Silicone Breast Implant-Associated Scarring Dystrophy

Of The Arm, " Archives of Dermatology 131(1):54-56

(1995) [Record No. 2282]; see also Presentation of

M.E. Gershwin, 7/23/97, p. 506, and slide showing

ulcerated skin in the arm from migrating silicone gel.

182. Carrothers, N., Memo to Hogan and Eckardt re:

Synopsis of Meetings Attended, MB 184506-184507

(5/12/76) [Record No. 7213].

183. Garrido, L., Pfleiderer, B., , B.C., et.

al., " Migration and Chemical Modification of Silicone

in Women with Breast Implants, " Mag. Reson.

Med.31(3):328-330 (1994) [Record No. 1725].

184. See later discussion on silicone

particularization in this section.

185. Ford, R.D., Simpson, W.D., " Massive Extravasation

of Traumatically Ruptured Buttock Silicone

Prosthesis, " ls of Plastic Surgery (1992) [Record

No. 7075].

186. Brinton, L.A., Brown, S.L., " Breast Implants and

Cancer, " J. Natl. Cancer Inst.89(19):1341-1349 (1997)

[Record No. 7063].

187. Weyenberg, D., Memo to re:

Immunomodulation Study, DCCKMM 369357 (9/23/85)

[Record No. 0474].

188. Silicone lymphadenopathy is the replacement of a

lymph node by silicone and reactive cells, namely

macrophages and giant cells. Lu-Feng

Presentation, 7/22/97, at p. 69 and accompanying

slide. See, also, Sergent, J. S., Fuchs, H., ,

J.S., " Silicone Implants and Rheumatic Diseases, "

Textbook of Rheumatology, Update 4, pp. 1-13 (1993)

[Record No. 1666]; Tabatowski, K., Elson, C.E.,

ston, W.W., " Silicone Lymphadenopathy in a Patient

with a Mammary Prosthesis, Fine Needle Aspiration,

Cytology, Histology and Analytical Electron

Microscopy, " Acta Cytol. 34:10-14 (1990) [Record No.

1205].

189. Lu-Feng Presentation, 7/22/97, at p. 69.

190. Kao, C.C., Rand, R.P., Holt, C.A., et. al.,

" Internal Mammary Silicone Lymphadenopathy Mimicking

Recurrent Breast Cancer, " Plast. Reconstr.

Surg.99(1):225-229 (1997) [Record No. 7064]. It is

extremely difficult to distinguish clinically whether

hard masses in the breasts and lymph nodes are

cancerous, thus causing much concern in women with

breast implants who discover a lump. There are reports

in the literature of women who underwent bilateral

mastectomies as a result, or who had bilateral

mastectomy because of silicone mastitis from silicone

injections.

191. Wintsch, W., Smahel, J., Clodius, L., " Local and

Regional Lymph Node Response To Ruptured Gel-Filled

Mammary Prosthesis, " Brit. J. Plast. Surg. 38:349-352

(1978) [Record No. 0988]; Capozzi, A., DuBou, R.,

Pennisi, V.R., " Distant Migration of Silicone Gel From

A Ruptured Breast Implant: Case Report, " Plast.

Reconstr. Surg. 62(2):302-303 (1978) [Record No.

0983]; Hausner, R.J., Schoen, F.J., Mendez-Fernandez,

H.A., " Migration of Silicone Gel To Axillary Lymph

Nodes After Prosthetic Mammaplasty, " Arch. Pathol.

Lab. Med. 105:371-372 (1981) [Record No. 1050]; Lin,

R.P., DiLeonardo, M., y, C.A., " Silicone

Lymphadenopathy: A Case Report and Review of the

Literature, " The American Journal of Dermatopathology

15(1):82-84 (1993) [Record No. 7220]; and Rivero,

M.A., Schwartz, D.A., Mies, C., " Silicone

Lymphadenopathy Involving Intramammary Lymph Nodes: A

New Complication of Silicone Mammaplasty, " American

Journal of Roentgenology 162:1089-1090 (1994) [Record

No. 7221].

192. See Table 2.

193. Dow Corning Medtox Report [Record No. 0479]

citing Epstein, Pathbiol. Annual 7:1-30 (1977).

194. Dow Corning Medtox Report [Record No. 0479]

citing Boros, Allergy 24:184-287 (1978).

195. Id.

196. Winer, L., Sternberg, T., Lehman, R., et. al.,

" Tissue Reactions to Injected Silicone Liquids, "

Archives of Dermatology 90:588-593 (1964) [Record No.

0822] (ape); Ben-Hur, N., Neuman, Z., " Siliconoma -

Another Cutaneous Response to Dimethylpolysiloxane:

Experimental Study in Mice, " Plastic and

Reconstructive Surgery 36(6):629-631 (1965) [Record

No. 0832] (white mice); Ben-Hur, N., Ballantyne, D.,

Rees, T., et. al., " Local and Systemic Effects of

Dimethylpolysiloxane Fluid in Mice, " Plastic and

Reconstructive Surgery39(4):423-427 (1967) [Record No.

0846](female mice); Rees, T., Ballantyne, D., Seidman,

I., et. al., " Visceral Response to Subcutaneous and

Intraperitoneal Injections of Silicone in Mice, "

Plastic and Reconstructive Surgery 39(4):402-410

(1967) [Record No. 0845] (female albino mice of CF and

Swiss Webster strains); Brody, G. L., Frey, C. F.,

" Peritoneal Response to Silicone Fluid, " Archives of

Surgery 96:237-241 (1968) [Record No. 0856] (male

Sprague Dawley rats).

197. Symmers, W. St. C., " Silicone Mastitis in

'Topless' Waitresses and Some Other Varieties of

Foreign-Body Mastitis, " British Medical Journal

3:19-22 (1968) [Record No. 0857] (breasts);

Ortiz-Monasterio, F., Trigos, I., " Management of

Patients with Complications from Injections of Foreign

Materials into the Breasts, " Plastic and

Reconstructive Surgery 30(1):42-47 (1972) [Record

1830] (breasts, face, legs, hands and other areas);

Delage, C., Shane, J., , F., " Mammary Silicone

Granuloma " Migration of Silicone Fluid to Abdominal

Wall and Inguinal Region, " Archives of Dermatology

108:104-106 (1973) [Record No. 0906](breasts); Kuiper,

D., " Silicone Granulomatous Disease of The Breast

Simulating Cancer, " Michigan Medicinepp. 215-218

(1973) [Record No. 2878] (breasts); Parsons, R. W.,

Thering, H. R., " Management of the Silicone-Injected

Breast, " Plastic and Reconstructive

Surgery60(4):534-558 (1977) [Record No.

1340](breasts); Wilkie, T.F., " Late Development of

Granuloma After Liquid Silicone Injections, " Plastic

and Reconstructive Surgery 60(2):180-188 (1977)

[Record No. 0974] (face); Pearl, R. M., Laub, D. R.,

Kaplan, E. N., " Complications Following Silicone

Injections for Augmentation of the Contours of the

Face, " Plastic and Reconstructive Surgery

61(6):888-891 (1978) [Record No. 0997] (eyebrow,

glabella and nose, lower eyelids); Wustrack, K. O.,

Zarem, H. A., " Surgical Management of Silicone

Mastitis, " Plastic and Reconstructive Surgery

63(2):224-229 (1979) [Record No. 1013] (breasts);

Lavey, E. B., Pearl, R. M., " Inflammation in a

Silicone-Induced Granuloma Caused by a Tuberculosis

Skin Test, ls of Plastic Surgery 7:152-154 (1981)

[Record No. 1039] (lower lips, glabella and nose);

Christ, J., Askew, J., " Silicone Granuloma of the

Penis, " Plastic and Reconstructive Surgery

69(2):337-339 (1982) [Record No. 2969](penis); Kozeny,

G. A., Barbato, A. L., Bansal, V.K., et. al.,

" Hypercalcemia Associated with Silicone-Induced

Granulomas, " Medical Intelligence 311(17):1103-1105

(1984) [Record No. 1118] (face, breasts and hips);

Cruz, G., Gillooley, J., Waxman, M., " Silicone

Granulomas of the Breast, " New York State Journal of

Medicine 85(10):599-601 (1985) [Record No. 3010]

(breasts); Truong, L. D., Cartwright, J., Goodman,

M.D., et. al., " Silicone Lymphadenopathy Associated

with Augmentation Mammaplasty: Morphologic Features of

Nine Cases, " American Journal of Surgical

Pathology12(6):484-491 (1988) [Record No.

1164](breasts); Frey, C., Naritoku, W., Kerr, R., et.

al., " Tarsal Tunnel Syndrome Secondary to Cosmetic

Silicone Injections, " Foot & Ankle14(7):407-410 (1993)

[Record No. 7065](calves); Wilkie, C.P., Woods, J.E.,

" Use of Tissue Expanders in Reconstruction After

Excision of Multiple Large Silicone Granulomata, "

ls of Plastic Surgery 30:367-370 (1993) [Record

No. 7066] (face, forehead, cheeks, chin, lips,

breasts, hips, buttocks); Wasserman, R. J., Greenwald,

D. P., " Debilitating Silicone Granuloma of the Penis

and Scrotum, " ls of Plastic Surgery 35:505-510

(1995) [Record No. 7067] (penis); Aoki, R.,

Mitsuhashi, K., Hyakusoku, H., " Immediate

Reaugmentation of the Breasts Using Bilaterally

Divided TRAM Flaps After Removing Injected Silicone

Gel and Granulomas, " Aesthetic Plastic Surgery

21:279-279 (1997) [Record No. 7068] (breasts);

Helbich, T. H., Wunderbaldinger, P., Plenk, H., et.

al., " The Value of MRI in Silicone Granuloma of the

Breast, " European Journal of Radiology 24:155-158

(1997) [Record No. 7069] (breasts).

198. Eisenberg, H., Bartels, R., " Rupture of a

Silicone Bag-Gel Breast Implant by Closed Compression

Capsulotomy, " Plastic and Reconstructive Surgery

59(6):849-850 (1977) [Record No. 0972] (Heyer

Schulte); Barker, D. E., Retsky, M. I., Shultz, S.,

" 'Bleeding' of Silicone From Bag-Gel Breast Implants,

and its Clinical Relation to Fibrous Capsule

Reaction, " Plastic and Reconstructive Surgery

61(6):836-841 (1978) [Record No. 0998]; Capozzi, A.,

Du Bou, R., Pennisi, V.R., " Distant Migration of

Silicone Gel From a Ruptured Breast Implant: Case

Report, " Plastic and Reconstructive Surgery

62(2):302-303 (1978) [Record No. 0983] (Heyer

Schulte); Goin, J. M., " High Pressure Injection of

Silicone Gel Into an Axilla - A Complication of Closed

Compression Capsulotomy of the Breast, " Plastic and

Reconstructive Surgery62(6):891-895 (1978) [Record No.

2418]; Hausner, R. J., Schoen, F. J., Pierson, K. K.,

" Foreign-Body Reaction to Silicone Gel in Axillary

Lymph Nodes After an Augmentation Mammaplasty, "

Plastic and Reconstructive Surgery62(3):381-384 (1978)

[Record No. 1002]; Huang, T., Blackwell, S., ,

S., " Migration of Silicone Gel After the 'Squeeze

Technique' to Rupture a Contracted Breast Capsule:

Case Report, " Plastic and Reconstructive

Surgery61(2):277-280 (1978) [Record No. 0993]; Edmond,

J., " Late Complication of Closed Capsulotomy of the

Breast (Letter), " Plastic and Reconstructive Surgery

66(3):478-479 (1980) [Record No. 1036] (Dow Corning);

Mason, J., Apisarnthanarax, P., " Migratory Silicone

Granuloma, " Archives of Dermatology 117:366-367 (1981)

[Record No. 1048]; Baruch, J., Wechsler, J., Bodin,

B., et al. " Siliconomes Mammaries a Longue Evolution, "

Ann Chir Plast27:183-184 (1982) [Record No. 7070];

, W., Springfield, D., Brown, K., " Pseudotumor

of the Arm Associated with Rupture of Silicone-Gel

Breast Prosthesis: Report of Two Cases, " Journal of

Bone and Joint Surgery, pp. 548-550 (1983) [Record No.

1089]; Apesos, J., Pope, T., " Silicone Granuloma

Following Closed Capsulotomy of Mammary Prosthesis,

ls of Plastic Surgery pp. 403-406 (1985) [Record

No. 1126]; Truong, L. D., Cartwright, J., Goodman,

M.D., et. al., " Silicone Lymphadenopathy Associated

with Augmentation Mammaplasty: Morphologic Features of

Nine Cases, " American Journal of Surgical Pathology

12(6):484-491 (1988) [Record No. 1164]; Kaiser, W.,

Biesenbach, G., Study, U., et. al., " Human Adjuvant

Disease: Remission of Silicone Induced Autoimmune

Disease After Explantation of Breast Augmentation, "

ls of Rheumatic Diseases 49:937-938 (1990) [Record

No. 1202]; Klykken, P.C., Memo re: Differentiation of

Foreign Body Reactions and Immune Granulomas, M 850018

(2/13/92) [Record No. 7071]; Mitnick, J.S., Vazquez,

M.F., Plesser, K., et. al., " Fine Needle Aspiration

Biopsy in Patients with Augmentation, Prostheses and a

Palpable Mass, " ls of Plastic Surgery 31:241-244

(1993) [Record No. 7072]; Teuber, S., Howell, L.,

Yoshida, S.H., et. al., " Remission of Sarcoidosis

Following Removal of Silicone Gel Breast Implants, "

International Archives of Allergy and Applied

Immunology 105:404-407 (1994) [Record No. 1732]; Ahn,

C.Y., Shaw, W.W., Narayanan, K., et. al., " Residual

Silicone Detection Using MRI Following Previous Breast

Implant Removal: Case Reports, Aesthetic Plastic

Surgery 19:361-367 (1995) [Record No.7050]; Hameed,

M., Erlandson, R., Rosen, P., " Capsular Synovial-Like

Hyperplasia Around Mammary Implants Similar to

Detritic Synovitis: A Morphologic and

Immunohistochemical Study of 15 Cases, " American

Journal of Surgical Pathology 19(4):433-438 (1995)

[Record No. 0645]; Hardt, N.S., Emery, J. A., Latorre,

G., et. al., " Macrophage-Silicone Interactions in

Women with Breast Prostheses, Immunology of Silicones,

pp. 245-252 (1996) [Record No. 0157]; Brawer, A. E.,

" Clinical Features of Local Breast Phenomena I 300

Symptomatic Recipients of Silicone Gel-Filled Breast

Implants, " Journal Clean Technol Environ Toxicol &

Occup Med5(3):235-247 (1996) [Record No. 5049]; Raso,

D. S., Greene, W. B., Harley, R.A., et. al., " Silicone

Deposition in Reconstruction Scars of Women with

Silicone Breast Implants, " Journal of American Academy

of Dermatology35(1):32-36 (1996) [Record No. 1928];

, D.R., Schwartz, J., Cottrill, C.M., et al.,

" Silicone Granuloma in Acral Skin in a Patient with

Silicone Gel Breast Implants and Systemic Sclerosis, "

International Journal of Dermatology35(1):36-38 (1996)

[Record No. 7073]; Aoki, R., Mitsuhashi, K.,

Hyakusoku, H., " Immediate Reaugmentation of the

Breasts Using Bilaterally Divided TRAM Flaps After

Removing Injected Silicone Gel and Granulomas, "

Aesthetic Plastic Surgery 21:276-279 (1997) [Record

No. 7068] (breasts); and Carpaneda, C.A.,

" Inflammatory Reaction ad Capsular Contracture Around

Smooth Silicone Implants, " Aesthetic Plastic Surgery

21:110-114 (1997) [Record No. 7074].

199. Ford, R.F., Simpson, W.D., " Massive Extravasation

of Traumatically Ruptured Buttock Silicone

Prosthesis, " ls of Plastic Surgery 29:86-88 (1992)

[Record No. 7075] (Dow Corning gel buttock implant).

200. Gordon, M., Bullough, P.G., " Synovial and Osseous

Inflammation in Failed Silicone-Rubber Prostheses: A

Report of Six Cases, " Journal of Bone and Joint

Surgery64:574-580 (1982) [Record No. 1067]; Manes, H.,

" Foreign Body Granuloma of Bone Secondary to Silicone

Prosthesis: A Case Report, " Clinical Orthopaedics and

Related Research199:239-241 (1985) [Record No.

1128](navicular prosthesis); , W.D., Balogh, K.,

Abraham, J. L., " Silicone Granulomas: Report of Three

Cases and Review of the Literature, " Human Pathology

16:19-27 (1985) [Record No. 2474] (hip implant);

Rahman, H., Fagg, P., " Silicone Granulomatous

Reactions After First Metatarsophalangeal

Hemiarthroplasty, " Journal of Bone and Joint Surgery

75B:637-639 (1993) [Record No. 3035] (first MP joint);

Hirakawa, K., Bauer, T., Culver, J., et. al.,

" Isolation and Quantification of Debris Particles

Around Failed Silicone Orthopedic Implants, " The

Journal of Hand Surgery21A95 (1996) [Record No.

7076](various orthopedic devices).

201. Matsumoto, K., Kohmura, E., Tsuruzoni, K., et.

al., " Silicone Plate-Induced Granuloma Presenting

Pituitary Apoplexy-Like Symptoms: Case Report, "

Surgical Neurology 43:166-169 (1995) [Record No.

7049].

202. Dolwick, M. F., Aufdemorte, T.B.,

" Silicone-Induced Foreign Body Reaction and

Lymphadenopathy After Temporomandibular Joint

Arthroplasty, " Oral Surgery 59:449-452 (1985) [Record

No. 0572] (silicone TMJ).

203. Senn, P., Buchi, E., Daicker, B., et al.,

" Bubbles in the Bleb - Troubles in the Bleb? Molteno

Implant and Intraocular Tamponade with Silicone Oil in

an Aphakic Patient, " Ophthalmic Surgery 25(6):379-385

(1994) [Record No. 7077] (Molteno implant for

bilateral glaucoma surgery with silicone oil

tamponade); Kalicharan, D., Jongebloed, W.L., Van Der

Veen, G., " Ingrowth in a Silicone Plombe, " Documenta

Ophthalmologica 78:307-315 (1991) [Record No. 7078]

(silicone plombe implanted in the sclera).

204. Barrett, D.M., O'Sullivan, D.C., Malizia, A.A.,

et al., " Particle Shedding And Migration From Silicone

Genitourinary Prosthetic Devices, " J. Urology

146:319-322 (1991) [Record No. 1574].

205. Bommer, J., Ritz, E., Waldherr, R., et. al.,

" Silicone Cell Inclusions Causing Multi-Organ Foreign

Body Reaction in Dialysed Patients, " Lancet 1:1314

(6/13/81) [Record No. 2443]; Bommer, J., Waldherr, R.,

Gastner, M., et. al., " Iatrogenic Multiorgan Silicone

Inclusions in Dialysed Patients, " Klinische

Wochen-Schrift 59:1149-1157 (10/15/81) [Record No.

1053]; Parfrey, P. S., " Refractile Materials in the

Liver of Hemodialysis Patients, " Lancet pp. 1101-1102

(5/16/81) [Record No. 5270]; Leong, A., Path, M.,

Disney, A., et. al., " Spallation and Migration of

Silicone from Blood-Pump Tubing in Patients on

Hemodialysis, NEJM 306(13):135-140 (1/21/82) [Record

No. 1064].

206. Hirsh, B.C., , W.C., " Concepts of

Granulomatous Inflammation, " Intl. J. Dematology

23:90-100 (1984) [Record No. 7040].

207. Id.

208. Id.

209. A toxicologist named Cutting interpreted similar

lesions found in kidneys of rabbits fed DC 200

silicone fluid as indicating " widespread . . . toxic

manifestations. " Cutting, W.C., " Toxicity of

Silicones, " Stanford Medical Bulletin 10(1):23-26

(1952) [Record No. 0789] .

210. Medtox [Record No. 0479].

211. Supplemental statement of Dr. Hardt to the

706 Science Panel (9/97) [Record No. 7044].

212. Obviously, Dr. Hardt did not conduct the initial

examination of all of these tissues.

213. Supplemental statement of Dr. Hardt to the

706 Science Panel (9/97) [Record No. 7044].

214. The cellular structure of immunogenic granulomas

found in well accepted Granulomatous Diseases such as

Berylliosis, Tuberculosis, Syphllis, Sarcoidosis,

Leprosy and Schistosomiasis, is remarkably similar to

that of silicone granulomas. Presentation of Dr.

Epstein on July 23, 1997 at p. 413.

215. Epstein, 7/23/97, Transcript of Panel

Meeting, pp. 427-428.

216. Presentation of Epstein, 7/23/97, pp.

416-417.

217. Epstein, W.L., Fukuyama, K., " Granulomatous

Hypersensitivity to Silicone Breast Implants, "

Abstract presented at International Congress on

Sarcoidosis, Granulomatous and Vasculitis Disorders,

5th WASOG Meeting (9/17/97) [Record No. 7242].

218. Potter, M., on, S., Wiener, F., et al.,

" Induction of Plasmacytomas With Silicone Gel in

Genetically Susceptible Strains of Mice, " J. Natl.

Cancer Inst. 86(14):1058-1065 (1994) [Record No.

1772].

219. Medtox [Record No. 0479].

220. Hirsch, B.C., , W.C., " Concepts of

Granulomatous Inflammation, " Int. J. Dermatology

23:90-100 (1984) [Record No. 7040].

221. Dow Corning Medtox Report [Record No. 0479];

Vinnik, C.A., " Spherical Contracture of Fibrous

Capsules Around Breast Implants: Prevention and

Treatment, " Plastic and Reconstructive Surgery

58(5):555-560 (11/76) [Record No. 0961]; Vinnik, C.A.,

Letter to Bob Rylee re: Failed Silicone Gel Implant, F

685-686 (6/23/81) [Record No. 2784]; Vinnik, C.A.,

Letter to Jakubczak enclosing operative and pathology

reports, M 490041 - 490045 (2/6/84) [Record No. 2814].

222. Rees, T., Ballantyne, D., Seidman, I., et. al.,

" Visceral Response to Subcutaneous and Intraperitoneal

Injections of Silicones in Mice, " Plast. Reconstr.

Surg. 39(4):402-410 (1967) [Record No. 0845].

223. , F., Braley, S., Rees, T., et. al., " The

Present Status of Silicone Fluid in Soft Tissue

Augmentation, " Plast. Reconstr. Surg. 39(4):411-420

(1967) [Record No. 0844].

224. Ben-Hur, N., Ballantyne, D., Rees, T., et. al.,

" Local and Systemic Effects of Dimethylpolysiloxane

Fluid in Mice, " Plast. Reconstr. Surg. 39(4):423-426

(1967) [Record No. 0846].

225. Carson, S., " Summary of Histopathological

Findings in Primates, " T 822-832 (3/21/67) [Record No.

1303].

226. , F., Lab Notebook, MEI 4539 - 4668 (6/67 -

1/71) [Record No. 2595].

227. Brody, G., Frey, C., " Peritoneal Response to

Silicone Fluid, " Arch. Surg. 96: 237-241 (1968)

[Record No. 0856] (histiocytes, inflammatory cells,

lymphocytic response seen in the depths of the

silicone granuloma, heterophils, and mast cells).

228. Nosanchuk, J., " Injected Dimethylpolysiloxane

Fluid: A Study of Antibody and Histologic Response, "

Plast. Reconstr. Surg. 42(6): 562-566 (1968) [Record

No. 0860].

229. Minagi, H., Youker, J.E., Knudson, H.W., " The

Roentgen Appearance of Injected Silicone in the

Breast, " Radiology 90:57-61 (1968) [Record No. 7082]

(silicone granulomas following injections in the

breast).

230. Symmers, W., " Silicone Mastitis in 'Topless'

Waitresses and Some Other Varieties of Foreign-body

Mastitis, " British Medical Journal 3:19-22 (1968)

[Record No. 0857].

231. Vinnik, C.A., Russel, W.M., " Silicone Mastopathy

with Complications in Facial Injections, " presented to

the American Society of Aesthetic Plastic Surgeons'

Annual Meeting, M 290183-290197 (5/6/75) [Record No.

7083].

232. Lavey, E.B., Pearl, R.M., " Inflammation in a

Silicone-Induced Granuloma Caused by a Tuberculosis

Skin Test, " ls of Plastic Surgery 14(5): 152-154

(1985) [Record No. 1039].

233. Pearl, R.M., Laub, D.R., Kaplan, E.N.,

" Complications Following Silicone Injections For

Augmentation Of The Contours Of The Face, " Plast.

Reconst. Surg. 61(6):888-891 (1978) [Record No. 0997].

234. Chaplin, C.H., " Loss of Both Breasts from

Injections of Silicone (with Additive), " Plastic &

Reconstructive Surgery 44:447-450 (11/69) [Record No.

7080]; Delage, C., Shane, J., , F., " Mammary

Silicone Granuloma: Migration of Silicone Fluid to

Abdominal Wall and Inguinal Region, " Archives of

Dermatology 108:104-106 (7/73) [Record No. 0906].

235. Dennett, F.L., " Silicone Fluid and Soft Tissue

Augmentation, " M 360096 - 360141 (11/15/65) [Record

No. 0492].

236. Lavey, E.B., Pearl, R.M., " Inflammation in a

Silicone Granuloma Caused by a Tuberculosis Skin

Test, " ls of Plastic Surgery 7:152-154 (1981)

[Record No. 1039]; Vinnik, C.A., " The Hazards of

Silicone Injections, " JAMA 236(8):959 (8/23/76)

[Record No. 0959]; Wilkie, T.F., " Late Development of

Granuloma After Liquid Silicone Injections, " Plastic

and Reconstructive Surgery 60(2):180-188 (8/77)

[Record No. 0974].

237. See Table 1.

238. Yamachika, R. (Medical Engineering Corporation),

Memo to W. Lynch and L. Oxley attaching Interim Report

on Tissue Tolerance of Silicone XD Material, MED 66493

- 66503 (8/21/70) [Record No. 2715].

239. Biotech Report for Heyer-Schulte re: 90-Day

Animal Implantation Study with Histopathology, MC

236914-236918 (1/26/77) [Record No. 7029].

240. Friedlander, Pathology report on examination of

tissue from right breast area, MCG 29480 (1/4/77)

[Record No. 7258].

241. lin, B., Dow Corning Memo to Dennett, et al.

re: preliminary report - histology evaluation of

mammary capsular contracture tissues, M 190427-190430

(2/24/77) [Record No. 7058].

242. Phone call report by Silas Braley, Dow Corning,

of a call from Dr. Vinnik on September 10,

1975 (DCC 240000054) [Record No. 7084]; Phone call

report by Silas Braley, Dow Corning, of a call from

Dr. Vinnik on November 26, 1974 (DCC

240000051) [Record No. 7085].

243. Smahel, J., " Foreign Material in the Capsules

Around Breast Prostheses and the Cellular Reaction To

It, " British Journal of Plastic Surgery 32:35-42

(1979) [Record No. 1006]

244. Gayou, R., " A Histological Comparison of

Contracted and Non-Contracted Capsules Around Silicone

Breast Implants, " Plastic and Reconstructive Surgery

63(5): 700-707 (1970) [Record No. 1016]

245. Surgitek " Risks and Benefits of Silicone

Gel-Filled Breast Implants: A Summary of Findings in

the Literature, " MEX 120859 - 120899 [Record No.

7211].

246. Dolwick, M.F., Aufdemorte, T.B.,

" Silicone-Induced Foreign Body Reaction and

Lymphadenopathy After Temporomandibular Joint

Arthroplasty, " Oral Surgery 59:449-452 (1985) [Record

No. 0572].

247. Kalicharan, D., Jongebloed, W.L., Van Der Veen,

G., et. al., " Cell Ingrowth in a Silicone Plombe,

Interactions Between Biomaterials and Scleral Tissue

After 8 Years In Situ: ASEM and TEM Investigation, "

Documenta Ophthalmologica 78:307-315 (1991) [Record

No. 7078].

248. Klykken, P.C., Memo re: Differentiation of

Foreign Body Reactions and Immune Granulomas (1992)

[Record No. 7071].

249. Mitnick, J.S., Vazquez, M.D., Plesser, K., et.

al., " Fine Needle Aspiration Biopsy in Patients with

Augmentation Prostheses and a Palpable Mass, " ls

of Plastic Surgery 31:241-244 (1993) [Record No.

7072].

250. Presentation of Darryl , 7/23/97, at p.

625.

251. Id. at p. 625.

252. Epstein, 7/23/97 Transcript of Panel

Hearing, pp. 428-429.

253. Supplemental statement of Dr. Hardt to the

706 Science Panel (9/97) [Record No. 7044].

254. Affidavit of Shanklin, M.D. (9/26/97)

[Record No. 7214].

255. Pathology report of Dr. Epstein [patient

name redacted] (2/13/97) [Record No. 7045].

256. Darryl , 7/23/97 Transcript of Panel

Hearing at p. 625.

257. Id. at p. 625.

258. Affidavit of Shanklin, M.D. (9/26/97)

[Record No. 7214].

259. Affidavit of Shanklin, M.D. (9/26/97)

[Record No. 7214].