Fw: Several Studies on Silicone

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> 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 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. , 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., BaBantyne, Jr., Ph.D., 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: ph

> 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 , 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 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, 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, P.

> Ph.D., et

> al., Reprinted ls 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, 0. Lanzafame, 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,

> 0.

> Lanzafame, 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. 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. ls 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., H. Yoshida, Ph.D. and 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.

> 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 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

> L.

> Smalley, R. Shanklin, F. Hall and V. s 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

> R.

> Shanklin and 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

>

> Smalley, F. Hall, R. Shanklin and NCchael s 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 L. Smalley, R. Shanklin, Mazy F.

> Hall,

> V. s 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 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 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. Ira Lewy, M.D.,

> FACP;

> 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, Varga,

> J.

> Gomez-Reino, 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

> H. Yoshida, Shanna Swan, Suzanne Teuber and M. 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.

> 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.

> --- End forwarded message ---

>

>

>

[Guest guest]

> 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 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. , 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., BaBantyne, Jr., Ph.D., 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: ph

> 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 , 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 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, 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, P.

> Ph.D., et

> al., Reprinted ls 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, 0. Lanzafame, 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,

> 0.

> Lanzafame, 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. 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. ls 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., H. Yoshida, Ph.D. and 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.

> 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 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

> L.

> Smalley, R. Shanklin, F. Hall and V. s 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

> R.

> Shanklin and 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

>

> Smalley, F. Hall, R. Shanklin and NCchael s 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 L. Smalley, R. Shanklin, Mazy F.

> Hall,

> V. s 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 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 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. Ira Lewy, M.D.,

> FACP;

> 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, Varga,

> J.

> Gomez-Reino, 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

> H. Yoshida, Shanna Swan, Suzanne Teuber and M. 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.

> 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.

> --- End forwarded message ---

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