**Silicone Breast Implants **

**in Relation to Connective Tissue Diseases and Immunologic
Dysfunction**

**A Report by a National Science Panel **

**to the Honorable Sam C. Pointer Jr., **

**Coordinating Judge for the Federal Breast Implant Multi-District
Litigation**

Betty A. Diamond

Barbara S. Hulka

Nancy I. Kerkvliet

Peter Tugwell

Table of Contents

Executive Summary 1

***Chapter I: * *Review of Animal Studies Relevant to Silicone
Toxicity***

I. What Is Silicone? I-1

II\. Utility and Significance of Animal Studies for Human Toxicity
Assessment I-1

III\. Rationale for Analysis of Specific Animal Studies Relative to
Silicone Toxicity I-3

IV\. Animal Models for Atypical Connective Tissue Diseases I-4

V. Historical Perspectives on Silicone Toxicity I-5

VI\. Silicone and "Adjuvant Disease" I-7

VII\. Adjuvant Activity of Silicone I-8

VIII\. Effects of Silicone in Animal Models of Autoimmune Disease I-9

Arthritis-Prone DBA/1 Mice I-10

MRL ^lpr/lpr^ Model of Lupus I-11

New Zealand Black (NZB) x New Zealand White (NZW) F1

Murine Model of SLE I-12

Tight Skin Mouse Model of Scleroderma I-12

Type II Collagen- Induced Arthritis I-13

Nzb Mouse Model of Autoimmune Hemolytic Anemia I-14

IX\. Immunotoxicity of Silicone in Animals I-15

Evidence That Silicone Alters Immune Responsiveness of Animals I-16

Evidence That Silicone Can Act as an Antigen I-17

Evidence That Silicone Induces Inflammation I-19

Evidence That Silicone Can Activate Macrophages I-20

X. Potential Contribution of Other Materials in SBIs to Toxicity I-23

Low Molecular Weight Cyclosiloxanes I-23

Silanols I-23

Platinum I-23

XI\. Conclusions I-24

References I-26

Tables I-33

***Chapter II. Clinical Immunology***

I.  Introduction to the Immune System II - 1** **

Antigen Stimulation: Role of MHC II - 2

Production of Antibodies by B Cells II - 3

Autoimmunity II - 3

I.  Studies on the Immune Response to Silicone in Animals II - 4** **

II. Analytic Approach to Studies in Humans II - 5** **

III. Studies of the Innate Immune Response II - 8** **

Cytokines as an Indicator of Inflammation II - 8

Natural Killer Cell Function II - 9

Superantigen Activity of SBI II -10

I.  Studies of the Adaptive Immune Response II -11** **

HLA in Symptomatic Women with SBI II -11

T Cell Activation in Women with SBI II -13

Anti-Nuclear Antibodies II -16

Patient Selection II -19

Control Population II -20

Methodology for ANA Determination II -20

Multiple Samples II -20

Prospective Studies II -20

Summary of ANA Results II -20

Specific Autoantibodies II -21 Anti-collagen Antibodies II -21

Anti-microsomal Antibodies II -23

Anti-silicone Antibodies II -23

Anti-polymer Antibodies II -24

### VI. Monoclonal Gammopathy & Multiple Myeloma II -25** **

VII\. Summary II -27

References II -29

Table 1 II -40

***Chapter III: Epidemiological Analysis of Silicone Breast Implants ***

*** ** and Connective Tissue Disease***

I. Introduction III-1

II\. Descriptive Epidemiology and Diagnostic Criteria for Specific
Connective

Tissue Diseases III-2

Rheumatoid Arthritis III-2

Systemic Lupus Erythematosus III-3

* * Scleroderma or Systemic Sclerosis* *III-4

Sjögren's Syndrome III-4

* * Dermatomyositis/Polymyositis III-5

III\. Meta-analysis of Epidemiological Studies III-5

* * Rationale III-5

Disease Entities Included in the Meta-analyses III-7

Types of Implants Included in the Analysis III-8

* * Sources of Studies* *III--9

Inclusion/Exclusion Criteria for Studies III-10

Statistical Analyses III-11

Meta-analysis of Unadjusted Effect Estimates III-11

Meta-analysis of Adjusted Effect Estimates III-13

Results III-14

*  * Description of Individual Study Results* *III-14

Unadjusted Results from Meta-analyses III-14

*  * Results Adjusted for Confounding Variables* *III-15

Results from Silicone Gel-Filled Implants Only III-16

Discussion III-17

*  * Limitations of the Meta-analyses* *III-18

Potential Biases in Studies of Silicone Breast Implants and Connective

Tissue Diseases III-19

IV\. Power of the Meta-analyses* *III-21

V. Population Attributable Fraction III-23

VI\. Summary and Conclusions III-23

References III-25

List of Abbreviations III-33

Tables III-34

Figures III-45

Appendix A III-A-1

Appendix B III-B-1

Appendix C III-C-1

Appendix D III-D-1

Appendix E III-E-1

***Chapter IV: Rheumatology: Clinical Case Definitions/Diagnoses and
Clinical Associations***

I. Introduction IV-1

II\. Classic Accepted Connective Tissue Diseases IV-2

Clinical Case Definition IV-3

Strength of Association IV-3

Methodology IV-3

Study Results Reported for Accepted Diagnoses IV-6

III\. Atypical Presentations of Connective Tissue Diseases:

Undifferentiated Connective Tissue Disease (UCTD) IV-15

Clinical Case Definition IV-15

Strength of Association IV-16

Methodology IV-16

Study Results Reported for Atypical Presentations (UCTD) IV-16

IV\. Atypical Presentations of Connective Tissue Diseases;

Proposed Systemic Silicone Related Diseases (SSD) IV-17

Clinical Case Definition IV-17

V. Symptoms IV-23

Clinical Case Definition IV-23

Strength of Association IV-24

Methodology IV-24

Study Results Reported for Symptoms IV-25

VI\. Concluding Comments IV-40

References IV-42

Table 1 IV-46

Appendix A IV-A-75

Appendix B IV-B-82

**Silicone Breast Implants **

**in Relation to Connective Tissue Diseases **

**and Immunologic Dysfunction **

**Executive Summary**

Four scientific experts in the fields of immunology, epidemiology,
toxicology, and rheumatology were appointed by the Honorable Sam C.
Pointer, Jr., Coordinating Judge for the Federal Breast Implant
Multi-District Litigation, to serve on a National Science Panel. Members
of the panel include:

Betty A. Diamond, MD, Professor, Department of Microbiology and
Immunology, Albert Einstein College of Medicine, Bronx, New York;

Barbara S. Hulka, MS, MD, MPH, Kenan Professor, Department of
Epidemiology, School of Public Health, University of North Carolina at
Chapel Hill, Chapel Hill, North Carolina;

Nancy I. Kerkvliet, MS, PhD, Professor of Toxicology and Extension
Toxicology Specialist, Department of Environmental and Molecular
Toxicology, Oregon State University, Corvallis, Oregon; and

Peter Tugwell, MBBS, MD, MSc, FRCP \[Canada and United Kingdom\],
Professor and Chairman, Department of Medicine, University of Ottawa,
Ottawa, Ontario, Canada.

The panel was instructed to review and critique the scientific
literature pertaining to the possibility of a causal association between
silicone breast implants and connective tissue diseases, related signs
and symptoms, and immune system dysfunction. The panel met, received
instructions from the judge, and heard testimony from experts selected
by the counsels for the plaintiffs and for the defendants in October
1996. Additional hearings were held in July 1997, when experts
identified by the parties provided testimony, and in November 1997 when
the panel's invited experts presented their research material.

In spring 1997, over 2000 documents were submitted to the panelists from
the legal counsels for both parties. Subsequently, the counsels pared
these numbers down to the approximately 40 most important documents from
each side for each panel member. The source of references, whether
counsel for the plaintiffs or counsel for the defendants, was not
identified to the panelists. The panel members also used their own
literature search strategies, and were neither limited to nor obligated
to use those submitted by the respective legal counsels.

**Organization of Report **

The report is divided into four chapters, each based on the expertise of
one of the four panelists. They follow in sequence: toxicology,
immunology, epidemiology, and rheumatology. A summary and bibliography
are provided at the end of each chapter and some chapters contain
appendices. This executive summary precedes the chapters to state the
judge's charge to the panelists, indicate the process undertaken by the
panel, and provide a brief overview of the panel's main findings and
conclusions.

**Charge from Judge Pointer**

The court-appointed experts were asked to respond to the following
questions:

"(a). Issues. To what extent, if any and with what limitations and
caveats do existing studies, research, and reported observations provide
a reliable and reasonable scientific basis for one to conclude that
silicone-gel breast implants cause or exacerbate any of the conditions
described in (b) below? If, in the process of making these findings, you
believe that there are related or subordinate issues that should be
separately addressed, please do so.

(b). Scope. You are asked at this time to consider the relationship, if
any, between implants and the following:

'classic' connective tissue diseases, such as systemic lupus
erythematosus, Sjögren's syndrome, etc.

'atypical' presentations of connective tissue diseases or symptoms
immune system dysfunctions

Listed in the appendix to this order are various diseases, symptoms,
conditions, or complaints that have sometimes been asserted as possibly
associated with silicone-gel implants. To the extent you believe
appropriate and without being asked to address separately each of these
diseases, symptoms, conditions, and complaints you are encouraged to
comment on the scientific basis, if any, for any such claimed linkage.
You are not being asked to consider purely local complications, such as
breast disfigurement, tenderness, or capsular contracture.

(c). Contrary Opinions. To what extent, if any, should any of your
opinions referenced in (a) above be considered as subject to sufficient
genuine dispute as would permit other persons, generally qualified in
your field of expertise, to express opinions that, though contrary to
yours, would likely be viewed by others in the field as representing
legitimate and responsible disagreement within your profession?"

**Background to Charge **

While silicone breast implants have been in use since the early 1960s,
it was not until 1976 that legislation was passed giving the Food and
Drug Administration (FDA) responsibility to oversee the safety of
medical devices. Because implants had been used for over a decade, their
safety was presumed and their continued use was permitted. Furthermore,
while it was known that local complications could occur with silicone
breast implants and that rupture of the implant occurred in a portion of
recipients, safety studies in animals had suggested no systemic toxicity
of silicone gel. In 1982, the FDA proposed that the manufacturers of
implants should provide additional evidence on the safety of breast
implants. In 1988, the FDA mandated that manufacturers provide such
evidence. This ruling was not enforced until 1991, when public attention
became focused on the question of the risks of implants and their
possible association with connective tissue diseases. The FDA convened
two advisory committees in 1991. After the first, David Kessler, then
head of the FDA, asked for a voluntary moratorium on the use of silicone
gel-filled implants; after the second in 1992, he banned their use
except in clinical trials of breast reconstruction after cancer surgery.
He stated that the ban was implemented not because gel-filled implants
had been shown to be unsafe, but rather, that the manufacturers had not
provided adequate data proving their safety.

The first suggestion that there might be adverse systemic reactions to
augmentation mammaplasty were reports of autoimmune disease in Japanese
women who received liquid paraffin or silicone injections for breast
augmentation. Subsequently, concerns were raised regarding an
association of silicone breast implants with classic connective tissue
diseases and less well-defined atypical syndromes. These initial
concerns were expressed in case reports in the medical literature and
raised the call for examination of the effects of silicone on the immune
system. In December 1990, Connie Chung reported in a nationally
televised program that breast implants might be unsafe. Although
litigation against the manufacturers of breast implants started in 1982,
the number of suits brought by women claiming that they had developed
systemic connective tissue disease following silicone breast
implantation increased markedly in the 1990s. It has been in this
adversarial atmosphere, with high stakes for plaintiffs and defendants,
that immunologic and epidemiologic studies of silicone and silicone
breast implants have been performed.

**Major Findings and Conclusions **

***Toxicology ***

Testing of chemicals, pharmaceuticals, and other products in animal
models serves to prevent potentially hazardous compounds from reaching
the human population. Animal toxicology studies provide information
regarding the potential toxicity of a substance, the doses required to
elicit toxicity, and the spectrum of possible toxic effects. Because
potentially confounding variables (e.g., age, sex, environmental
factors) can be controlled experimentally, animal studies provide
information that often cannot be obtained directly in humans.

Toxicologic testing with silicone goes back almost 50 years. In the
early years, silicone had an enviable record of safety, having been
shown consistently to be inert with respect to systemic effects. Only,
localized reactions analogous to those induced by other foreign bodies
were observed. However, in the late 1980s, case reports of a possible
link between silicone breast implants and autoimmune diseases in women
reinvigorated toxicologic testing of silicone gels and related
compounds. The majority of these more recent studies reaffirmed the low
systemic toxicity of silicone.

Animal studies have addressed the possibility that silicone may promote
systemic disease in women by acting as an adjuvant or an antigen to
induce immune responses, by altering normal

regulation of the immune system, or by inducing systemic inflammation.
These potential effects have been tested in specialized animal models of
autoimmune diseases. The preponderance of data from these studies
indicate that silicone implants do not alter incidence or severity of
autoimmune disease. Although silicone gel has been shown to possess weak
adjuvant activity when it is injected as an emulsified preparation with
a foreign antigen, there is no evidence that silicone breast implants
precipitate novel immune responses or induce systemic inflammation. The
only reasonably consistent effect of silicone on the immune system in
animals is a depression in natural killer cell activity. However, no
physiologic consequence of this depression has been demonstrated.

Considering the broad range of testing systems that have been used in
the study of silicone effects, the toxicologic and immunologic responses
are few in number and questionable in significance. Yet, the results of
animal testing may not fully predict the human effects.

***Immunology ***

The evaluation of immunologic responses to silicone breast implants in
humans faces significant challenges. There are large numbers of diverse
immunologic responses that may be evoked in humans, whether the subjects
are healthy or ill, for which the biological meaning and clinical
interpretation is uncertain. Furthermore, many of the studies available
for analysis are methodologically inadequate with ill-defined or
inappropriate comparison subjects, unorthodox data analyses, and the
potential for systematic biases in laboratory methods, exemplified by
the analysis of cases and controls separately, at different time
periods, by different technicians using different batches of reagents.
Not surprisingly, inconsistent results in studies purporting to evaluate
the same immunologic parameter are common.

While there are data showing that silicone may cause local activation of
inflammatory responses, there are no consistent data to suggest systemic
inflammation or systemic induction of anti-silicone or autoreactive
responses in women with silicone breast implants. Immunologic responses
studied include: cytokines as indicators of inflammation, natural killer
cell activity, superantigen stimulation of T cells, antigen-specific T
cell activation, and autoantibodies of various types (anti-nuclear
antibodies, anti-collagen antibodies, and anti-microsomal antibodies),
and anti-silicone antibodies. In these studies, employing different
immunologic response markers, when appropriate comparisons were made,
(ill women with implants compared to

healthy women with implants, or healthy women with implants compared to
healthy women without implants), neither immune system activation nor
autoreactivity could be reproducibly demonstrated in women with silicone
breast implants. Furthermore, no unique human lymphocyte antigen
haplotypes in ill women with implants have been identified. The
frequency of different human lymphocyte antigen haplotypes is the same
in ill women with or without implants. The main conclusion that can be
drawn from existing studies is that women with silicone breast implants
do not display a silicone-induced systemic abnormality in the types or
functions of cells of the immune system.

In a mouse strain predisposed to the development of plasmacytomas, tumor
formation was enhanced after the intraperitoneal injection of silicone
gel. How this information translates to humans is currently unknown.
Existing data in humans do not suggest an effect of silicone breast
implants on either gammopathy or myeloma, but the number and size of
studies is inadequate to produce definitive results.

***Epidemiology ***

The evaluation of epidemiologic studies of silicone breast implants and
connective tissue diseases focused on several definite connective tissue
diseases (rheumatoid arthritis, systemic lupus erythematosus,
scleroderma, Sjögren's syndrome, and dermatomysitis/polymyositis) and a
grouping of less well-defined entities, which we labeled "other
autoimmune/rheumatic conditions." The latter included a mixture of
signs, symptoms, and diagnoses provided by the authors of the relevant
studies. Several meta-analyses, which pool data from multiple studies,
were conducted to identify a possible association between breast
implants and connective tissue diseases.

No association was evident between breast implants and any of the
individual connective tissue diseases, all definite connective diseases
combined, or the other autoimmune/rheumatic conditions. Sjögren's
syndrome was a possible exception to this statement. This entity
requires salivary gland biopsy to meet the published diagnostic
criteria. Whether biopsy was actually performed for cases in the studies
cited is unknown. The remaining criteria based on dryness of the eyes
and mouth with possible immunologic alterations are nonspecific and
relatively common in any population group. Thus, the accuracy of
diagnosis of Sjögren's syndrome in the studies incorporated in this
meta-analysis is questionable.

One meta-analysis included only those studies that distinguished
silicone gel-filled breast implants from any other type. The results
from this meta-analysis were consistent with those from the other
meta-analyses where breast implants were more broadly defined. There was
no association between silicone gel-filled implants and any of the
definite connective tissue diseases (including Sjögren's syndrome) or
the other autoimmune/rheumatic conditions.

***Rheumatology ***

The term *atypical connective tissue disease* has been used to describe
constellations of signs, symptoms, and abnormal laboratory tests,
insufficient by themselves to meet the specified criteria of a classic
connective tissue disease. Among these descriptive groupings, mixed
connective tissue disease and undifferentiated connective tissue disease
are distinctive in that they have established case definitions, which
include substantive and sustained symptoms. In most studies of breast
implants, however, neither of these diagnostic entities has been
evaluated as a separate disease category. Rather, they have been
included in a combined grouping of ill-defined connective tissue
diseases. The one study that specifically addressed undifferentiated
connective tissue disease found no association with silicone breast
implants. Another reported disease entity is "systemic silicone related
disease," for which the case definition includes the presence of a
silicone breast implant. This inclusion criterion makes scientific
evaluation difficult, since there is no possibility of comparing the
incidence of the syndrome in women with and without implants.

Breast implant patients have reported a diversity of symptoms and signs
that are also associated with rheumatic or autoimmune diseases. For each
sign or symptom showing an association with breast implants in a given
study, other studies found no association. Symptoms associated with
breast implants in at least one study included: arthralgias, swollen or
tender lymph glands, myalgias, dryness of mouth or eyes, skin changes,
and stiffness. Problems in analyzing these studies were numerous: the
same complaint appeared in more than one disease category; self-report
was not verified; timing of the complaint in relation to the implant was
not known; indication for the implant was ignored; and in individual
studies, the number of affected women was small. Furthermore, many of
the rheumatologic complaints reported are common in the general
population and as presenting complaints in physicians' offices. No
distinctive features relating to silicone breast implants could be
identified.

Little is known about the effect of silicone breast implants on clinical
course and immunologic parameters in women with pre-existing classic
connective tissue disease or in women who develop such a disease
following an implant.

***Contrary Opinions ***

The panel members are in agreement on the findings and interpretations
of the data on silicone breast implants and connective tissue diseases,
and their immunologic correlates, as presented in this report. The
material presented represents an analysis of the most rigorous and
relevant scientific information currently available. It is our informed
opinion that the large majority of scientists in our respective
disciplines would find merit in our reviews and analyses. Nevertheless,
as in every field of endeavor, a few individuals may find disagreements
with our statements. As individual scientists and as a group, we have
taken no predetermined position on the issues, nor have we designed the
report to refute or enhance any point of view. On the contrary, we have
allowed the existing research data to lead us to the conclusions
presented. We cannot anticipate what research findings may appear in the
future.