Historical Background - History of Manufacturing - Liquid Silicone Injection Experience - Internal Studies Consistently Demonstrated Adverse Reactions

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INTRODUCTION

Plaintiffs recognize the enormity of the Panel's

charge and of the task that lies ahead. The Panel has

received thousands of scientific articles, heard a

full day of introductory information, heard three days

of testimony from experts, and held its own

conferences. The subjects involved in the silicone gel

breast implant controversy are complex, interrelated,

and multidisciplinary. After evaluating all of the

information, the Panel's charge, as presented by Judge

Pointer, is to answer two questions:

1. To what extent, if any, do existing studies,

research, and reported observations provide a reliable

and scientific basis for one to conclude that silicone

gel breast implants can cause or exacerbate one or

more symptoms, diseases, or immune system dysfunction?

2. To what extent, if any, should any of the Panel

members' opinions be considered as subject to

sufficient dispute as would permit other qualified

scientists to express contrary opinions which would

likely be viewed by others in the field as

representing legitimate and responsible disagreement

within your profession?

(Order No. 31E). Plaintiffs submit that, after

considering the parties' submissions, after hearing

from scientists on both sides of the debate, after

conducting its own independent review, and after

thoroughly evaluating the evidence, the Panel will

conclude not only that there is room in their field

for legitimate and responsible disagreement but also

that there is abundant evidence to support a finding

that silicone gel breast implants are capable of

causing and/or exacerbating immune system dysfunction

and signs and symptoms of disease in some women.

Preliminarily, however, the important debate on the

question of whether silicone breast implants or their

degradation products are causing and/or exacerbating

adverse physiological effects in women seems to have

become diverted to arcane but protracted arguments

about defining diseases and the complex interpretation

of data from often poorly designed epidemiology

studies relating to classically defined diseases. The

Plaintiffs urge this Panel to recognize, based upon

the parties' submissions, that existing studies,

research, and reported observations provide a reliable

and scientific basis for one to conclude that silicone

gel breast implants can cause or exacerbate diseases,

and, also, to refocus the debate to the crucial

underlying issue: can silicone gel breast implants

cause or exacerbate adverse physical reactions in the

body through symptoms and/or immune system dysfunction

in some women, whether or not those symptoms or that

dysfunction have been defined, labeled, or subjected

to pristine and uncontroverted controlled epidemiology

studies.

Plaintiffs' submission is divided into nine sections.

The first provides an historical perspective of

silicone gel breast implants. It details the

manufacturers' knowledge that silicone breast implants

are an " infinite sink " or reservoir from which gel

bleeds, that silicone migrates to major organs, that

it causes a chronic inflammatory response, that it is

capable of producing immunologic effects, and that the

devices lacked the necessary safety testing for

long-term implantation. The second section addresses

the issue of " biological plausibility. " It addresses

the scientific evidence concerning silicone-induced

granulomas and their associated immunological

implications, evidence of chronic inflammation and the

presence of cytokines in implanted women, and the

strong evidence that silicone gel acts as an adjuvant.

From these sources, it is " biologically plausible "

that silicone causes immune system dysfunction and

causes symptoms of disease. This section also

discusses the silica analogy - the evidence silica has

immunogenic properties and causes symptoms of disease.

Section three addresses significant pathologic

findings in and around breast implant capsules and

beyond in other areas to which silicone has migrated

and the consistency of these findings when viewed

along with the findings from other silicone medical

devices. It describes the immunogenic significance of

inflammatory granulomas and explains how rupture and

local and systemic migration, via lymphatics and

vascular channels, significantly increases the amount

of and surface area of silicone available in the body.

It then summarizes the rupture data from almost twenty

studies in which implants have been examined upon

removal. Section four, immunopathology, substantiates

that silicone gel is subdivided by the body, that

minute microdroplets or particles are intensely

inflammatory, and that activated macrophages secrete

cytokines known to cause systemic symptoms of disease.

Sections five and six overview the available

immunological and toxicological literature -- both

that supporting the conclusion that silicone and its

breakdown products are immunogenic and that on which

the manufacturers rely for their contrary position.

The seventh section outlines the clinical experience

of highly respected and experienced clinicians -- the

rheumatologists, immunologists, and neurologists who

have treated thousands of women with implants and the

signs and symptoms which these physicians believe, to

a reasonable degree of medical certainty, are caused

by silicone gel breast implants. The section also

presents the many documented examples of symptoms

remitting, resolving, or significantly improving

following explantation. Section eight reviews the

controlled epidemiology studies conducted to date and

discusses and exposes the myths surrounding that

literature while summarizing what this area of science

has thus far contributed. Finally, Section nine

contains proposed findings for the Panel members' use

in the drafting of their report.

Plaintiffs, as non-scientists, acknowledge their

reluctance in attempting to assist this Panel in

understanding these complex scientific issues but hope

that this submission will be of use to the Panel as it

continues its important role in this debate.

I. HISTORICAL BACKGROUND

Silicones, synthetic compounds made from the elements

silicon and carbon, were first developed in the 1930's

for industrial purposes. In the late 1940's The Dow

Chemical Company performed the first short-term

toxicology testing on silicone fluids.(1) Dow Chemical

knew in 1956 that Dow Corning(2) was interested in

developing silicones for medical applications, so the

companies performed testing on liquid silicone. The

studies revealed that liquid silicone, when injected

both intraperitonally and submuscularly, migrated to

all the major organs, including the spleen, heart,

lung and brain.(3) In 1959, Dow Chemical discovered

inflammation in animals caused by D4 (the

organosilicon compound which is the building block of

all silicones contained in implants) and DC fluid 200,

the chemically equivalent silicone fluid which makes

up 80% of the silicone gel used in breast implants.(4)

Meanwhile, in the 1940's and 1950's, attempts were

made at breast enlargement in Japan and Korea by

direct injection of paraffin, silicone and other

substances.(5) By the 1960's, there were reports of

chronic and granulomatous inflammation and granuloma

formation in these patients, and many women were

reported to develop arthralgias, myalgias and skin

changes.(6) The Japanese investigators labeled these

signs and symptom complexes, and specifically its

atypical nature, " human adjuvant disease. "

A. HISTORY OF MANUFACTURING

Dow Corning Corporation manufactured the first

silicone(7) gel breast implant(8) in 1962. Dow Corning

had no competitors in this market until the late

1960's when other companies, primarily fueled by

former Dow Corning employees, began to manufacture

silicone breast implants. These competitors were

primarily start-up companies such as Heyer-Schulte,

McGhan Medical Corporation and Medical Engineering

Corporation ( " Surgitek " ) and were later acquired

directly, or through a parent company merger, by

Baxter, 3M, and Bristol-Myers Squibb, respectively.

With the exception of McGhan Medical Corporation,

which began manufacturing its own silicone materials

in 1977, these companies purchased the silicone

components for their breast implant products from Dow

Corning Corporation.(9) The manufacturers conducted,

at best, very limited short term testing and

acknowledge that they relied heavily on Dow Corning

for the alleged safety and biocompatability of

silicone gel breast implants and its components. For

example, when Heyer-Schulte converted to Dow Corning

gel in 1976, the company sent a scientist to Dow to

review its internal studies. He reported back that

" Dow Corning's data was lacking in quality " and " the

data does not answer the key questions I presented to

Dow concerning migration and its consequences. " (10) In

response, Heyer-Schulte hired an outside lab to

conduct a 90-day animal implantation study on the Dow

Corning gel. The investigators reported a " chronic

inflammatory reaction, granulomatous in nature, "

" fairly extensive infiltration of mononuclear

phagocytes, lymphocytes and occasional neutrophils "

and " chronic granulomatous inflammatory lesions. " (11)

They concluded that the gel " does not meet the

requirements of the muscle implant test, and is not

approved. " Nevertheless, Heyer-Schulte continued to

use the Dow Corning gel and never re-ran the 90-day

test.

B. LIQUID SILICONE INJECTION EXPERIENCE

Up to ninety percent (90%) of the silicone gel in a

breast implant is uncrosslinked silicone fluid,(12)

the same liquid silicone which was injected

experimentally in test animals and in humans during

the 1960's. Since all intact implants leak or " bleed "

liquid silicone through the elastomer or, in cases of

rupture, release large quantities of liquid silicone,

the liquid silicone injection experience is applicable

to silicone breast implants.

The earliest widespread use of liquid silicone for

breast enlargement began outside the United States. By

the 1950's, such usage had spread to the U.S.,

particularly in certain areas of the country (i.e.,

Nevada and California, where many women were being

injected with liquid silicone for breast enlargement.)

Physicians became alarmed at the adverse reactions and

consequences they were seeing from these injections,

even when only sterilized, unadulterated medical-grade

silicone fluid was being used.(13) These physicians

reported the problems of migration and the alarming

similarity of the severity of foreign body reactions

to silicone injections and silicone from ruptured

breast implants.(14) As a result of the adverse

consequences of silicone injections in the breast, the

practice was made illegal in Nevada and California in

the mid-1970's.

The FDA also took action in response to the reports of

adverse consequences, classifying silicone fluid as a

drug when administered by injection. Rigid

requirements existed in the 1960's for approval of a

new drug though, at that time, there were virtually no

regulatory requirements for medical devices.(15) In

1965, Dow Corning sought and received permission from

the FDA to begin clinical trials for the injection of

silicone fluid for various cosmetic uses under an

Investigational New Drug (IND) Application. However,

because of the experience with injections of silicone

fluid for breast augmentation, the mammary area was

declared off-limits for silicone injections, even in

these limited clinical trials. (16)

In 1967, the FDA notified Dow Corning that its IND did

not contain sufficient data to support a conclusion

that it was " reasonably safe " to continue clinical

investigation and invited Dow Corning to provide

additional data. Dow Corning supplied additional data

but the FDA again notified the company that its

submission was inadequate and, as a result, the IND

was terminated in 1976.(17)

Thereafter, Dow Corning attempted to develop an

" implantable gel, " or gel which could be implanted

directly in the body without an elastomer or

covering.(18) They implanted silicone gel

intramuscularly and subcutaneously in rabbits for 3,

7, 14, 30, 90 and 180 days. While the short term

results were noted as " satisfactory, " the results at 3

and 6 months showed subdivision of the gel mass by

bands of fibrous connective tissue, extensive

fragmentation of the mass into smaller particles and

gel particles being engulfed by macrophages and

carried away from the implant site. Based on these

results, Dow Corning abandoned this project, reasoning

that commercialization would require long-term animal

studies with sophisticated analysis and a campaign to

overcome the " bad press " and emotions associated with

the " disastrous results " from silicone fluid

injections.(19) When Dow Corning first manufactured

silicone gel breast implants in 1962, the only testing

conducted on this device was by two plastic surgeons,

Drs. Cronin and Gerow, who worked with Dow in

developing the implant. They examined the tensile

strengths of four to six balloons of an elastomer

shell filled with either Datran Plasma, electrolyte

solution or silastic R.T.V.(20) These were then

implanted in twelve dogs. The bags were removed at

varying periods from a few days to one and a half

years. There is no information given as to how long

the bags filled with the Silastic R.T.V. were

implanted. While not explicitly stated, it appears

that only gross pathology was conducted.(21)

As previously noted, the silicone gel in breast

implants is actually 80 - 90% liquid silicone fluid

contained within a matrix of cross-linked

polymers.(22) While often generally referred to as

polydimethylsiloxane, the fluid is itself thousands of

different polydimethylsiloxanes, including low

molecular weight cyclics D4, D5, D6, D7and linear

versions of the cyclic polymers.(23) Vinyl components

were also used as well as varying catalysts.(24) Thus,

the gel can be called a " chemical soup. "

The silicone elastomer, on the other hand, is more

cross-linked and contains a much larger percentage of

higher molecular weight components. To give it

strength, up to 30% of the shell consists of silica

(SiO2). Some of the manufacturers also used

phenylmethylsiloxanes in their elastomer shell, which

is of concern due to the well-documented estrogenic

effects of phenylmethylsiloxanes.(25) Contained within

both the elastomer and gel were a variety of

impurities including PCB's(26) and a variety of

metals, including zinc and platinum.(27)

C. INTERNAL STUDIES CONSISTENTLY DEMONSTRATED ADVERSE

REACTIONS

In the 1960's, Dow Corning discovered extreme

biological activity in a silicone compound called

2,6-cis, a compound closely related to D4except that

it contains a phenyl component. This development led

Dow to begin a research program called the Bioscience

Research Department led by a pharmacologist, Dr.

. Dow intended to develop commercial

products exploiting the biologic activity of the whole

range of silicone compounds. 's lab found

various silicones, including polydimethylsiloxanes, to

have unexpected effects on the immune system. (28) In

fact, by the late 1960's, Dow Corning believed that it

might be able to use silicones to cure autoimmune

disease.(29)

By the early 1970's, Dow Corning was focusing on the

effectiveness of various polydimethylsiloxanes,

including D4, as adjuvants. Initial studies in Dow's

laboratory, from 1971, established that silylated

bacterial cells evoked an antibody response which

differed from that of the unsilylated control with the

response remaining higher than in control cells for

the period studied.(30) By 1974, the Dow researchers

concluded that " [f]rom a modest number of compounds

examined over a period of ten months we have data

indicating that organosilicon compounds can stimulate

the immune response. " (31)

By January, 1975, Dow had found that " [v]arious

organosilicon fluids [including polydimethylsiloxane

fluids contained in breast implants] potentiated the

formation of humoral antibody, modulated cell mediated

immunity and promoted the induction of interferon by

stimulation of the immune system. " (32) Later that same

year, testing by a Dow Corning virologist revealed

that some of the polydimethylsiloxanes in breast

implants also produced eosinophilia,(33)and that the

low molecular weight silicones impaired the phagocytic

ability of macrophages.(34)

Concerned about both the ability of silicone to

migrate in the body and its local and systemic

biological activity, Dr. recommended the

establishment of a patient registry for breast

implants.(35) None of the manufacturers established

one. In the only long-term clinical study conducted by

Dow Corning, fifty women with silicone breast implants

were followed for ten years, primarily focusing on

aesthetic results. The results, which were never

published or disclosed to the FDA during hearings on

complications from silicone breast implants during the

1980s,(36) revealed that nine out of forty-two women

followed (eight were lost to follow-up) developed many

of the same symptoms previously reported in the

Japanese literature: (Patient 26 developed arthritis

in her fingers twelve years after implantation, and

patients 29, 36 and 50 also developed arthritic

problems in their upper extremities, back, shoulder

and fingers).(37)

In 1970, Dow Corning and Dow Chemical conducted an

injection study in albino rats which confirmed the

systemic migration of silicone. DC 360 fluid was found

to migrate into the bone marrow of animals and affect

brain weights.(38) Other internal studies demonstrated

migrating silicone particles from a finger joint which

were later found in the swollen lymph nodes of human

subjects, where they entered the cells and were

degraded.(39)

Other manufacturers also internally recognized the

problems with silicone gel. By 1975, Heyer-Schulte was

exploring the use of alternative materials for breast

implants, recognizing that " [t]here is currently a

need for a biocompatible and biodegradable organic

polymer gel to replace the polydimethylsiloxane

material used in the Heyer-Schulte mammary prostheses

.. . . there is the possibility of some low molecular

weight polymer migrating from the gel through the

prosthesis. This material can localize in the body and

possibly produce detrimental effects. " (40)

Heyer-Schulte also confirmed the work of Dow Corning

on the subdivision and migration of silicone. In 1978,

they found that, over time, the gel was broken up into

small particles, and that it was the small particles

that provoked the most inflammatory response and had

the greatest tendency to migrate.(41)

Bristol-Myers Squibb's subsidiary, Medical Engineering

Corporation (MEC/Surgitek), also did early animal

testing. MEC's founding president and chief silicone

scientist, Wilfred Lynch, testified that the only

long-term animal studies MEC ever conducted on

silicone were two-year dog studies (in two dogs) and

90-day rabbit studies.(42) MEC's purpose in doing the

dog studies was to determine whether the silicone

material was biocompatible and safe for long-term use.

The dog study showed adverse reactions. Despite this,

MEC undertook no additional pathology tests to follow

up(43) and, ultimately, MEC determined that the dog

studies were useless.(44)

Huntingdon Labs conducted three rabbit tests at MEC's

request in the early 1970s. The toxicological reports

showed adverse reactions in the brain and other

organs, chronic inflammatory reactions, proliferation

of connective tissue and formation of giant cells. The

response was more prominent in the female animals than

in males, particularly in the test sites around the

mammary glands.(45) MEC retained an outside consultant

to identify the chemical nature of compounds found in

the organs of the test animals. He reported " low but

definite concentrations of silicone in organs,

especially kidney and liver. " (46)

Because the local fibrotic reaction leading to

significant capsular contracture was now of major

concern to the plastic surgeons and manufacturers'

sales representatives, MEC's president launched a

" Scientific Affairs Committee, " or SAC, in 1977. SAC

consisted of several prominent scientists outside the

company.(47)

In 1977, the manufacturers of silicone breast implants

formed an official organization, " Breast Implant

Manufacturer's Association, " or BIMA, to respond to

plastic surgeons' concerns about the formation of

capsules in women with breast implants.(48) BIMA held

a two-day scientific conference at the University of

Michigan in November for plastic surgeons,

immunologists, neurologists and other interested

physicians regarding capsule formation and the

reaction of tissue to silicone gel. Several prominent

physicians participated. One of the proposals raised

at the conference was to study the immune response of

silicone in humans by conducting HLA typing (a

lymphocyte study) of 100 patients. Also proposed was

the " development of improved analytical techniques for

silicone in tissues and biological materials. " (49)

None of the breast implant manufacturers ever

conducted these studies.

Most of the manufacturers also failed to conduct

studies on the biodegradation of silicone gel,

elastomer and the various other components in the

body. Dow, however, did know that silicone undergoes

chemical changes in the body. Every test conducted by

Dow in the 1970's and 1980's looking for metabolic

byproducts had positive findings. Some found

depolymerization,(50) the conversion of high molecular

weight polydimethylsiloxanes to low molecular weight

polydimethylsiloxanes. Others found metabolism to

silanols through a hydrolysis reaction.(51) This was

of great concern as " [a]ll of the silanols which had

been tested had been found to have extreme

toxicity. " (52)

Other testing indicated that silicone ultimately

degraded into silica. In 1979, MEC/Surgitek (later

acquired by Bristol-Myers) also tested for metabolic

changes of silicone. Transmission electron microscopy

and energy dispersive x-ray analysis was conducted of

tissue samples obtained from the liver, kidneys,

thyroid and lymph nodes of dogs implanted with

silicone. Using a profile for a control silica

pattern, " all specimens exhibited an energy pulse in

the region of silica compatible with silica migration

to these organs. The kidney and liver appeared to have

greater peaks than the other tissues though thyroid

[from one sample] also exhibited a significant

peak. " (53) In studies on the effects of silicone in

the environment, Dow Corning also confirmed that the

ultimate degradation product of silicone was

silica.(54)

Meanwhile, in the published literature, case reports

of symptoms of disease from silicone gel breast

implants and silicone injections were increasingly

reported. In 1979, an article was published in which

the authors reported that a woman implanted with

silicone gel breast implants experienced low grade

fevers and joint aches.(55) Silicone was found in

various organs throughout her body and upon removal of

her implants, her condition improved dramatically.

Between 1979 and 1984, reports by Kumagai, Van Nunen,

Baldwin and Okano(56) discussed the occurrence of

symptoms of connective tissue disease after silicone

gel breast implants and/or silicone injections. After

Heggers and Kossovsky published their study in 1983

suggesting that silicone gel breast implants were

capable of eliciting a cellular immune response,(57)

two of the manufacturers (3M and Heyer-Schulte) left

the breast implant business.(58) Dow Corning reviewed

its data and acknowledged internally that " only

inferential data exists to substantiate the long-term

safety of these gels for human implant applications. "

(59)

In 1984, Dow Corning conducted a ninety-day implant

test of silicone gel implanted into the paravertebral

muscle and ventral subdural area of male rabbits.(60)

After 3, 10, 30 and 90 days, the animals' tissues were

examined and compared to USP polyethylene negative

controls. The pathologist noted the presence of an

eosinophilic infiltrate in the test animals,

" considered indicative of an allergic response. "

In 1985, Dow Corning conducted a repeat thirty-day

test to investigate the possibility of immunological

sensitization to a component of the gel

formulation.(61) Once again, increased numbers of

eosinophils were evident at the gel implant site.(62)

The pathologist noted that " eosinophils appeared to

diffusely infiltrate around and within the capsule,

often being concentrated around vessels on the outer

aspect of the capsule. " (63) Neither the 1984 study nor

1985 repeat test was ever published.

By 1985, Dow Corning began to consider conducting an

immunotoxicology program for silicone gel breast

implants. In a project proposal entitled

" Investigation of the Effects of Silicone Fluids, Gels

and Particles on the Immune System, " Dow Corning

scientists conceded that " [a]nimal studies . . . also

suggest that silicone materials may be able to modify

the immune system. The studies have indicated silicone

materials may have the ability to elicit a specific

immune response to silicone as well as nonspecifically

enhance or suppress the immune system. " (64) Dow

Corning reviewed its internal unpublished research on

silicone's adjuvancy properties because of the outside

work by Heggers published in 1983 (65) which found a

cellular immune response to silicone gel, and

Ben-Hur's work from the 1960's which demonstrated the

ability of polydimethylsiloxane fluid to prolong mouse

skin allograft survival by partial blockage of the

lymphatic system.(66) They concluded that " the

preponderance of available animal data also suggest a

potential for silicone materials to be involved in

immunologically mediated disease states. " (67)

Other manufacturers reached similar conclusions. In

1985, a small manufacturer, CUI, commissioned a study

to characterize its silicone materials. The study

confirmed that " oil migration from the gel into the

shell degrades the mechanical properties of the

shell. " (68) The researchers also conducted biological

testing and found tthat " [t]he gel does not appear to

be retained within the fibrous capsule. . . . " (69) In

fact, the investigators noted that " ome silicone

can be observed in close proximity to the vascular

system, further substantiating observations by other

investigators that silicone can migrate into the

bloodstream. " (70) They concluded that " the use of

silicone gel prosthesis represent a significant risk

to the patient. The literature suggest that

individuals can develop an allergic and immunologic

reaction to silicone and oil. " (71) Similarly, an

" Infor-Med " put out by one manufacturer stated that:

" [t]he hazards of free silicone, well documented in

silicone injections, are leading to more granulomas

and silicone gorged [sic] lymph nodes. The damaging

sequelae from these implants ask questions that remain

unanswered and although doctors are using the product,

plastic surgeons and the FDA continue to raise doubts

about its safety and efficacy. "

Further:

mooth surfaced silicone polymers do not yield

benign histological conditions as a result of their

implantation. Silicone granulomas in the lymph and

capsule, calcification, and recently 'arthritis' are

hazards of direct cellular contact with this smooth

polymer material.(72)

In late 1986, Dow Corning conducted a comprehensive

review of all internally conducted safety studies of

silicone materials to date and noted that " ilicone

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. " (73) At least internally, Dow Corning also

acknowledged that the gel from an implant was not

contained within the fibrous capsule: " [r]eleased

polydimethylsiloxane (and probably gel in the case of

a rupture) is phagocytized in part by macrophages,

giant cells, and possibly, PMN's. Phagocytic cells

transport engulfed silicone to at least regional lymph

nodes. " (74) Dow scientists " postulated that

phagocytized silicone will accumulate in draining

lymph nodes followed by slow transport to the liver.

It is anticipated that the liver will function as a

secondary long-term storage site from which phagocytic

bearing silicone will cycle to other tissues of the

reticuloendothelial system. Elimination is postulated

to occur at a slow rate via lung alveolar phagocyte

migration up the respiratory tree to the

esophagus. " (75)

Concerning the formally-conducted toxicity studies

done to date, Dow admitted that the majority " were

conducted for the purpose of evaluating local

implantation site reactions [and that] [t]he local

reaction has been characterized only with regard to

incidence and broad levels of severity. " (76) Notably,

Dow admitted that " n no case are the local

inflammatory reactions described and classified

according to criteria employed by researchers expert

in the study of inflammation nor have any studies been

designed to detect the range of systemic effects that

could attend a chronic inflammatory state. " (77) In

summarizing the major deficiencies in the

toxicological studies performed on silicone up through

1986 Dow Corning noted:

A. 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.

B. None of the existing studies critically assess

possible systemic effects arising from the local

inflammatory reaction or from material transport.

These substantive issues 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.(78)

In the late 1980's, Dow Corning began to conduct

toxicological testing of some of the various

polydimethylsiloxanes present in silicone gel breast

implants. A series of studies on D4and other low

molecular weight silicones confirmed increased liver

weights in animals(79) and more recent studies have

found a prenatal and/or neonatal toxicity as compared

to controls with a reduction in mean live litter size

and pup viability indices.(80)

D5, another component, was found to induce the

production of drug metabolizing microsomal enzymes in

the liver(81) and also to result in reduction in P-450

hemoprotein content and hepatomegaly. Studies on

D4produced similar results.(82)

In 1988, the FDA classified silicone gel breast

implants as Class III devices requiring the

manufacturers to produce data establishing their

safety and effectiveness. Dow Corning, Bristol-Myers,

Mentor and McGhan submitted Pre-Market Approval

Applications on their " low-bleed " implants in July

1991. All were rejected by the FDA and, in February

1992, a moratorium was imposed.

D. THE MANUFACTURERS' LITIGATION STRATEGY

In reaction to an increasing number of lawsuits, the

manufacturers developed a " litigation strategy " of

designing and funding epidemiological studies with the

purpose of giving silicone gel breast implants a clean

bill of health.(83) Before agreeing to funding any

studies, Dow's litigation attorneys reviewed them to

judge their impact on the litigation.(84) Epidemiology

studies were also funded through the Plastic Surgery

Education Foundation, an organization to which the

manufacturers contributed and in which the attorneys

for the manufacturers had direct input into selecting

which studies to fund. As the attorneys noted at one

meeting, " [t]he strategydirectly relates to which

study should be funded. " (85) Four conditions were

apparently required before funding approval was given:

1. that the studies look at classical, traditional

connective tissue diseases (and not the atypical

symptomatology reported by clinicians and found in the

literature).

2. that the studies include saline implants which do

not contain silicone gel or oil inside.(86)

3. That the studies use a two-tailed test of

significance instead of a one-tail test which had been

recommended by investigating institutions;(87) and

4. that all women who exhibited symptoms after 1991 be

excluded from the study although including all women

implanted through 1991.(88)

In the early and mid-1990's independent research on

silicones has proliferated. From clinicians'

documentation of their clinical experience with

thousands of ill women with breast implants to

laboratory studies exploring the immunological effects

of silicones in the body, the science continues to

develop to this day.

E. RECENT DEVELOPMENTS

There have been a few important new developments on a

variety of scientific issues since the July, 1997

Birmingham presentations. In the area of immunology,

Schaefer recently reported the first animal model

showing increased incidence and severity of autoimmune

disease in susceptible mice induced by exposure to

silicones nine months prior to immunization with

antigen. The same study detected multiple

perturbations in more than six different cytokines,

autoimmune biomarkers, and antibodies to different

silicone-bound proteins.(89) Naim reported that human

monocytes compared to other materials, cultured on

silicone, produced two times the amount of 3

cytokines,(90) and an Austrian research group

confirmed Claman's findings of excess high titer ANA's

in non-symptomatic implanted women.(91)

In addition, new clinical studies show a correlation

between levels of silicone in the liver and ANA's and

with peripheral neuropathy in implanted women vs.

controls. A correlation was also shown between

cognitive impairment and two brain metabolic

dysfunctions, with one of the dysfunctions improving

after explantation.(92) Finally, two large German

studies recently found powerful associations between

silica inhalation and scleroderma.(93)

Continue to Section II of Plaintiffs' Submission.

1. Rowe, V.K., Spencer, H.C., Bass, S.L.,

" Toxicological Studies on Certain Commercial Silicones

and Hydrolyzable Silane Intermediates, " Journal of

Industrial Hygiene and Toxicology 30(6):332-352 (1948)

[Record No. 0004].

2. The Dow Chemical Company and Corning, Inc. created

Dow Corning Corporation in 1943. Each of the parents

owns 50% of the stock in Dow Corning.

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

Physiological Assimilation of Dow Corning 200 Fluid "

(1956) [Record No. 0006].

4. Dow Chemical Letter to McGregor, R.R., Re:

Comparative eye irritation of specially prepared Dow

Corning 200 fluids (9/1/59) [Record No. 0011].

5. Kumagai, Y., Shiokawa, Y., Medsger, T.A., et al.,

" Clinical Spectrum of Connective Tissue Disease After

Cosmetic Surgery: Observations on Eighteen patients

and a Review of the Japanese Literature, " Arthritis &

Rheumatism 27(1):1-12 (1984) [Record No. 1111].

6. Kumagai, Y., Shiokawa, Y., Medsger, T.A., et al.,

" Clinical Spectrum of Connective Tissue Disease After

Cosmetic Surgery: Observations on Eighteen Patients

and a Review of the Japanese Literature, " Arthritis &

Rheumatism 27(1):1-12 (1984) [Record No. 1111]; See,

, W., Balogh, K., Abraham, J., " Silicone

Granulomas: Report of Three Cases and Review of the

Literature, " Human Pathology 16(1):19-27 (1984)

[Record No. 2474].

7. " Silastic " is the Dow Corning registered trademark

used to refer to all Dow Corning silicone-containing

products. It is frequently used interchangeably with

the word " silicone " to refer to the composition of a

medical device such as " silastic implants, " " silastic

shunts, " or " silastic tubing. "

8. There are four main types of silicone gel breast

implants: (1) Single-lumen - the most common breast

implant, consisting of a gel/fluid matrix encased by a

single silicone elastomer shell; (2) double-lumen - a

double walled implant consisting of a gel/fluid matrix

encased in a silicone elastomer that was, itself,

surrounded by a saline filled chamber enclosed in an

outer silicone elastomer shell; (3) polyurethane - a

foam covered implant consisting of a gel/fluid matrix

surrounded by a silicone elastomer one totally encased

in an outer covering of polyurethane; and (4) a low

bleed implant introduced in the early 1980's which was

an alternative implant with an additional liner

comprised of either thriflouropropy or additional

methylphenyl material. There were variations which

included textured shells introduced in the late 1980's

in an attempt to reduce capsular contracture. Saline

implants have only a silicone elastomer but no gel

matrix, instead being filled with a saline solution.

9. Heyer-Schulte and MEC began manufacturing silicone

gel breast implants in 1970 and, until 1976, received

their silicone components from General Electric.

McGhan Medical began manufacturing in 1975 and for the

first year purchased its silicone components from

General Electric. In 1976 General Electric ceased

selling silicone for use in medical implantation.

10. Frugard, G., Memo to Koorajian and Rudy re: Trip

to Dow Corning (7/14/76) [Record No. 2632].

11. Biotech Report to Heyer-Schulte re: 90-Day Animal

Implantation Study with Histopathology, MC 236914-918

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

12. Winn, R.A., memo to Tom Hyans re: Silicone gel

technology for July meeting of FDA gel mammary panel

(6/29/78) [Record No. 7030].

13. Dr. Vinnik, a plastic surgeon in Las Vegas, wrote,

in part: " Physicians have assumed that problems

associated with silicone injections were caused by

adulterated liquid silicone. This is not the case. In

Las Vegas and elsewhere, the injection of sterilized,

unadulterated medical-grade fluid has also been

implicated in adverse reactions. " Vinnik, C.A., " The

Hazards of Silicone Injections, " JAMA 236(8):959

(8/23/76) [Record No. 0959].

14. Dow Corning report of telephone call from Dr. C.A.

Vinnik (11/26/74) [Record No. 7031]; Vinnik, C.A.,

letter to Rylee, President of Dow Corning

(6/23/81) [Record No. 2784].

15. By crosslinking silicone fluid into a gel matrix

and surrounding it in a silicone elastomer, Dow

Corning was able to call the silicone gel breast

implant a medical device, and not a drug or drug

delivery device, even though up to 90% of the gel

remained liquid silicone and was known to diffuse

through the elastomer as " gel bleed. "

16. See discussion later in Section III.

17. Crout, J.R., FDA letter to Dow Corning (3/19/76)

[Record No. 0623].

18. Lentz, A.J., Chandler, M.L., LeVier, R.R.,

" Biological Evaluation of an Implantable Silicone Gel:

Summary of Acute and Chronic Studies, " Dow Corning

Report No. 4586 (5/17/78) [Record No. 7017].

19. s, S., Memo to Marlar, et al. re: Review of

Implantable Gel Concept (4/29/81) [Record No. 0501].

20. It appears that the Cronin study did not even test

the same silicone gel used in breast implants but

rather used a Silastic R.T.V. See, Cronin, T.D.,

Gerow, F.J., " Augmentation Mammaplasty: A New 'Natural

Feel' Prosthesis, " presented at Third International

Congress of Plastic Surgery (10/13-18/63) [Record No.

0817].

21. Id.

22. Batich, 7/22/97, Transcript of Panel

Hearing, pp. 147-97. (All subsequent references to the

July meeting of the National Science Panel will be as

follows: [Witness name] [Date], Transcript of

____Panel Hearing, p. ____].

23. This is a critical fact as different

polydimethylsiloxanes have very different biological

effects. For example, D4 has different effects than

D5. Most, such as D22, have never even been tested for

their toxicological properties..

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

" Induction of Plasmacytomas with Silicone Gel in

Genetically Susceptible Strains of Mice, " J. Nat.

Canc. Inst. 86(14):1058-1065 (1994) [Record No. 1772].

25. Hayden, J., Barlow, S., " Structure-Activity

Relationships of Organosiloxanes and the Female

Reproductive System, " Tox. & App. Pharm. 21(1):68-79

(1972) [Record No. 2394].

26. Nair, J. H., GE Letter to Dr. Keplinger

(Industrial Biotest Labs) GEG 001658-001659 (8/25/75)

[Record No. 7032]; Boretos, J.W., Letter from

Biomaterials Consultant to B. Liebler (HIMA), HIM 4112

(6/9/93) [Record No. 7023].

27. Duncan , E., Memo to Compton, et al. re: Summation

of findings - McGhan mammary prosthesis, MC 7041-7049

(6/28/77) [Record No. 7033].

28. , D.R., MDL Deposition, Vol. 1, pp. 210-213

(7/18/94) [Record No. 7236].

29. Isquith, A.J., Deposition, Vol. 1, pp. 110-113

(6/13/94) [Record No. 7034].

30. Dow Corning, Exploratory Antigen Modification

Research Project Description (5/22/73) [Record No.

0022].

31. Boley, W., Levier, R., Immunological Enhancing

Activities of Organosilicon Compounds and

Non-functional Fluids, Dow Corning Report No. 4319

(10/2/74) [Record No. 0023].

32. Boley, W., Lake, R., LeVier, R., Dow Corning

Patent Memorandum No. 4320 (1/31/75) [Record No.

0024].

33. Lake, R.S., Radonovich, A.F., " Actions of

Polydimethylsiloxanes on the Reticuloendothelial

System of Mice: Basic Cellular Interactions and

Structure - Activity Relationships, " Dow Corning

Report No. 4509 (10/30/75) [Record No. 0025].

34. Id.

35. Deposition, Vol. 3, pp. 768, 771 (7/20/94)

[Record No. 7035].

36. Dow Corning's legal counsel instructed Arthur

Rathjen, who coordinated the data collection from Dr.

Ben not to release the results of the study.

Rathjen MDL testimony at p. 138 (11/30/94) [Record No.

7037].

37. A full set of the documents has been previously

provided. Attached as Record No. 7036 are the study

records from the women who became ill. Also see

Rathjen Deposition, Vol. 1, pp. 115-146 (11/30/94)

[Record No. 7037].

38. Sparschu, G., Clashman, A., Pathology Report on

the Effects of Dow Corning 360 Fluid, TDC 8028 - 8078

(12/2/70) [Record No. 0018].

39. Quast Deposition, pp. 173-192 with Exhibit 7

(12/19/96 ) [Record No. 7038].

40. Siow, B.S., Memo to Mayhan re: Literature survey

of biodegradable polymers, BAX 84228-845 (11/9/75)

[Record No. 2589].

41. Pudenz, B., Talcott, T., Heyer-Schulte Memo to Tom

Hyans attaching report on gel bolus studies, MD

114595-114598 (5/23/78) [Record No. 7039].

42. Lynch, W., MDL Deposition, pp. 119-120, 1673

[Record No. 7243]. See also, MDL Deposition of

Stith, MEC's Vice President of Scientific Affairs, pp.

224, 277-279 [Record No. 7244].

43. Stith, W., Deposition, Vol. 1., pp. 219-230,

242-249, 260-262, 277-279, 400-403, 407 (12/13/93)

[Record No. 7243]; Speed memo from Olsen to

, President of MEC, et al., re: Beagle implant

study, autopsy pathology, MED 25034 (4/17/75) [Record

No. 7245].

44. Lock, B. (Director of Regulatory Affairs, MEC),

MDL Deposition, pp. 106-107 (12/27/93) [Record No.

7246].

45. Yamachika, R., memo to Lynch and Oxley attaching

interim report on tissue tolerance of silicone XD

material, MEO 66493-503 (8/21/70) [Record No. 2715];

Huntingdon 90-day rabbit test results showing chronic

inflammatory reaction, MEI 145252-61 (12/17/71)

[Record No. 7247]; Huntingdon Research Center,

Toxicology Report to MEC, MEI 149636-148648 (1/10/72)

[Record No. 2700] (shows prominent inflammatory

response in mammary glands of female animals).

46. Lynch, W., Memo to , BMS 56502-05 (7/17/79)

[Record No. 7248].

47. MEC, Announcement of formation of Scientific

Affairs Committee, MEM 281-284 (3/19/77) [Record No.

7249].

48. Helmer, J., Memo to Dave re: BIMA

California meeting, MEM 415-417 (5/16/77) [Record No.

7251].

49. Talcott, T., Memo to Tom Hyans of Heyer-Schulte

re: Ann Arbor Meeting, MC 114685-87 (11/23/77) [Record

No. 2587]; See also, Lynch W., MiniReport on Ann Arbor

Contracture Seminar, Lynch MDL Deposition Exhibit #41

(11/12/77) [Record No. 7252].

50. See, Annelin, R.B., Trace Analysis of

Organosilicon in Human Urine and Milk by the ASFT

Technique (5/29/80) [Record No. 0034].

51. See, e.g., Spielvogel, D., , R.,

Metabolism of Octamethylcyclotetrasiloxane in the

Monkey, Dow Corning Report No. 5265 (12/10/80) [Record

No. 0033].

52. McCarty, R., Speier, J., Chemical Research

Progress Report, Dow Corning Report No. 2964

(10/12/66) [Record No. 2640].

53. Lynch, W., Letter to Stith enclosing reports on

transmission electron microscopy and energy dispersive

x-ray analysis of tissue samples, MED 26077-26149,

Sec. MED 26084 (10/23/78) [Record No. 0031].

54. Lentz, C.W., " It's Safe to Use Silicone Products

in the Environment, " Industrial Research &

Development, pp. 139-143 (4/80) [Record No. 1352].

55. Uretsky, B., O'Brien, J., Courtiss, E.,

" Augmentation Mammaplasty Associated with a Severe

Systemic Illness, " ls of Plastic Surgery

3(5):445-447 (11/79) [Record No. 1023].

56. Kumagai, Y., Abe, C., and Shiokawa, Y.,

" Scleroderma After Cosmetic Surgery: Four Cases of

Human Adjuvant Disease, " Arth. & Rheum. 22(5):532-537

(1979) [Record No. 1015]; Baldwin, C., Kaplan, E.,

" Silicone-Induced Human Adjuvant Disease, " Ann. Plast.

Surg.10(4):270-273 (4/83) [Record No. 1088]; Van

Nunen, S., Gatenby, P., Busten, A., " Post-Mammoplasty

Connective Tissue Disease, " Arthr. & Rheum. 25

(6):694-697 (1982) [Record No. 1062]; Kumagai, Y.,

Shiokawa, Y., Medsger, T., et al., " Clinical Spectrum

of Connective Tissue Disease After Cosmetic Surgery, "

Arthr. & Rheum. 27(1):1-12 (1984) [Record No. 1111];

Okano, Y., Nishikai, M., Sata, A., " Scleroderma,

Primary Biliary Cirrhosis, and Sjogren's Syndrome

After Cosmetic Breast Augmentation with Silicone

Injection: A Case Report of Possible Human Adjuvant

Disease, " Ann. Rheum. Dis. 43:520-522 (1984) [Record

No. 5262].

57. Heggers, J., Kossovsky, N., Parsons, R., et al.,

Biocompatability of Silicone Implants, " Ann. Plast.

Surg. 11(1):38-45 (1983) [Record No. 1093].

58. Heyer-Schulte sold its silicone breast implant

line to Mentor Corporation in 1984 and, in the same

year, 3M sold its silicone breast implant line to a

newly constituted McGhan Medical Corporation.

59. Matherly, J., Memo to and Ziarno re:

Biological testing of gel for implants, M 170037-38

(9/23/83) [Record No. 0471].

60. Veresh, L., Ninety-Day Implant Study of Dow

Corning Q7-2218 Silicone Gel System (12/7/84) [Record

No. 2758].

61. Bejarano, M.A., Thirty-Day Implant Study of Dow

Corning Q7-2218 Silicone Gel System (8/8/85) [Record

No. 0475].

62. Id.

63. Id. at T-031532.

64. Boley, W., Malczewski, R.M., , J.G., " HCB

Research Immunotoxicology Program Project Proposal -

Investigation of the Effects of Silicone Fluids, Gel &

Particles on the Immune System, " DCCKMM 386643-659

(2/19/85) [Record No. 0476].

65. Heggers, J.; Kossovsky, N.; Parsons, R.; et al.,

" Biocompatability of Silicone Implants, " Ann. Plast.

Surg. 11(1):38-45 (1983) [Record No. 1093].

66. Ben-Hur, N., " Prolonged Allograft Survival by

Partial Block of the Reticuloendothelial System with

Silicone Fluid, " Europ. Surg. Res. 2:73 (1970) [Record

No. 7041].

67. Id., p. 4.

68. CUI Corporation, " Characterization of CUI Silicone

Elastomer Shells CUI 300317-414 at 359 (10/10/85)

[Record No. 0477].

69. Id., at CUI 300379.

70. Id., at CUI 300400.

71. Id., at CUI 300407.

72. Natural Y, Infor-Med re: Smooth Silicone Under

Fibrosis, MEI 4230-4233 (10/85) [Record No. 2812].

73. Dow Corning, MedTox Project, DCCKMM 298296-339

(2/23/87) [Record No. 0479] (hereinafter " Medtox " ).

74. Id., p. 8.

75. Id., p. 9.

76. Id., p. 9.

77. Id.

78. Id.

79. Zimmer, M., Bejarano, M.,

" Octamethylcyclotetrasiloxane - An Investigation of

Hepatic Weight Increases, " GEG 32621-32634 (1989)

[Record No. 0482].

80. Stump, A., " An Inhalation Range - Finding

Reproductive Toxicity Study of

Octamethylcyclotetrasiloxane (D4) in Rats, " Dow

Corning Report No. 1996-I000-41337, DCC

833-610016-6100190 (8/27/96) [Record No. 3096].

81. Mehendale, H. " Evaluation of the Liver Microsomal

Enzyme Induction Potential of D5, " Dow Corning Report,

pp. 15154-15182 (4/17/89) [Record No. 0481].

82. Dow Corning (McKim, J.), " Effects of

Octamethylcyclotetrasiloxane on Liver Size and Enzyme

Induction: A Pilot Feasibility Study, " Dow Corning

Report No. 1996-I0000-41772, DIC 835-610001-610039

(9/16/96) [Record No. 5106].

83. J. R. Affidavit, ¶ 4 (7/10/95) [Record No.

0486].

84. Id.

85. Plastic Surgery Education Foundation notes re:

Silicone Research Funding Summit Meeting, ASP 22922-28

(7/10/92) [Record No. 7043].

86. Cook, R., Letter to Hollis Coffee, DCC

010001189-010001194 (5/18/92) [Record No. 7256].

87. See generally, Epidemiology Section.

88. Cook, R., Letter to Helen Englert, DCC

279011607-279011609 (9/11/92) [Record No. 7046].

89. Schaefer, C.J., " The Influence of Silicone

Implantation Experimental Models of Autoimmunity, "

Ph.D. dissertation (9/11/97) [Record No. 7204].

90. Naim, J.O., Zhang, J.W., Van Oss, C.J., " In Vitro

Activation of Human Monocytes by Various Plasma

Proteins Adsorbed onto Silicone Elastomer, Gel and

Oils, " Surfaces in Biomaterials, pp. 105-106 (1996)

[Record No. 7106].

91. Zazgornik, J., Piza, H., Kaiser, W., et al.,

" Autoimmune Reactions in Patients with Silicone Breast

Implants, " Wein Klin Wochenschr 108(24):781-787 (1996)

[Record No. 7024].

92. Pfleiderer, B., Stanka, M., Bruns, H., et al.,

" Patients with Silicone Implants: Defect Diagnosis,

Exposure to Silicone and Correlation with

Symptomatology, " Abstract presented at Fifth

Scientific Meeting ISRM, Vancouver (4/97) [Record No.

7168].

93. Mehihorn, J., Ziegler, V., " Epidemiological

Analyses of the Relation Between Scleroderma, Exposure

to Quartz and Silicosis for Men in East Germany, " Int.

Epid. Assoc., p. 76, Abstract (9/5/97) [Record No.

7199].