TO

THE NATIONAL SCIENCE PANEL

ON SILICONE GEL BREAST IMPLANTS

 

July 21-23, 1997

  VI.             TOXICOLOGY

“That silicone is toxic in both animals and man is well proven.^[1]  From the earliest studies which found silicone toxicity in animals to findings that silicone suppresses natural killer cell activity, causes an activation of complement, generates a specific immune response, causes extensive fibrosis with chronic and granulomatous inflammation, causes immunogenic delayed hypersensitivity granulomas to form, leads to increased liver weight, and demonstrates parental toxicity by a reduction in mean live litter size and reduction in pup viability in Sprague-Dawley rats, the research collectively supports Dr. Sergent’s statement in the Textbook of Rheumatology that silicone is, indeed, toxic to animals and humans.

In this section analyzing the toxicity of silicones, it is difficult and ultimately quite arbitrary to draw lines between the scientific evidence on toxicity with that of its immunological and pathologic effects.  Much of that evidence has already been presented in previous sections and will not be repeated here.  Much like the Dow Corning Medtox^[2] analysis, the toxicology analysis here will focus on the following progression of events:

GEL BLEED, LEAKAGE, RUPTURE

 

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SYSTEMIC MIGRATION

 

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SUBDIVISION OF THE GEL/PARTICULIZATION OF THE ELASTOMER

 

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METABOLISM AND DEGRADATION INTO SILICA AND SILANOLS

 

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ADVERSE FINDINGS OF TOXICITY

 
Among the adverse toxicity findings are the following:

·                      Pathologic evidence of gel bleed and migration; calcification and mineralization; severe, painful capsular contracture; extensive - sometimes massive - angiofibrosis; chronic and granulomatous inflammation characterized by the presence of lymphocytes, eosinophils, mast cells, plasma cells, and giant cells; immunogenic delayed hypersensitivity granulomas; macrophage activation with secretion of cytokines; fat and tissue necrosis; ulcerated skin and skin atrophy; silicone lymphadenopathy; and silicone implant-related synovitis.

·                      Immunologic evidence that silicone is an adjuvant and is immunogenic, findings of abnormal biomarkers including elevated AnA and IgG, suppression of natural killer cell activity, modulation of serum corticosterone levels causing thymic atrophy, and evidence suggestive of plasmacytomas and immune-mediated cancers such as multiple myeloma.

·                      Other toxicity evidence related to silicone breast implants including metabolism and degradation of silicone to silica in vivo, an increase in liver weights, cytotoxicity data, parental toxicity data, and effects on cholesterol levels.

Other toxicity analogies.

Plaintiffs submit that the evidence of toxicity of silicones comes from a variety of diverse yet prolific areas of research which, when viewed collectively, demonstrate that in some women implanted with silicone breast implants there is credible evidence for scientists to reasonably conclude that silicone is not inert and indeed can cause physiological effects within the body.

1.                  HISTORICAL OVERVIEW OF THE TOXICOLOGIC LITERATURE

The Dow Chemical Company conducted the first major research on the toxicological properties of silicone in the 1940s.  The results of their research were published in the seminal article on silicone toxicity by Rowe, Spencer and Bass^[3] They studied two silicone fluid materials of low molecular weight and one of high molecular weight administered orally to rats and guinea pigs over a one-week period.  While the low molecular weight silicone caused a mild inebriation and central nervous system depression, the authors claimed that this one-week study showed that DC 200 fluid is “exceedingly low in oral toxicity” and that silicones are “inert.”

Dow Corning’s Center For Aid To Medical Research extensively promoted the Rowe study and claims of silicone’s inertness to the medical community throughout the 1960s and 1970s.  Dow Corning first manufactured and sold silicone breast implants in the mid 1960s. The published literature, at the time, including numerous references to the Rowe article and to Dow Corning (which cited Rowe) for the proposition that silicones are inert.  The myth of silicone’s inertness flourished in the medical community without any serious consideration of the reported findings in the literature on silicone gel breast implants until the early 1980s.

Unfortunately, overlooked by most persons - although Dow was aware of it  - was the 1952 Cutting article in the Stanford Medical Bulletin reporting “widespread” toxic manifestations in rabbits fed a high cholesterol diet containing DC 200 silicone fluid.^[4]  In Cutting’s study, nearly all of the 10 rabbits showed renal tubular damage and lesions in the kidneys in varying degrees when fed DC 200 silicone in concentrations of one percent for three to four months.  Microscopically, he observed capsular thickening in the spleens with deposits of DC Antifoam A silicone, and, in the kidneys, there was distension of tubular cells and large masses of macrophages between the tubules with a clear amorphous substance.^[5]

Despite Cutting’s findings of toxicity, further long-term toxicological research on silicones and silicone breast implants by the manufacturers was non-existent for some and very limited for others.  Dow Corning was the only manufacturer to have a formal toxicology department, and that was not established until the late 1960s.  The early studies, performed by outside laboratories in the 1960s including understaffing, lack of facilities and persons with expertise to interpret findings, inadequate resources to conduct studies,^[6]

Dow Corning’s Toxicology Department Continued to experience serious problems through the 1980s including understaffing, lack of facilities and persons with expertise to interpret findings, inadequate resources to conduct studies,^[7] and failure to follow GLP’s. For example, in 1989, an independent consulting toxicologist audited Dow Corning’s toxicology program.  The audit revealed serious problems including lack of competent management, lack of familiarity with GLP’s, documentation which was “extremely poor,” a general feeling within the lab ...of chaos,” a department that had “little depth” and no system to “assure either that bad science or poorly thought out procedures...do not get put into place,” “wrong people [who] are making decisions (in some cases the WRONG decision) which impact upon the science being performed,” and a “Dow Corning management style [that] is not conducive to running even an adequate toxicology laboratory.”^[8] The consultant recommended a “complete overhaul” of the department including the hiring of qualified, trained toxicologists and staff to bring the department up to industry standards.  The problems, however, were not corrected and another outside audit in 1994-95 uncovered instances of data falsification in several internal Dow Corning studies.^[9]

Understanding that these issues do not directly assist the Panel in completing its charge, plaintiffs nonetheless note these problems in this submission for several reasons: 1) with the exception of the research conducted by Dr. Bennett’s Bioscience Research Department in the mid 1960s to mid 1970s, much of the internal industry research on which Dr. Brent and the manufacturers rely is of questionable value;^[10] 2) very little toxicological research was conducted on silicones for many years because of the myth that Dow Corning propagated to the medical and scientific community that silicone was inert; and 3) the other manufacturers relied on Dow Corning, as the supplier of the silicone materials used in breast implants, for virtually all safety testing.  Because of the many deficiencies in the internal studies uncovered by outside audits, reliance on many of Dow Corning’s early studies for claims of biocompatibility, such as those made by Dr. Brent before this Panel, is misplaced.