TOXICOLOGY and Silicone - Plaintiff's submission

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PLAINTIFFS’ SUBMISSION AND PROPOSED FINDINGS

TO THE NATIONAL SCIENCE PANEL

ON SILICONE GEL BREAST IMPLANTS

July 21-23, 1997

VI. TOXICOLOGY

" That silicone is toxic in both animals and man is

well proven. From the earliest studies which found

silicone toxicity in animals to findings that silicone

suppresses natural killer cell activity, causes an

activation of complement, generates a specific immune

response, causes extensive fibrosis with chronic and

granulomatous inflammation, causes immunogenic delayed

hypersensitivity granulomas to form, leads to

increased liver weight, and demonstrates parental

toxicity by a reduction in mean live litter size and

reduction in pup viability in Sprague-Dawley rats, the

research collectively supports Dr. Sergent’s statement

in the Textbook of Rheumatology that silicone is,

indeed, toxic to animals and humans.

In this section analyzing the toxicity of silicones,

it is difficult and ultimately quite arbitrary to draw

lines between the scientific evidence on toxicity with

that of its immunological and pathologic effects. Much

of that evidence has already been presented in

previous sections and will not be repeated here. Much

like the Dow Corning Medtox analysis, the toxicology

analysis here will focus on the following progression

of events:

GEL BLEED, LEAKAGE, RUPTURE

SYSTEMIC MIGRATION

SUBDIVISION OF THE GEL/PARTICULIZATION OF THE

ELASTOMER

METABOLISM AND DEGRADATION INTO SILICA AND SILANOLS

ADVERSE FINDINGS OF TOXICITY

Among the adverse toxicity findings are the following:

· Pathologic evidence of gel bleed and migration;

calcification and mineralization; severe, painful

capsular contracture; extensive - sometimes massive -

angiofibrosis; chronic and granulomatous inflammation

characterized by the presence of lymphocytes,

eosinophils, mast cells, plasma cells, and giant

cells; immunogenic delayed hypersensitivity

granulomas; macrophage activation with secretion of

cytokines; fat and tissue necrosis; ulcerated skin and

skin atrophy; silicone lymphadenopathy; and silicone

implant-related synovitis.

· Immunologic evidence that silicone is an adjuvant

and is immunogenic, findings of abnormal biomarkers

including elevated AnA and IgG, suppression of natural

killer cell activity, modulation of serum

corticosterone levels causing thymic atrophy, and

evidence suggestive of plasmacytomas and

immune-mediated cancers such as multiple myeloma.

· Other toxicity evidence related to silicone breast

implants including metabolism and degradation of

silicone to silica in vivo, an increase in liver

weights, cytotoxicity data, parental toxicity data,

and effects on cholesterol levels.

· Other toxicity analogies.

Plaintiffs submit that the evidence of toxicity of

silicones comes from a variety of diverse yet prolific

areas of research which, when viewed collectively,

demonstrate that in some women implanted with silicone

breast implants there is credible evidence for

scientists to reasonably conclude that silicone is not

inert and indeed can cause physiological effects

within the body.

1. HISTORICAL OVERVIEW OF THE TOXICOLOGIC LITERATURE

The Dow Chemical Company conducted the first major

research on the toxicological properties of silicone

in the 1940s. The results of their research were

published in the seminal article on silicone toxicity

by Rowe, Spencer and Bass They studied two silicone

fluid materials of low molecular weight and one of

high molecular weight administered orally to rats and

guinea pigs over a one-week period. While the low

molecular weight silicone caused a mild inebriation

and central nervous system depression, the authors

claimed that this one-week study showed that DC 200

fluid is " exceedingly low in oral toxicity " and that

silicones are " inert. "

Dow Corning’s Center For Aid To Medical Research

extensively promoted the Rowe study and claims of

silicone’s inertness to the medical community

throughout the 1960s and 1970s. Dow Corning first

manufactured and sold silicone breast implants in the

mid 1960s. The published literature, at the time,

including numerous references to the Rowe article and

to Dow Corning (which cited Rowe) for the proposition

that silicones are inert. The myth of silicone’s

inertness flourished in the medical community without

any serious consideration of the reported findings in

the literature on silicone gel breast implants until

the early 1980s.

Unfortunately, overlooked by most persons - although

Dow was aware of it - was the 1952 Cutting article in

the Stanford Medical Bulletin reporting " widespread "

toxic manifestations in rabbits fed a high cholesterol

diet containing DC 200 silicone fluid. In Cutting’s

study, nearly all of the 10 rabbits showed renal

tubular damage and lesions in the kidneys in varying

degrees when fed DC 200 silicone in concentrations of

one percent for three to four months. Microscopically,

he observed capsular thickening in the spleens with

deposits of DC Antifoam A silicone, and, in the

kidneys, there was distension of tubular cells and

large masses of macrophages between the tubules with a

clear amorphous substance.

Despite Cutting’s findings of toxicity, further

long-term toxicological research on silicones and

silicone breast implants by the manufacturers was

non-existent for some and very limited for others. Dow

Corning was the only manufacturer to have a formal

toxicology department, and that was not established

until the late 1960s. The early studies, performed by

outside laboratories in the 1960s including

understaffing, lack of facilities and persons with

expertise to interpret findings, inadequate resources

to conduct studies,

Dow Corning’s Toxicology Department continued to

experience serious problems through the 1980s

including understaffing, lack of facilities and

persons with expertise to interpret findings,

inadequate resources to conduct studies, and failure

to follow GLP’s. For example, in 1989, an independent

consulting toxicologist audited Dow Corning’s

toxicology program. The audit revealed serious

problems including lack of competent management, lack

of familiarity with GLP’s, documentation which was

" extremely poor, " a general feeling within the lab

....of chaos, " a department that had " little depth " and

no system to " assure either that bad science or poorly

thought out procedures...do not get put into place, "

" wrong people [who] are making decisions (in some

cases the WRONG decision) which impact upon the

science being performed, " and a " Dow Corning

management style [that] is not conducive to running

even an adequate toxicology laboratory. " The

consultant recommended a " complete overhaul " of the

department including the hiring of qualified, trained

toxicologists and staff to bring the department up to

industry standards. The problems, however, were not

corrected and another outside audit in 1994-95

uncovered instances of data falsification in several

internal Dow Corning studies.

Understanding that these issues do not directly assist

the Panel in completing its charge, plaintiffs

nonetheless note these problems in this submission for

several reasons: 1) with the exception of the research

conducted by Dr. ’s Bioscience Research

Department in the mid 1960s to mid 1970s, much of the

internal industry research on which Dr. Brent and the

manufacturers rely is of questionable value; 2) very

little toxicological research was conducted on

silicones for many years because of the myth that Dow

Corning propagated to the medical and scientific

community that silicone was inert; and 3) the other

manufacturers relied on Dow Corning, as the supplier

of the silicone materials used in breast implants, for

virtually all safety testing. Because of the many

deficiencies in the internal studies uncovered by

outside audits, reliance on many of Dow Corning’s

early studies for claims of biocompatibility, such as

those made by Dr. Brent before this Panel, is

misplaced.

2. SUMMARY OF ADVERSE FINDINGS WHICH HAVE

TOXICOLOGICAL IMPLICATIONS

1. Chronic and Granulomatous Inflammation Can

Stimulate the Immune System, Causing Systemic

Symptoms, Signs and Symptoms of Disease, and Immune

Dysfunction.

The adverse and immunopathologic reactions to silicone

within the body and their clinical significance are

documented extensively in the pathology and

immunopathology sections. Many of the studies that the

industry conducted in the 1960s and 1970s are also

found chronic inflammation and granuloma formation.

Because of the earlier extensive discussions, both in

the Historical section and in the Pathology, the

evidence will not be repeated here.

2. Immunologic Evidence Demonstrates That Silicone Is

Immunogenic.

The immunologic evidence, also previously discussed,

is convincing and substantial. It forms a credible

basis for physicians and researchers to conclude that

silicone is immunogenic and acts as an adjuvant in the

body, which results in immune system dysfunction and

clinical signs and symptoms.

3. OTHER EVIDENCE ON SILICONE BREAST IMPLANT TOXICITY

PROVIDES FURTHER SUPPORT FOR THIS PANEL

Additional evidence of silicone’s toxicity in animals

and humans is found in studies on the effect of low

molecular weight cyclics on liver weight, the data

from animal teratology studies supported by data

showing that silicone can have cytotoxic and

cytopathic effects.

1. Low Molecular Weight Cyclics Affect Liver Weight

In 1989, several Dow Corning studies showed that low

molecular weight silicones — specifically, D3, D4 and

D5 — resulted in toxic changes in various animal

models. Mehendale evaluated D5 via oral administration

in female rats at 2000 mg/kg body weight/day at 24

hours and 4, 8 and 12 days, followed by a period of

recovery of 24 days. He found that D5 induced:

[h]epatomegaly with recovery after cessation of

dosing. The enlargement appeared to be due to a net

enlargement in the liver mass. D5 was found to be an

inducer of drug metabolizing microsomal enzymes and to

resemble phenobarbital in this regard. However, D5

differed from phenobarbital in that it decreased the

P-450 hemoprotein content of the microsomes.