THE CONCEPT OF A NEW DISEASE CAUSED BY SILICONE
IS BIOLOGICALLY PLAUSIBLE AS SILICONE IS NOT INERT
1. Investigation at Dow Corning into use of silicones as pesticides:
in 1968, found that Dow Corning 360 fluid both attracted and killed cockroaches; also repelled mites and mealy bugs; killed and repelled aphids. (Plaintiffs' Exhibit 705)
2. Dow Corning Report, 'Histopathological Findings In Animals of Various Species from Experiments Conducted by Thomas D. Rees", 4/22/68. (Plaintiffs' Exhibit 548)
Silicone injected into various animals produced organ damage including chronic inflammation of liver, kidneys and occasional pancreas and gonad abnormalities seen in mice; similar but less prevalent organ damage in rats; and liver abnormalities and chronic kidney inflammation in guinea pigs. Additionally, holes in cytoplasm of cells commonly observed in all species.
3. Dow Corning Research: Immunological Enhancing Activities of Organosilicon Compounds and non-functional fluids, 10/2/74. (Plaintiffs' Exhibit 120)
Study carried out to determine if certain silicone oils could act as adjuvants in experimental animals. An adjuvant is a chemical that will enhance or prolong the immune response when given mixed with a foreign protein (antigen). Study concluded that nine of the forty-nine adjuvants tested showe6 adjuvant activity similar to that of known adjuvant (CFA).
CONCLUSION: Silicone oils can act as adjuvants to enhance the antibody response to a standard antigen in experimental animals.
ANIMAL STUDIES SHOW SILICONE INDUCES BIOLOGICAL AND CHEMICAL CHANGES AND IS SYSTEMICALLY DISTRIBUTED
4. "Summary of Histopathological Findings in Primates", 3/21/67 Dow Corning Document. (Plaintiffs' Exhibit 774)
T'welve monkeys injected with silicone fluids in both breasts and left cheek. Animals sacrificed at two years after first injection; findings included holes in cells (vacyated cells) in lungs, cheeks and breasts; abnormal adrenal glands and chronic kidney inflammation. These tests signal potential immunological impact of long term presence of polysiloxane in primate fluids in primates.
5. Structure-Activity Relationships of Oral Organosiloxanes on the Male Reproductive System.
by D.R. Bennett, S.J. Gorzinsid, and J.E. LeBeau. Toxicology and Applied Pharmacology. 21, 55-67 (1972). (Plaintiffs' Exhibit 545)
Oral organosiloxanes depressed male reproductive function in the mouse, rat and rabbit.
6. Local & Systemic Effects of Dimethylpolysiloxane Fluid In Mice
by N.Ben-Hur, M.D., Donald BaBantyne, Jr., Ph.D., Thomas Rees, M.D. and @g Seidman, M.D. Plastic & Reconstructive Surgery. Aprfl 1967. pp.423-426. (Plaintiffs' Exhibit 544)
Mice and rats injected subcutaneously with silicone fluid; on autopsy, silicone found in the vital organs and lymph nodes. Phagocytes ingested silicone fluid and caused granuloma-like lesions; silicone also engulfed by wandering histiocytes and transported to lymph nodes and throughout the reticuloendothelial system to liver, spleen and other organs.
7. Changes In the Lung Following Injections of Silicone Gel
by Marcus Castro Ferreira, M.D., Victor Spina, M.D. and Kyoshi Iriya, M.D. British Journal of Plastic & Reconstructive Surgery. pp.173-176. 1975. (Plaintiffs' Exhibit 546)
Injections of silicone gel in 38 MI. rats produced findings of silicone gels in lungs on autopsy, the result of phagocytosis of the silicone by macrophages, carried to the lungs in blood stream or through lymphatics. Authors conclude that silicone gel behaves like silicone fluid and is not so inert as solid silicone as was previously supposed.
8. Dow Corning Corp Research Dept Report# 3977
Authors: Joseph LeBeau & Stanley J. Gorzinski DMPS fluid (Dow Corning 360 Medical Fluid) distribution and disposition in rats following subcutaneous injection. (Plaintiffs' Exhibit 687)
Dow Corning 360 medical grade silicone administered to rats. With assistance from radioactive labeling, silicone fluid found in expired air, urine and feces as well as in times and organs. Migration of silicone through lymphatic system confirmed.
9. Dow Corning Report # 3323 Project # 464 by Ruth M. Lacefield, et al. Biological Distributions of DMPS. (Plaintiffs' Exhibit 688) Radioactive labeled medical grade 360 fluid traced to determine biological distribution in test animal; silicone found in brain, blood, bile, internal organs.
10. 2, 6-cis-Diphenylhexamethyl - cyclotetrasiloxane Chemistry Analytical Chemistry, Biological Effects and Excretion.
By Bennett, Don R. Aborg, Bertfl. Editors ACTA, Pharmacological et To;dcologir-al. Vol. 36, Supp- III, 1975. (Plaintiffs' Exlubit 553)
2, 6-cis being evaluated as an estrogen by Dow, noted to produce changes in male genital organs of rabbits and dogs. 11. Structure Activity Relationships of Organosiloxanes and the Female Reproductive System. by James F. Hayden & Sue A. Barlow. To7dcology and Applied Pharmacology. Vol.21, 1972 pp.68-79. (Plaintiffs' Exhibit 689) 2, 6-cis is biologically active in the female rat and produced estrogen-like effect.
12. Investigation of the Toxicologic Properties of a Phenylmethylcyclosiloxane
by R.J. Palazzolo et al. Toxicology and Applied Pharmacology. Vol.21, 1972. pp.15-28. (Plaintiffs' Exhibit 691) Experiments by oral ingestion and by skin applications on various species showed silicone material to be biologically active by mouth in monkeys leading to testicular atrophy and decrease or absence of seminal fluid.
13. Peritoneal Response To Silicone Fluid. A Histologic Study
Brody, Gerald L., M.D. and Frey, Charles F., M.D. Arch Surg. Vol. 96, February 1968, PP 237-241. (Plaintiffs' Exhibit 586)
Injection of silicone fluid into rats produced histiocytic granulomas. Fact that granulomas exist and that silicone is transported to draining lymph nodes indicates that silicone is not inert.
14. Biocompatibility of Silicone Implants
by Heggers, John P. Ph.D., et al., Reprinted Annals of Plastic Surgery. Vol. 11, No. 1, July 1983, PP 37. (Plaintiffs' Exhibit 592)
Silicone is capable of eliciting a cellular immune response. This may indicate that silicone acts like an incomplete antigen. THE IMMUNE RESPONSE TO SILICONE: FROM THE ANIMAL MODEL TO THE HUMAN
15. The Adjuvant Effect Of Silicone-Gel On Antibody Formation In Rats
by Naim, John 0. Lanzafame, Raymond J. Oss, Carl J. The University of Rochester School of Medicine and Dentistry, Rochester, New York. (Plainiffs' Exhibit 604)
Silicone gel is a potent, immunological adjuvant and may also be able to mediate an auto- immune reaction.
16. The Effect of Silicone Gel on the Immune Response
by Naim, John 0. Lanzafame, Raymond J. Oss, Car] J. Journal of Biomaterials Science accepted 2/10/94.
Silicone gel is capable of eliciting auto-antibodies in the series of animal experiments; silicone gel from McGhan commercial breast implant behaves both as a potent humoral adjuvant and relatively weak cellular-mediated immunity adjuvant. Silicone gel also capable of inducing auto-antibodies in the rat. THE IMMUNE RESPONSE IN HUMANS FROM SILICONE
17. Antibodies To Silicone Elastomers and Reactions To Ventriculoperitoneal Shunts.
Goldblum, Randall M. Ronald P., et al., The Lancet, Vol. 340: August 29, 1992. PP 510-513. (Plantiffs' Exhibit 595)
Severe immune reactions seen in patients with silicone elastomer (shunts).
18. "Antinuclear Autoantibodies In Women with Silicone Breast Implants"\
11/28/92, Press RI et al. Lancet 340: pp.1304-1307.
Antinuclear Autoantibodies (ANAS) found in women with silicone breast implants; some of the ANAs similar to those found in idiopathic auto-immune disorders but some other putative antigens could not be identified and may represent novel auto-antibody/autoantigen systems.
19. "A Clinical and Immunologic Evaluation of Women with SBI and Symptoms of Rheumatic Disease".
6/15/1993 Bridges A.B et al. Annals Int. Med. 118 (12): 929-936.
Physical exams and lab work conducted on 156 women with silicone breast implants and rheumatic disease complaints; controls for lab studies were 12 women with silicone implants and no rheumatic symptoms and 174 with fibromyalgia without silicone implants. Findings suggest that most women with SBI and rheumatic disease symptoms do not have classical connective tissue diseases; however possibility that atypical auto-immune illness, may be associated with silicone exposure in small number of women exists.
20. Immunopathologic Effects of Silicone Breast Implants
Suzanne S. Teuber, M.D., Steven H. Yoshida, Ph.D. and Eric Gershwin, M.D. Western Journal of Medicine, Vol.162, No.5, May 1995. pp.418-425. (Plaintiffs' Exhibit 516)
This review of studies on silicone and immunity concluded that silicones are neither biologically nor chemically inert and that there is clinical and theoretical reason for concern. AUTHORS COMMENT ON IACK OF POWER SUFFICIENT FOR STUDIES TO BE CONSIDERED DEFINITIVE OF ENGLERT SCLERODERMA STUDY FROM AUSTRALIA AND MAYO CLINIC STUDY.
21. Immunological Reactions to Silicone Implants: Risk and Management.
Robert F. Spiera, et al. Clinic Immunother 1 (6) 1994, pp.406-411. (Plaintiffs' Exhibit 517)
Scleroderma-like illnesses are markedly over-represented in women with silicone implants and identifiable connective tissue disease, mimicking the earlier reported Japanese experience with injectable silicones. Although authors clinically recommend to their patients removal of implants if symptomatic, some patients with scleroderma-like illness may have a progression of disease and even death despite explantation perhaps due to migration of silicone distantly in the host and the consequent inability to remove the substance entirely. Exposure may thus initiate a self- perpetuating disease process no longer requiring the presence of the initial silicone stimulus.
22. "Surface Dependent Antigens Identified by High Binding Affinity of Serum Antibodies in a Subpopulation of Patients with Breast Prosthesis".
12/93 Kossovsky, Nir et al. Journal of Applied Biomaterials 4 (33): pp.1-8. (Plaintiffs' Exhibit 538) Silicones found to function as human adjuvants by denaturing native macromolecules. Hypothesis tested by two assays of sera from three groups: 249 with SBI, 47 non-implanted age-matched healthy women; 39 non-implanted women with various known rheumatological diseases. Conclusion is that silicone may function as an adjuvant by inducing changes in the confirmation of native molecules.
23. Silicon and Silicones Theoretical and Clinical Implications of Breast Implants.
by Steven H. Yoshida et al. in Regulatory Toxicology and Pharmacology. Vol.17, 1993, pp.3-18. Authors review the element silicon, the chemistry of silicone, the immunogenicity of silicone, and the know biological functions of silicone to demonstrate how silicone might promote auto-immune disease in pre-disposed individuals. Review of case reports of 27 people with immunological reactions as well as literature on silicone exposures in animal studies leads authors to conclude that silicone can generate inflammatory and immune responses despite its long standing and incorrect representation as a chemically and biologically inert substance. SOLID, SCIENTIFICALLY VALID LABORATORY DATA DEMONSTRATE THE DISEASE
24. Autoantibodies In Patients with Silicone Breast Implants.
by Alan J. Bridges. Seminars in Arthritis & Rheumatism, Vol.24, No.1, Supp.1, Aug. 1994, pp.54-60. (Plaintiffs' Exhibit 488)
Review of literature as well as 1992 American College of Rheumatology abstracts from annual meeting show differences in the clinical and serological features of patients with connective tissue disease associated with silicone implants compared with patients with idiopathic connective tissue disease. A DEFINITIVE EPIDEMIOLOGICAL STUDY TO DETECT REIATIONSHIP BETWEEN SILICONE IMPLANTS AND CONNECTIVE TISSUE DISEASE MAY NEVER BE ABLE TO BE PERFORMED BECAUSE OF THE LONG LATENCY PERIOD AND THE RARUY OF CONNECTIVE TISSUE DISEASES. THUS, A STUDY OF CLINICAL AND SEROLOGICAL FEATURES OF PATIENTS WITH IMPLANTS WHO DEVELOPED DISEASE BECOMES PARTICULARLY IMPORTANT.
25. Multiple Autoantibodies In Patients with Silicone Breast Implants,
E. Bar-Meir, S.S. Teuber, et al. Journal of Autoimmunity, 8, 1995, pp.267-277. (Plaintiffs' Exhibit 509) Sera from 250 patients tested blindly (116 women with SBI and 134 controls) to analyze twenty auto-antibodies. Chief complaints of implanted patient group included polyarthralgias, fatigue, myalgias, morning stiffness and decreased memory. Statistically significant greater frequency of auto-antibodies in women with implants for fifteen of the twenty auto-antigens. The association of auto- antibodies in implants suggests an adjuvant action of silicon/silicone by- products.
26. Detection of Lymphocyte Simulation by Silicon Dioxide,
by David L. Smalley, Douglas R. Shanklin, Mary F. Hall and Michael V. Stevens in International Journal of Occupational Medicine and Toxicology Vol. 4, No.1, pp.63-70. (Plaintiffs' Exhibit 594)
In the continuing work investigating the immune response to silicone, the authors adapted standard mitogen testing which demonstrated cell-mediated immune responses of T-lymphocytes to purified silicon dioxide or silica in the implanted patients. These test were run on 50 symptomatic patients with SBI and 50 normal age matched female controls without implants or symptoms. T-lymphocytes were harvested from each group. This test method distinguishes the immune disorders found in mammary implant patients due to sensitization to silicon dioxide (silica) from other altered immune disorders unrelated to implants.
27. Quantitative Aspects of Cellular Responses to Silicone
by Douglas R. Shanklin and David L. Smalley, International Journal of Occupational Medicine and Toxicology Vol. 4, No.1, 1995 pp.99-111. (Plaintiffs' Exhibit 762)
A study of pathology slides from 100 consecutive but random patient consultations and mammary capsular tissue surrounding which had surrounded SBI. Cellular responses occur in women with mammary, as seen in histopathological examination. Lymphocytic response with resulting formation of granulomas and macrophages.
28. Immunologic Markers In Silicone Breast Implant Recipients,
by David Smalley, Mary F. Hall, Douglas R. Shanklin and NCchael Stevens in International Journal of Occupational Medicine and Toxicology Vol. 4, No. 1, 1995 pp.147-153. (Plaintiffs' Exhibit 763)
The presence of various autoantibodies and the significant number of symptomatic implantation is taken as evidence for a range Atypical Immune responsiveness consistent with a primary cellular immune response. The name - silicone associated disease - is understood as an inclusive term fota new form of autoimmunity caused by an alien material (silicones and related substances) which mimic known and better defined autoimmune diseases.
29. Immunologic Stimulation of T-lymphocytes by Silica After Use of Silicone Implants.
by David L. Smalley, Douglas R. Shanklin, Mazy F. Hall, Michael V. Stevens and Aram Hanissian. The FASEB Journal, Vol. 9, Mar. 1995, pp.424-427. (Plaintiffs' Exhibit 504)
Standard lymphocyte stimulation test performed on 70 implant patients, 76 normal controls without implants or symptoms, and 18 patients with classic rheumatic disorders without a history of SBI. Lymphocytes harvested from all groups. Results show implant patients with increased stimulation index compared to controls in those with rheumatic disorders. Follow-up study with 220 normal controls, no SBI, 942 implants with symptoms, and 34 implant patients without symptoms. CONCLUSION: Silicone Implant patients respond immunologically to the silicone dioxide (silica) contained in mammary prostheses.
30. Affidavit of Douglas R. Shanklin, M.D. (Plaintiffs' Exhibit 764) Dr. Shanklin, a Board Certified pathologist, discusses the six independent reports by six independent labs, each documenting silcone/silica memory T- Lymphocytes.
31. Curriculum Vitae of Douglas R. Shanklin, M.D. (Plaintiffs' Exhibit 765)
32. Affidavit of Donard S. Dwyer, Ph.D. (Plaintiffs' Exhibit 766) Dr. Dwyer, former Director of Immunology at Procept (owned by Bristol-Myers Squibb), managed the research program on T-cell receptors funded by Bristol- Myers Squibb, a former manufacturer of silicone breast implants. The Smalley/Shanklin laboratory data was evaluated by Dr. Dwyer and found to be based on the standard and acceptable method for measuring T-cell proliferation which has been reproduced and is consistent in the Procept laboratory. Thus, the conclusions that patients with SBI have a T-cell mediated Immune response to silicon dioxide (silica) is justified.
33. Curriculum Vitae Donard S. Dwyer, Ph.d. ((Plaintiffs' Exhibit 767)
34. Antinuclear Antibodies in Breast Implant Patients are Exposure- Duration Dependent But Not Age Dependent. Robert Ira Lewy, M.D., FACP; Edward Ezraffson, Ph.D. Departments of Medicine, Baylor College of Medicine and University of Texas Health Science Center of Houston, Houston, TX. Immunology of Silicones Workshop. March 13-14, 1995. National Institute of Health, M.D. (Plaintiffs' Exhibit 495)
35. Autoantibodies In Sera from Patients with L-Tryptophan-Associated Eosinophilia-Myalgia Syndrome. by Leed D. Kaufman, John Varga, Juan J. Gomez-Reino, Sergio Jimenez, and Iran N. Targoff, Clinical Immunology and Immunopathology, Vol.76, No.2, August, pp.115-119, 1995. (Plaintiffs' Exhibit 508) Study found unique auto-antibodies in sera from patients with EMS (Eosinophilia-Myalgia Syndrome) associated with exposure of L-Tryptophan. These auto-antibodies were clearly distinct from the aut-antibodies commonly recognized in systemic auto-immune conditions.
36. Silicone Breast Implants: Immunotoxic and Epidemiologic Issues. by Steven H. Yoshida, Shanna Swan, Suzanne Teuber and M. Eric Gershwin, Life Sciences Vol. 56, No. 16, pp.1299-1310, 1995. (Plaintiffs' Exhibit 695) Discussion of adverse immune effects from silicone from literature analysis including local responses in animals, systemic responses in animals, inflammatory responses in humans and autoimmune disease in humans. Discussion of limitations of epidemiological studies of silicone related diseases to date, including Mayo Clinic Study, Wells and Englert.
37. Repeated Exposure to Silicone Gel
Can Induce Delayed Hypersensitivity. Phillip P. Narini, M.D., et al. Plastic &
Reconstructive Surgery, Vol.96, No.2. August 1995. pp.371-380. (Plaintiffs' Exhibit 519) Study performed to investigate
a possible cell-mediated immune response to silicone gel. Authors demonstrated an antigen-specific lymphocyte-mediated
response in the animals primed only with silicone gel. A delayed type hypersensitivity to silicone gel was induced.
38. Antinuclear Antibodies and Breast Implants. Henry Claman, M.D. and Alastair D. Robertson, Ph.D. The Western Journal of Medicine. Vol. 160, No.3. March 1994. pp.225-228. (Plaintiffs' Exhibit 513) Antinuclear antibodies tested in the sera of four groups of women. Four groups studied: Group 0 = 19 women without SBI, healthy; Group I = 38 women with SBI, healthy and pleased with implants; Group II = 82 women with SBI with various symptoms but no definite diagnosis of autoimmune connective tissue disease; Group III= 11 women with SBI with overt connective tissue diseases. Results: no positive ANA tests in Group 0. Significant positive ANA tests in higher than expected frequency (18%) of Group I women, healthy women with SBI. Many women have a variety of complaints and also have positive ANA tests (26%). In women with breast implants with later connective tissue disease, scleroderma was far more prevalent than rheumatoid arthritis or SLE.
39. Self-Reported Signs & Symptoms In Breast Implant Patients with Novel Antibodies to Silicone Surface Associated Antigens [anti-SSAA(x)]. Nir Kossovsky, Journal of Applied Biomaterials, Vol.6, 1995, pp.153-160. (Plaintiffs' Exhibit 520) Previous sera studies that had shown statistically significant levels of antibodies to Silicone Surface Association Antigens were correlated to symptoms by clinical survey sent to sera positive SBI women. Results showed statistically significant differences in 3 symptoms of anti-SSAA positive patients.
40. Immune Functional Abnormalities In Patients With Chemical Abnormalities and Silicone Breast Implants. by Campbell, Andrew W., M.D. Vojdani, Aristo, Ph.D., Brautbar, Nachman, M.D. (Plaintiffs' Exhibit 587) Forty patients with SBI and forty healthy sex and age-matched controls selected for study including physical examination, history and laboratory tests. Many immunological abnormalities are found in individuals with SBI; conclusion is mechanism of fime injury causing auto-immune diseases or syndromes.
41. A Pathophysiological Examination of the Biophysics and Bioreactivity of Silicone Breast Implants. by Nir Kossovsky and John Stassi. Seminars in Arthritis & Rheumatism, Vol.24, No.1, Supp.1, Aug. 1994, pp.18-21. (Plaintiffs' Exhibit 573) Biological responses to implanted silicone are initiated by surface adsorption of native proteins to the implant. Proteins then undergo conformational changes and denature on complexing silicone. Bioreactivity is thus surface dependant and affected by characteristics such as surface area, shape, charge in chemistry. Biological response occurs with possible immunological activation.
42. Silicone Toxicology, by Harris Busch. Seminars in Arthritis & Rheumatism, Vol.24, No.1, Supp.1, Aug. 1994, pp.11-17. (Plaintiffs' Exhibit 572) Silicone is not inert; silicone and/or the multiple chemical contaminants within elicit foreign body reactions associated with granulomatous inflammation and fibrosis and have potential for significant toxicity in the implanted recipient.
43. Abstracts and Presentations from the Workshop on Immunologies of Silicones Sponsored by National Institute for Health, NCI and DCBDC held March 13, 1995. (Plaintiffs' Exhibit 772)
44. Silicone-Specific Blood Lymphocyte Response in Women with Silicone Breast Implants, by Emmanuel A. Ojo-Amaize, Victor Conte, Hun-Chi Lin, Robert Brocker, Milcon Agopian and James Peter. COIN. Giagn Lab. Immunol. Nov. 1994, pp. 689-695. Vol. 1, No.6. (Plaintiffs' Exhibit 621) Blinded cross-sectional study with 99 women, 44 with SBI. SBI group divided into asymptomatic, symptomatic and implanted women and symptomatic explanted women. Control was 55 healthy volunteer women without SBI. Conclusion: Silicon specific T-cell responses observed in twice as many symptomatic as asymptomatic women exposed to SBI, sugggesting cell mediated immunogenicity plays a role In the development of abnormal immune reactions associated with silicone. This provides a new apparently specific screening blood test.
45. Human Immune Response to Polydimethylsilaxe (silicone): Screening Studies in a Breast Implant Population. Wolf, Lappe, Peterson and Ezrailson. Vol. 7, Oct. 1993, FASBE Journal, pp. 1265-1268. (Plaintiffs' Exhibit 622) THE BIOLOGICAL PIAUSIBILITY OF A SILICONE ASSOCIATED DISORDER: SILICA EXPOSURE AND AUTO-IMMUNE DISEASES 46. Portions of Lot History from 3M Implants - Lot # S04-19747 implanted in Mildred Merlin showing silica as component material.
47. Report from the Instructional Course of the Int'l Society of Aesthetic Plastic Surgery, Uppsala, Sweden, March 16-18, 1993. in Memorandum from Curt Sahlgren, 3M Sweden to: Bruno Lowinger, 3M Europe. March 18, 1983. (Plaintiffs' Exhibit 483) 3M acknowledges that recent investigations have shown that gel bleed from an intact implant leaves "...particles of elemental silica and organic silicone within the systemic organism of the body with not yet known adverse effects."
48. Adjuvant Effects of Amorphous Silica on the Immune Response to Various Antigens in Guinea Pigs., by D. Mancino and N. Bevilacqua Int. ARchs. Allergy appl. Immun. S31 97-103 (1977). (Plaintiffs' Exhibit 480) Amorphous silica is able to enhance the humoral immune response to various antigens, widely differing in molecular weight. Silica has been shown to influence the immune response with either depressive or stimulators effects depending on the type and amount of substance used.
49. Pathological Effects of Inhaledled Amorphous Silicas in Animals, by David H. Groth, M.D., Choudari Kommieni, D.V.M., Ph.D., William J. Moorman, Lloyd E. Stettler, Ph.D., William D. Wagner. Presented at ASTM International Symposium on Health Effects of Synthetic Silica Particulates, Torremolinos, Spain 6 November 1979. (Plaintiffs' Exhibit 479) Exposure by inhalation to monkeys of amorphous, fumed silica produced findings of large quantities of silica in macrophages in lungs and tracheal lymph nodes of monkeys and early nodular fibrosis in the lungs of monkeys.
50. The Biological Action of Degussa Submicron Amorphous Silica Dust (Dow Corning Silica). Inhalation Studies on Rats. by Gerrit Schepers, M.D., D.Sc., Thomas M. Durkan, M.E., Anthony B. Delahant; Francis T. Creedon AMA ARCH. of IND. Health. Vol.16. Aug. 1957. pp.125-146. (Plaintiffs' Exhibit 484) Inhalation studies on rats exposed to amorphous silica dust from Dow Corning silica died from pulmonary vascular obstruction coupled with pulmonary insufficiency and emphysema.
51. Myoflbroblasts and Free Silicon Around Breast Implants. by Ross Rudolph, MD Jerrold Abraham, M.D., Thomas Vecchione, M.D., Steven Guber, M.D. and Marilyn Woodward. Plastic And Reconstructive Surgery. Vol.62. No.2. Aug. 1978. pp.185-196. (Plaintiffs' Exhibit 485) Breast tissue and capsules (scar tissue) explanted from women during explantation surgery revealed presence of the element silicon via scanning electron microscopic technique. Such a technique cannot identify silica. Such a technique must be developed because silica in tissue can cause silicosis, a fibrotic disease.
52. The Association of Progressive Systemic Sclerosis (Scleroderma) with Coal Miner's Pneumoconiosis & other Forms of Silicosis. Gerald Rodnan, M.D. et al. Annals of Internal Medicine. Vol. 66, No.2 February 1967, pp.323- 334. (Plaintiffs' Exhibit 602) Silica exposure is a hazard of coal mining; the authors describe an association of progressive systemic sclerosis (scleroderma) within coal miners or in other occupations marked by heavy exposure to silica dust
53. Health Effects of Synthetic Silica Particulates. A Symposium sponsored by ASTM Committee E-34 on Occupational Health and Safety and the Industrial Health Foundation Benalmadena-Costa (Torremolinos), Spain 5-6 No. 1979. ASTM STP 732. D.D. DUNNOM, Ed., American Society for Testing and Materials, 1981, pp.82-93. (Plaintiffs' Exhibit 478) Chapter by Robert Burrell "Immunological Aspects of Silica".
54. Effects of a Crystalline Silica on Antibody Production to T-Dependent and T-Independent Antigens In Balb/c mice. by D. Mancino, M.L. Viotte, M. Minucci. Int. ARchs Allergy appl. Immun. 73:10-13 (1984). (Plaintiffs' Exhibit 481)
55. Adjuvant Effects of Silica (Tridymite) on Antibody Production, by Benvenuto Pernis and Florenzo Paronetto (Introduced by Hans Popper). Dept of Experimental Pathology, Institute of Industrial Medicine, University of Milan, Italy. Received 12 April, 1962. PSEBM, 1962, v.110. (Plaintiffs' Exhibit 482)
56. Endothelial Metaplasia of the Alveolar Capillaries In Experimental Silicosis of Rats. by Mochimura H., Kawanami O., Kudoh S., Niitani H. Japanese Journal of Thoracic Diseases. 33(3):268-74, 1995 Mar. (Plaintiffs' Exhibit 672) Silicosis induced in rats by administration of silica particles.
57. Mortality Study of Gold Miners Exposed to Silica and Nonasbestiform Amphibole Minerals: An Update with 14 More Years of Follow-up. by Steenland K, and Brown D. American Journal of Industrial Medicine. 27(2): 217-29, 1995 Feb. (Plaintiffs' Exhibit 673) Follow-up study of over 3,000 gold miners reveals significant excesses of arthritis, muscular skeletal diseases including systemic lupus and sclerosis and skin conditions including scleroderma and lupus, all diseases of auto- immune origin which have been associated with silica exposure.
58. Silicosis in Brazilian pit diggers: relationship between dust exposure and radiologic findings. by Holanda NM, Holanda NM, Martins MP., Felismino PH., and Pinheiro VG. American Journal of Industrial Medicine. 27(3):367- 78, 1995 Mar. (Plaintiffs' Exhibit 674)
59. Detection of anti-topoisomerase I antibodies using a full length human topoisomerase I recombinant protein purified from baculovirus expression system. by Whyte J., Earnshaw WC., Champoux JJ., Parker LH., Stewart L., Hall ND., and McHugh NJ. Clinical & Experimental Immunology. 100(2):214-8, 1995 May. (Plaintiffs' Exhibit 675)
60. Occupational silicosis-Ohio, 1989-1994 [published erratum appears in MMWR Morb Mortal Wkly Rept 1995 Apr 28;44(16):325]. by Anonymous. Morbidity & Mortality Weekly Report. 44(4):61-4, 1995 Feb.3. (Plaintiffs' Exhibit 676)
61. Shedding of Silicone Particulates From Inflated Breast Implants. by Alex Vargas, M.D. Plastic & Reconstructive Surgery. Vol.34, No.2. pp.252- 253. Aug. 1979. (Plaintiffs' Exhibit 486) Explantation of a saline implant showed collections of "sand" on the surface; on infrared spectroscopy, demonstrated the silicon-carbon bond.
62. Silica Exposure In Auto-Immune Disease. by Steenland, Kyle, Ph.d. and Goldsmith, David, MSPH, Ph.d. American Journal of Industrial Medicine 28:603-608 (1995). (Plainfiffi' Exhibit 489) Authors summarize the evidence of association of silica exposure to a variety of auto-immune diseases including systemic sclerosis, rheumatoid arthritis, lupus and chronic renal disease. Authors posit the link between silicone exposure and auto-immune disease, and whether silicone breast implants have same causal relationship with auto-immune disease.
63. Silica-Induced Scleroderma, Haustein, Ziegler, Hurrmann. Panel of the American Academy of Dermatology., 1990; 22:444-8 (Plaintiffs' Exhibit 507). CLINICAL EVIDENCE OF A SILICONE RELATED SYSTEMIC DISEASE: CASE REPORTS AND CASE SERIES PUBLISHED IN MEDICAL AND PEER-REVIEWED JOURNALS
64. Silicone in the Liver. Possible Late Effects. By J. Hunt, M.J.G. Farthing, L.R.I. Baker, P.R. Crocker, D.A. Levison. Gut. 1989, 30, 239-242. (Plaintiffs' Exhibit 540) Silicone identified in liver of two patients that had abnormal liver function and liver scarring. 'nese patients had been on dialysis prior to renal transplant and siliconized blood pump insert had liberated silicone into liver.
65. Migration and Chemical Modification of Silicone In Women w/Breast Prostheses. by Lencio Garrido, MRM Vol.31, 1994, pp.328-330. (Plaintiffs' Exhibit 692) NMR (Nuclearmacnetic resonance) spectroscopy performed on women with SBI and 3 without implants revealed silicone and other silicon compounds in both blood and liver of implanted women, whether or not implants were clinically ruptured; however total concentration was lower when implants appear to be intact.
66. Migration and Accumulation of Silicone In the Liver of Women with Silicone Gel-Filled Breast Implants. Bettina Pfleiderer & Leonicio Garrido. Magnetic Resonance in Medicine Jan. 1995 33(l): pp.8-17 (Plainfiffi' Exhibit 664) Authors formed NMR spectroscopy in liver of human volunteers with implants and results clearly reveal presence of silicone in the liver. Prior work by same authors on rat model demonstrated a considerable amount of free silicone migrates from gel-filled implants and that silicone is not chemically inert but undergoes chemical degradation. CONCLUSION: Migration of free material from silicone implants to local and distant sites occurs through lymphatic or hematogenous pathway.
67, Rheumatic Disease Among 1167 Women Reporting Local Implant and Systemic Problems After Breast Implant Surgery. Elizabeth Ann Coleman, R.N.P., Ph.D., et al. Journal of Women's Health, Vol.3, No.3, 1994. pp.165- 177. (Plaintiffs' Exhibit 518) National Cancer Institute (NCI) investigators contacted 1,167 women who had had breast implant surgery and who had reported local implant or systemic problems to the FDA. Out of the 820 women interviewed, statistically significant associations that were found included breast implant type with scleroderma, breast implant manufacturer with systemic lupus.
68. Siliconosis: A Spectrum of Illness, by David Borenstein. Seminars in Arthritis & Rheumatism, Vol.24, No.1, Supp.1, Aug. 1994, pp.1-7. (Plaintiffs' Exhibit 632) This, and ensuing papers published in Seminars in Arthritis and Rheumatism, emanated from a symposium held in 1992 at George Washington University Medical Center. Information reported at the symposium presented initial data supporting the notion that patients with exposure to silicone gel are experiencing a new illness, previously described as "human adjuvant disease" or chronic silicone arthropathy. Symposium presenters used terms such as siliconosis or silicone implant syndrome. Conclusion: Siliconosis is a musculoskeletal pain syndrome characterized by overwhelming fatigue, arthraigias and myalgias. Additionally, alopecia, fever, sleep disturbances, Sjogren's-like Syndrome, lymphadenopathy and arthritis have also been identified.
69. Clinical Findings In Symptomatic Women with Silicone Breast Implants. by Frank B. Vasey, Deborah L. Havice, Thomas S. Boranegra, Mitchel J. Seleznick, Paul H. Bridgeford, Pindaro Martinex-Osuna, and Luis R. Espinoza. Seminars in Arthritis & Rheumatism, Vol.24, No.1, Supp.1, Aug. 1994, pp.22- 28. (Plaintiffs' Exhibit 633) Fifty women seen in clinic between 1977 and 1991 with SBI were followed. The most common clinical findings included chronic fatigue, muscle pain, joint pain, joint swelling and lymphadenopathy. 33 women underwent explantation: 24 of them improved clinically, 8 did not change and one worsened. Authors believe that this case series supports the relationship between SBI and rheumatic disease signs and symptoms.
70. A Clinical and Laboratory Profile of Symptomatic Women with Silicone Breast Implants. by Gary Solomon. Seminars in Arthritis & Rheumatism, Vol.24, No.1, Supp.1, Aug. 1994, pp. 29-37. (Plaintiffs' Exhibit 634) 276 patients with SBI evaluated to describe frequency of various symptoms in symptomatic patients. Conclusion: siliconosis Is a novel systemic disease with symptoms of chronic fatigue, cognitive disfunction, sicca syndrome and arthralgia occurring in women with longstanding implants who have antecedent local pathology in the form of capsular contracture and/or implant ruptue.
71. Epidemiology of Silicone Related Disease. by Shanna Swan. Seminars in Arthritis & Rheumatism, Vol.24, No.1, Supp.1, Aug. 1994, pp.38-43. (Plaintiffs' Exhibit 635) Author discusses problems inherent in epidemiology of silicone related diseases, especially due to atypical nature of the disease, which complicates disease definition and renders study of classic disease unlikely to check risks of silicone exposure. The report addresses the most important study design issues -- disease and exposure definitions, bias, confounding and power -- in the context of studies of silicone related disorder.
72. A Profile of Symptomatic Patients with Silicone Breast Implants; A Sjogren's-like Syndr-ome. by Bruce Freundlich, Charles Atman, et al. Seminars in Arthritis & Rheumatism, Vol.24, No.1, Supp.1, Aug. 1994, pp. 44- 53. (Plaintiffs' Exhibit 636) Prospective non-controlled study on first fifty consecutive women with SBI at the Graduate Hospital of Rheumatology revealed the most prominent complaints to be fatigue, generalized stiffness, poor sleep and arthalgias. Other problems included Raynaud's phenomenon, alopecia, adenopathy, night sweats and frequent soar throats. Fifty percent of the women complained of dry eyes and dry mouth. Positive ANA or rheumatoid factors in 38% of patients. Conclusion: Findings indicate the presence of a unique syndrome associated with silicone breast implants characterized by musculoskeletal pain and aut- immune features.
73. Scleroderma After Silicone Augmentation Mammoplasty, by Spiera, H., JAMA 260: 236-238, 198838 (Plaintiffs' Exhibit 773) Case-control study showed a much higher incidence of prior silicone implantation in scleroderma patients when compared with patients with rheumatoid arthritis.
74. Case Report- Scleroderma, Primary Bilary Cirrhosis and Sjogren's Syndrome After Cosmetic Breast Augmentation with Silicone Injections: A Case Report of Possible Human Adjuvant Disease. Y. Okano et al. Annal of the Rheumatic Diseases, 43, pp.520-522, 1984 (Plaintiffs' Exhibit 599) A 52 year old women developed scleroderma, liver disease and sjogren's syndrome after cosmetic injections with silicone.
75. Silicone Implants and Rheumatic Diseases. by John S. Sergent, et al. Textbook of Rheumatology, Update 4. 1993 pp.1-12. (Plaintiffs' Exhibit 623) This chapter in Kelly's Rheumatology discusses silicon, silica and silicones as well as the diseases associated with these materials. That silicone is toxic in both animals and man is well proven, according to author. Author discusses local reactions to silicone implants, lymphadenopathy and granuloma formation and silicone implant related synovitis, the immune reaction in humans to silicone, and the musculoskeletal and rheumatic diseases associated with silicone.
76. Causal Inference In Syndromes Associated with Silicone Breast Implants: Psychogenic and Environmental Factors, by Marc Lappe, International Journal of Occupational Medicine and Toxicology, Vol 4, No.1 1995. pp.165-175. (Plaintiffs' Exhibit 768) Author discusses three hypotheses that could explain the occurrence of illness in silicone gel implanted women and rules out all but the causal hypothesis that silicone is responsible for bonafide systemic, immunological illnesses in some breast implant patients.
77. Silicone-Reactive Disorder, a New Auto-immune Disease Caused by Immunostimulation and Supemntigens, by M.A. Lappe, Medical Hypotheses (1993) 41, 348-352. (Plaintiffs' Exhibit 769) Silicone related illness is a unique disease complex best described as "silicone-reactive disorder. The author supports his theory with five lines of evidence: 1) silicone breast implant components include immunostimulating substances including amorphous fumed silica; 2) silica-stimulated macrophages can induce auto-immune disease; 3) silicone has been shown to provoke antibody production in concert with certain antigens; 4) autoimmune reactions following exposure to superantigens have been associated with a wide range of bacteria; 5) some of these bacteria are found in the silent infections that have been reported in breast implant recipients. CLINICAL METHODOLOGY OF DIAGNOSING A DISEASE AND ITS CAUSE
78. Cecil Textbook of Medicine, 18th Edition, Edited by James Wyngarrden and Lloyd Smith, 1988 W.B. Saunders Co. (Plaintiffs' Exhibit 770) Clinical tests to reach a diagnosis include medical history, chronological events and symptoms to test diagnostic hypotheses, physical examination and laboratory studies. Physician must gather data and interpret data in order to reach diagnosis.
79. Preliminary Criteria for Silicone Related Disease (SSRD), Berkeley Delphic Panel 10/22/95, Consensus Statement on Systemic Silicone Related Disease. (Plaintiffs' Exhibit 771) PRIOR TESTIMONY REGARDING METHODOLOGY IN DIAGNOSIS OF NEW SILICONE RELATED DISORDER AND ITS CAUSE.
81. Testimony of Eric N. Gershwin, M.D., Thiess v. 3M. (Circuit Court State of Oregon, No. 9401-00139), June 8, 1995 page 789/14 - 790/3 page 790/10 - 795/17 page 796/5 - 811/20 page 813/25 - 830/2 Dr. Gershwin, Board Certified in Internal Medicine, Rheumatology and Immunology, a Professor at U.C. Davis for the past twenty years, formerly of NIH, Editor in Chief of Clinic Reviews in Allergy and Immunology, has six to eight articles relating to silicone exposure and disease in peer-reviewed journals, testified in this case against 3M that there is a new, unique disease in which women have a constellation of symptoms that are not ordinarily seen in other circumstances, but which experience has occurred in the past from other exposures such as drugs or environmental agents such as silica. Dr. Gershwin has assembled a bibliography listing over 600 articles about silicone gel and autoimmune disease.
82. CV of Dr. Eric N. Gershwin 83. Excerpts from Trial Testimony of Luis Espinoza, M.D. from case of Brenda Toole v. Baxter Healthcare, Tried before the Honorable Sam C. Pointer, U.S. District Court Northern District of Alabama, January 1995 pp. 1891 - 1922 Dr. Espinoza, a Board Certified Rheumatologist and Professor of Medicine, Chief of Rheumatology, LSU School of Medicine at New Orleans, Board Certified in Internal Medicine, Rheumatology, and Diagnostic Immunology and Laboratory Rheumatology, with 8 published Peer-Reviewed articles relating to the effects of silicone breast implants on women, testified that in the Department of Rheumatology at the LSU Medical School, Dr. Espinoza supervises 5 faculty members, 6 research fellows, 1 clinical fellow in rheumatology, as well as other technicians. There, approximately 3,000 women with silicone breast implants have been seen and evaluated and treated, since 1984. At LSU College of Medicine, the rheumatology department has confirmed that anti-nuclear antibodies system (ANA) is positive in over 50% of women with silicone breast implants, as compared with less that 20% of women in the general population who will show a positive ANA. The conclusion of Dr. Espinoza is that the typical symptom complex that women with silicone breast implants consists of painful muscles, painful joints, debilitating fatigue. In symptomatic women, these symptoms are present in approximately 80-85% of the symptomatic patient population. Other symptoms that are common to women with SBI are skin rashes, telangiectasias which are dilatations of the capillary vessels, commonly seen in patients with connective tissue disease, atypical synovitis, nerve entrapment, and Raynaud's phenomenon.
84. Excerpts of testimony from 2 doctors in the case of Toole v. Baxter before Judge Pointer. (USDC Northern District of Alabama, Southern Div. Cv94-P-13, 5595 - Dr. Gloria Gastone, Dr. Robert Kirwin Schneider. Gloria Gastone: page 1702/14 - 1702/21 page 1707/6 - 170917 page 1714/18 - 1714/25 page 1722/16 - 1724/21 Robert Kerwin Schneider page 1386/9 - 1388/3 page 1390/9 - 1391/10 page 1395/1 - 1399/24 page 1412/18 - 1422/15 page 1451/7 - 1453/3
85. Affidavits From Physicians Attesting to Silicone Related Disease identified, Diagnosed and Treated in Their Patient Population William Bethea, M.D. Lenore Brancato, M.D. Nachman Brautbar, M.D. David E. Burns, M.D. J.D. Doll, M.D. Bruce Freundlich, M.D. Joseph Markenson, M.D. Lige Rushing, M.D. Andrew Solomon, M.D. Gary Solomon, M.D. Phillip Sumner, M.D. Affidavits from other physicians have been promised but have not yet been forwarded to this office for inclusion in this Exhibit List.
86. Curriculum Vitae Shanna Helen Swan, Ph.D.
87. Curriculum Vitae of Arthur Brawer, M.D.
88. CV Mark Lappe, Ph.D.
89. CV David F. Goldsmith, M.S.Ph., Ph.D.
90. Affidavit of Gary Solomon, M.D.
91. Affidavit and Curriculum Vitae of Daniel Wallis, M.D. THE EPIDEMIOLOGY TO DATE.
92. Letters to the Editor, Arthritis and Rheumatism, Vol.38, No.5, May 1995, pp. 719-726., by Robert Spiera in respect to the Sanchez-Gueffeo study. (Plainfiffi' Exhibit 600)
93. Letters to the Editor, Vol. 333, No. 21, England Journal of Medicine, pp. 1423-1424. Nov. 23, 1995. These letters and correspondence concern some of the limitations and problems perceived by other physicians practicing in the field of medicine, rheumatology and internal medicine, concerning the Harvard Study.
94. Affidavit of James R. Jenkins, General Counsel to Dow Corning, sworn to on July 10, 1995 in support of Dow Corning Motion for Summary Judgment against Insurance Carrier to pay, as defense costs, the Dow Corning funding of Medical Research and Epidemiology.
95. Portions of the proceedings on the record before Honorable Robert J. Columbo, Jr., August 11, 1995, State of Michigan, Circuit Court for the County of Wayne. Case No. 93-325-788CK. Dow Corning Corporation v. Hartford Accident Indemny Co., granting Dow Corning's Motion for Summary Judgment on Transamerica's duty to pay all Dow Corning's costs for medical research as defense cost in defense of claims for systemic illness and autoimmune disease caused by silicone breast implants.
96. Letter, Plastic Surgery Educational Foundation (PFES) 8/5/92 to Dr. Sherine Gabriel - PSEF wiU fund 90% of costs of Mayo Clinic Study.
97. Portions of Testimony of R. Barrett Noone, M.D., Vol. 2, Sept. 1994. Re: All PSEF Funding for Epidemiology came from SBI Manufacturers.
98. Letter to the Editor, New England Journal of Medicine, July 8, 1994 from Plaintiffs Steering Committee for MDL-926 concerning and enclosing 1994 research funding to PSEF by manufacturers for "epidemiology research".
99. Dow Corning Bankruptcy Schedule dated 6/30/95 showing all funding for external mammary research studies by Dow Corning.
100. Excerpts from Deposition of Graham Colditz, Ph.D. 1/21/95 In Re: Silicone Breast Implant Product Liability Litigation concerning regarding receipt of Dow Corning money for Harvard Study. Page 11115 - 11/25 Page 13/24 - 14/3 Page 17/10 - 17/18 Page 19/23 - 26/21 Page 49/8 - 50/14 Page 70/18 - 85/12
101. Excerpts of Deposition of Matthew H. Liang, M.D. 1/21/95 In Re: Silicone Breast Implants MDL-926 Page 15/6 - 15/20 23/9 - 24/1 36/23 - 38/4 41/20 - 56/13 64/15 - 69/4 81/12 - 86/21 126/16 - 132/3 141/24 - 142/13 153/19 - 158/10 181/8 - 188/7
102. Excerpts of Deposition Testimony of Pierre Blais, Ph.D. 11/14/95 from the case of Merlin v. 3K Vol.2, pps. 243-252. Dr. Blais is of the opinion that the presence of silica in the McGhan/Merlin implants was a defect (silica is hydrophilic and absorbs lipids to some degree as well as water) and there is no distinction in fact between amorphous silica and the crystalline silica, as amorphous is simply silica that is reduced through a fine state of division although the crystalline structure is the same as crystalline silica. Cite pages 261/19 - 268/8 In addition to platinum, used as a catalyst there are other impurities and additives to the silicone gel. The gel consists of only 80-909'o PUTE silicone and the balance are additives, impurities and such things as D4.
103. Excerpts from Deposition Testimony of Noel Richard Rose, M.D., Ph.d. September 16, 1995 and September 17, 1995 - designated as defense expert immunoligist in case of Merlin v. 3M. page 37/21 - 40/11 page 43/9 - 43/21 page 45/6 - 55/2 page 71/2 - 72/14 page 75/4 - 75/16 page 84/18 - 85/1 page 95/14 - 96/21 page 115/19 - 116/1 page 122/12 - 123/1 page 127/21 - 128/11 page 129/18 - 130/18 page 170/8 - 171/6 VOL. II page 185/17 - 186/5 page 208/14 - 209/14 page 219/4 - 219/8 page 227/7 - 227/17 page 234/14 - 238/8 page 241/3 - 241/13 page 245/2 - 249/2 page 254/18 - 255/2 page 261/14 - 262/1 page 266/11 - 267/18 page 268/19 - 269/1 page 283/13 - 284/7
104. A Rheumatologist's View of Silicone, by Frank B. Vasey, International Journal of Occupational Medicine and Toxicology, Vol.4, No.1 1995, p.203- 209.
105. The Epidemiology of Scleroderma: A Population-based Case-Control Study, Principal Investigator - David Schottenfeld, M.D., University of Michigan, School of Public Health
106. T-Cell Modified Immune Response... by Shanklin & Stevens
107. Connective Tissue Effects..., Abstract by Martin, Edworthy &_______
108. Immunological Aspects of Silica, by Robert Burrell, Health Effects of Synthetic Silica Particulates, ASTM STP 732, American Society for Testing of Materials, 1981, pp.82-93.
109. Mortality Study of Gold Miners Exposed to Silica, by Steenland & Brown (See Exhibit 57.)
110. Silica-Associated Connective Tlssue A Study of 24 Cases, By Anne- Claude Koeger, M.D., Thierry Lang, M.D., Didier Alcaix, M.D., Bernard Milleron, M.D., Sylvie Rozenberg, M.D., Pascal Chaibi, M.D., Josiane Arnaud, D.Pharm, Charles Mayaud, M.D., Jean-Paul Camus, M.D. and Pierre Bourgeois, M.D., Medicine, Vol.74, No.5, September 1995.
111. Photos made from slide presentation testimony of Dr. Arthur Brawer at Merlin
v. 3M Daubert Hearing USDC District of Nevada CV N-95-696HDM on December 11, 1995.