Breast Implants and Disease

[Guest guest]

Dr Egilman, Breast Implants & Disease aprox.

Bio_Community_Health168C

http://www.brown.edu/Courses/Bio_Community_Health168C/

degilman2@...

Breast Implants and Disease - 1992

I, Dr. S. Egilman MD, MPH, state the following:

I am a medical doctor and clinical associate professor

of Community Medicine at Brown University.

I am board certified in Internal Medicine and

Preventive Occupational Medicine.

My office address is 759 Granite Street, Braintree,

Massachusetts, 02184.

I received a Bachelor of Science from Brown University

in Molecular Biology in 1974. I received a medical

degree from Brown University in 1978. I completed a

three year medical residency in Internal Medicine at

Strong Memorial Hospital in Rochester, New York, in

1981.

I completed a three year training program in

epidemiology, called the National Institutes of Health

Epidemiology Training Program in 1984. As part of this

program, I completed a Master's in Public Health at

the Harvard School of Public Health. At Harvard, I

studied epidemiology, statistics and occupational

medicine.

I served two years at the National Institute for

Occupational Safety & Health (NIOSH), designing and

conducting small and large epidemiologic studies.

Since 1978, I have published a variety of letters and

medical articles on the issues that relate to the

manner in which cause-effect determinations are made

in medicine (the epistemology of medicine). I have

discussed the normal, accepted process of causal

determination in medicine (described below) in several

peer-reviewed articles. [2] In addition, these ideas

were accepted for presentation and were presented at

the American Public Health Association meetings, in

1984. For the past five years, I have taught a course

at Brown University that addresses the development of

medical and scientific knowledge in the 20th century.

This course deals specifically with the issues

outlined in this report.

Finally, some of my opinions are based in part on my

clinical experience and awareness of the ways that

normal physicians in normal medical practice make

decisions about etiologic relationships that affect

patients' lives every day. Over 40 hours per week of

my time is devoted to direct patient care.

As a practitioner, I utilize the epistemological

method described below to make the following medical

decisions: determining cause-effect relationships,

judging drug side effects, judging therapeutic

interventions, judging the presence of disease,

providing forensic testimony and judging the causes of

disability and death. The described methodology is

consistent with the normal methods physicians use in

the usual practice of medicine.

My opinions in this case are based on my training and

experience in molecular biology, medicine, physics,

chemistry, epidemiology, philosophy, ethics, public

health, medical practice, review of corporate

documents in this and other cases, review of

depositions and deposition exhibits, discussions with

researchers, and various medical literature.

1. PRINCIPLES OF GENERAL CAUSATION

In making such judgments regarding medical causation,

doctors utilize epidemiological data as one tool among

many. Although doctors consider epidemiological

research to be an important facet of medical

epistemology, it is not regarded as being the sole or

the most important contributor to decision-making. The

branch of medical science concerned with the causes

and origins of disease is called etiology.

Epidemiology is not a synonym for etiology. Rather,

etiologists use epidemiological evidence along with

other evidence to draw conclusions about causal

connections. Medical knowledge is based on empirical

tests. Empirical tests are those gained from

observation or experience. [3] Epidemiology is but one

form of empirical knowledge.

The evidence used to determine disease etiology may

come from chemistry, physics, biochemistry, pathology,

molecular biology, toxicology, clinical experience and

other scientific disciplines. Types of data relied

upon include observation, experiment, analogy,

computer models, animal experiments, and bacteriologic

experiments, as well as epidemiologic studies. Doctors

consider the whole data set available to establish a

causal nexus.

2. THE EPISTEMOLOGICAL APPROACH OF SBI MANUFACTURERS

Prior to the onset of litigation related to silicone

breast implants (SBI), manufacturers never suggested

that epidemiologic studies were necessary to determine

the relationship of any health problem to SBI. SBI

manufacturers never conducted, proposed nor sponsored

any epidemiologic study of any known problem

associated with SBI including contracture, migration,

infection, hematoma, or rheumatologic complaint. The

manufacturer's lack of interest in following the

health effects of their products in women with

epidemiological surveillance is further demonstrated

by their failure to establish a registry of users or a

systematic complaint mechanisms for users.

The SBI manufacturers evaluated the relationship

between all of the above complaints and SBI based on

case reports, clinical cases series, and animal

studies. For example, Medical Engineering Corporation

Founder Wilfred Lynch wrote, constrictive capsule

formation is the complication of breast augmentation

which is most troublesome at the moment. Its etiology

is perplexing and most of the theories of contributing

phenomena are quite subjective. [4] Lynch did not base

this statement of causation upon epidemiologic

research. The fact that the specific mechanism was

unknown did not prevent Lynch from concluding that the

contracture was caused by the implant. Another comment

by Wilfred Lynch, published in his 1978 Handbook of

Silicone Rubber Fabrication, illustrates the type of

testing the industry recommended:

All basic materials which are to be used in the

fabrication of implantable devices, or devices which

will be in contact with fucous membrane for extended

periods, must undergo long term implant tests in

animals. In the course of these tests it must be

demonstrated that there is no toxicity to the host, no

undue inflammation of the tissues with which it has

been in contact, and no migration of by-products to

vital organs. The material itself must not show signs

of deterioration. [p.217]

According to Lynch, animal testing is the sine qua non

for determining product hazards.

In 1991, Micheal Syzcher, a consultant for

Bristol-Myers, published the following opinion on

causation of SBI and disease:

Autoimmune disease, with its attendant immunological

sensitization may indeed be a serious risk associated

with silicone gels. Human adjuvant disease or

autoimmune disease after implantation of foreign

material occurs subsequent to injection or

implantation of paraffin/silicone, and possibly,

silicone polymers. Patients develop signs, symptoms,

and laboratory abnormalities suggestive but not

diagnostic of a connective-tissue or autoimmune

disease. [5] [Emphasis added]

Syzcher goes on to reveal his reliance on case

reports, mechanistic understanding and animal studies

to determine causation in humans:

Several published reports have linked silicone fluids

to various autoimmune diseases such as =93human

adjuvant disease (110). Based on animal models of

adjuvant arthritis and experimental immunologic

principles of adjuvant stimulation of the immune

system, the term human adjuvant disease was applied to

those diseases caused by exposure to

silicone-containing materials (111). Other syndromes

were also implicated, such as scleroderma (112, 113),

localized post traumatic musculo-skeletal conditions

or interphalangeal osteoarthritis.

Heggers et al (115) conducted a study from which they

concluded that although apparently inert, silicone is

capable of eliciting a

cellular immune response demonstrated by the migration

inhibition technique. This response is comparable to

that elicited by purified protein derivative and may

indicate that silicone acts as a hapten-like

incomplete antigen.

Silicone-filled breast implants also contain

silica(Si02) as a reinforcing filler in the device

envelopes and gels (116). Silica is known to be

immunologically active, and may potentiate the

development of autoimmune diseases induced by

mycobacterial or other antigens present in resident

microorganisms. An association of tuberculosis,

silicone implants, and the subsequent development of

connective tissue disease has been reported, and

closely corresponds to an animal model of =93adjuvant

disease. (117)

Silicone fluids have been used in surgery for many

years, notably in joint and breast augmentation

prostheses. Silicones have generally been regarded as

a relatively inert material that provokes little or no

tissue reaction. (118) However, as the use of this

material increases, reports of local and systematic

reactions have emerged. This led Endo (119) to state

that the notion that silicone is without important

biologic effects may be na=EFve and require

reexamination.

[references in original text]

Syzcher based his opinion on case reports and case

series and thus followed the normal medical practice

used to determine the relationship between an exposure

and a disease. This process which does not require the

sine qua non presense of a positive controlled

epidemiolgic study.

Testimony and exhibits demonstrate that Medical

Engineering Corp. (MEC) and/or Bristol Myers (BMS)

made claims about its products based on evidence other

than statistically significant epidemiology studies.

MEC did not base business decisions about sale of

breast implants on epidemiology, as one of its

documents notes:

" We don't have to PROVE validity to sell products,

i.e. SCL's there's no proven validity there either... "

It continues: " Remind Lynn that we are not making any

profit now, we have no alternative but to grasp at

straws or anything else that might make a buck, we are

desperate and we have to take risks or die. " [6]

Labeling instructions were based on only the

publication of particular case reports and in some

cases were included without citation to any

publication at all. For example the Bilumen Implant

insert carried a protocol by Munna, M.D. [7] Not

only did MEC not have any epidemiologic evidence

supporting Munna's protocol, they entered into an

arrangement with Munna where he received a percentage

of each bilumen implant sale in exchange for his

writing certain " scientific " papers.

Warnings included in the packaging are further

examples of acceptance of association by manufacturers

based only on case reports. The statement " closed

capsulotomy (i.e., manual compression of the breast)

is not recommended because it may cause rupture with

potential gel extravasation " was added to the package

insert after case reports appeared in the medical

literature reporting rupture after closed

capsulotomies. [8]

Based on a case report published by MEC consultant Dr.

Baker concerning closed capsulotomy as an

alternative to open capsulotomy, MEC added this

article to many other case reports cited in its

Bibliography of its Biocompatibility Data Sheets. [9]

Company sales representatives used these sheets and

they were intended to be left with physicians to

encourage them to purchase MEC's implants. The

bibliography contained many references to

non-epidemiological studies. [10]

There are other MEC documents which demonstrate the

company relied on studies, articles and case reports

for a variety of different reasons. Several articles

discussing surgical technique are included as part of

the company's Training Manual for MEC Sales

Representatives. [11] In 1982 when the FDA wanted to

classify breast implants as Class III devices

requiring a Premarket Approval Application ( " PMA " ),

MEC opposed the Class III classification. Betty Lock's

letter to ASPRS, the society of plastic surgeons which

joined in opposition with the implant manufacturers,

cited case reports in support of the company's claims

that implants add to the " quality of life, " claims

concerning capsular contracture, and claims concerning

gel bleed. [12] Similarly, the Health Industry

Manufacturer's Association letter from Harold Buzzell

to FDA attaching " Health Industry Manufacturers

Association Comments on FDA's Proposed Classification

of General and Plastic Surgery Devices " also cites

non-epidemiological articles for support. [13]

3. PROBABILISTIC CAUSAL ANALYSES

In determining the etiology of infectious diseases

(caused by a microorganism), doctors have used Koch's

postulates as a basis for deciding what experimental

evidence is necessary to establish cause. Koch's

postulates are: (1) the microorganism must be observed

in every case of the disease; (2) it must be isolated

and grown in pure culture; (3) the pure culture must,

when inoculated into a susceptible animal, reproduce

the disease; and (4) the microorganism must be

observed in, and recovered from, the experimentally

diseased animal. [14]

Although epidemiology plays absolutely no role in

Koch's postulates, the medical community has

completely accepted them as valid epistemological

criteria for certain causal relationships.

However, doctors do not apply Koch's postulates

directly or by analogy to determine causation for

injuries and non-infectious diseases. Like infectious

disease, the etiology of non-infectious diseases and

injuries is multi-factorial, and most of the factors

are unknown. However, in contrast to infectious

diseases, no single factor is always a sine qua non of

non-infectious disease. For example in the infectious

disease tuberculosis, all patients with the disease

have the TB bacillus in their bodies. But all

non-infectious disease have multiple causes and have

no sine qua non causal factor. For example, smoking

and asbestos are both independent causes of lung

disease and lung disease occurs in non-smoking,

non-asbestos exposed people.

Both TB and lung cancer demonstrate the

multi-factorial nature of disease etiology. Only a

very small percentage of smokers, and a very small

percentage of persons carrying the TB bacillus, ever

get either lung cancer or tuberculosis. A combination

of other known and unknown factors determine which

smokers develop cancer or which individuals with the

bacillus develop tuberculosis. Although doctors accept

that asbestos and cigarette smoking cause cancer,

cancer occurs in less than 20 percent of smokers and

slightly over half of asbestos insulation workers.

Therefore, the reliance on microscopic evidence

implicit in Koch's postulates is not a universal

causal criterion for non-infectious diseases. Neither

pathologists nor epidemiologists nor clinicians

require the presence of microscopic evidence of

previous smoking to attribute lung cancer to a

person's smoking. Case reports and uncontrolled

population data convinced most physicians that smoking

was a cause of lung cancer, and that exposure to

ionizing radiation caused certain cancers. Astute

pathologists and readers of pathologic literature were

the first to recognize that asbestos was a carcinogen;

epidemiologists did not make this association until

many years later. [15] [16] Pathologists and

pathologic evidence is still the most important type

of evidence for most legal proceedings and is usually

the arbiter of choice for the determination of the

cause of death. Epidemiologist are not called to the

morgue to determine cause of death for death

certificates.

In non-infectious diseases, probability analyses can

be used to determine disease etiology. It is possible

to integrate different data sets into one causal

probability through a model influenced by Bayesian

decision-making (see Figures 1, 2). This method

integrates available information into one model for

causation, representing the results of each study type

on a continuous line from 0 to 100, with 0

representing no evidence for causation and 100

representing the certainty of evidence of causation.

Then the study types are arranged hierarchically, and

the overall probability of causality is sequentially

modified by each study type in turn, until a final

value between 0 and 100 is reached.

It is necessary to describe this model for causation

because of misrepresentation of the scientific method

in public discourse. Some researchers have attempted

to elevate one entire class of data to the level of

final arbiter of causal proof. For instance,

scientists working for tobacco companies argued that

cigarettes had not been proven to cause lung cancer

because of the lack of animal studies establishing

such a relationship, because the exact mechanism of

cancer induction is unknown and the specific

carcinogenic substance(s) is (are) unknown. Some

scientists argue that the evidence linking silicone

breast implants to disease is not sufficient to

establish a cause-effect relationship because of the

insufficiency of epidemiological data. The scientific

community has never exclusively relied upon

epidemiology as the accepted method of evaluating

cause-effect relations for making normal medical

decisions. It is reasonable for different people to

assign a different priority to different classes of

studies. However, it is not reasonable to ignore

entire classes of data, or, in an ad hoc manner, to

elevate one class of data as carrying the ultimate

burden of proof, especially for making public policy

decisions regarding potential health risks.

4. IMPORTANCE OF CLINICAL EXPERIENCE

The textbook titled Medical Decision Making identifies

the following information available to physicians

making medical decisions: personal experience,

published experience, and attributes of the patient.

[17] A physician's opinion is guided by personal

experience with similar events or by the experiences

of colleagues. Thus, a surgeon's estimate of the

probability that a patient will survive an

appendectomy is guided by personal experience with

this operation in similar patients. [18] In addition,

physicians rely upon published experience, in the form

of reports quantifying the risk or success associated

with a certain procedure. For instance, the above

mentioned surgeon may rely on a report giving the rate

of death after appendectomy in order to estimate the

probability that a patient may die from the operation.

Published experience is particularly influential when

the physician has little personal experience. [19]

[emphasis added] Finally, attributes of the patient

are important to alert the physician for unusual

characteristics of the patient that put him at higher

or lower risk than the average. [20]

These principles of making medical decisions are

exactly analogous to making cause-effect evaluations.

In the case of appendectomy and likelihood of dying,

the appendectomy is a determinant and the outcome is

risk of dying. As can be seen from the above, in

making these decisions, physicians rely heavily on

their prior experience. Clinicians use their prior

experience with similar events to estimate

probability. Experienced clinicians have seen so many

patients that they have a good intuitive understanding

of which events occur commonly and which events are

unusual. Personal experience is, and will continue to

be, the principal factor influencing a physician's

probability estimates. [21]

Doctors relying on clinical experience depend on an

implicit control or comparison group -- all the other

patients they have seen. A case report is essentially

a small epidemiologic study. A case report is made

because the case is unusual or informative with

respect to all other cases the doctor has seen.

Clinical experience is considered particularly

important in the diagnosis of occupational and

environmental diseases because of the importance of

the history. The history is the most important piece

of information in determining if an individual case of

disease or injury is related to exposure. For example

possible causes of asthma include, cold air, exercise,

pollen, chemical exposures, and dust. Doctors

determine general and specific individual causation

and causal factors from the history of the time course

of exposure and symptoms onset and relief of symptoms

correlated with removal of exposure. Physical

examination and laboratory tests are helpful, but

ultimately it is information obtained from an

occupational history that determines the likelihood

that a medical problem is work-related [22] The

history is also critical in determining whether or not

SBI induced disease in an individual. The time course

of exposure correlated with the onset and continuation

of symptoms, the pattern of signs, symptoms and

laboratory abnormalities and the effect of

explantation on symptoms are all considered in the

physician determination of general and specific

causation. This is the usual method used by physicians

in determining disease causation and in selecting

treatments. This is particularly true in dealing with

specific criteria for causation, such as temporality

(discussed in more detail below). With a well-taken

history, the course of a patient's complaint can

provide evidence as to whether the complaint is caused

by an exposure. Doctors ask questions like: 93Do the

symptoms begin after the start of the exposure? Do

they disappear if the exposure is removed? Do

laboratory abnormalities follow the exposure? Are

local effects present? Is there a pattern of symptoms

or signs? A physician's clinical experience, and the

quality of their history, is especially important in

cases where an injury or disease has multiple known

causes.

5. EXAMPLES FROM MEDICAL PRACTICE

1. Injuries

When someone is run over by a car and dies, their

death can be attributed to the traumatic injury of

being struck by an automobile, even in the absence of

specific knowledge of the cause of death. The

immediate cause of death may have been a heart attack,

a broken neck, or suffocation. Furthermore, even if

the exact mechanism whereby an injury is produced is

unknown, causal conclusions may safely be drawn. An

epidemiological study is not necessary to determine

that the trauma from the car caused death. In

addition, if an epidemiological study of Chevrolets

indicated that Chevrolets can kill people hit in

traffic it is not necessary to perform another study

to establish that Fords can kill people. Normal

medical practice is the application of inference, not

the deductive process of mathematical proofs.

2. Diseases

A further example is that of diabetes. There were no

epidemiologic studies done to show that insulin was

related to diabetes. The causal connection was

established through animal studies only. Treatment

with insulin began as soon as insulin was available,

without controlled trials to demonstrate proof of its

effectiveness. Clinical experience combined with

animal experimentation was sufficient.

3. Proposed Treatments

Penicillin was used to treat infections as soon as it

was available. No epidemiology was cited in support of

the use of penicillin for the treatment of patients

sick with pneumonia. The first epidemiologic studies

on the effectiveness of penicillin and pneumonia were

not published until the 1970's. The epidemiologic

studies failed to find any reduction in short term

mortality from the use of penicillin. Doctors used

penicillin because of laboratory studies and because

they had a vague understanding of the mechanism of

action (they knew it killed bacteria).

6. EXAMPLES FROM MEDICAL LITERATURE

The importance of case reports, or personal

experience, in making medical decisions is reflected

in assessments of causation relied upon every day by

physicians. When physicians turn to textbooks for

opinions on general causation, they find all sources

of data presented, often with no distinction made

between epidemiologic and other data.

To assess the importance of animal studies and human

health, the US Congress' Office of Technology

calculated the percentage of papers In journals that

relied on animal, non-animal or human data. In all but

one of the biomedical and behavioral journals

reviewed, the majority of papers published were

animals studies [23]. The same publication contained a

diagram of the steps in biomedical research that

preceded successful coronary artery bypass graft

surgery. The diagram visually illustrated the

importance of and reliance upon various types of

animal research for medical decision making. See

Attachment 1.

The Physician's Desk Reference, which includes

sections on side effects and precautions for

prescribed medications, is one example. [24] The

information contained in this text is supported by

case reports, animal studies, and epidemiologic

literature. The entries are not separated according to

the source of information. All of the sources are

considered important in making decisions about whether

a certain drug may cause a side effect in a specific

patient. A physician will reduce dosage, or change

medications, when a patient reports side effects

consistent with those described in the PDR.

The textbook Principles of Surgery identifies the

following causes of low back pain: Compression

fracture, vertebral process fracture, sprain and

strain, ruptured disc. [25] This list is derived from

an article published in 1960. At the time of

publication, these relationships were not supported by

epidemiologic studies. The relationships were then and

are now understood to be causal by virtue of case

reports, and physicians' general understanding of

bio-mechanics.

In texts devoted exclusively to occupational medicine,

causal associations are frequently made without

reference to epidemiology. The following diseases are

attributed to occupational causes in the absence of

epidemiologic data:

Hand infections: Mycobacterium marinum infections are

unusual infections related to puncture wounds suffered

from handling fish, crab, shrimp, or coral. [26]

=93Sporotrichosis is caused by the fungi Sporothix

schenkii and usually presents with cutaneous

cellulitis and lymphangitis after a puncture wound

secondary to a contaminated thorn [27]

Chronic Paronychia: Repeated immersion of the finger

tips with consequent paronychia affects, in

particular, bar tenders, kitchen workers, and laundry

workers. Prolonged immersion of the hands in water,

particularly hot water that contains detergents,

increases the risk of paronychia [28]

Onycholysis:Enzymes in laundry detergent have been

reported to cause painful onycholysis with hemorrhage.

Onycholysis has also been reported from hydrofluoric

acid in a rust-removing agent and to sodium

hypochlorite in an 18-year-old lifeguard who added 16%

sodium hypochlorite to the pool daily. [29] [emphasis

added]

Koilonychia: Koilonychia has been reported in a woman

who was employed as a wire coil winder. Koilonychia

has been reported from organic solvents used to clean

metal parts and accessories in an office furnishing

factory. [30] [emphasis added]

These examples show that physicians sometimes require

only one case study in order to warn the medical

community that certain occupations may be at risk of

work-related disease. Furthermore, case reports serve

to establish other important causal connections,

especially for diseases or injuries that have many

possible causes . Thus, case reports can make a new

link between an occupation and an established disease

or injury. This is an example of the use of the causal

criterion analogy (see below for further detail), in

which, because of similar types of exposure, a case

report documents the existence of a risk within an

occupation not known to be at risk. (Also see appendix

1 for more examples cause effect relationships

established with case series.)

Table 1 Causal Relationships Established By Case

Reports:

Thalidomide and malformation.

Omniflox and liver failure

Isocyantes and asthma

Cold exposure and asthma

Allergen exposure and asthma

Vinyl chloride and cancer

Vinyl chloride and scleroderma

Adulterated rapeseed oil and scleroderma

Vaginal cancer and DES (early epidemiologic studies

failed to confirm but did not impact on the acceptance

of the causal relationship)

Silica dust and scleroderma

Solvents and scleroderma

Epoxy resins and scleroderma

L-Tryptophan and scleroderma

Bleomycin and scleroderma

Pentazocine and scleroderma

Specific side effects of hundreds of drugs e.g.

Chloramphenicol and aplastic anemia

Case reports have also provided a basis for many

treatment modalities. Table 2 contains examples from

the rheumatologic literature.

Table 2. TREATMENT MODALITIES IN RHEUMATOID DISEASE

BASED ON CASE

REPORTS/SERIES

Hypertrophic osteoarthropathy:

Steinfeld, A.D., and Munzenrider, J.E.: The response

of hypertrophic pulmonary osteoarthropathy to

radiotherapy. Radiology 113:709, 1974.

-Enriquez, E. Morales, A. R., and F.:

Effect of atropine sulfate in pulmonary hypertrophic

osteoarthropathy. Arthritis Rheum. 23:822, 1980.

Lokich, J. J.: Pulmonary osteoarthropathy; association

with mesenchymal tumor metastases to the lungs,

J.A.M.A. 238:37, 1977.

Leung, F.W., , A.J., and Fan, P.: Indomethacin

therapy for hypertrophic pulmonary osteoarthropathy in

patients with bronchogenic carcinoma, West J. Med.

142: 345, 1985.

Primary and Secondary Hemochromatosis

Angevine, C.D., and Jacox, R.F.: Unusual connective

tisue manifestations of hemochromatosis. Arthritis

Rheum. 17: 477, 1974.

McCarthy, J.T., Libertin, C.R., , J.C., III,

and Fairbands, V. F.: Hemosiderosis in a dialysis

patient: Treatment with hemofiltration and

deferoxamine chelation theraphy. Mayo Clin. Proc.

57:439, 1982.

Cohen, A., Cohen, I.J., and Schwartz, E.: Scurvy and

altered iron stores in thalassemia major. N. Engl. J.

Med. 304:158, 1981.

Sarcoidosis

Kaplan, H.: Sarcoid arthritis with a response to

colchicine. N. Engl. J. Med. 263:778, 1960.

Kaplan, H.: Further experience with colchicine in the

treatment of sarcoid arthritis. N. Engl. J. Med.

268:761, 1963.

, E. D., Jr., and Millis, M.: Treatment with

colchicine of the periarticular inflammation

associated with sarcoidosis: A need for continued

appraisal. Arthritis Rhem. 14:130, 1971.

Neville, E., Carstairs, L.S., and , D.G.: Bone

sarcoidosis. Ann. N.Y. Acad. Sci. 278:475, 1976.

Franco-Saenz, R., Ludwig, G.D., and , L.W.:

Sarcoidosis of the skull. Ann. Intern. Med. 72:929,

1970.

Baldwin, D.M., , J.G., and Croft, H.W.:

Vertebral sarcoidosis. J. Bone Joint Surg. 56:629,

1974.

Perlman, S.G., Damergis, J., Witorsch, P., et al.:

Vertebral sarcoidosis with paravertebral ossification,

Arthritis Rheum. 21:271, 1978.

, R.C., and Cahen, I.: Pathological fracture in

long bone sarcoidosis. J. Bone Joint Surg. 55:613,

1973.

Marcove, R.C., Rooney, R. and Weis, L.D.:

Osteosclerotic lesions in sarcoidosis. Clin. Orthrop.

Rel. Res. 129:248, 1977.

Schriber, R.A., and Firooznia, H.: Extensive

phalangeal cystic lesions-limited sarcoidosis.

Arthritis Rheum. 18:123, 1975.

Amyloidosis

Stone, M.J., and el, E.P.: The clinical syndrome

of light chain myelome. A study of 35 patients with

special reference to the occurence of amyloidosis. Am.

J. Med. 58:601, 1975.

, M.E., and Byuwaters, E.G.L.: Mortality and

prognosis related to the amyloidosis of Still's

disease. Ann. rheum. Dis. 27:137, 1968.

Goldfinger, W.E.: Colchicine for familial

Mediterranean fever (letter). N. Engl. J. Med.

287:1302, 1972.

Polychondritis

Svenson, K.L.G., Holmdahl, R., Klareskog, L., Wibell,

L., Sjoberg, O., Klintmalm, G.B.G., and Bostrom, H.:

Cyclosporin A treatment in a case of relapsing

polychondritis. Scand. J. Rheumatol. 13:229, 1984.

Osteoarthritis (Drug therapies)

, R.J., Potts, D.W., Gabow, P.A., et al.:

Unrecognized adult salicylate intoxication. Ann.

Intern. Med. 85:745, 1976.

Hodgkinson, R., and Woolf, D.: A five-year clinical

trial of indemethacin in osteoarthrosis of the hip.

Practitioner 210:372, 1974.

Articles in the medical literature discuss the

importance of evidence besides epidemiology.

Fleming et al. reviewed and evaluated whether the

investigation of disease clusters continues to play an

important role in establishing disease-toxin

connections in the workplace. [31] They identified 87

original disease cluster reports that established

disease-toxin connections in occupational medicine

(from 1775 to 1990). They identified four advantages

in using cluster reports from the workplace to

identify new hazards: natural denominator boundaries,

shared exposures, the ability to form intermediate

hypotheses, and the possibility of locating comparable

populations in which to study these hypotheses.=94

They stated that, =93because new products,

intermediate products, and procedures are introduced

into working environments faster than epidemiologic

and toxicological studies can be designed to evaluate

their potential risks, disease cluster investigations

will remain central to the understanding of disease,

and to protecting workers.[32]

1.. THE INTERPRETATION OF EPIDEMIOLOGY IS SUBJECTIVE

As illustrated above, epidemiology is not necessary

when making traditional medical conclusions regarding

causes and effects. It is one piece of evidence among

many. Epidemiology is an aspect of various disciplines

that contributes to the general knowledge present in

the field. It does not constitute a field of knowledge

in and of itself:

Instead, a multitude of medical sciences and areas of

practice embody epidemiologic problems. Hence, cancer

epidemiology is a specialty within oncology,

malformation epidemiology within teratology,

health-care epidemiology within health-care

administration, and so on. In this regard epidemiology

is akin to morphology, for example - an aspect of

various sciences and other fields as opposed to a

science or other subject-matter in itself. [33]

Because of this, the interpretation of epidemiologic

evidence is inherently subjective. This is true of any

piece of evidence used to evaluate cause-effect

relationships. A cause-effect analysis that rests

solely on a definitive evaluation of the sum of

epidemiologic evidence regarding a certain

determinant-disease relationship will not do justice

to the universe of non-epidemiologic evidence that is

also available. Thus, despite all the studies on, for

example, the effects of smoking, physical exercise, or

diet on the risk of myocardial infarction, or on the

efficacy of anticoagulant medication in the prevention

of its recurrence, the opinions of even experts on

these topics remain quite diverse and, hence,

subjective. [34]

1.. HILL'S CRITERIA FOR DETERMINING CAUSALITY

As an overall model for determining causality, Hill's

criteria are well accepted. [35] They are:

temporality, biologic gradient (dose-response),

consistency, biologic plausibility, strength of

association, analogy, experimental evidence,

coherence, and specificity. All of Hill's criteria are

subject to criticism, and only temporality is

individually necessary to prove causality. Of Hill's

nine criteria epidemiologic data is only required for

determination of strength of association.

Strength of association is a reflection of the

strength of effect of a study. The relevance of

strength of association is limited because the

strength of an effect measured in a study is related

in large part to the prevalence of other co-factors

and not to the factor studied. Strength of association

is not a measure of the importance of a particular

factor in causation. While studies with large rate

ratios are less likely to suffer from errors due to

bias or confounding, it is important to note that weak

causal associations are as likely to be causal and as

important as are strong associations. [36] In

addition, a rate ratio of two is not required to

establish that a factor contributed to a disease in a

particular individual. For example chronic smoking of

less than a pack a day induces less than a two fold

increase in the risk of heart disease, nonetheless all

physician's would state that smoking contributed to an

individual smokers heart disease if he/she smoked at

this rate. Epidemiologic studies can, when evaluated

together provide more confidence in an association

even in the absence of a statistically significant

finding in any individual study. Consider for example

five different polls that all indicate that a

particular candidate for office is ahead by between

two and three points all of which are within the

sampling era of each individual poll. It would be

reasonable to conclude that the candidate was going to

win on a more likely than not basis.

The temporality criterion requires that the cause

precede the effect. While this is generally relevant,

conformity with temporality does not mean every study

must evaluate this issue. In addition, there will be

some cases where strict temporality is not necessary

in order to evaluate etiologic relationships. As Weed

states, It is interesting to note that, in general

terms, causality need not require antecedence. Counter

examples include simultaneous cause-effect

relationships [37] Temporality is usually established

through non-epidemiologic evidence. Tobacco companies

argue correctly that the current body of epidemiology

literature cannot distinguish temporality from a

genetic link between the tendency to smoke and risk

factors for cancer.

Conclusive support for the temporal relation of

smoking and cancer is derived from molecular and

animal data.

Biologic gradient is the existence of a dose-response

relationship for the proposed cause-effect

combination. A dose-response relationship is not

always necessary in order to establish causation. This

is true for several reasons:

First, it is possible for sufficient evidence to be

amassed for an association to be considered causal

without any form of dose-response relation being

observed. As two notable examples, most

epidemiologists found persuasive the early evidence of

association between vinyl chloride and angiosarcoma of

the liver, and between diethylstilbestrol and

adenocarcinoma of the vagina, even though no

dose-response relations were demonstrated. The

acceptance of these two cancer-exposure relations was

firmly established on case reports only. The presence

of a dose-response pattern in epidemiologic data is,

after all, partly a function of the opportunity to

study such a pattern. Second, the interpretation of an

apparent dose-response relation in the data must

include the possible non-causal reasons for its

appearance, such as confounding and other sources of

bias. Hence, one might expect to see a non-causal

dose-response relation between alcohol consumption and

lung cancer due to a correlation between alcohol and

smoking. Third, a dose-response curve reflects complex

biological mechanisms and may take any form. For

instance, there may be a `threshold' dose below which

there is no effect or a flat portion along which all

doses produce the same magnitude of effect =85

Finally, estimates of effect made in relative terms

(i.e., with the rate ratio) may obscure or present the

misleading appearance of a relation of dose to the

absolute magnitude of response, which is measured by

the rate difference. [38]

Consistency requires that a proposed effect be

observed repeatedly under different circumstances.

This criterion is useful, and it can be met by many

different conditions and types of study. However

repetition of findings under similar conditions is not

necessarily supportive of this criterion.

Specificity requires that each cause have a single

effect. This is rarely a useful criterion because many

causes have multiple effects. Asbestos causes

asbestosis, lung cancer mesothelioma and other

cancers. Smoking causes heart disease, lung cancer,

oral cancer, etc. Trauma from a car accident can cause

many different injuries.

Biological plausibility (mechanistic understanding)

asks if the theory of causation (mechanistic) fits

known mechanisms of injury causation. But usually,

doctors do not require a specific understanding of the

underlying mechanism of an injury or disease before

assessing causation. For instance, doctors still do

not understand exactly how smoking causes cancer, yet

we routinely attribute cancers to smoking. In

addition, when an exposure may result in many

different intermediate causes of an outcome, it is not

necessary to know which particular mechanism caused

the outcome, within a reasonable degree of medical

certainty. For example, a bullet wound in the chest

may damage many different organs and cause the death

of the person who is shot. Damage to the heart, lung

or aorta may have caused the death. Despite the lack

of knowledge of a specific causal mechanism, no doctor

would hesitate to state that the bullet wound caused

the death. This is true, even though the dead

individual may have suffered a heart attack at the

exact time that he/she was shot. This and other

possible error is the reason doctors' opinions are

given to a reasonable degree of medical certainty.

Coherence asks if the causal theory is not

inconsistent with what is already known of the injury

or disease.

Experimental evidence can consist of laboratory

studies, animal studies, controlled clinical trials,

or observational pathology studies. This includes

articles discussing mechanisms of injury production,

whose authors use experimental evidence and

observation as the basis for their conclusions. Animal

studies are relevant to human inference. Animal

studies are performed for application to human health,

not to animal health. Animal studies are not conducted

to determine risks to mice, rats, dogs or cats. They

are not conducted out of concern for mouse or rat

health. They are done because it is generally felt

that inferences can be drawn from animal studies about

human risks. If inferences are not to be drawn, there

should be a specific justification for failure to do

so since many studies indicate that illnesses in

humans are reproduced in animals. Animal studies

comprise the major criteria for Koch's postulates and

thus have been the fundamental basis for medical

epistemology since the 19th century. If negative

animals studies are relevant, positive studies must

also be relevant. It is for this reason that

regulatory agencies including the NIH, FDA, EPA, NIOSH

and the National Toxicology Program rely on, conduct

and fund animal studies. Eighteen of 21 agents found

carcinogenic in animals have also been found to cause

cancer in humans. Of 23 human carcinogens 21 have

produced some indication of cancer in animals. [39]

Animal models are used to test causation and

treatments for a variety of non-cancer effects

including drug side effects, teratogenicity, asthma,

heart disease, and medical device testing.

Analogy asks if epidemiological and other studies have

established that an environmental exposure analogous

to the exposure being considered may cause diseases

similar to those reported for the exposure being

considered.

Hill noted, None of my nine view points can bring

indisputable evidence for or against the cause and

effect hypothesis, and none can be required as a sine

qua non. [40]

Hill's final emphasis placed responsibility on

scientists for making causal judgments with available

known facts. He recognized that decisions have to be

made in the absence of perfect data noting, All

scientific work is incomplete--whether it be

observational or experimental. All scientific work is

liable to be upset or modified by advancing knowledge.

That does not confer upon us a freedom to ignore the

knowledge we already have, or to postpone the action

that it appears to demand at a given time. [41]

9. SBI and Disease [42]

A. Evaluating the relationship using the general model

Sufficient information is available in the medical

literature to establish that the use of SBI can cause,

aggravate, or exacerbate certain diseases, signs and

symptoms.

These diseases are defined as follows:

a.. Capsular contracture

b.. Granuloma formation

c.. Atypical connective tissue disease (ATCD)

characterized by some or all of the following symptoms

including:fatigue, myalgia, arthralgia, memory loss,

paresthesias, dry eye, dry mouth, dysphagia,

photosensitivity, Raynaud's phenomenon, pleurisy,

stiffness, adenopathy, joint swelling and others, and

or signs including:

Enlarged or tender thyroid, enlarged parotid, abnormal

Schirmer, telangectasia, carpal tunnel syndrome, or

erythema of the chest wall and others and or,

associated laboratory abnormalities include: elevated

cholesterol, ANA, esr, IgG, IgA, IgM, RF, anti-Ro

(SSA), anti-La (SSB), and anti-microsomal antibody

and/or others.

a.. Myeloma and Monoclonal gamopathy of unknown

significance (MGUS)

b.. Scleroderma

Using all types of available data, it is possible to

evaluate the relationship between SBI and disease.

This can be accomplished through the application of

the Hill model and Bayesian process. This framework

asks two questions. The first is, Does the

substance/factor cause the effect in general? In other

words, does SBI use, in general, cause and disease?

This can be answered, by considering Hill's criteria

for causation, and using those criteria to place the

proposed causal factor somewhere on the line between 0

and 100 in the proposed model. The second question is,

Has the substance/factor contributed to the effect in

a particular individual? No guidelines to approach

this second question are proposed here, but it is the

subtext of any discussion of general causation.

I will now apply Hill's criteria for causation to the

question of the association of SBI and disease.

1. Specificity requires that each cause have a single

effect. This

criterion is not relevant because SBI causes disease

through local or distant immune mechanisms. These

mechanisms would be expected to result in different

patterns of sign and symptoms in different

individuals. This is the pattern of disease in other

rheumatologic and immune based diseases.

2. Temporality requires that the cause precede the

effect. temporality is a sine qua non for SBI and

disease. In the case of breast implants the strongest

evidence of temporality comes from the improvement in

symptoms generally seen after explantation. This

improvement is gradual and is therefore less likely to

be due to a placebo effect. Of the 517 patients who

underwent explantation, 188 improved, yielding a

40.65% improvement rate. In the explant studies that

reported the ANA titer levels pre- and

post-explantation 27 of the 48 patients had reductions

in post explant ANA levels . For a summary of the

studies of breast implant explanations see Appendix 2.

3. Consistency requires that a proposed effect be

repeatedly observed under different circumstances.

This criterion is satisfied by the observation that

similar signs and symptoms of disease in women with

SBI have been independently observed by different

researchers in different locations. Biomarkers of

immune system dysfunction are consistently found in

symptomatic SBI patients, although it is expected that

not all SBI implanted patients will be abnormal for

all or even most abnormalities. Patient's with SLE, SS

and RA have differing patterns of biomarkers

positivity. The epidemiological evidence of lab

abnormalities in women with silicone implants are

presented in more detail in Appendix 3. Appendix 4

reviews the case series furthering describing the

constellation of abnormalities in support of this

criterion.

The studies that failed to find a difference in

symptoms need to be examined closely. For example,

s failed to find a difference in ANA percentage

between controls and SBI patients. [43] However his

control group had a 28% positivity rate, a rate five

times higher than that reported in the general medical

literature. The prevalence of 26 % positivity in the

implant group is comparable to the rate reported by

other authors in SBI patients and is elevated based on

most (if not all) other published sets of rates of ANA

positivity in general populations. In the s

study, it is of interest that four of the SBI patients

had CTDs ( three atypical), while none of the controls

did.

Research in animals is consistent with the findings in

human data. Comparable studies of animals and humans

exposed to silicone gel implants have found identical

effects. [44] A list of animal studies with findings

supportive of the conclusions from human research is

in Appendix 5.

4. Biologic gradient is the existence of a

dose-response relationship for the proposed etiologic

factor. In the case of implants dose is related to

latency, bleed rate, rupture, explantation, and type

of implant (saline vs. gel vs. type of gel vs. size of

implant). It has been shown that the rate of ANA

induction increased with increasing duration of

implantation. [45] Pleiderer and Garrido found that

the concentration of silicone found in human livers

increased with decreased implant integrity. [46] Wolf

et al found that women with ruptured implants had

higher anti-silicone anti-body titers in women with

ruptured implants compared with intact and unimplanted

women. [47] Cuellar et al found that auto-immune

abnormalities increased with duration of implantation.

[48] See appendix 6 for a summary of biologic gradient

data.

5. Biological plausibility (mechanistic understanding)

asks if the theory of causation (mechanistic) fits

known mechanisms of injury causation. The mechanism of

SBI induced disease is supported by the known

mechanism of other immune diseases, the known biologic

action of silicone, the pattern of laboratory

abnormalities in humans and animals, the distribution

of silicone in the body, the in vivo distribution of

reactive silica in the body.:

Silicone is known to induce interferon production in

animals and to induce antibody production in animals.

[49] [50] [51] [52] Interferon levels are elevated in

humans in response to inflammation. Silicone has been

shown to induce inflammation and act as an adjuvant in

humans and animals. Silicone and has been shown to

migrate throughout the body. Human data indicates that

chronic elevation of interferon can result in

auto-immune disease, and central nervous system

abnormalities. Therefore there is a plausible

mechanism of disease induction by silicone.

Although the exact mechanism(s) of silicone induced

inflammation remains under investigation, much is

known about silicone induced disease. Multiple studies

indicate that there is a probable specific silicone

antigen or anti-silicone immune cause. However, even

if the inflammation is non-specific, that is, there is

no specific understanding of the exact mechanism,

non-specific inflammation in and of itself can produce

the symptoms noted in silicone breast implants

patients and is responsible for inflammation, scarring

in silicate induced disease and silicosis.

6. Coherence asks if the theory is not inconsistent

with what is already known of the injury. SBI as a

cause for disease is not inconsistent with what is

known about the immune diseases and SBI effects or

current epidemiologic data. There is no data

inconsistent with the causal induction of ACTD by SBI

in patients.

7. Experimental evidence can consist of laboratory or

animal studies, controlled clinical trials, or

observational studies. This includes articles

discussing mechanisms of injury production, whose

authors use experimental evidence and observation as

the basis for their conclusions. Animal and other

studies provide valuable evidence that silicones can

cause disease, on the mechanism of disease production.

The biologic activity of silicones in animals has been

reproduced in several different species and has human

parallels and its importance has been recognized for

silicone since 1964. Silicones have induced cancer in

rats and on the basis of this data, in 1964, the head

of the NCI, environmental cancer section stated:

The conclusion therefore is sustained that an

indiscriminate use of Silastic for parenteral

implantation in man is potentially dangerous and thus

inadvisable on the grounds of medical ethics and the

exercise of good judgment. [53] [54]

Animal studies, in particular with respect to silicone

gel implants, provide important information on

biologic plausibility and mechanistic understanding.

Table 3 (below) includes the areas of knowledge

demonstrated by animal studies.

Table 3 Silicone Animal Studies: Their Relevance to

Human renference

Number Topic

1496, 1511, 930, 2222 Adjuvant arthritis model.

2483, 2484, 2222 Amorphous silica and scarring,

Mechanism of

biologic reactivity

1857, 518 Antibody stimulation.

1915, 1926, 1713, 518, 965 Biologic activity of

silicones and polyurethane and effects on the immune

system, hematopoietic system and natural killer cell

activity

111, 2024, 2075 2115 Bony destruction by silicone.

215, 1927, 2058 Cancer and implants.

985, 1346 , 2115, 1316, 1500, 1109 Capsule formation

and impact of infection on capsule formation.

1726 Degradation of silicon

2379 Immune reactivity of silicone in animal and

humans; the effects were found to be identical.

1003 Immune reactivity of the shell.

2486 Impact of sheering on immunogenicity.

2051 Induction of vascular reaction by silicone.

Granuloma formation by silicone.

1695, 1826, 1845, 1261 826, 1827, 823, 1261 Migration

and degradation and immune reactivity of silicone. The

mechanism of gel diffusion.

1064 Reactivity of fumed silica.

2304 Relative value of MR and CT for determination of

rupture.

2331 Silicone and emboli.

595 Surgical techniques with the use of silicone

prosthesis.

80 Testing for the efficacy of birth control devices

using silicone.

1400 The reactivity of silica.

2450 Silicones stimulate interferon production and

cellular immune

response.

1859 Silicones can elevate serum cholesterol.

Silicone can induce anti-insulin antibodies.

1192 Amorphous silica causes fibrosis in animals and

induces LDH and beta glucuronidase in mouse

macrophages.

2385 Amorphous silica (as added to elastomere shells)

causes death

when injected into the lung or peritoneal cavity of

rats.

1230 Silicone causes histologic changes in the human

breast

including lymphocyte, plasma cell, and fibroblast

infiltration.

402 Silicone causes cellular changes including

increased hyaluronic acid and IL-2 in human breast

tissue.

In human research silicones have been shown to produce

a variety of biochemical and other abnormalities.

Table 4 is a summary of experimental data in humans.

Table 4 Silicone Human Mechanism Data

Reference Effect

Silicone can cause capsular formation (fibrosis).

Silicones can induce granuloma.

1912 Silicone implants decompose to silica and other

intermediates.

912 Silicones can and do migrate throughout the body.

1876 Subcutaneous silicones can cause severe local and

systemic

disease.

2336 Silica can cause lung fibrosis.

1436 SBIs frequently rupture.

494 Silicones are associated with myeloma and MGUS in

humans.

2095 Silicone can cause osteitis, synovitis and bone

resorption.

Silicone can induce anti-insulin antibodies in animals

and humans.

[55]

1859, 385 Silicone can cause elevated cholesterol

levels in man and animals.

Since a picture is worth a thousand words and seeing

is believing, I have attached five photomicrographs of

silicone in action in a human being: [56]

Photograph 1 demonstrates a foreign body reaction to

silicone gel in a `silicone granuloma' after an

implant rupture.

Photograph 2 is a foreign body reaction to silicone

elastomere and

polyurethane.

Photograph 3 are foamy macrophages containing silicone

gel in an

axillary (armpit) lymph node.

Photograph 4 is a fibrous capsule around an implant

and polyurethane fragments.

Photograph 5 are foamy macrophages containing silicone

gel in the tissue near an implant.

These are histologic proof of migration, capsule

formation and inflammation . This evidence cannot be

rebutted or even addressed with an epidemiologic

study.

8. Analogy asks if epidemiological and other studies

have established that silicones or to other agents can

induce similar diseases when placed into the body. The

following causal associations are analogous to the

association between silicone breast implants and

disease:

Freund's adjuvant can induce arthritis in rats. [57]

Silicosis can result in scleroderma. [58]

Silicones induced hepatic fibrosis in dialysis

patients. [59]

Silicones induced severe immune mediated disease in

patient's with silicone shunts. [60]

Silicones induced granuloma of the penis. [61]

Vinyl Chloride, some medications can cause

scleroderma.

1.. Strength of association. As described above, weak

associations (rate ratios less than 10) may be as

causal as strong associations. Strength of association

is a relevant consideration of the epidemiological

evidence to the extent that an epidemiologic study is

less likely to miss a large rate ratios due to issues

of study design, conduct or analysis. Many of the

epidemiological studies of the laboratory

abnormalities in symptomatic SBI patients found

statistically significant associations compared to

controls (Appendix 3). Of the epidemiological studies

of connective tissue disease, only two investigated

the relationship with atypical connective tissue

disease (see Appendix 7 and section below for more

detail). Giltay et. al. found rate ratios from 2.26 to

5 for a variety of symptoms associated with SBI

induced disease. Hennekens et al found a relative risk

for other connective tissue disease of 1.30 (95%CI:

1.05-1.62). McLaughlin et al also found a large

increase risk for scleroderma among exposed women (27-

95%CI - 3.1-99.8). When combined the epidemiological

evidence suggests an association between women exposed

to silicone breast implants and lab abnormalities,

scleroderma, and atypical connective tissue disease.

Thus, the data on the relationship between SBI and

disease satisfy

Hill's criteria for causation.

10. Analysis of Controlled Epidemiological Studies of

Connective Tissue Diseases (CTDs):

Epidemiological studies have found biomarkers of

immune system dysfunction in SBI patients. This body

of epidemiological evidence is presented in Appendix

3. Here, I review the published articles and abstracts

of cohort and case-control epidemiological studies

that evaluated the risk of developing connective

tissue diseases and disorders for women with silicone

breast implants. The small set of controlled

epidemiological studies is, to a large extent,

compromised by poor methodologies, small sample sizes,

and exclusion of the symptoms reported for atypical

connective tissue disease. The summary information of

this group of published studies is presented in

Appendix 7. While the combined body of evidence

suggests that women with breast implants do not have a

large increased risk for developing classically

defined Rheumatoid Arthritis, or Lupus, the evidence

is not conclusive of an absence of an effect. The

studies reviewed here, unlike those reviewed in

Appendix 3, for the most part (see Hennekens et al,

and Giltay et al, for exceptions) did not evaluate the

outcome of interest: atypical disease and symptoms.

Concluding that silicone breast implants do not cause

atypical connective tissue disease based on these

studies would be comparable to concluding that smoking

does not cause cancer based on investigations of

smoking and brain tumors. Below, I discuss the

methodological issues of the studies and evaluate

their impact on the studies' findings.

Definition of Disease

The most frequent disease believed to be caused by

silicone implants is atypical connective tissue

disease. Many of the disease characteristics described

in case series such as chronic fatigue and

musculo-skeletal pain (myalgias or fibromyalgia) were

deliberately excluded from the definition of disease

in this group of epidemiological studies. Of the

studies listed in Appendix 7, only Giltay et al

considers these atypical characteristics. Hennekens et

al allowed for women to code their disease as =93other

connective tissue disease=94 but deliberately excluded

separate questions about diseases like fibromyalgia.

-Guerrero et al. did not address the question

of whether the frequency of symptoms of atypical

diseases was higher in the exposed group than the

unexposed group. The reported signs and symptoms were

only evaluated for the group of exposed and unexposed

who reported a connective tissue disease earlier and

therefore qualified to receive a questionnaire. The

failure of the studies to consider the complaints most

frequently reported undermines their ability to

determine whether women with silicone breast implants

are at a higher risk of developing atypical

auto-immune disease than women without implants.

Sample Size/Power

The power of a study is related to the sample size of

the study, the proportion of the general population

that is exposed (for case control studies) or diseased

(for cohort studies), and the magnitude of the effect

under investigation. Although the power of a study is

an important consideration prior to investigating a

study, it is also an important consideration when

interpreting the results. Power is an especially

relevant consideration for studies that look at rare

disease and exposures. Because power is in part a

function of the prevalence of disease or exposures for

these studies, the sample size to detect a rare

disease must be very large to have adequate power.

Power was a significant limitation for the majority of

the studies. The effect of low power for these studies

is that they would not have found an effect, even if

one existed. In other words, these studies can not be

offered as evidence that connective tissue diseases

are not caused by silicone breast implants. et

al made the following calculation:

Indeed, we calculated that it would require a sample

of 62,000 women with implants and 124,000 women

without implants, followed for an average of 10 years

each, for a doubling of the relative risk of this

condition to be detected among women with implants,

assuming that the annual incidence of systemic

sclerosis is 1.6 cases per 100,000 women (p.1701)

Even Hennekens et al, a large study lacked the power

to detect a relative risk of 2 for systemic sclerosis.

Hennekens et al, published in 1996, is the only cohort

study with adequate power to detect a relative risk of

2 or less for the combined diseases. Based on the

census data for women over 21 (92,576,899) in the

United States, and conservative estimates of the

number of women with breast implants (800,000 to

1,500,000) in the United States, the number of women

to detect a two-fold increase risk range from 1412 to

2574 women in each case and control group. None of the

case control studies conducted thus far have had study

groups remotely this large. In conclusion, the

Hennekens study is the only one conducted to date with

power large enough to detect a two fold increase.

Immortality Bias

This bias originates from an attempt to conduct a

retrospective cohort study based on ascertainment of

exposure at the end of the study period. For a

retrospective cohort study to be free of this bias, it

should utilize data collection from the beginning of

the study period. For example, a 20 year retrospective

follow-up study of insulators and lung cancer

conducted in 1996 should collect data based on

documents from 1976 such as employment rosters. A

study that determined exposure status for the time

period of interest, 1976 to 1996, based on interviews

with workers conducted in 1996 would fail to capture a

significant percentage of the population of insulators

who developed lung cancer: by 1996 the insulators with

disease would be dead and thus not available for

interview. Because all the individuals had to be alive

to be included in the study, none will die and all are

immortal during the study period. Thus, the

immortality bias occurs in retrospective studies by

following exposed and unexposed populations backwards

in time, instead of following the populations from a

far point in time forward. This serious bias removes

individuals with death or disease effecting their

ability to participate, and thus could cause a study

to underestimate a risk.

The studies by Wells (1994), Weisman (1988), Giltay

(1994), Guerrero (1995), and Hennekens (1996)

suffer from this bias. Inclusion in all of these

studies required that participants respond to the

questionnaire sent out at the end of the follow up

time. They administered questionnaires to all study

participants in the 1990s and then attempted to follow

the participants backwards in time. Women with disease

would have been less likely to respond, from

debilitating weakness or death. The effect of this

bias for these studies was likely to underestimate the

risk.

Latency

The studies were also characterized as a whole by the

short follow-up periods. Latency, the time from

exposure to disease onset, was not adequately

addressed. Despite the fact that case series document

latency periods greater than 20 years [62] [63] [64]

[65] [66], none of the c ohort studies followed

patients for longer than an average of 9.9 years (see

Appendix 7). The Schusterman study followed patients

for as short as only 2 years. The impact of following

participants for a time period shorter than the

latency period is to miss the detection of disease.

Had Doll studied smokers for ten years after they

began smoking, he would have failed to find an

association between smoking and lung disease.

Inappropriate Control Groups

Other problems that affected this group of studies

include the selection of inappropriate controls and

low response rates. Goldman et al included as controls

patients referred to a rheumatologist, but not

diagnosed with a classical connective tissue disease.

This is a significant example of bias due to

misclassification of disease: women with atypical

symptoms and complaints would have been classified as

non-diseased. The impact of this misclassification is

to underestimate the effect. Strom et al recruited a

second control group after the intended control group

did not develop disease. Many of the studies provided

only brief methodologies, making it difficult to

evaluate whether the case and control groups were

comparable. Additionally, many of the studies suffered

from a low response rate from cases and controls

invited to participate in the research. This source of

bias that will impact the effect observed if the

response rate is differential for the exposed and

unexposed, or for case controls, the disease and

disease free individuals. In the case of Weisman et

al, only 33% of the cases responded. Plausibly, women

with problems related to their implants would

disproportionately choose not to participate in a

study sponsored by their plastic surgeon. In this

case, the exposed group most likely to develop disease

would be removed from the study, leading to an

underestimation of the effect.

Inappropriate Analysis

The authors of several of the case control studies

(Burns, 1994; Goldman, 1995; Hochberg, 1994) excluded

from their analysis women who developed disease prior

to exposure. Classification in a case control study

should be based on assignment of disease, not

exposure. If the investigators chose to remove cases,

they should have also removed matched controls. By

removing only the cases, the investigators

artificially lowered the background rate of disease

for the cases only, making the data non-comparable.

The effect is to bias the study towards an

underestimation of risk.

Conclusions based on studies:

Despite the multiple design and methodology problems,

there were studies that found statistically

significant positive results. The only two studies to

consider atypical symptoms found positive results:

Giltay et al found a relative risk greater than 2 for

painful joints, burning eyes, skin abnormalities, and

reporting at least one symptom three months after

surgery. The study by Hennekens et al, while likely

biased by the inappropriate retrospective study

design, had an adequate power, and an appropriate

control group. The Hennekens study found a relative

risk, for any connective tissue disease 1.24

(1.08-1.41) and other CTD 1.30 (1.05-1.62). It is

finally worth noting that two studies found risks of

significant elevated risk for scleroderma. The

Hennekens study found an increased risk for

scleroderma of 1. 84 (.98-3.46) and the study by

McLaughlin et al found an increased of 27 (3.1-99.8).

Although a prospective, large epidemiological study

investigating atypical symptoms and disease would

clearly contribute to underestimating of the strength

of association between silicone breast implants and

disease, the available epidemiologic evidence is

suggestive of a causal association for silicone breast

implants and atypical connective tissue diseases and

scleroderma.

11. CORPORATE INTERPRETATION: The Bristol Story

The materials from the manufacturer's files, including

copies of published research, internal correspondence,

internal unpublished research, advertising and product

information, and correspondence with other industry

members and the public, indicate that the

manufacturers knew of the association between breast

implants and disease. The files reflect the

manufacturers' disregard for the safety of product

users, their unethical conduct, and their subsequent

misrepresentation of the health effects of their

products to users, doctors, and regulatory agencies.

1. Knowledge of duty to test

A section from Medical Engineering Corporation

Founder, Wilfred Lynch's Handbook of Silicone Rubber

Fabrication, published in 1978 illustrates what the

industry considered adequate testing:

All basic materials which are to be used in the

fabrication of implantable devices, or devices which

will be in contact with mucous membrane for extended

periods, must undergo long term implant tests in

animals. In the course of these tests it must be

demonstrated that there is no toxicity to the host, no

undue inflammation of the tissues with which it has

been in contact, and no migration of by-products to

vital organs. The material itself must not show signs

of deterioration. [p.217]

2. Inadequate and biased testing

The manufacturer's files suggest that none of these

prerequisites was met for breast implants. Multiple

documents refer to the lack of long term data. For

example, an executive for Scotfoam Corporation

summarizes in 1987 an earlier conversation with Tom

, a Aesthetech executive, regarding the

medical use of polyurethane foam.

I explained our position of implants- namely we do not

recommend such uses due to a lack of long-term data on

suitability, health effects, etc. [67]

On September 23, 1983 a Dow Corning employee described

the long term research of breast implants:

However, and as Bill points out, only inferential data

exists to substantiate the long-term safety of these

gels for human implant application. [68]

A Surgical employee evaluated the status of

their research in 1988 in an internal memo,

While we have a long way to go with our clinical

studies, we've made considerable progress in my

opinion.

The regulatory pressure from the US and Canadian

governments forced the industry to address the

inadequacy of its data. An internal memo from

Goldwitzer to Bill Duffell, October 23, 1991, is

illustrative:

In lieu of the great amount of concern that the FDA

had placed on data concerning the amount of silicone

gel that can bleed through the outer shell of all

mammary products I believe further gel bleed studies

should be conducted. The gel bleed studies that have

been conducted to date have only been run for a period

of eight (8) weeks.

The small number of data points recorded is not

sufficient to statistically analyze for any trend as

to the long term total gel bleed characteristics. [69]

Another example of the concern related to the lack of

data is provided by Markam in (1989):

The US and now Canadian government demands are serious

enough to shut us down if any submission item is

lacking or absent. I am beginning to feel a little in

the dark about where we are with both the GCMS work

and the ultimate bio-transformation segment of the

protocol: Have you begun the actual testing? Can you

please bring me up to date and, truthfully, assuage my

concerns by providing a report and estimated

completion date as soon as your busy schedule permits?

, I can hear the beating of the jungle drums;

they are restless. [70]

In the case of Medical Engineering Corporation's

research with beagles, rather than analyzing data

available from expensive animal experiments, the

corporation chose to terminate its study. The

preliminary results of a number of dogs sacrificed

found inflammatory responses, fibrosis, hyperplasia

and hemorrhaging in the implanted dogs, but not the

controls. [71] The reactions were characterized on a

scale of 0-4, and there were multiple samples

described as Score 3, explained on page 4 as Moderate

Toxic Reaction. On October 23, 1978, Wilfred Lynch

wrote to Dr. Stith a recommendation for further

analysis based upon initial migration findings from

the dogs' tissue samples:

The microscopist's report, based on the tissues he

examined, indicates the presence of low concentrations

of silicone.

The data at this point suggests there is a high

suspicion of the presence of a silica containing

compound in very low concentrations. It is recommended

that more tissues be examined. [72]

The hand written recommendation the next year (April

26, 1979) concerning the fate of the remainder of the

dogs and analysis indicate My rec.-kill dog! Forget

organs. [73]

In addition to demonstrating the lack of data, the

manufacturers' files show the industry's policy to

only pursue research that yielded results considered

favorable. For example, an internal Surgitek

memorandum discussed a survey planned to be free of

bias and of course, newsworthy. [74] The design of the

study was described:

A sample of women with breast implants will be mailed

a questionnaire designed to explore their pre-surgery

expectations, their post-surgery satisfaction, the

extent and type of problems experienced, the degree to

which they felt informed about the risks/benefits of

breast surgery, and the frequency of their breast

examinations.

The memo went on to explain the qualifications of the

study,

Market Facts is fairly confident in this prediction,

however, they have assured the committee that they

will extend the screening if the initial results are

not encouraging. [75]

Another Surgitek memo in 1987 provides a further

example of unethical conduct in setting conditions for

research sponsorship:

I have real reservations about funding and supporting

a research endeavor in which we have little or no

control over the researcher selection process, the way

in which the combined research data is collected or

the way in which the results would be reported. [76]

The manufacturer's knew the status of their research

was inadequate, and rather than extending their

experiments upon initial adverse findings, terminated

their studies.

3. Knowledge of Health Effects and Subsequent Response

Despite their policy of terminating research, from

their own internal research, published literature, and

reports from plastic surgeons and users,

Bristol-Myers-Squibb and its subsidiaries knew of

multiple risks associated with use of breast implants.

These risks were misrepresented to the public.

Examples of the manufacturer's knowledge of health

effects, and response to knowledge follow.

a. Gel Bleed

Early on the industry acknowledged the phenomena of

gel bleed. A letter from Medical Engineering

Corporation in 1979 indicates the universality

attributed to bleed,

As pointed out by Dr. Gayou in his recent article in

Plastic and Reconstructive Surgery all gel-filled

implants are observed to weep or bleed- that is to

develop a greasy substance on the surface of the

implant. Dr. Gayou states that Barker has reported the

greasy material to be a silicone substance. [77]

Wilfred Lynch's paper makes clear that both high and

low molecular weights migrate through the shell,

Also, MEC's own in vitro experiments showed, that

although low molecular weight silicones migrate

faster, high molecular weight species do migrate

through the shell. [78]

Returned goods reports documented cases of extreme gel

bleed (Appendix 8). For example one file reported in

1983,

Exploration of the left side was also performed and it

was found that this prosthesis while not being

ruptured had bled to such an extent that a good

portion of the gel was on the exterior surface of the

prosthesis. [79]

In a memo dated April 26, 1986 Markham

relates the industry's internal impression of the

effect of gel bleed expressed at the 19th Annual

Aesthetic Society meeting in New Orleans:

The question turned to silicone bleed. This is

information I urge you to use. Everyone agreed that

the less silicone gel we expose to the lymphatic

system, the better, simply because it's less load on

the immune system. The high bleed implants were in

disfavor. [80]

Despite this early acceptance of the phenomena and

concern about the impact on the immune system, in its

submission to the FDA, the industry minimized the

migration and misrepresented the health effects,

Gel bleed absent rupture has been reported but has

never been associated with any clinical consequences

or risks.

In vivo and in vitro tests quantitatively measure gel

bleed to be in very low concentrations. [81]

b. Rupture:

Rupture was another early recognized phenomena,

although sometimes coded as implant deflated or tear.

Returned Goods Reports in the early 80's describe

rupture frequently (see appendix 8 for excerpts of

some of the reports).

Ruptures in fact were so common that Bob Wiles

recommended to Dave

in 1979 to classify returned, ruptured

implants not as complaints, but merely standard

returned goods: [82]

After my conversation with , I suggested that

for the common rupture occurrences where the doctor is

looking for replacements, these items be entered in

the returned good procedure and the replacement

system, but are not maintained in a customer complaint

file. If we do receive a complaint from a doctor

concerning a rupture, that specific incident should be

listed as a complaint and follow our normal complaint

procedure.

The industry's submissions to FDA regarding rupture

again were misleading:

Rupture of the prosthesis is not a common occurrence.

When it does

occur, it is commonly the result of uncontrollable

external forces such as trauma. Furthermore, the

device factors which affect rupture, such as envelope

strength, are readily controllable by standards.

c. Gel Cohesion

In 1981 Surgitek undertook an internal study to

evaluate the problems with cohesiveness of their gel.

[83] The conclusion of the report was that The

sporadic bad gel cohesion continues to occur for

reasons unknown at this time.

The next year, on April 8, 1982 Surgitek president

wrote to Dr. Stone, As you probably

know, Dr. Stone our gel is very, very consistent and

will not run.(MEJ 6445).

d. Gel Migration

Gel migration is another adverse outcome known by the

manufacturers to be associated with use of silicone

breast implants. Numerous returned goods reports offer

further evidence of migration. For example,

onfiltered= physician described removal of an implant

in 1986 [see also appendix 8]:

Direct removal of eight different pockets of migratory

silicone particles in the axilla and the left arm down

to the elbow. [84]

The internal research with beagles is another example

of the industry's familiarity with gel migration.

Their research was summarized in a 1979 memo to Dave

by Wilfred Lynch: [85]

On October 23, 1978, I reported to Dr. Stith that

Energy Dispersive X-Ray analysis of tissues samples

obtained from selected organs of 2 dogs, which had

been recipients of a variety of long-term silicone

implants showed the presence of low, but definite

concentrations of silicon in these organs with the

highest concentrations observed in kidney and liver

tissue.

In addition to conducting their own research and

receiving feedback from plastic surgeons documenting

migration, the industry was knowledgeable of the

medical literature concluding gel migration. A draft

advertisement for Surgitek quotes a conclusive

published study and provides an example of their

knowledge: [86]

`An organosilicone polymer of lower viscosity can

migrate directly to distant sites and be carried into

the lungs'

Dr. T Huang 1978 Journal of Plastic and Reconstructive

Surgery

Despite the clear evidence on this issue, HIMA (the

industry organization) made the following counter

points:

Migration Due to Gel Bleed

Available literature concerning silicone gel bleed and

the presence of silicone gel in capsule tissue can be

summarized as follows:

3. There appears to be no gel migration to distant

sites.

There is no evidence in the medical literature,

including this cited reference of silicone migration

from breast implants to distant sites.

Gel Migration from Ruptured Prostheses

The only reports in the literature that describe

silicone migration in the body are those on liquid

injectable silicone.

In this example, the industry clearly mischaracterized

literature that information available only to the

industry from internal research and correspondence

with plastic surgeons.

e. Toxicity

Internal, unpublished industry research indicated

immune responses in animal research to breast

implants. An early example comes in 1972 in a report

for Medical Engineering Corporation from Huntington

Research Center regarding tests of rabbits with

implants:

A slightly to moderately more severe response was seen

in intramuscular and mammary test sites when compared

to corresponding control tissue. There was little

difference in the degree of connective tissue

proliferation on cellular infiltration which occurred

immediately surrounding the implantation site.

However, in many of the test sites there was a rather

prominent chronic inflammatory process which extended

avariable distances from the implantation site. [87]

Medical Engineering's research with Beagles, detailed

above, is another example of toxic findings of

fibrosis and inflammation. These findings were

directly misrepresented by Surgitek in their mammary

implant product information in 1982, three years after

their research was completed: [88]

Long Term Implant Studies in Dogs

Materials used in the Surgitek mammary implant were

subjected to implant evaluation in beagle dogs for

periods of up to seven years. Test animals were given

frequent physical examinations for determination of

untoward results such as carcinogenic reaction.

Specific animals were sacrificed annually with

complete histopathic examinations of the implant

sites, the implanted prosthesis and up to 24 body

organs. Those materials implanted into dogs have shown

no adverse reactions or carcinogenic activity.

Manufacturers also had access to the medical

literature documenting toxic and immune reactions. The

following excerpt from a 1982 letter from Heggers to

the Surgitek is case where the authors alerted the

industry of their findings prior to publication:

To date, in the experimental animals referred to in

the manuscript, we have been able to show an immune

response to silicone challenges by immune fluorescein

(IF).

The enclosed article further notes,

The silicone prostheses, irrespective of their

manufacturer, can evoke in the human female the

formation of highly collagenous capsules that contain

myofibroblasts and giant cells characteristic of a

large scale foreign body response.

The manufacturers of Natural Y provide another example

in 1985 of the familiarity of the industry with the

published literature indicating toxic reactions: [89]

The Kossovsky study was definitive in proving how

micro surface blebs of smooth silicone envelopes,

thought to be stable, are `grazed' by macrophages and

released as `chips' of free-floating breakdown

material.

Smooth-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.

Despite the knowledge from their own research as well

as outside published studies, the manufacturers

mischaracterized the data for immune and toxic

responses as nonexistent. Again, HIMA provides another

example of misrepresentation of risk by the industry.

Regarding adverse effects they wrote: There is no

evidence of the toxic effects of silicone.

f. Autoimmune Disease

Dow Corning Memo dated July 16, 1980 Subject: A report

of an Adverse Reaction to Mammary Gel Implants:

I received a call this date from Dr. H. Stone,

MD of Dover-Fox Croft , Maine reporting that two of

his patients within the last 6-9 months rejected gel

implants between 3 and 6 weeks after surgery. There

was rapid evolution of would edema with subsequent

inflammation of peri-implant tissue and tissue

break-down. There was neither infection or fever in

either case. Both patients have a history of broad

allergy....

Subsequently, I have heard from Ed Hobbs that he

recalls a dermatologist in New York City

(Orentriech?)[sic] claiming to have 8 patients with an

allergic response to silicone fluid.

It may be that there is a small population capable of

a vigorous immune rejection response to silicone

fluid/elastomer; could be a complement mediated

response.

Syzcher, a consultant for MEC, provided

another summary of the evidence for the existence of

autoimmune disease: [90]

Autoimmune disease, with its attendant immunological

sensitization may indeed be a serious risk associated

with silicone gels. Human adjuvant disease or

autoimmune disease after implantation of foreign

materials occurs subsequent to injection or

implantation of paraffin/silicone, and possibly,

silicone polymers. Patients develop signs, symptoms,

and lab abnormalities suggestive but not diagnostic of

= a connective tissue or autoimmune disease.

This passage noting the occurrence of autoimmune

disease was in a paper edited by Surgitek as explained

in an internal memorandum dated October 29, 1990:

Attached is the latest draft of Szycher's first paper,

Breast Prostheses: A Critical Review.

This draft incorporates the changes in Sections 1 -7

already suggested by Surgitek, but not suggested

changes to Section 8 which you have my input, or

Section 9, 10, or now Section 11.

To expedite submission for peer review and journal

publication, Surgitek's changes need to be sent to Dr.

Syzcher by the end of this week.

Not only was Surgitek aware of this passage because

Syzcher was a consultant, but they edited the paper

anonymously. The failure to reveal this corporate

influence over a published medical journal was

unethical.

Breast implant manufacturers knew of multiple risks

associated with implants, and responded by terminating

studies, sponsoring only research they could control,

and by misrepresenting the risks to the users,

physicians, and regulatory agencies. The examples

provided in this report are illustrative, but not

exhaustive. Attached is a more complete list of the

corporate documents demonstrating the manufacturer's

duty to warn and test, their knowledge of design

defects, adverse health effects, and immune responses,

and their subsequent response of misrepresentation of

risks to users, physicians, and regulatory agencies.

Footnotes

[1]For purposes of this report SBI induced disease is

considered an iatrogenic environmental disease.=20

[2] Egilman, D, Punnett L, Wigaeus Hjelm E., Welch L.,

Keyboarding can cause Injury (letter), JOM [Accepted

for publication]

Egilman, D., Reinert, A.: Asbestos Exposure and Lung

Cancer: Asbestosis is Not Necessary. Am. J. Ind. Med.

[Accepted for publication]

Egilman, D.: Public Health and Epistemology. Am. J.

Ind. Med,

22:457-459.1992.

[3] Webster' Dictionary and Thesaurus, 1991 p. 55

[4] W. Lynch, A current review of constrictive

capsules, Medical

Engineering Corporation. MEM 10294.

[5] Syzcher, M. Lee SJ, and AA Siciliano, p. 256.

Breast Prostheses: A Critical Review. Volume 5, Number

4/ April 1991.Journal of biomaterials applications,

[6] MEP 52886 - MEP 52887

[7] MEC 11998 at 999

[8] MEA 521 at 522 citing: Plastic and Reconstructive

Surgery, August 1978, " Closed Capsulotomy Causing

Fractures of the Scar Capsule and the Silicone Bag of

a Breast Implant, " by Addington and Mallin and

" Distant Migration of Silicone Gel from a Ruptured

Breast Implant " by Capozzi, DuBou and Pennisi.

[9] MEP 69483-84 and MEG 5026-5027, citing Baker,

Bartels, and , Closed Compression Technique For

Rupturing A Contracted Capsule Around A Breast

Implant. ( 3/16/94, Vol. 7, p. 188,11)

[10] Lynch MDL Depo Vol. 8, p. 1891,8-1892,25.

[11] MEP 69553 and MEP 67762

[12] MEJ36566 at 368 and 369

[13] Letter at 120

[14] Dorland's Illustrated Medical Dictionary. W.B.

Saunders Co.:

Philadelphia, p. 1208.

[15] Doll, R.: Mortality from lung cancer in asbestos

workers. Br. J. Ind. Med. 2:81-86, 1955

[16] Hueper, W.C.: Occupational Tumors and Allied

Disease. C. : Springfield, IL, pp.

399-405, 1942 Hueper, W.C.: Cancer in its relation to

occupation and environment. Bull. Am. Soc. Control

Cancer 25:63-69, 1943

[17] Sox, H.C., Blatt, M.A., Higgins, M.C., ,

K.I.: Medical Decision Making. Butterworth-Heinemann:

Boston, pp. 33-34, 1988 (Tab 9).

[18] Id., p. 33.

[19] Id., p. 34.

[20] Id. p. 34.

[21] Id. p. 34.

[22] Levy, B. S., Wegman, D.H.: Occupational Health:

Recognizing and Preventing Work-Related Disease.

Little Brown and Company: Boston, p. 29, 1988

[23] Congress of the United States, Office of

Technology Assessment. Alternatives to animal use in

research, testing, and education. Marcel Dekker: New

York, New York, 1988.

[24] Physician's Desk Reference, supra.

[25] Schwartz, S.I., Lillehei, R.C., Shires, G.T.,

Spencer, F.C., Storer, E.H.: Principles of Surgery.

McGraw-Hill: New York, p. 1682, 1974.

[26] Kasdan, M.L., , J.H.: Hand infections seen

in the industrial clinic. Occ. Med. SOA Rev.

4(3):463-471, 1989, p. 469

[27] Id., p. 470.=20

[28] Hogan, D.J., Tanglertsampan, C.: The less common

occupational dermatoses. Occ. Med. SOA Rev.

7(3):385-401, 1992, p. 388 .

[29] Id., p. 389.=20

[30] Id., p. 389.=20

[31] Fleming, L.E., Ducatman, A.M., Shalat, S.L.:

Disease clusters: a central and ongoing role in

occupational health. J. cc. Med. 33(7):818-25, 1991.

[32] Id., p. 818.

[33] Miettinen, O.S., supra., p. 3-4.

[34] Id., p. 107.

[35] Rothman, K.J. supra., pp. 16-20 .

[36] Lanes, S. F.: Error and uncertainty in causal

inference. In Causal Inference, supra., pp. 182-183 .

[37] Weed, D.L.: Causal criteria and Popperian

refutation. In K.J. Rothman: Causal Inference.

Epidemiology Resources Inc.: Chestnut Hill, pp. 15-32,

p. 17, 1988.=20

[38] Lanes, S.F., Poole, C.: Truth in packaging? The

unwrapping of hepidemiologic research. J. Occ. Med.

26(8):571-574, p. 572-3, 1984.

[39] , A.,DVM: Carcinogen Testing, Fact and

Fallacy, Cancer 62: 1688-1690, 00/00/88=20

[40] Hill, A.B.: The environment and disease:

Association or causation? Proc. Roy. Soc. Med.

58(5):295-300, p. 299, 1965.

[41] Id., p. 300.

[42] References relate to silicone elastomere/gel

implants only and are meant as representative of the

general medical literature.

[43] s et al, Ann. Plas Surg., Vol 32, Number1,

January 1994: 1-7

[44] Kossovsky,Nir, M.D.,, Heggers,,P, Ph.D.,,

Parsons,,P, M.D., and Robson,,C, M.D.:

Anaysis of the Surface Morphology of Recovered

Silicone Mammary Prostheses, Plastic And

Reconstructive Surgery : 795-803, 06/16/82

[45] Liau, Merry,Ito, S.,Koren, Gideon, MD: Letter to

the Editor -

Sclerodermalike Esophageal Disease in Children of

Mothers with Silicone Breast Implants, JAMA 272, 10:

769-769, 09/14/94

[46] fleiderer,Bettina,Garrido,Leoncio: Migration and

Accumulation of Silicone in the Liver of Women with

Silicone Gel-Filled Breast Implants, Magnetic

Resonance in Medicine 33: 8-17, 01/95

[47] 2228 Wolf et al

[48] Cuellar ,Espinoza ,Ochs ,Tan: Development of

Monoclonal Gammopathy and Hypergamma-Globulinemia

Silicone Breast Implant (SBI) Women after Long-Term

Exposure, National Scientific Meeting- CA : 13-14,

1995

[49] Lake and Radonovich: Action of

Polydimethylsiloxanes on the Reticuloendothelial

System of Mice: Basic Cellular Interactions and

Structure Activity Relationships Causal Interference

In Syndromes Associated With Silicone Breast Implants:

Psychogenic and Environmental Factors, Dow Corning

Corporation : -, October 30

[50] Naim, O.,Lanzafame, J.,van Oss,

Carel J.: The Adjuvant Effect of Silicone-gel on

Antibody Formation In Rats, Immunological

Investigations 22, 2: 151-161, 00/00/93

[51] Naim ,Lanzafame ,Oss: The Effect of Molecular

Weight and Gel Preparation at Humoral Adjuvancy on

Silicone Oils and Silicone Gels, Immunologic

Investigations 24: 537-547, 1995

[52] Nicholson J., G.Wong, C. Frondoza, N. Rose:

Silicone Gel and Octamethylcyclotetrasiloxane

Potentiate Antibody Production to Bovine Serum Albumin

in Mice, In Immunology of Silicone : 139-144

[53] Hueper, W.C.: Experimental Producion of Cancer by

Means of Implanted Polyurethane Plastic, American

Journal of Clinical Pathology 34,4: 328-333, 10/04/60

[54] Hueper, W.C.: Cancer Induction by Polyurethane

and Polysilicone Plastics, JOURNAL OF NATIONAL CANCER

INSTITUTE 33: 1005-1027, 00/00/64

[55] Jovanovic- L, Sparks S, Plamer JP, CM

. Jet injected insulin is associated with

decreased antibody production and postprandial glucose

variability when compared with needle-injected insulin

in gestational diabetic women. Diabetes Care.

1993;16:1479-1484.

[55] Kossovsky N, Gelman A, Hnat6ysyn J, et al.

Adjuvant effect of silicone on the formation of

anti-insulin and anti-fibronection antibodies. ACR

abstract. 1984; 668.

[55] Leong, A, Disney A, B Gove. Retractile particles

in liver of haemodialysis patients. Lancet. 1981; 1:

889-890.

[55] RS Lake, MF Radonvich, for Dow Corning. Action of

polydimethoysiloxanes on the reticoloendothelial

system of mice: basic cellular interactions and

structure-activity relationships. Dow Corning

Corporation Research Department. 1975: 10030;4509.

[56] Picture courtesy of Jerrold Abraham MD

[57] Chang, Yi-Han,Pearson, Carl M.,Abe, Chiyuki:

Adjuvant Polyarthritis, IV. Induction by a Synthetic

Adjuvant: Immunologic, Histopathologic, and Other

Studies, ARTHRITIS AND RHEUMATISM 23, 1: 62-71,

01/00/80

[58] Haustein, U.F., MD,Ziegler, V., MD,Hermann et

al.: Silica-Induced Scleroderma, Journal of the

American Academy of Dermatology 22,3: 444-448, March

1990

[59] Leong, ASY, MD: Pathologic Findings in Silicone

Spallation: Autopsy and Biopsy Studies, ls Academy

of Medicine 12, 2: 304-310, 04/00/83

[60] Goldblum, Randall M.,Pelley, P.,O'Donell,

Alice A.,Pyron, Debra,Heggers, P.: Antibodies to

Silicone Elastomers and Reactions To

Ventriculoperitoneal Shunts, THE LANCET 340: 510-513,

08/29/92

[61] Christ, E.,MD,Askew, J.B., MD: Case Report -

Silicone Granuloma of the Penis, PLASTIC AND

RECONSTRUCTIVE SURGERY 69, 2: 337-339, 02/00/82

[62] Borenstein, , MD: Siliconosis: A Spectrum Of

Illness, Seminars In Arthritis and Rheumatism 24, 1

supp: 1-7, 08/00/94

[63] Field,T.Bridges,A.J.: Clinical and laboratory

features of patients with scleroderma and silicone

implants, Curr.Top.Microbiol.Immunol. 210: 283-290,

1996

[64] Fock, K.M.,Feng, P.H.,Tey, B.H.: Case Report -

Autoimmune Disease Developing After Augmentation

Mammoplasty: Report of 3 Cases, THE JOURNAL OF

RHEUMATOLOGY 11, 1: 98-100, 00/00/84

[65] Kumagai, Yasuo,Shiokawa, Yuichi,Medsger,

,Rodnan, Gerald P.: Clinical Spectrum of

Connective Tissue Disease After Cosmetic Surgery,

ARTHRITIS AND RHEUMATISM 27, 1: 1-12, 01/00/84

[66] Spiera, Harry, MD: Scleroderma After Silicone

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[67] MEP 26330

[68] M-17037

[69] MEX 134036

[70] MEI 29533

[71] BMS 56639

[72] MED 26077

[73] BMS 56506.

[74] BMS 37548, May 11, 1990

[75] BMS 37552

[76] MEM 27729

[77] MEO 78967

[78] MEM 10297

[79] MEO 98676

[80] MEI 4239

[81] FDA 3595

[82] MEM 251

[83] MEA 9165

[84] MEJ 24588

[85] BMS 56502

[86] MEG 4625

[87] MEI 148636

[88] MEG 5034

[89] MEI 4231

[90] Draft version, BMS 28282, published version,

Breast Prostheses: A Critical Review, Syzcher et al,

Journal of Biomaterials Applications, V.5, April 1991