Opinion

Hall v. Baxter Healthcare Corp.

947 F. Supp. 1387
46 Fed. R. Serv. 26
1996 U.S. Dist. LEXIS 18960
1996 WL 730693

Court: District Court, D. Oregon
Filed: Dec 18, 1996
Status: Published
Author: Jones
On the bench: Jones
Cited by: 68 cases
Authority: More cited than 95.7%

finding that “case reports and case studies are universally regarded as an insufficient scientific basis for a conclusion regarding causation because case reports lack controls”; hence, they do not supply scientific knowledge upon which an opinion can be based under Daubert

How later courts described this case

finding that “case reports and case studies are universally regarded as an insufficient scientific basis for a conclusion regarding causation because case reports lack controls”; hence, they do not supply scientific knowledge upon which an opinion can be based under Daubert
excluding testimony that silicone is capable of causing certain symptoms because the experts were making "too great a leap of faith”; animal studies could not be reliably extrapolated to humans without explanation, case reports were insufficient to prove causation, and studies of crystalline silica were irrelevant because the plaintiffs had not shown that silicone breast implants were associated with the presence of crystalline silica
finding a Rule 403 analysis applicable but unnecessary in making its decision to exclude testimony
holding that differential diagnosis cannot establish general causation because the method “assumes that general causation has been proven”

Written by the judges who cited it.

The opinion

OPINION AND ORDÉR

ROBERT E. JONES, District Judge:

INTRODUCTION

Currently pending in this court are a number of silicone breast implant cases brought by or on behalf of the plaintiffs against various breast implant manufacturers.

Plaintiffs seek damages for injuries they claim to have suffered as a result of implantation with silicone gel breast implants.

Among other things, the plaintiffs assert that silicone from the implants has migrated and degraded in their bodies and has caused a systemic syndrome or illness, which they generally refer to as “atypical connective tissue disease” (ACTD). In essence, plaintiffs claim a “unique constellation of symptoms” consisting of hundreds of symptoms commonly experienced by the general population.

This opinion addresses the defendants’ motions in limine to exclude testimony by plaintiffs’ experts concerning any causal link between silicone breast implants and the alleged systemic disease - or syndrome.

To resolve these motions, the court, in its role as “gatekeeper”

(see Daubert v. Merrell Dow Pharmaceuticals, Inc.,

509 U.S. 579 , 113 S.Ct. 2786 , 125 L.Ed.2d 469 (1993) (hereinafter

Daubert I),

initiated proceedings under Federal Rule of Evidence 104. The process through which the court has endeavored to ■ resolve the pending motions, a process the

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court believes to be unique in federal practice to date, is described below.

II.

FACTS AND PROCEDURAL BACKGROUND

The breast implant cases at issue here were either filed initially in this court or removed from state court. The cases were then transferred to the Judicial Panel for Multidistrict Litigation,

In re Silicone Gel Breast Implant Products Liability Litigation,

MDL No. 926, 1994 WL 114580 , where they have been managed expeditiously under the watchful eye of the transferee judge, Chief Judge Sam C. Pointer, Jr. In 1995 and 1996, Judge Pointer remanded a number of cases to Oregon for trial.

All breast implant cases remanded to Oregon, federal district court have been assigned to this judge. After a series of status conferences involving all interested parties and counsel, I determined that, at least initially, similar cases should grouped for trial. I designated the following three trial groups:

Plaintiffs Defendants)

Group 1

Hall Pope Stern Preskey Baxter

Group 2

. Andrews , Johnston Eisele Bentley Tytlar Bristol-Myers Squib

Group 3

Shervey Zingarelli Adamson D. Hall Young Mitchel Bristol-Myers and Medical Engineering Corp.

After initial trial dates were set, the court instructed counsel for Groups 1 and 2 to provide a list of all lay and expert witnesses to be called at trial, together with a narrative statement of each witness’ proposed testimony. The court also instructed counsel to summarize each expert witness’ opinion, to identify all the materials upon which each expert would rely for his or her opinions, and to submit transcripts of any testimony given by the witness in similar cases.

Once the witness materials were duly filed, in July 1996, defendants jointly filed a series of motions in limine to exclude plaintiffs’ experts’ testimony concerning causation.

To address these motions, I scheduled an integrated hearing under Rule 104(a) on the admissibility of the scientific evidence. All interested parties and counsel were invited to attend the hearing, which I set for August 1996.

In view of the complicated scientific and medical issues involved and in an effort to effectively discharge my role as “gatekeeper” under

Daubert I,

I invoked my inherent authority as a federal district court judge to appoint independent advisors to the court.

See, e.g., Goetz v. Crosson,

967 F.2d 29, 37 (2d Cir.1992) (VanGraafeiland, J., concurring and dissenting) (citing

Scott v. Sponger Bros., Inc.,

298 F.2d 928 (2d Cir.1962));

see also Lust,

89 F.3d at 598.

Accordingly, in resolving the pending issues before me, this court will examine the evidence to ensure, as Judge Becker noted in

Paoli II,

that

every

step in the expert’s reasoning process, including the expert’s formulation of conclusions, are grounded in good science.

IY.

FINDINGS AND CONCLUSIONS

Physicians have used silicone

products in the human body for various purposes since the 1950s. Medical devices made from hard silicone include shunts, finger joints, hip joints, and heart valves. In addition, the United States and Japan experimented with injecting liquid silicone' directly into the human body in the 1950s and 1960s. However, the FDA eventually classified silicone liquid directly injected as a drug and has approved it only for experimental investigations. The silicone- gel breast implants involved in this litigation consist of 80 to 90 percent liquid silicone combined with 10 to 20 percent silicone gel, contained in a silicone rubber shell.

Plaintiffs’ theory of causation — or, as they refer to it, bioplausibility — begins with the premise that silicone from breast implants is released into a woman’s body, either through implant rupture or through “gel bleed,” the slow but continuous release of very small droplets (“mierodroplets”) of silicone gel through the silicone rubber implant cover. Once released into the body, plaintiffs assert, silicone migrates throughout the body, either by diffusing through cell membranes or by being carried by macrophages, the cells in a person’s body that devour and eliminate invading foreign bodies and wastes. In the process, the silicone degrades, or is chemically converted, into more reactive molecules such as silanols. The released silicone and the reactive products of silicone degradation purportedly elicit an autoimmune response from the woman’s immune system, essentially turning her immune system against her. The result, plaintiffs conclude, is general, systemic disease and particular signs and symptoms such as muscle and joint pain, headaches, rashes, and an inability to concentrate.

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Plaintiffs’ theory of causation thus brings four general areas of science into play: epidemiology; rheumatology; immunology/toxicology; and polymer chemistry. As has been described, the Rule 104 hearings and many of the parties’ arguments have been generally structured around these scientific fields. Thus, while I am mindful that the motions in limine actually address the exclusion of particular expert witnesses, my findings and conclusions will track the various disciplines at issue.

A. Atypical Connective Tissue Disease

Plaintiffs premise many of their claims on the existence of a variously-titled atypical connective tissue disease (ACTD).

This “disease” allegedly manifests itself through a constellation of various symptoms

and is allegedly caused by an autoimmune response to silicone from breast implants. Plaintiffs have offered Dr. Eric Gershwin and Dr. Kip Kemple as experts in rheumatology' to testify that silicone exposure is the probable cause of plaintiffs’ atypical constellation of symptoms.

By definition, ACTD is not one of the classical autoimmune diseases, such as lupus, scleroderma, or rheumatoid arthritis. In addition, plaintiffs’ expert Dr. Goldsmith testified that ACTD does not exist even as a hypothesis yet. “Epidemiologically, the question that you have asked me twice is where we are with these atypical diseases. And I am telling you we are back at the beginning of formulating studiable hypotheses to test. We are really at the beginning of that.” TRANS. Of Pretrial Hearings before the Honorable Robert E. Jones (hereinafter Portland Trans.), Aug. 6, 1996, at 164:23 to 165:2. A silicone research group has proposed criteria for this alleged disease, but these criteria have not yet been tested, nor does the rheumatology community generally accept the existence of ACTD. Dr. Gershwin has acknowledged that he would not rely on these criteria as authoritative for his medical opinion. Portland Trans., Aug. 5, .1996, at 78:25 to 79:23. He also admitted that there is no specific diagnostic test for this alleged disorder. Portland Trans., Aug. 5,1996, at 88:1-4,15-19. Finally, women who allegedly have ACTD do not uniformly exhibit the same signs and symptoms, and there is no “signature” disorder to suggest either that the cause is silicone exposure or that the cause is the same for all women showing this constellation of symptoms.

Instead, the asserted constellation of symptoms comprising ACTD overlaps significantly with those comprising chronic fatigue syndrome and fibromyalgia.

Because ACTD is at best an untested hypothesis, there is no scientific basis for any expert testimony as to its causes and presence in plaintiffs. Therefore, defendants’ motions are GRANTED as regards any expert testimony relating to the existence and causation of any atypical, silicone-caused, autoimmune disorder.

With the possible exception of plaintiff LeaAnn Hall, moreover, plaintiffs have not been diagnosed as having classical autoimmune disorders. Therefore, the rest of this

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opinion will address expert testimony in regards to plaintiffs’ individual signs and symptoms.

B. Epidemiology

Plaintiffs offer Dr. David Goldsmith as an expert to testify that there is epidemiological and other scientific data showing that women with silicone breast implants have significantly elevated probability of suffering from classical diseases when compared to women without breast implants.

In contrast, plaintiffs offer Dr. Shanna Swan, through transcripts of her previous testimony in other cases, to testify that no valid epidemiological studies regarding the relationship of silicone breast implants and disease have been completed as of August 1996.

Epidemiology is the medical science devoted to determining the causes of disease in human beings. Epidemiologists compare control groups of unexposed individuals to groups of individuals exposed to a hypothetical cause of the disease being studied to determine whether exposed individuals have a greater risk of manifesting that disease. In epidemiological terms, any difference in risk of getting the disease between the two groups is the exposed individuals’ relative risk. The existence or nonexistence of relevant epidemiology can be a significant factor in proving general causation in toxic tort cases.

Daubert II,

43 F.3d at 1320-21 ;

Brock v. Merrill-Dow Pharmaceuticals, Inc.,

874 F.2d 307, 311-13 (5th Cir.1989).

To support admissible expert opinions, epidemiological evidence must fit the legal as well as the substantive issues of the case. Because this is a diversity action, Oregon substantive standards of law must apply.

Erie Railroad Co. v. Tompkins,

304 U.S. 64 , 58 S.Ct. 817 , 82 L.Ed. 1188 (1938).

As discussed above, under Oregon law, a plaintiff seeking to prove causation must “ ‘introduce evidence which affords a reasonable basis for the conclusion that it is more likely than not that the conduct of the ■ defendant was a substantial factor in the result.’”

Griffin v. K.E. McKay’s Mkt.,

125 Or.App. at 451-52 , 865 P.2d 1320 (quoting

Eitel v. Times, Inc.,

221 Or. 585, 594 , 352 P.2d 485 (1960)). This burden requires plaintiffs to demonstrate that exposure to breast implants more than doubled the risk of their alleged injuries.

Daubert II,

43 F.3d at 1320 .

In epidemiological terms, Oregon’s standard of proof means that plaintiffs must be able to show a relative risk of greater than 2.0:

The threshold for concluding that an agent was more likely the cause of a disease than not is relative risk greater than 2.0. Recall that a relative risk of 1.0 means that that agent has no effect on the incidence of disease. When the relative risk reaches 2.0, the agent is responsible for ah equal number of cases of disease as all other background causes. . Thus, a relative risk of 2.0 implies a 50% likelihood that an exposed individual’s disease was caused by the agent.

Bailey,

et al.,

Reference Guide on Epidemiology, REFERENCE MANUAL ON SCIENTIFIC EVIDENCE at 168. The Ninth Circuit has reached a similar conclusion under California’s standard of proof, which is very similar to Oregon’s, holding that “[f]or an epidemiological study to show causation under a preponderance standard,, ‘the relative risk of [the condition at issue] arising from the epidemiological data ... will, at minimum, have to exceed “2”.’ ”

Daubert II,

43 F.3d at 1321 (quoting

DeLuca v. Merrell Dow Pharmaceuticals,

911 F.2d 941 , 958 (3d Cir.1990)).

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Although, as discussed above, epidemiological studies showing a relative risk of less than 2.0 might be relevant under some circumstances, here, as in

Daubert II,

“plaintiffs’ experts did not seek to differentiate these plaintiffs from the subjects of the statistical studies. The studies must therefore stand or fall on their own.”

Id.

at 1321 n. 16.

Plaintiffs’ experts base their proffered expert opinions on the sixteen epidemiological studies

assessing the relationship of silicone breast implants to classical connective tissue disease. In addition, plaintiffs have called this court’s attention to the 1996 Liang-Schottenfeld abstract recently presented at a meeting of the American College of Rheumatology that reports a relative risk of 2.27 for Undifferentiated Connective Tissue Diseases (UCTD).

Dr. Goldsmith testified in the proceedings before this court that he was not willing to testify, based on the 16 then-available studies, that silicone more likely than not could cause disease in women. That testimony was as follows:

DR. GREENLICK: You were asked a question if you had an opinion on causality based on whatever other evidence was left, case studies, other animal evidence. I think there is a sense that when you talked about there was a suggestion from some of the things that would mean you had a very low certainty of causality and that causality could go from saying, “We don’t know if there’s any link at all,” all the way to saying, “We are really quite certain, short of randomly implanting women, we are very certain.”

Given the fact that there is no epidemiological data on this, where would you say your sense of certainty of your causality is? How close to zero as opposed to 100 percent are you? Are you in certainty with your opinion that there is a causal relationship with breast implants and atypical connective tissue disease?

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DR. GOLDSMITH: Let me also make sure that I give you an answer that I think is reflective of the — of the question in front of us. I don’t believe it should go from zero to — to fully sure. I think it’s also possible that breast implants could, in fact, be negatively related to those atypical syndromes as well.

DR. GREENLICK: Right. I was just starting from a zero, yes, could you have gone all the way from they are highly protective through no relationship, all the way to certain causality.

But let’s just — I assume you don’t — you are not suggesting that the current data would tell you they are protective against atypical disease. So let’s start from zero at “I have no certainty whatever there’s a relationship,” all the way to “I am absolutely certain there’s a relationship from the existing data given no epidemiological data.” I was wondering where you would—

DR. GOLDSMITH:

At the moment, I must suggest to you that the evidence looks to me as if it’s just that, that it’s a possibility, and I would have to characterize it as less than 50 percent.

That would be where I am at the moment.

But where the new evidence is going to show that there is or is not an association, I think we have to wait for the science to tell us. We have to wait for the epidemiology.

PORTLAND Trans., Aug. 6, 1996, at 241:14 to 243:4 (emphasis added).

With the release of the Liang-Schottenfeld abstract, Dr. Goldsmith now indicates a willingness to testify that such causation is “more likely than not.”

This court cannot accept his proffered change in testimony because it finds the methodology supporting this changed testimony unreliable under

Daubert I

and

Daubert II.

First, none of the- 16 epidemiological studies found that women with silicone breast implants faced a relative risk of classical diseases or disease signs and symptoms of anywhere near 2.0. Indeed, only one study — the Hennekens study — found any statistical relationship between the presence of silicone breast implants and disease, and there the relative risk was only 1.24. Therefore, these studies cannot support expert testimony that silicone “more likely than not” causes disease or signs and symptoms of disease in women.

Second, the Liang-Schottenfeld abstract cannot in itself support Dr. Goldsmith’s change in testimony. The abstract is not yet published, nor is a full write-up of the study, including the supporting data, yet available. Indeed, Dr. Goldsmith admitted in his New York testimony that his only knowledge of the details of the study came from a telephone inquiry. New YorK Trans., at 71:17-24. According to the abstract, moreover, the study included only three women with breast implants, calling its epidemiological significance severely into question. In addition, the abstract explicitly concludes that “silicone breast implants were not significantly associated with UCTD,” suggesting that silicone gel breast implants are

not

associated with disease. In contrast, the abstract concludes overall that, “[ajmong all types of implanted devices, including breast implants, both those containing silicone * * * and those that did not contain silicone * * * were significantly associated with UCTD.” This apparent internal contradiction within the abstract’s conclusions calls the value of this study further into question. In light of these shortcomings

and in the face of the other 16 studies, which Dr. Goldsmith has already admitted do not support expert testimony that silicone “more likely than not” causes

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disease in women, this court GRANTS defendant’s motion to exclude Dr. Goldsmith’s epidemiological testimony.

As for defendants’ motion to exclude Dr. Swan’s proffered testimony, the motion must be GRANTED because Dr. Swan’s testimony is unreliable and no longer “fits” plaintiffs’ theory of the case. I first note that several courts have rejected Dr. Swan’s testimony and her “reanalysis” approach as unreliable.

Dr. Swan’s reanalysis of the silicone epidemiology has never been subjected to peer review.

Merlin

HEARING TRANS., at 73-76. Moreover, her theory has not been espoused by any other scientist whose work has been subjected to the peer review process.

Merlin

Hearing Trans., at 73-74. Peer review and publication weigh heavily in the calculus of the reliability of expert testimony because such peer review “increases the likelihood that substantive flaws in methodology will be detected.”

Daubert I,

509 U.S. at 594 , 113 S.Ct. at 2797 . Thus, the lack of peer review for Dr. Swan’s theories weighs heavily against the admissibility of Dr. Swan’s testimony.

In addition, Dr. Swan’s testimony involves only her opinions and criticisms of others’ work; as such, it is-not based on any technique that can be scientifically tested. Moreover, her criticisms of the existing epidemiology for silicone gel breast implants have not been generally accepted. In fact, they have not been accepted at all.

Merlin

Hearing Trans., at 92-93. In contrast, Dr. Swan admits that no studies have established a causal link of any scientific significance between silicone breast implants and disease,

Merlin

Hearing Trans., at 82, and this is the reeog-nized consensus of the relevant scientific community.

As the Supreme Court stated, “widespread acceptance can be an important factor in ruling particular evidence admissible, and a known technique that has been able to attract only minimal support within the community may properly be viewed with skepticism.”

Daubert I,

509 U.S. at 594 , 113 S.Ct. at 2797 . Many courts have recognized that an unexplained conflict with the generally accepted methodology or theories in a given scientific field can be a basis for excluding proffered expert testimony.

See Turpin v. Merrell Dow Pharmaceuticals, Inc.,

959 F.2d 1349, 1360 (6th Cir.),

cert. denied,

506 U.S. 826 , 113 S.Ct. 84 , 121 L.Ed.2d 47 (1992) (finding no scientific basis for testimony of a causation expert who did “not testify on the basis of the collective view of his scientific discipline^ nor [did] he take issue with his peers and explain the grounds for his difference”);

O’Conner v. Commonwealth Edison Co.,

807 F.Supp. 1376, 1398 (D.Ill.1992),

aff'd

13 F.3d 1090 (7th Cir.),

cert. denied

— U.S. -, 114 S.Ct. 2711 , 129 L.Ed.2d 838 (1994) (holding that “an expert opinion that

actually contradicts directly

the scientific consensus is inadmissible”);

Conde v. Velsicol Chem. Corp.,

804 F.Supp. 972, 1024 (S.D.Ohio 1992),

aff'd

24 F.3d 809 (holding that “when an expert expresses an opinion which is not generally accepted within the medical and scientific communities, he has an obligation to provide a reasoned explanation of why his methodology and opinions differ”). In addition to not being peer-reviewed and to being untestable, Dr. Swan’s proffered testimony inexplicably conflicts with the general con

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sensus of the epidemiological community. Thus, it is unreliable and hence inadmissible.

In addition, Dr. Swan’s testimony has no “fit.” As discussed above, even if the proponents of expert testimony establish that that testimony is reliable scientific knowledge, the court must still exclude the evidence if it does not fit the issues to be decided in the case.

Daubert I,

509 U.S. at 591 , 113 S.Ct. at 2795-96 . In the Ninth Circuit, testimony only “fits” a ease if it logically advances a material aspect of the proponent party’s case.

Daubert II,

43 F.3d at 1315 . Here, Dr. Swan seeks to testify that current epidemiology regarding the relationship of silicone breast implants and classical disease is invalid. However, this court has already determined that the proffered testimony based on that epidemiology is inadmissible, and it will determine, see discussion below, that plaintiffs cannot base their entire case on differential diagnosis. In addition, to the extent that plaintiffs intended to use Dr. Swan’s testimony to support their argument that silicone breast implants can cause ACTD, I have already ruled that no- testimony regarding ACTD will be permitted. Therefore, Dr. Swan’s testimony is now a stepping stone that leads nowhere; it no longer “fits” plaintiffs’ case.

There is no doubt but that Dr.- Swan has impressive credentials, as Justice Black-mun himself recognized in

Daubert I,

509 U.S. at 583 n. 2, 113 S.Ct. at 2792 n. 2 (noting that Dr. Swan has “a master’s degree in biostatics from Columbia University and a doctorate in statistics from the University of California at Berkeley, is chief of the section of the California Department of Health and Sciences that determines causes of birth defects, and has served as a consultant to the World Health Organization, the Food and Drug Administration,, and the National Institutes of Health.”) However, as Judge Wein-stein noted in the Agent Orange litigation, the jury should “not be permitted to be misled by the glitter of an expert’s accomplishments outside the courtroom” if the expert opinion is based on “untrustworthy” data or is otherwise not reliable.

In re “Agent Orange” Product Liability Litigation,

611 F.Supp. 1223, 1245 (E.D.N.Y.1985) (citations omitted). As in that ease, “‘the speculation and unfounded assumptions underlying [the] testimony [of Dr. Swan] decrease its probative value, perhaps to the level of the gossamer.’ ”

Id.

at 1256 (quoting

American Bearing Co. v. Litton Indus., Inc.,

729 F.2d 943 , 950 n. 14 (3d Cir.1984)). In this litigation, Dr. Swan’s well-traveled opinions are no more than educated guesses dressed up in evening clothes. Therefore, for all of the above reasons, I GRANT defendants’ motions to exclude Dr. Swan’s testimony.

C. Immunology and Toxicology

Plaintiffs have offered Dr. Eric Gershwin as an expert in immunology to testify that silicone is capable of causing plaintiffs’ constellation of symptoms because (1) silicone in contact with human tissue results in chronic inflammation through immune activation and cellular reactions; (2) silicone is an immune adjuvant and thus can produce enhanced immune responses when in the presence of a triggering condition and exacerbate existing

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immune-mediated conditions; and (3) the surface of silicone changes or degrades

in vivo

into silanol groups and/or silica. He relies on the epidemiological studies discussed above, his own clinical experience, biomarker, immune activation, and toxicological studies,

and the work of the Harvard

*1409

NMR Center on the degradation of silicone as the bases of his proffered opinion.

Plaintiffs also offer Dr. Kip Kemple to testify that silicone can produce an immunological response in women. Dr. Kemple relies on immunological studies showing that autoantibodies are elevated in women with breast implants

and his own study of anti-ganglioside antibodies in women with breast implants.

The court submitted immunological/toxicological issues to its expert, Dr. Mary Stenzel-Poore,

who specifically looked at the adju-vant potential of silicone gel implants, the potential for immune stimulation of T cells by silicone gel implants, altered natural, killer cell activity, and immune system cancer formation in rodents. She opined that the studies relied upon by plaintiffs’ experts justified the following conclusions regarding silicone gel adjuvant potential:

la. Silicone gel

emulsified with antigen

may act as an adjuvant in humoral and cell-mediated immune responses in rodents.

lb. Silicone oils that are both linear and low molecular weight,

emulsified with antigen

do not act as adjuvants in rodents.

le. Silicone oils that are low molecular weight and cyclic (D4)

emulsified with antigen

may act as adjuvants.

Appendix D, at 2. However, “[djirect attempts to demonstrate that immunization with these agents emulsified with ‘auto-antigens’ or given in the absence of antigens failed to show evidence of autoimmune disease despite obvious disease induction by Freund’s adjuvant,” except in a genetic strain of rat developed to have a high susceptibility of developing arthritis.

Id.

Thus,

in rodents only,

“enhanced immune responses are not found if the antigen is not emulsified with the silicone agents * *

Id.

at 2-3 (citations omitted).

Dr. Stenzel-Poore 'further stated that “[fjorming the conclusion that elicitation of autoimmune and/or inflammatory disease occurs in women with SBI based on the evidence that silicone gel acts as an adjuvant

when emulsified with antigen

is unsupported by the data since peer-reviewed, studies failed to show evidence of any autoimmune-mediated disease.” Appendix D, at 3. Although “[t]he scientific methodology used in the aforementioned studies is generally sound,” -

Dr. Gershwin’s opinion regarding the adju-vant properties of silicone gel

requires a substantial leap of faith

since it is undeter.mined from these studies whether silicone gel breast implants would lead to adjuvant actions, much less autoimmune responses or systemic inflammation; indeed, studies designed to test this hypothesis argue

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against such an outcome. Thus, the position of Dr. Gershwin is not well-supported by the data available in the published scientific literature nor is it derived from valid conclusions of the studies cited above.

Id.

(emphasis added).

With regard to T-cell stimulation, Dr. Stenzel-Poore opined that “[t]he view that SBIs stimulate antigen-specific T cell mediated responses in vivo is not well substantiated by the experimental studies reported in the literature.” Appendix D, at 4. Moreover, although “[s]everal studies have been performed attempting to establish a link between silicone breast implantation in women and silicone-specific T-cell responses,” “these studies have a number of methodological shortcomings and thus should not form the basis of an opinion.”

Id.

at 5. As a result,

those opinions of Dr. Gershwin regarding the role of silicone gel breast implants in stimulating specific T cell immunity and thereby providing a plausible mechanism of autoimmune induction are not upheld by the literature discussed above. The position of Dr. Gershwin is simply not well-supported by studies available in the published scientific literature nor is it derived from appropriate conclusions regarding the studies cited above.

Id.

at 8.

Dr. Stenzel-Poore also examined the literature regarding changes in natural killer cell function. . She noted that “[c]hanges in natural killer (NK) cell function have been reported to be associated with silicone gel exposure in rodents and humans.” Appendix D, at 9. Such an association could be significant because “changes in NK cells have also been associated with increased susceptibility to pathogens and tumor formation.”

Id.

However, “[g]iven the concerns raised by the degree of irreproducibility and fluctuations in time and dose-dependency [in the silicone gel/NK cell studies], conclusions made regarding the suppressive effect of silicone gel on NK function based on these studies are premature.”

Id.

Moreover, “although the data indicate that 50% of symptomatic women with implants had lower NK activity prior to removal of the implant, it is misleading since the degree of variation is not shown in the implanted women, or in women without implants. It is invalid to conclude that silicone-gel breast implants in women lead to a depressed NK cell activity that is reversible with explanation.”

Id.

at 10.

Finally, in evaluating the studies evaluating the development of immune system cancer in response to silicone, Dr. Stenzel-Poore stated that “Dr. Gershwin’s opinions regarding the development of immune system cancers in women with silicone breast implants is unwarranted” from the current studies, which are all animal studies. Appendix D, at 11. “There is no conclusive evidence to date that this model of tumor formation in mice has any human correlate.”

Id.

I agree with and accept Dr. Sten-zel-Poore’s assessments of Dr. Gershwin’s scientific methodology in fight of legal standards for

Daubert

hearings. As a preliminary matter, I note that most if not all of the studies that Dr. Gershwin and Dr. Kemple rely upon are animal studies (generally involving rodents), case reports or collections of case reports, and/or studies involving crystalline silica. Extrapolations of animal studies to human beings are generally not considered reliable in the absence of a scientific explanation of why such extrapolation is warranted.

See Viterbo v. Dow Chemical Co.,

826 F.2d 420 (5th Cir.1987) (excluding the evidence where there was only a single animal study of picloram and it showed a link to a disease completely different than plaintiffs diseases);

Richardson v. Richardsort-Merrell, Inc.,

857 F.2d 823, 830 (D.C.Cir.1988) (excluding animal studies of Bendeetin because of the overwhelming body of contrary epidemiological evidence and the admissions of the expert that animal studies merely raise a suspicion of causation in humans);

Lynch v. Merrell-National Laboratories,

830 F.2d at 1194 (excluding animal studies of Bendeetin where they stood in the face of significant contrary epidemiological data);

Turpin v. Merrell Dow Pharmaceuticals, Inc.,

959 F.2d at 1360 (excluding testimony where the record failed to make clear how the animal studies were sufficient to show that Bendeetin causes birth defects more probably than not). Plaintiffs offer no explanation of why extrapolations from the rodent

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studies their experts rely upon to humans are warranted here.

Similarly, case reports and case studies are universally regarded as an insufficient scientific basis for a conclusion regarding causation because case reports lack controls.

Casey v. Ohio Medical Products,

877 F.Supp. 1380 (N.D.Cal.1995);

Muzzey v. Kerr-McGee Chemical Corp.,

921 F.Supp. 511, 519-20 (N.D.Ill.1996);

In re Three Mile Island Litigation Cases Consolidated II,

911 F.Supp. 775, 795-96 (M.D.Penn.1996);

Grimes v. Hojfmann-LaRoche, Inc.,

907 F.Supp. S3, 35 n. 2 (D.N.H.1995). Therefore, these cannot be the basis of an opinion based on scientific knowledge under

Daubert.

Third, as will be discussed below, studies based on crystalline silica cannot support the testimony of plaintiffs’ experts because plaintiffs make no showing that silicone breast implants are associated with the presence of crystalline silica in women. In other words, the purported disease-causing agent in the silica studies has not been show to be scientifically relevant regarding the purported disease-causing agent — namely, silicone gel — in these cases.

Finally, Daubert’s establishment of the court as gatekeeper requires that proffered scientific expert opinions that make too great a leap of faith from the scientific knowledge currently available be excluded. As . discussed above, an evaluation of whether scientific methodology is valid for

Daubert

purposes should include an examination of how the proffered conclusions relate to the bases upon which the expert relies. The court’s neutral technical advisor has advised that Dr. Gershwin — and, by implication, Dr. Kemple, who relies on most if not all of the same studies as Dr. Gershwin — has made too great a leap from the underlying data to his conclusions. In other words, those conclusions are themselves not the result of the faithful application of valid scientific methodology. Therefore, defendants’ motions to exclude Dr. Gershwin’s and Dr. Kemple’s testimony on these issues is GRANTED.

D. Chemistry

Plaintiffs offer Dr. Christopher Batich as an expert in chemistry to testify that: (1) silicone migrates out of breast implant capsules; (2) there is an increase in surface area of silicone from gel breast implants to which the body reacts over time; (3) silicone changes in the body and forms bioreactive silanol groups on its surface; (4) silicone degrades into silica in the body; and (5) there is similar surface chemistry in all silox-ics (silicones, silicates, and silicas) that make the siloxics reactive in humans. In addition, plaintiffs offer Dr. Harold Alexander, a biom-aterials engineer, to testify that: (1) silicone microdroplets and/or particles are released from breast implants through gel bleed or rupture and have a high potential to cause inflammatory reactions in body tissues, and (2) the small size-’ of silicone microdroplets and/or particles allows them to migrate through the body via microphages and other migrating cells, and' their low molecular weight allows them to diffuse through tissue.

The court’s technical advisor for polymer chemistry, Dr. Ronald McClard, carefully reviewed the question of whether the scientific evidence supports Dr. Batich’s and Dr. Alexander’s proffered testimony that silicone degrades to silica

in mvo.

In reviewing the plaintiffs’ main scientific support for silica-induced biological reactions, a paper published by B. Razzaboni and P. Bolsaitis in

Environmental Health

Perspectives,

Dr. McClard stated that:

The Razzaboni article * * * clearly attempts to offer a biochemical explanation for the silica-caused hemolytic process. This article seems scientifically sound. If silicones are converted to silica then this article seems relevant to the issue at hand.

I am unaware that any of the papers that I reviewed clearly demonstrated the conversion of silicone to silica (most likely amorphous forms thereof),

though the process seems possible given the known chem

*1412

istry of silicon.

The link between silicones and the Razzaboni article is a prospective one.

Appendix E, at 11 (emphasis added). In other words, the opinions plaintiffs’ experts proffer regarding the

in vivo

degradation of silicone to silica are currently unsupported by the scientific literature. As with the immunological/toxieological conclusions discussed above, plaintiffs’ experts again make too great a leap of faith in their proffered testimony that silicone gel from breast implants degrades to silica. This is especially true for any testimony that silicone gel degrades

in vivo

to crystalline, as opposed to amorphous, silica. Therefore, I hereby GRANT defendants’ motions as pertains to such testimony.

In addition, because there is no scientifically valid evidence to support the conclusion that silicone gel degrades to silica in the human body, any other immunological or toxicological studies involving the inhalation, ingestion, or absorption of crystalline, silica cannot “fit” the issue of whether silicone breast implants can cause signs or symptoms of disease in women. Therefore, as discussed above, I must also exclude testimony based on this evidence under the “fit” prong of

Daubert I

and

Daubert II.

■ Dr. McClard also had several strong reservations about the other chemical studies upon which Dr. Batich and Dr. Alexander rely. Nevertheless, Dr. McClard consistently reported that these studies are supported by. valid scientific reasoning and methodology. Moreover, while plaintiffs’ experts’ opinions are, in his view, “controversial,” he concluded that those opinions are generally scientifically valid in that they properly may be derived from the chemical studies:

It’s a bit like two doctors looking at a chest X-ray (having both agreed that a chest X-ray was the correct diagnostic procedure to use) and disagreeing, sometimes heatedly, over the interpretation of a shadow on the film and perhaps how long the exposure should have been. I have no doubt that all of the chemical studies examined in these hearings are based on appropriate methods, whether or not there are serious questions about fine points of technique or far-reaching conclusions. Indeed some of the work is inadequately documented and of clearly debatable value, but that is really not for me to decide, to be sure.

Appendix E, at 12.

I find Dr. McClard’s exposition of the numerous methodological flaws in the other chemical studies troubling. Nevertheless, I need not decide whether this evidence is admissible on the basis of valid scientific methodology because the evidence now does not “fit” plaintiffs’ case, as

Daubert I,

509 U.S. at 594 , 113 S.Ct. at 2797 , and

Daubert II,

43 F.3d at 1315 , require. Testimony as to how silicone behaves chemically inside the human body cannot, in itself, establish that silicone gel breast implants cause signs and symptoms of disease in women in the absence of any epidemiological, rheumatological, or immunological/toxicological evidence linking those breast implants to disease. Thus, such testimony no longer logically advances a material aspect of the proponent party’s case.

Daubert II,

43 F.3d at 1315 . Therefore, I hereby GRANT defendants’ motions to exclude the testimony of Dr. Batich and Dr. Alexander.

E. Differential Diagnosis

Plaintiffs have offered Dr. Robert Bennett, M.D., both to testify that silicone gel breast implants can cause disease in women and to testify as a case-specific expert in

LeaAnn Hall v. Baxter

Healthcare.

Dr. Bennett is plaintiff Hall’s treating physician and is prepared to testify, on the basis of differential diagnosis, that plaintiff Hall suffers from systemic sclerosis sine scleroderma, manifested by her pulmonary fibrosis, as a result of having silicone gel breast implants.

As has been noted, the issue before me in this

Daubert

hearing is silicone gel’s ability to cause disease in women with breast implants. Courts, however, have recognized two levels of causation: general causation

*1413

(la, whether silicone gel can cause disease in anyone) and specific causation

(ie.,

whether silicone gel breast implants caused disease, in this plaintiff).

In Re: Silicone Gel Breast Implants Products Liability Litigation,

887 F.Supp. 1469 , 1477 (N.D.Ala.1995);

Jones v. United States,

933 F.Supp. 894, 900 (N.D.Cal.1990);

DeLuca v. Merrell Dow Pharmaceuticals, Inc.,

911 F.2d at 958;

Rutigliano v. Valley Business Forms,

929 F.Supp. 779, 783 (D.N.J.1996).

Differential diagnosis is a patient-specific process of elimination that medical practitioners use to identify the “most likely” cause of a set of signs and symptoms from a list of possible causes. However, differential diagnosis does not by itself

prove

the cause, even for the particular patient. Nor can the technique speak to the issue of general causation. Indeed, differential diagnosis

assumes

that general causation has been proven for the list of possible causes it eliminates:

The process of differential diagnosis is undoubtedly important to the question of “specific causation.” If other possible causes of an injury cannot be ruled out, or at least the possibility of their contribution to causation minimized, then the “more likely than not” threshold for proving causation may not be met.

But, it is also important to recognize that a fundamental assumption underlying this method is that the final, suspected “cause” remaining after this process of elimination must actually be capable of causing the injury.

That is, the expert must “rule in” the suspected cause as well as “rule out” other possible causes. And, of course, expert opinion on this issue of “general causation” must be derived from scientifically valid methodology.

Cavallo v. Star Enterprise,

892 F.Supp. 756, 771 (E.D.Va.1995) (emphasis added),

aff'd on this ground, rev’d on other grounds

—100 F.3d 1150 (4th Cir.1996).

Testimony regarding specific causation in a given patient is irrelevant unless general causation is established.

DeLuca,

911 F.2d at 958;

Jones,

933 F.Supp. at 900 ;

Rutigliano,

929 F.Supp. at 783 ;

Grimes,

907 F.Supp. at 38.

Hopkins v. Dow Corning Corp.,

33 F.3d 1116 (9th Cir.1994), does not require a different conclusion for differential diagnosis. First, nothing in

Hopkins

indicates that any witness used differential diagnosis to establish

any

level of causation, let alone both general and specific causation.

Second, even if the expert’s medical examination of the plaintiff in

Hopkins

were a differential diagnosis (and that is far from clear), it was not, as would be the case here, the

only

evidence of causation proffered. Although the court concluded “that Hopkins’ experts based their opinions on the types of scientific data and utilized the types of scientific techniques relied upon by medical experts' in making determinations regarding toxic causation where there is no solid body of epidemiological data to review,”

id.

at 1124 , this data was collective ánd included: toxicological experience; reviews of medical records; reviews of Dow’s studies; “general scientific knowledge of silicone’s ability to cause immune disorders as established by animal studies and biophysical data”; published scientific studies; personal research; “participation in a preliminary epidemiological study involving over 200 women”; animal studies; clinical experience; “preliminary results of an epidemiological study”; medical literature;

and

an examination of the plaintiff.

Id.

at 1125 . Most of- this information; as this

Daubert

hearing has demonstrated, would have been offered to establish general causation — that is, the issue of whether silicone gel breast implants can cause disease in anyone.

Finally, the

Hopkins

court, because of the timing of the case, was reviewing a pre-

Daubert

district court decision to admit the

*1414

expert testimony. As a result, the district court had reached that decision on a record not shaped by Daubert’s elucidation of the court’s gatekeeping function, nor did the Ninth Circuit delve into the methodology underlying the scientific data upon which Hopkins’ experts relied. Because I have done so and have excluded all proffered testimony regarding general causation, Dr. Bennett’s testimony now stands in isolation — an evi-dentiary predicament substantially different from that in

Hopkins .

Plaintiffs have consistently claimed that this court has jumped the gun in stating that plaintiffs cannot make out a prima facie case. Plaintiffs assert that they have more evidence to present at trial in the nature of differential diagnosis as well as pursuing their theory of “bioplausibility.” The fact of the matter is that plaintiffs cannot resort to these purported additional arrows in their legal quiver because neither differential diagnosis nor their bioplausibility theory can make out a prima facie case to prove specific causation of a systemic disorder or particular signs and symptoms absent proof of general causation. Moreover,, plaintiffs cannot use Dr. Bennett’s testimony, by itself, as part of their proof of general causation because a single differential diagnosis is a scientifically invalid methodology for such a purpose. Therefore, I must exclude Dr. Bennett’s testimony for all cases to the extent that plaintiffs proffer it to prove general causation.

Nor is Dr. Bennett’s testimony admissible to prove specific causation in LeaAnn Hall’s case, and for two reasons. General causation issues aside, an expert must rule out other potential causes of the patient’s condition in order for differential diagnosis testimony to be admissible.

Conde v. Velsicol Chemical Corp.,

24 F.3d 809, 814 (6th Cir.1994);

Paoli II,

35 F.3d at 759 . Here, Dr. Bennett has not testified as to how he eliminated other potential causes of Ms. Hall’s disease. Moreover, ■ his conclusion is inconsistent with the epidemiology for classical diseases. Therefore, his testimony is unreliable and exclusion of it is warranted on that basis.

See Conde v. Velsicol Chemical Corp.,

24 F.3d at 814 (upholding the district court in excluding doctors’ opinions purporting to link plaintiffs health problems to ehlordane exposure when they failed to exclude other potential causes for the symptoms and their theories were inconsistent with the scientific literature).

In addition, in the absence of proof of general causation, Dr. Bennett’s testimony regarding his differential diagnosis does not “fit” LeaAnn Hall’s case because there will be no evidence that silicone gel breast implants are a legitimate possible cause of Ms. HalTs disease.

Therefore, for all of the above reasons, I hereby GRANT defendants’ motions to exclude the testimony of Dr. Bennett.

CONCLUSION

For the reasons stated above, those portions of defendants’ motions in limine (## 69, 70, 72, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, and 95 (filed in Group 2)) that seek exclusion of any expert testimony concerning a general causal link between silicone gel breast implants and ACTD or any systemic illness or syndrome are GRANTED. The remaining portions of the above-listed motions are MOOT, with leave to refile as necessary in further pretrial proceedings.

In light of these rulings, the court will sever plaintiffs’ local injury claims

from their claims for ACTD or any systemic illness or injury. The eases that do proceed to trial will do so on a much more restricted basis than Judges Weinstein and Baer may even contemplate in the New York litigation.

Specifically, I will exclude as irrelevant any testimony or evidence of the following: ACTD; any systemic illness or syndrome or autoimmune disorder of any kind; any emotional distress claims arising out of any alleged fear of developing any

*1415

systemic disease or injury or fear of cancer.

Finally, as stated earlier, I will defer the effective date of this decision pending the reports of the national Rule 706 panel, and likewise will defer plaintiffs’ motion to incorporate the panel members as witnesses. Nonetheless, I wish to make it abundantly clear that while I will evaluate the Rule 706 panel reports before finalizing my decision, I am unlikely to amend these findings and conclusions absent substantial and compelling developments in the scientific arena.

I am mindful that this opinion goes farther in evaluating and in eliminating plaintiffs’ claims than any other opinion in breast implant litigation pending in this country. However, litigation over the ability of silicone gel breast implants to cause disease in women has been chaotic in its results, in part because, as

Hopkins

demonstrates, the interjection of the

Daubert

standards into the screening process for proposed scientific evidence has substantially heightened the scrutiny through which such evidence must pass. In my opinion,

Daubert I

and

Daubert II

and their progeny command this disposition. Postscript: It should be noted, as a matter of

ease management in mass toxic tort litigation, that at the outset of proceedings after remand from the MDL, counsel for all sides presented an all-day “tutorial” to the court on the complex science involved in these cases. The tutorial demonstrated the need for and prompted the court to appoint the technical advisors. It should also be noted that Judge Sam Pointer appointed Dr. Richard Jones to serve with Professor Margaret Berger, Chair, on the national Rule 706 selection panel.

APPENDIX A

Jonathan M. Hoffman, OSB # 75418

MARTIN, BISCHOFF, TEMPLETON

LANGSLET & HOFFMAN

3100 First Interstate Tower

1300 SW Fifth Avenue

Portland, OR 97201-5667

Telephone: (503)’224-3113

Fax: (503)224-9471

Mary A. Wells

WELLS, ANDERSON & RACE LLC

1700 Broadway, Suite 1850

Denver, CO 80290

Telephone: (303) 830-1212

Fax: (303)830-0898

Kelly P. Corr

BOGLE & GATES

Two Union Square, 51st Floor

601 Union Street

Seattle, WA 98101

Telephone: (206)682-5151

Fax: (206) 621-2660

Of Attorneys for Defendants,

BAXTER. HEALTHCARE .CORPORATION and BAXTER INTERNATIONAL INC.

IN THE UNITED STATES DISTRICT COURT

FOR THE DISTRICT OF OREGON

LeaAnn DeGraw Hall, Plaintiff, v. Baxter Healthcare Corporation, et al., Defendants.

Case No. CV 92-182-JO-LEAD .

94-892-JO

94 — 903-JO

94-907-JO

PROPOSED QUESTIONS REGARDING . METHODOLOGY UTILIZED BY PLAINTIFFS’ EXPERT ORGANIC CHEMIST, CHRISTOPHER BATICH, Ph.D.

Defendants, Baxter Healthcare Corporation and Baxter International Inc., Bristol-Myers Squibb, and 3M, propose the following questions regarding the methodology utilized by plaintiffs’ expert organic chemist, Christopher Batich, M.D.:

*1416

QUESTION 1

Are Dr. Batich’s opinions that silicone degrades into silica in the human body supported by scientifically rehable methodologies?

QUESTION 2

Even if it is biologically plausible that silicone degrades in the human body, is that sufficient evidence to support scientifically a conclusion that silicone breast implants cause “atypical” connective tissue disease as described by Drs. Gershwin, Bennett, or Kem-ple?

QUESTION 3

Does the potential rate of error associated with the methodology employed by Dr. Ba-tich render unreliable his conclusion that silicone degrades to silicates or silica in the human body?

QUESTION 4

Is Dr. Batich qualified to opine that silicone degradation results in disease in implanted women?

QUESTION 5

Does the methodology employed by Dr. Batich support his conclusion that silicone degrades to silanol groups, converts to silica, and results in disease in implanted women?

QUESTION 6

Is any portion of Dr. Batich’s opinion that silicone gel degrades into silica which leads to disease in implanted women based on speculation, hypotheses, or assumptions?

QUESTION 7

Does the underlying methodology in the Garrido Nuclear Magnetic Resonance (NMR) spectroscopy studies, and the conclusions therein, relied upon by Dr. Batich, support his conclusion that silicone degrades to silicates or silica resulting in disease in implanted women?

QUESTION 8

What “fit” (or relevancy) do the Batich opinions have if the opinions of Drs. Gershwin, Bennett, and Kemple are not founded on accepted scientific methodology?

DATED this 16th day of August, 1996.

MARTIN, BISCHOFF, TEMPLETON, LANGSLET & HOFFMAN

By: /s/ Jonathan Hoffman

Jonathan Hoffman, OSB # 75418

WELLS, ANDERSON & RACE

By: /s/ Mary Wells

Mary Wells, Pro Hac Vice

Of Attorneys for Defendants,

BAXTER HEALTHCARE CORPORATION

and BAXTER INTERNATIONAL INC.

TOOZE, SHENKER, HOLLOWAY & DU-DEN

By: -

Paul Duden, OSB # 66035

Of Attorneys for Defendant, BRISTOL-MYERS SQUIBB

MILLER, NASH, WIENER, HAGER & CARLSEN, LLP

By: -

William Crow, OSB # 61018

Of Attorneys for Defendant,

MINNESOTA, MINING & MANUFACTURING COMPANY (3M)

Jonathan M. Hoffman, OSB # 75418

MARTIN, BISCHOFF, TEMPLETON

LANGSLET & HOFFMAN

3100 First Interstate Tower

1300 SW Fifth Avenue

Portland, OR 97201-5667

Telephone: (503)224-3113

Fax: (503)224-9471

Mary A. Wells

WELLS, ANDERSON & RACE LLC

1700 Broadway, Suite 1850

Denver, CO 80290

Telephone: (303) 830-1212

Fax: (303)830-0898

Kelly P. Corr

BOGLE & GATES

Two Union Square, 51st Floor

601 Union Street

Seattle, WA 98101

Telephone: (206) 682-5151

Fax: (206)621-2660

*1417

Of Attorneys for Defendants, BAXTER HEALTHCARE CORPORATION and BAXTER INTERNATIONAL INC.

IN THE UNITED STATES DISTRICT COURT

FOR THE DISTRICT OF OREGON

Leaann DeGraw Hall, Plaintiff, v. Baxter Healthcare Corporation, et al., Defendants.

Case No. CV 92-182-JO-LEAD

94-892-JO

94-903-JO

94-907-JO

PROPOSED QUESTIONS REGARDING METHODOLOGY UTILIZED BY PLAINTIFFS’ BIOMATERIALS EXPERT, HAROLD ALEXANDER, Ph.D.

Defendants, Baxter Healthcare Corporation and Baxter International Inc., Bristol-Myers Squibb, and 3M, state that plaintiffs have failed to satisfy their burden of proof concerning the admissibility of the testimony of Dr. Harold Alexander. Plaintiffs did not submit any briefing in opposition to defendants’ motion to exclude the testimony of this witness, nor did plaintiffs submit an affidavit from any expert supporting the methodology utilized by this witness in forming his opinions. Therefore, defendants request that this Court grant their motion

in limine

and exclude the testimony of Dr. Alexander.

To assist the Court in making its decision, defendants propose that the following questions be considered regarding the methodology utilized by Dr. Alexander.

QUESTION 1

Based upon his own research, as well as the generally accepted definition of biocom-patibility, is "it scientifically sound for Dr. Alexander to conclude that silicone as used in silicone breast implants is not bioeompatible?

QUESTION 2

Is the methodology utilized in Dr. Alexander’s research regarding silicones associated with an unreasonably high rate of error? QUESTION 3

Is Dr. Alexander’s research regarding sil-icones consistent with the published scientific literature on the biocompatibility of silicones? QUESTION 4

Based upon his research as well as the generally accepted bioeompatibility testing methodology standards, is it scientifically sound for Dr. Alexander to conclude that silicone has not been adequately tested for biocompatibility?

. DATED this 16th day of August, 1996.

MARTIN, BISCHOFF, TEMPLETON, LANGSLET & HOFFMAN

By: /s/ Jonathan Hoffman

Jonathan Hoffman, OSB # 75418

WELLS, ANDERSON & RACE

By: /s/ Mary Wells

Mary Wells, Pro Hac Vice

Of Attorneys for Defendants,

BAXTER HEALTHCARE CORPORATION

and BAXTER INTERNATIONAL INC. TOOZE, SHENKER, HOLLOWAY & DU-DEN

By: -

Paul Duden, OSB # 66035

Of Attorneys for Defendant,

BRISTOL-MYERS SQUIBB

MILLER, NASH, WIENER, HAGER & CARLSEN, LLP

By:-

William Crow, OSB # 61018

Of Attorneys for Defendant,

MINNESOTA, MINING & MANUFACTURING COMPANY (3M)

Jonathan M. Hoffman, OSB # 75418

MARTIN, BISCHOFF, TEMPLETON

LANGSLET & HOFFMAN

3100 First Interstate Tower

1300 SW Fifth Avenue

Portland, OR 97201-5667

*1418

Telephone: (50B) 224-3113

Fax: (503)224-9471

Mary A. Wells

WELLS, ANDERSON & RACE LLC

1700 Broadway, Suite 1850

Denver, CO 80290

Telephone: (303) 830-1212

Fax: (303)830-0898

Kelly P. Corr

BOGLE & GATES

Two Union Square, 51st Floor

601 Union Street

Seattle, WA 98101

Telephone: (206) 682-5151

Fax: (206)621-2660

Of Attorneys for Defendants,

BAXTER HEALTHCARE CORPORATION and BAXTER INTERNATIONAL INC.

IN THE UNITED STATES DISTRICT COURT

FOR THE DISTRICT OF OREGON

LeaAnn DeGraw Hall, Plaintiff, v. Baxter Healthcare Corporation, et al., Defendants.

Case No. CV 92-182-JO-LEAD

94-892-JO

94-903-JO

94-907-JO

PROPOSED QUESTIONS REGARDING METHODOLOGY UTILIZED BY PLAINTIFFS’ EXPERT PATHOLOGIST, NANCY HARDT, M.D.

Defendants, Baxter Healthcare Corporation and Baxter International Inc., Bristol-Myers Squibb, and 3M, state that plaintiffs have failed to satisfy their burden of proof concerning the admissibility of the testimony of Dr. Nancy Hardt. Plaintiffs did not submit any briefing in opposition to- defendants’ motion to exclude the testimony of this witness, nor did plaintiffs submit an affidavit from any expert supporting the methodology used by this witness in forming her opinions. Therefore, defendants request that this Court grant their motion

in limine

and exclude the testimony of Dr. Hardt.

To assist the Court in making its decision, defendants propose that the following questions be considered regarding the methodology utilized by Dr. Hardt:

QUESTION 1

Have plaintiffs established by the greater weight of the evidence that Dr. Nancy Hardt’s opinion, that silicone migrates through the breast capsule, is based on valid scientific methodologies?

QUESTION 2

Given that Dr. Nancy Hardt has not examined tissue slides from any portion of the anatomy of the four

Andrews

plaintiffs other than the breast capsule, is her opinion that silicone has migrated outside the breast capsule in these women based on accepted scientific or medical practices or methodologies? QUESTION 3

Is any portion of Dr. Hardt’s opinions as described in her witness statement based on speculation, hypotheses, or assumptions?

QUESTION 4

Is Dr. Hardt qualified to testify as to any alleged chemical interaction between silicone and protein?

DATED this 16th day of August, 1996.

MARTIN, BISCHOFF, TEMPLETON, LANGSLET & HOFFMAN

By: /s/ Jonathan Hoffman

Jonathan Hoffman, OSB # 75418

WELLS, ANDERSON & RACE

By: /s/ Mary Wells

Mary Wells, Pro Hac Vice

Of Attorneys for Defendants,

BAXTER HEALTHCARE CORPORATION

and BAXTER INTERNATIONAL INC.

TOOZE, SHENKER, HOLLOWAY & DU-DEN

By: -,-

/s/Paul Duden, OSB # 66035

Of Attorneys for Defendant, BRISTOL-MYERS SQUIBB

*1419

MILLER, NASH, WIENER, HAGER & CARLSEN, LLP

By: -

William Crow, OSB # 61018

Of Attorneys for Defendant,

MINNESOTA, MINING & MANUFACTURING COMPANY (3M)

Michael L. Williams, OSB # 78426

Gayle L. Troutwine, OSB # 83106

Kathleen M. Dailey, OSB # 88188

Kathryn A. Stebner, OSB # 93126

WILLIAMS & TROUTWINE, P.C.

1001 S.W. Fifth Avenue, Suite 1900

Portland, Oregon 97204

(503) 295-2924

Of Attorneys for Plaintiffs

IN THE UNITED STATES DISTRICT COURT

FOR THE DISTRICT OF OREGON

In re Breast Implant Litigation Pending in the United States District Court, District of Oregon (Group 1)

Case Nos.

Group 1: 92-182-JO LEAD

94-892-JO

94-903-JO

94-907-JO

PLAINTIFFS’ PROPOSED QUESTION REGARDING NMR TECHNOLOGY AND THE PUBLISHED PEER-REVIEWED STUDIES OF DR. GARRI-DO AND OTHERS

Plaintiffs propose the following question regarding nuclear magnetic resonance (NMR) technology:

QUESTION

Is nuclear magnetic resonance (NMR) technology, as used by Leoncio Garrido and his colleagues and other groups conducting research on silicone, a scientifically valid method to identify and monitor the presence of silicon compounds in tissue and blood and to detect changes in the chemical composition of silicone after it has been introduced into animals and humans when:

A. Results have been published in three different peer-reviewed journals on eight different occasions between 1991 and 1995, as follows:

1. Garrido, L., Mark, J.E., Sun, C.C., Ackerman, J.L., Chang, C.,

NMR Characterization of Elastomers Reinforced With In Situ Precipitated Silica,

24(14) Macromolecules, 4067-72 (1991).

2. Pfleiderer, B., Ackerman, J.L., Garrido, L.,

In Vivo1

Chemical Shift Imaging of Silicone Implants,

29(5) Magnetic Resonance in Medicine 656-6549 (1993).

3. Garrido, L., Pfleiderer, B., Papisov, M.; Ackerman, J.L.,

In Vivo Degradation of Silicones,

29(6) Magnetic Resonance op Medicine, 839-843 (1993).

4. Pfleiderer, B., Ackerman, J.L., Garri-do, L.,

In Vivo Localized Proton NMR Spectroscopy of Silicone,

30 Magnetic Resonance in Medicine 149-154 (1993).

5. Pfleiderer, B., Ackerman, J.L., Garri-do, L.,

Migration and Biodegradation of Free Silicone Gel-Filled Implants after Long-Term Implantation,

30 Magnetic Resonance in Medicine 534-543 (1993).

6. Garrido, L., Pfleiderer, B., Jenkins, B.G., Hulka, C.A., Kopans, D.B.,

Migration and Chemical Modification of Silicone in Women with Breast Prostheses,

31 Magnetic Resonance in Medicine 328-330 (1994).

7. Pfleiderer, B., Xu, P., Ackerman, J.L., Garrido, L.,

Study of Aging of Silicone Rubber Biomaterials with NMR,

29 JJBiomedical Materials' Research 1129-MO (1995).

8. Pfleiderer, B., Garrido, L.,

Migration and Accumulation of Silicone in the Liver of Women with Silicone Gelr-Filled Breast Implants,

33(1) Magnetic Resonance in Medicine 8-17 (1995).

B. Additional abstracts have been published or presented to colleagues at scientific conferences, as follows:

1. Garrido, L., Pfleiderer, B., Ackerman, J.L., Moore, J.,

Characterization of Biom-aterials with NMR,

Materials Research Society Symposium Proceedings, 217:49-54 (1991).

2. Pfleiderer, B., Moore, J., Ackerman, J.L., Garrido, L.,

Study of the Aging Pro

*1420

cess of PDMS Implants In Vivo and Ex Vivo by Nuclear Magnetic Resonance Spectroscopy and Imaging,

330 PolymeR PREPRINTS (published by the American Chemical Society) 767-768 (1992).

3. Garrido, L., Pfleiderer, B., Ackerman, J.L., Brady, T.J.,

Detection of Silicone Migration and Biodegradation with NMR,

Abstract Presented at the National Institutes of Health Immunology of Silicones Workshop, Bethesda, Maryland, Mar. 13-14,1995.

C. Data is the result of a collaborative effort of multiple scientists at the NMR Center, Department of Radiology, Massachusetts General Hospital and Harvard Medical School;

D. Data is the result of numerous tests run on animal and human tissue and blood samples;

E. Other scientists in the field, including those who work for the Center for Devices and Radiological Health, FDA, use almost identical methods to identify silicone in tissue and blood;

F. Local NMR specialist, Dr. David Pey-ton, from Portland State University agrees that Dr. Garrido is most likely seeing a real silicone signal, even in the one study that is being questioned by Dr. Peter Macdonald.

G. Only one paper exists that criticizes a single conclusion made by Dr. Garrido’s group when they used a single NMR technique

to identify silicone levels in the blood but which does not address any other conclusions made, the appropriateness of NMR techniques to identify molecule structure in general

or other NMR techniques used by Dr. Garrido in identifying or analyzing silicone in any other circumstance;

and has

*1421

only used one set of samples in attempting to confirm the work of Dr. Garrido and his colleagues;

H. Even the study which allegedly brings Dr. Garrido’s methodology into question confirms Dr. Garrido’s ultimate conclusions.

DATED this 13th day of July, 1996.

Respectfully Submitted,

WILLIAMS & TROUTWINE, P.C.

/s/ [Signature]

Michael L. Williams, OSB # 78426

Gayle L. Troutwine, OSB # 83106

Kathleen M. Dailey, OSB # 88188

Kathryn A. Stebner OSB # 93126

Of Attorneys for Plaintiffs

Mike L. Williams, OSB # 78426

Gayle L. Troutwine, OSB # 83106

Kathleen M. Dailey, OSB # 88188

Kathryn A. Stebner, OSB # 93126

WILLIAMS & TROUTWINE, P.C.

1001 SW 6th Avenue, Suite 1900

Portland, OR 97204

Telephone: (503) 295-2924

Of Attorneys for Plaintiffs

Pursuant to L.R. 120-l(e), a complete list of all counsel submitting this document for filing appear on the signature page to this motion.

IN THE UNITED STATES DISTRICT COURT

FOR THE DISTRICT OF OREGON

In re Breast Implant Litigation Pending in the United States District Court, District of Oregon (Group 1)

Case Nos.

Group 1: 92-182-JO-LEAD;

94-892-JO

94-903-JO;

94-907-JO

PLAINTIFFS’ PROPOSED QUESTIONS REGARDING CHEMISTRY AND PLAINTIFFS’ EXPERT CHEMIST

Plaintiffs propose the following questions regarding chemistry and expert chemist, Christopher D. Batich, Ph.D.

QUESTION 1

Have plaintiffs established by the greater weight of evidence that Dr. Batich used a scientific methodology to arrive at his conclusion that silicone liquid, in the form of micro-droplets, as well as isolated small molecules, diffuse through the thin silicone elastomer and migrate throughout the body, by using the following methodology?

A. Reviewing the medical literature that demonstrates silicone fluids injected into animals are picked up by macrophages and migrate throughout the body? (Ex. C, # 1, 2, 3)

B. By reviewing the medical literature on migration of silicone in women:

*1422

(1) Dr. Nancy Hardt’s studies; (Ex. A # 100,162,163)

(2) Dr. Garrido’s studies on migration in animals; Ex. C, # 4, 5, 6, 7, 8)

(3) Dr. Garrido’s studies on migration in women; (Ex. A, # 3, 6)

(4) The FDA abstract confirming migration of silicone to the liver of women using NMR techniques; (Ex. A, #80)

(5) Published studies showing elevated levels of silicon in tissue and blood of implanted women. (Ex. A, # 97, 98, 166,167; Ex. C, # 9)

C. By reviewing internal Dow Corning reports showing migration of silicone in animals to distant parts of the body; (Ex. C, # 10; Ex. B, Le78.DC, La68, K087, Cu85, Re67, Tr88)

D. By conducting his own studies showing that silicone leaves the implant and migrates to the brains of animals; (Ex. C, # 11)

E. By reviewing the literature indicating that the 80% liquid constituting the bulk of the silicone gel materials inside an implant steadily depolymer-izes, forming new low molecular weight silicone chains as the earlier formed ones bleed out and diffuse into the body; (Ex. C, # 13; Ex. B, MC87-DC)

F. By conducting his own peer-reviewed, published gel bleed study? (Ex. C, #12)

QUESTION 2

Have plaintiffs established by the greater weight, of the evidence that Dr. Batich used scientific methodology to arrive at his conclusion that silicone is chemically changed in the body in ways that would make it more biologically active?

A. By reviewing internal Dow Corning studies on metabolism of silicone compounds in animals? (Ex. C, # 14, 15)

B. By reviewing published reports in the scientific literature, and sworn expert testimony of Dow Corning chemists, on the degradation of silicones into silica in the environment? (Ex. C, #16, 17; Ex. B, An94-Dc; Ex. B, Vo82, Ge82 & Ma83)

C. By reviewing published reports in the scientific literature showing that silicone physical properties decline over time when exposed to the body’s environment? (Ex. A, # 18; Ex. C, # 22, 23)

D. By reviewing internal Dow Coming studies showing that in people who accidentally inhaled vapors of silicone, the methyl groups were chemically removed before the material was excreted in urine? ■ (Ex. B, An80-Dc)

E. By conducting his own experiment with his masters student, Mr. DePal-ma, using contact angle measurements to estimate the rate of change to a hydrophilic surface, (i.e., rate of formation of silanol groups on silicone surfaces in the body), and by reviewing the Dow Coming (Kennan) study which confirmed thé DePalma data? (Ex. C, # 20,21)

F. By reviewing studies which show that the toxic effects of both crystalline and amorphous silica derive from the surface chemistry of silanol group formation on particles inside cells, indicating that there is no qualitative difference, only a quantitative difference, between the cellular toxicity of amorphous and crystalline silica? (Ex. A, # 30, 40, 45, 115,112; Ex. B, Zh87a, Le78de, Ra90)

G. By conducting his own research to conclude that the surface area of silicone mierodroplets exposed to the body’s chemical machinery greatly increases over time? (Ex. A, # 45)

H. By reviewing published, peer reviewed studies demonstrating silicone degradation in animals? (Ex. B FE70, FE67; Ex. C, 19)

I. By reviewing published, peer-reviewed articles containing evidence of silicone degradation in

in vitro

experiments, animals and humans? (Ex. A #43, 169; Ex. B Ga93a, COc76, SP80-dc)

*1423

Respectfully submitted, this 13th day of August, 1996.

WILLIAMS & TROUTWINE, P.C.

By /s/ [Signature]

Michael L. Williams OSB # 78426

Gayle L. Troutwine, OSB # 83106

Kathleen M. Dailey, OSB # 88188

Kathryn A. Stebner, OSB # 93126

Of Attorneys for Plaintiffs

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*1424

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*1425

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*1427

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Cur

*1429

rent Topics in Microbiology and Immunology

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*1430

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*1431

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130. Smedley, H.; Katrak, M.; Sikroa, C.; Wheeler, T.; “Neurological Effects of Recombinant Human Interferon”,

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*1432

141. Wagner, M.M.F.; Wagner, J.C.; “Lymphomas in the Wister Rat After Intrapleural Inoculation of Silica”,

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148. Digby, J.M.; “Malignant Lymphoma With Intranodal Silicone Rubber Particles Following Metacarpophalangeal Joint Replacements”,

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149. Koeger, A-C; Lang, T.; Alcaix, D.; Milleron, B.; Rozenberg, S.; Chaibi, P.; Arnaud, J.; Mayaud, C.; Camus, J-P.; Bourgeois, P.; “Silica-Associated Connective Tissue Disease”,

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154. Niezborala, M.; Garnier, R.; “Allergy to Complex Platinum Salts: A Historical Prospective Cohort Study”,

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157. Harbut, M.R.; Churchill, B.C.; Green, M.A.; ' “Asthma in Patients With Breast Implants: Report of a Case Series”, Submitted for publication (1994) — not yet accepted.

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164. Love, L.A.; Weiner, S.R.; Yasey, F.B.; Crofford, L.J.; Oddis, C.V.; Starr, M.R.; Bridges, A.J.; Targoff, I.N.; Gurley, R.C.; Miller, F.W.; “Clinical and Immunogenetic Features of Women Who Develop Myositis After Silicone Implants”, Abstract accepted for presentation; (1992).

165. Cuellar, M.L.; Espinoza, L.R.; Ochs, R.; Tan, E.M.; “Development of Monoclonal Gammopathy and Hypergam-maglobulinemia in Silicone Breast Implant (SBI) Women after Long-Term Exposure”, Abstract presented 2/1/96 to Southern Regional Meeting of the American Federation for Clinical Research, New Orleans, LA.

166. Sun, L.; Ricci, J.L.; Alexander, H.; Klein, A; Lattarulo, N.; Blumenthal, N.C.; “Silicone in the Blood and Capsule of Women with Breast Implants”, Fifth World Biomaterials Congress, Toronto, Canada (1996).

167. Lugowski, S.; Smith, D.C.; Semple, J.; Peters, W.; McHugh, A; “Silcon levels in blood, breast milk and breast capsules of patients with silicone breast implants and controls”, Fifth World Biomaterials Congress, Toronto, Canada (1996).

168. Nicholson, III, J.; Hill, S.L.; Frondo-za, C.G.; Rose, N.R.; “Silicone Gel and Octamethyleyclotetrasiloxane [D4] Enhances Antibody Production to Bovine Serum Abumin in Mice”, Fifth World Biomaterials Congress, Toronto, Canada (1996).

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Dr. Chris Batieh

Aug., 1996

*1434

EXHIBIT B

OUTLINE WITH REFERENCES

I.Silicone is released from breast implants into the body

A. Rupture of gel implants

1. PNS involvement (SA92)

2. many papers, eg. (R089), 38% ruptured

3. gel depolymerized at 36 deg C, penetration 70-350 (MC87-dc)

B. Gel bleed

sweating of gel — contracture (WI83)

implants in rats (GA93a)

imaging 29Si (GA93b)

in capsules (GA79)

implants in rabbits (Habal + EPG) (HA93) UF/Lenny Yu

sticky surfaces on explants (27%) (R089)

C. Also released from saline filled (low mol. wt. in envelope) (WI83)

(VA79)

“Grazing” caused by pectoralis muscle friction (K083)

Adjuvant effect in saline implant (HE92)

in capsule (GA79)

erosion

of edges->leakage (gel too) (SC80)

sheet used to treat burns (HA94)

extraction of shell (2-6%) and bioresponse (CU85)

D. Gel had much lower mol. wt. sol. (PE77)

(ST77) (DU77)

II.Silicone is distributed to various organs from the capsule surrounding the implant

A. Sub Q to throughout body (LA68-dc)

B. Oral (Le73-de),(LA68-dc)

C. Molecular weight makes little difference (LA68)

(FDA83)

(K087)

D. Injection and implants in rats, to liver (GA93a)

E. Histology in rats, likely to RE system (CU85)

F. Below hexamers of PDMS, readily absorbed and distributed (LE78)

G. Lungs pick-up 20% of breathed mist and excrete in urine in 8 (AN80) hrs. for 344 cs fluid (mainly D4)

H. Sub-Q or peritoneal, thru RE system in mice (RE67)

I. Lymphoadenopathy if ruptured (TR88) TEM shows in vacuoles

J. Contrary Data vs. Garrido (MA95)

III.Silicone is biologically active

A. Protein, Lipid ad/absorption (K087)

B. Thrombogenesis, worse when filled (OP94)

C. Cell stimulation

1. Monoeyte/macrophage

a. IL-1 production (MI89)

b. interferon (p. 219 LA94d-dc)

e. increased numbers (scores) (MA94)

2. Fibroblast

a. proliferation and collagen synthesis (MI89)

(K087)

b. faster growth from sheet with D4, cf. 85 paper by Quinn on burns (HA94)

c. cellularity (CU85)

3. liver, 38% inc. in 2 wks of D4 (BI90)

*1435

D. calcification of capsule (PR83, VA79)

without steroid (FE84)

F. eye inflammation — gone in 24 hrs. p351 “as with any good solvent, avoid repeat contact” ocular toxicity (Nadamura and Refojo) (R048-Dow) (NA91)

G. possible teratogen

H. Adjuvant

1. PDMS to Si02 “a well known adjuvant” (GA93a)

2. 10/10 ANA’s in saline/silieone women (SH93)

3. Plasma cells in one case (GA79)

4. Cell-mediated immunologic response (K087a)

5. in “Ab to PDMS”S looks like to Alb] (W093)

6. D4 an adjuvant in mice 0.1 to 0.4ml/mouse (Lake’s study) overt toxicity at 0.4 + most tests. (LA75-de)

7. Scleroderma reversal on removal very unusual. (SC92 p.

8. 10/4 with ANA’s in silicone gel patients w. symptoms. (PR92)

9. Gel an adjuvant, fluid not (DC) (MA93a)

10. " " " " " (Naim) (NA93)

11. of silicone-protein complexes (K087b)

12. DNA changes in lymphocyte (DA92)

13. Antigenicity of collagen augmented by silicone in mice. (TA92)

14. D4 0.05ml. emulsion and BSA in rats 10” x saline, lasts 2 mo. (B074)

15. sililized S aureus provoked reduced but lengthened immune response (IS73de)

I. Capsule Formation

1. Thicker for textured PDMS (BE92)

2. B cells and others present (GA79)

J. Pharmaceutical use/activity

1. brain dopamine increase from diphenyl D4 (DC patent) (BE74p)

2. D4 is an for (LE78)

3. 2,6-cis and D4 iner. rat uterus (HA72-Dow)

K. Inhibition

1. immune (fluid) (NA93)

2. allows bacteria in valve to grow (MA92)

L. Embolism (YU93)

M. Wt. loss in rabbits, hence spontaneous abortion (BI90)

N. dimethicone toxic to lice (L079)

O. (as seen in autoimmun) (p225 LA94d-dc)

P. hepatomegly, enzyme induction in rats (ME89-dc)

Potentiates infection depletes C3a (MA96)

IV. Composition changes in PDMS

A. Reactions (hydrolysis and oxidation)

1. hydrophobic to hydrophilic (LE91pl4), (BA92) ie us

2. oral D4 in rats to MeSi03 species in urine [crosslinking reaction?] oxidative removal of Me groups in D5 called “adverse effect” (MA88-dc)

3. oxidation in rat livers to Si02 (GA93a)

4. environmental degradation, clays in rivers cause hydrolysis (Fe and Ca aid oxidation of Me groups) (MA83)

also PDMS to silanols in soil then silica DC lit. (AN94)

5. silicone compounds more reactive than carbon esp. to nucleo-attack 476)

6. loss of Et group seen in rat urine (FE67), also breathed of D4 formed 20% in urine in 8 hrs and monomethyl silicon seen (demethylated in human) (AN80-dc)

7. oxidation of Ph and CH3 in PhSilanes (FE70,SP80-de)

8. slow increase in sol in extracted elastomers under mild conditions (V082)

9. increased adhesion to polar surfaces (GE82)

*1436

10. stress relaxation 25 deg, moist air (OS54)

11. rupture increases with age (de93)

12. RT hydrol. in dioxin/H20 if piperidine cat. (V078)

13. Ultrasound accelerates SiO bond cleavage (V078,p85)

14. Depolymerization at >1.75 ppm K at 36 deg C seen by penetration (Mc87-dc), normal gel is lOOppm K (WE70-dc)

15. non-enzymatic hydrolysis if low mol wt pdms due to solubility (LE88-dc)

16. yeast grow into and under pdms surface (NE93)

B. Background on oxidation

1. long lived oxidants in PMN’s (WE83)

2. oxidative burst by opsonized PEC + bact (GI85)

C. Silanols

1. conjugation

a., stable in vivo (LE78-dc)

b. surf silanols adsorb proteins in electrophoresis (TO90)

2. reactivity

a. for cryst. or amor. Si02, inc. in SiOH gives inc. in cell lysis (RA90)

b. bioaetivity of silicones proportional to hydrolysis rate (LE78-dc)

3. surface silanols

a. toxicity of Si02 depends on silanols (reduced after heating to 800 deg) (SH89, p 442)

b. SiOH dep. on processing, not type of Si02 (ZH87)

c. scleroderma inc. with Si02 exposure (C087)

d. all a-Si02’s c.4.9 OH’s per nm2 (ZH87a)

e. Si diols more reactive than C (LE78-dc)

f. modification of surface changes react (LE91-dc,pl2)

g. catalase lowers hemolysis, more needed per OH (RA90)

4. related silica phenomena not mentioning SiOH a.

V. Data not perfect

A. variable mfg. and materials, FDA

B. ETO release?

C. elong. data discarded by DC if low (C091)

D. uncertain adjuvant study? (CR93)

E. DC altered implant data (AP92)

F. gel formulation is trial and error (Mc87-de,p6)

EXHIBIT B

Cited Literature:

AN80-dc

Annelin, R B

DC Toxicology Dept. Report

May 29,1980

344 cs mist (mainly D4), breathed gave 20% in urine in human in 8 hrs, showed monome-thyl silicone, hence demethylated.

Same general results in human milk (but more mono Me than di)

AN94~dc

anonymous

Materials News (DC literature)

Jul/Aug 94 p. 11

Degradability of silicone fluids pdms goes to silanols in soil, then to silica

BE74p-dc

Bennett, D. and Levier, R.

US Patent 3,821,373 (June 28,1974)

Organosilicone compositions in methods of treatment involving increasing the dopamine content of the brain (2,6-cis)

BE92

Bern, S. et al.

Biophysical and histologic properties of capsules formed by smooth and textured silicone

*1437

implants in the rabbit

Has Recon Surg 89:1037-1042 (1992) textured silicone surface forms thicker, more inflammatory

capsule than smooth surfaced saline implants (how does cell know?) [applied stress]

BI90-de

Birdsáll, A.

D4 — US EPA Reports (a DC repori/sum-mary to Stark et al.)

Nov 5,1990 (+related later reports)

14 day exposure to high oral levels of D4 in rats

data: 38% increase of liver wt., chronic inflammation

liver hyperplasia, not hypertrophy

conclusion: “no health risk”

also rabbit wt loss and spontaneous abortions

BL71

Blocksma, R

Experience with Pdms fluid in soft tissue augmentation

Pías Reeon Surg 48:564^567 embolism problems, migration noted

B074-dc

Boley, W. and LeVier, R.

Immunological enhancing activities of orga-nosilicone compounds and non-functional fluids

DC report 4319

0.05 ml emulsion plus BSA in rat footpad, D4 10b6 X salinej lasts 2 months

CA92

Callahan, Thomas (FDA report)

Significance of Dow Corning Studies Omitted From Their PMAs June 24,1992

CE93

Centeno, J. and Johnson, F.

Microscopic Identification of Silicone in Human Breast Tissue by IR-microscopy and X-ray

Applied Spectroscopy, vol 47, p. 341-345

? CH92

Chwirut, L.

Dow Corning Single and Double Lumen SI-

LASTIC II and MSI Breast Prostheses

March 13,1992

CH91

Chemistry Group Leader (FDA?)

Pharmacologist, Chemistry Group, DMMS,

OST, HFZ-150

Pg. 10; September 20,1991

variable production p7

ETO release p9

COe76

Cotton and Wilkinson

Advanced Inorganic Chemistry, 2nd ed. silicon more reactive than carbon, esp. nu-cleophilic attack

C087

Cowie, R.

Silica dust exposed mine workers with sclero-derma (systemic sclerosis)

Chest 92:260-262 increased in gold miners

C091

Coyne, Laurence

Dow Corning Single and Double Lumen Si-

lastic II and Silastic MSI

Breast Protheses: In-Depth Review of Gel

Bleed and Mechanical

testing Submitted in December 13 Amendment

December 20,1991

elongation at b values discarded if low hard to read data

CR93

Cruzas, Susan

Immunology Studies on Silicone Gel March 22,1993

FDA release mentions Naim and DC studies, uncertainties

CU85

anonymous Cox-Uphoff international report Oct. 10,1985

Characterization of C-U silicone elastomer shells

pl7 shell extract (2-6%) c. 1000 mol wt, low bleed extracts

sometimes had aromatic residue from diPh+di-Me layer;

absorbs oil from gel and weakens (plastici-zation)

artifacts on surface , ,. silicone lost from paraffin histology (not plastic)

*1438

■ less response (lymphocytes) to extracted shells

? DA81

Davies, R

Effects of Synthetic Silicas on Mouse Peritoneal Macrophages In Vitro American Society for Testing and Materials 1981 pg 67-81

? D091

Dow Corning Corporation

Pharmacologist, Chemistry Group, DMMS,

OST, HFZ-150

pg 7, 9 September 20,1991

DU77

Duncan, E

3M Memo: McGhan Mammary prostheses

analysis

28 June 1977

Molecular weight distributions and percent solubles

? EP88

Epidemiology Branch

A review of the article titled “the Relationship Between Breast Cancer and Augmentation Mammaplasty....”

July 25,1988

FE70

Fessenden, R Et al

Metabolic Fate of Phenyltrimethylsilane and Phenyldimethylsilane

Journal of Medical Chemistry 12 52- (1970) Phenyl group oxidized, and Me group in Ph silanes

FE67

Fessenden, Ralph Et al

The Metabolic Fate of Come Silicon-Containing Carbamates

Journal of Medical Chemistry 10 810 (1967) dealkylation a metabolic path for organosili-cones in rat urine

GA79*

Gayou, R.

Histological comparison of contracted and non-contracted capsules

around silicone breast implants Pías Recon Surg 63:700-707 (1979)

Si in most capsules, inc. saline, saw some plasma cells

GA93a

Garrido, Leoncio et al

In Vivo Degradation of Silicones [vinyl 7% ] Mag. Res. in Med. 29:839-843 (1993) silicones not inert in rats, form Si02, known adjuvant

GA93b

Garrido, Leoncic et al

Echo-Planar Chemical Imaging of Silicone Gel Prostheses

Mag. Res. Imaging 11:625-634 (1993) shows gel bleed (14-28% extractable), can see rupture

GA93c

Garrido, L

Mag.Res. in Med. p. 53 Human livers

GA94

Gabriel, S. et al.

Risk of connective-tissue diseases and other disorders after breast implantation

NE JM 330:1697-1749

only morning stiffness effect, did not look at age of implant,

did look at classical forms of scleroderma etc. GE82

Gent A and Vondracek P Spontaneous adhesion of silicone rubber

J Appl Polym Sci 27:4357-4364 erosslinked rubber slowly adheres to polar surface with time,

accelerated by moisture, due to hydrolysis GI85

Ginsburg, I. et al

Chemiluminescence and superoxide generation by leukocytes

stimulated by polyeleetrolyte-opsonized bacteria

Inflammation 9:245-271 oxidative burst background

HA72 (DOW)

Hayden, J and Barlow, S

Toxicology and Appl. Pharm. 21 p68-79

Structure activity relationships of Organosi-lanes on the female reproductive system. 2,6-cis active (+ 4), D4 active (+1 +)

HA94

Haggard, W; Lemmons, J

Response of normal dermal and keloid scar

fibroblasts to cyclic siloxanes

*1439

Trans Soc Biomat 20th meeting, pl47 D4, D5 etc most common low mol wt released caused altered fibroblast growth

HA93

Habal M., ... Goldberg

Evaluation of silicone gel mammary

prostheses in a rabbit implant model Trans soc biomat. 19th meeting,

2-12 mg pdms per gm of tissue in capsule

* * *move to “M” * * * MA93a MalczewaM, R et al

A Humoral Adjuvant Study in the Rat of

Dow Corning Silicone Gel

Preparations and Mammary Gel Bleed

September 1,1993

confirms Naim’s results, gel is an adjuvant, fluid not

HE92*

Heredero, F. and Semper, E.

Polyarthralgia after augmentation mamma-plasty with saline-filled implants Eur J Pías Surg 15:1-8 (1992)

ANA’s and pain resolved after removal

IL79

Iler, Ralph

The Chemistry of Silica

Pg. 753, 764, 768, 769, 770, 774, and 776;

1979

p770: exposure in open wound very bad but unlikely

IS73de Isquith, A.

Exploratory antigen modification proj. 0833-01

exhibit D in silicone toxicity symposium (Texas Oct. 1994)

sililated S aureus provoked lowered but longer (X2) immune resp.

J073

Jolles, P and Parf A

Chemical and Biological Basis of Adjuvants Springer 1973

p70 reported in 1958, Ab to autologous RBC’s with adjuvant, did not cause persisting disease

KH93

Khan, M. et al.

Evaluation of_for sustained release of antigen

Int. J Pharmaceutics 90:255-262 (1993) continuous release of BSA antigen much more effective than 3X bolus.

K083

Kossovsky, Nir et al.

Analysis of the surface morphology of recovered b. implants

Plast. and Recon. Surg. v.71, 795-802

cells embedded in shell; rubbing or grazing

K087a

Kossovsky, Nir et al.

Bioreactivity of silicone

CRC Crit Rev Bioeompatibility 3:53-85 (1987)

cell mediated immunological reaction, lit review, inhibits also

silanol groups can interact with protein K087b

Kossovsky N, Heggers J and Robson M Experimental demonstration of the immuno-genicity of silicone-protein complexes J Biomed Mat Res 21:1125-1133 pll31 silica free high surface area fluid

KL93

Klykken, P Et Al

A Humoral Adjuvaney Study of Dow Corning Silicone Fluids Alone

(360 Fluid, 20 cs, 7-2317, 1000 cs) and DOW CORNING 360 Fluid,

20 cs, Mixed with Dow Coming Mammary Gel (Q7-2159A) or McGhan Mammary Gel in the Rat.

March 9,1993; Pg 9

KL94^dc

Klykken, P. et al.

Humoral adjuvaney study of D4, gel bleed, sheared gel, etc. DC report 3-29-94 sheared gel amarked adjuvant, bleed and D4 not so

LA68

Lacefield, R. et al (Stark)

Biological distribution of PDMS (restricted report)

DCC Report # 3323, June 3,1968

D4 and linear in bile, brain, fat and liver

LA75-de

Lake, R. and Radonovich, M

Action of PDMS on the reticuloendothelial

system of mice: basic

cellular interactions and structure/aetivity relationships

*1440

DC report 4509, Oet 30,1975

Fig 1 shows lowest dose (0.1ml) gave adju-vant effect (IF after endotoxin), overt toxicity at 0.4ml, most tests at 0.4ml.

Max effect at 2 days

L3, L4, D4, D5: incr. interferon production after endotoxin

deer, e-partiele clearance larger than 5-dms units, caused eosinophilia

? LA94d-de

Lake, Robt. depo

April 20,1994

pl60 in 70’s DCC worked with Beecham to develope adjuvant

p219 D4 stimulates MPh to produce interferon

p219 D6, L6 and above cause eosinophilia, ef autoimmune dis.

Le73-dc

LeBeau, J. and S. Girwunski (Dow-Corning) Primate Absorption and Elimination Balance Studies Studies

Including Pulmonary, Urinary, biliary and

fecal excretion of 2,6-eis and D4

Soc of Toxicology, March 19, Abstract # 18

pl3

absorbed and passed thru the liver, excreted in urine and air

LE78-dc

LeVier, R., et al.

The Pharmacology of silanes and siloxanes

from ‘Biochemistry of silicon and related

problems’ ed. G. Bendz and I. Lindquist,

Plenum pub. 1978

p480 silanols stable in vivo

481 inertness required for biomat.

486 below hexamers of pdms absorbed

487 antifoams absorption and excretion 499 silicone diol more reactive

501 activity related to ease of hydrolysis (silanol formation)

507 rapid distribution, reversible sequestering in tissues

*496 D4 is agonistic to reserpine

LE88-dc

Levier letter 1-2-88 revised 1-20-88 (DCC-010006223)

possible immunotox study.

We have known DMS’s of low mol wt have extensive in vivo

degradation dependent on non-enzymatic hydrolysis if siloxane is sufficiently soluble in water.

LE91

LeVier, Robt.

“Shanklin Manuscript”

May 14,1991

DC report(?) to Jack Fisher, M.D. attack on some submitted paper?

pl2 surf adsorp. on Si02 decreases bioactivity

pl4 superoxide may oxidize off a Me group

surface becomes hydrophilic, then hydrophobic

pl5 “no in .vivo mechanism that can reduce the chain length.”

[hydrolysis and also redistribution]

L079P

Lover, Myron et al (Block Drug Co.)

Siloxane Toxicants (patent) simethicone toxic to lice

? MA83

Mahone, L. et al.

Method for qualitative and quantitative characterization of waterborne organosilicones

Env.Tox. and Chem. 2:307-313 Clay in rivers causes hydrolysis, Fe and Ca cause oxidation

MA88 -dc

Malczewski, R.M. et al.

An assessment of the MeSi03/2 content of feces and urine obtained 24 hours after oral

Administration of D4 to Rats Dow-Corning Study, (internal) Aug 17,1988

? MA92

Marshall, Wilm, and Leggett, J.

Misdiagnosis, a timely reminder

Ann Plast Surg 29:444-445 valve stems of double lumen HS implants had coag. neg Staph

showed palindromic rheumatism resolved when removed

MA94

Malczewski, RM et al

Comparative histology study of cellular responses to common implant materials Trans soc biomat. 20th meet p 436 all low level responses to 120 days

*1441

Pdms fluids caused significantly higher macrophage scores

* * *move to right spot* * *MA66

Martellock A (Wayne state U)

The hydrolytic degradation of silicone polymers

Int. Conf in Elastoplastics Technology March 24,1966

t, T, acids, bases cause hydrolysis, mol wt equilibration, see some cross-linking (Si-C cleavage p5)

MA95

McDonald, Peter et al (u. Toronto)

Anal-Chem. v.67, p3799-3801 Si-29 sensitivity for Garrido’s work too low to detect Si in liver (DC funded)

Mc87-dc

MA96

Marosok, R. et al.

Contribution of vascular catheter material to the pathogenesis of infection: Depletion of complement by silicone elastomer in vitro

J Biomed.Mat.Res. v30,245-250 quotes Sherertz paper showing PDMS worse than PU, PTFE, PVC for infection in catheters.

McCoy, Sharon

DC report 0058 April 1,1987

Potassium >1.75 ppm causes depolymerization of gel at 36 deg C

cured at 160 deg, penetration spec 70-320, trial and error used to formulate gel

Me88

McCauley

effects of pdms on fibroblast growth Surg.Forum v39, 632-633 tissue culture effects

ME87

Medtox Project

Analysis of Internal Safety Studies Relevant

Health Care

Materials and Products

pg. 4,10,11,12, 25, 33, and 35; February 23, 1987

p 11 bolus gives 1-2 weeks response pl2 prolonged response may promote autoan-tibodies

ME89-dc

Mehendale, H.

Evaluation of the liver microsomal enzyme induction potential of D5 DC file no. 3724-10 April 17,1989

2000mg/kg orally in rats, hepatomegly, induction of drug metabolizing enzymes (similar to phenobarbitol), reversed upon cessation

? MI36

Miller, J. et al.

The Physiological Response of Peritoneal Tissue to Certain Industrial and Pure Mineral Dusts

U.S. Public Health Repts 51:1677-99: December 4,1936

MI89

Miller, k. et al. (Jim Anderson)

ILl-like activity due to implants ...

JBiomedMatRes v23,1007-1026

Polymer surfaces change growth and IL-1 production

NA66

Nash, T. et al.

Physio-chemical properties of silica in relation to its toxicity Nature 210 p 259-261

long known that silicic acid reacts with proteins/lipoproteins

large H-donor molecules are tanning agents (eg. silicic acid)

stronger interaction with phospholipids than

proteins

NA93

Naim, J., Lanzafame and van Oss

The adjuvant effect of silicone-gel on antibody formation in rats

Immunological investigations 22, 151-161 (1993)

c lmg gel strong adjuvant, fluid weaker and inhibits immune response in rats.

NA91

Nakamura, K.: Refojo, M. et al.

Ocular toxicity of Low-molecular weight components of silicone and flurosilieone oils Investigative Ophthalmology and visual science 32:3007-3020

D4 causes severe inflammation and edema in

eye

NE93

Neu, T. et al.

Biodegradation of medical grade silicone rubber used in voice protheses: SEM study

*1442

Biomat. vl4, 459-463

yeast grow under surface of PDMS and 700 microns into surface.

OP94

Oppelt, William

deposition

Jan. 11,12,1994

static developed during dipping which attracted particles which stuck to shell

OS54

OsthoffR. etal(GE)

Chemical stress relaxation of PDMS JAmerChemSoc 76:4659-4668 moist air at 25 deg

(move) RA90a Randurangi, R. et al.

Surface and bulk infrared mikes of crystalline and amorphous

silica particles: study of the relation of surface structure to cytotoxicity of respirable silica.

Environ Health Perspect 86:327-36 more silanols for both crystalline and amorphous, more cell lysis

PE77-dc Peters, S.

Mammary Gel Review, Part II

Oct. 20,1977

much extractable

? PF93

Pfleiderer, Bettina et al (and Garrido)

In Vivo H Chemical Shift Imaging of Silicone

Implants

1993

can detect Si at .5%, see none in nodes at 3 or 6 months

? PF93

Pfleiderer, Bettina et al

In Vivo Localization Proton NMR Spectroscopy of Silicone

Mag.Res. in Med. 30:149 (1993)

? PF93

Pfleiderer, Bettina

Migration and Biodegradation of Free Silicone from Silicone Gel-Filled Implants after Long-Term Implantation July 7,1993

PR92

Press, R. et al

Antinuclear autoantibodies in women with silicone breast implants

The Lancet 340:1304-1307 10 of 11 patients with autoimmune symptoms had ANA’s

RA90

Razzaboni, B. et al. (MIT)

Evidence of an oxidative mechanism for the hemolytic activity of silica particles Environmental Health Perspectives 87, 337-341

more catalase needed for crystalline Si02 than amorp. to reduce hemolysis. Propose H202 production by silanols, reaction with Cu or Fe to produce OH rad. ref 6 (Nolan) shows SiOH hemolysis

relation. SiOH known to react with C = 0 in proteins.

RE 67

Rees, Thomas et al. (NYU)

Visceral response to subcutaneous and Intra-peritoneal injections of silicone in mice

Pías Rec Surg vol 39, p402-410 DC’s MDX 4-4011 pdms fluid went thru RE system (nodes, spleen etc.), nice histology

? RE78

Research Veterinary Medical Officer

Pathology Report on Monkeys Exposed to

Amorphous Silica-F

September 6,1978

R048-Dow

Rowe, V. et al.

Toxicological Studies on certain commercial silicones and ...

J Ind Hygene and Tox v30, 332 R089

Rolland C et al. (Quebec)

Nondestructive investigations of 97 excised mammary pros.

J Biomed.Mat res 23, p285-298

sticky surfaces, 38% ruptured, memory folds,

deposits

SA88 and SA73

Saunders, k.j.

Organic Polymer Chemistry Chapman and Hall

p. 397 process of equilibration for mixtures of siloxanes

p. 408 oxidation of Me group above 150 C in air increases fluid

viscosity (cross-linking), -CH3 to -CH200H

*1443

to SiO + CH20 (p. 365 in SA73)

SA92

Sanger, J et al.

Gel infiltration of Nerve.

Plast ree surg 89, p949

SC(57?)

Sehepers G W et al

Biological action of Degussa submicron amorphous silica dust (Dow Corning Silica)

AM.A. Archives of Industrial Health 16:125— 146

a-Si02 toxic, effects resolve when exposure stops (breathing) surface highly variable

SC92

Seheer, Robt. and O’Connor, Kathleen The Cosmetic Surgery Revolution

Summit Pines Press (1992) p 99 reversal of scleroderma on removal very unusual

SC80*

Schmidt, G

Mammary implant shell failure

AnnPlasSurg 5:369-371 (1980) shell of gel and saliné types erode

SH89

Shi, X. et al.

The chemical properties of silica particle surface in relation to silica-cell interactions J Toxicology and Environ.Health 27:435-454 silanols cause cell lysis, few years acute, 20-30 yrs chronic

SH93*

Shoaib, B. and Patten, B Systemic disease in women following the insertion of saline breast implants

Southern med ass abstract, Oct 1993 10/10 ANA’s plus other neuropathies

SP80-de

Spielvogel, D. and Robinson, R.

Metabolism of D4 in monkey [oral delivery] DC report Dec 10

about 75% recovered in urine and feces as HO(Me2Si)nOH, n=1,2,3 p3 refers to 2,6 cis study showing PhSi(OH)3 formed

ST77

Stutheit, Jan

GPC Study of Mammary Bleed Silicones American Hospital Supply Corp. study

Sept 23 report to Tom Taleott/Heyer-Schulte, all 4 types showed much D4 mol wt and also 10,000 mol wt

ST83-dc, vol I and II Stark, F

.FDA Advisory Panel Hearing on Mammary Prothesis Classification January 26-27,1983

vol I: no C-14 detected in C02, heneé no loss of Me

p25 more oil added to make more responsive implant 1976

vol II: small cyclies teratogen at high dose TA92

Takayama E et al.

Is injectable collagen truly safe?

J Laryngology and Otology 106:704-708 collagen becomes antigenic when mixed with silicone

TE93 ■ !

Teuber, S., et al..

Anti-collagen autoantibodies are found in women with silicone breast implants J Autoimmunity 6:367-377 (1993)

35% of implant women had anti native type II collagen, all developed symptoms after 2 years

TR88

Truong, L. et al.

AmerJSurgPath 12, 484-491

Silicon lymphoadenopathy with implantation, shows TEM of vacuoles

TO90

Towns, J and Regnier, F J Chrom v516, 69-78

SiOH groups on silica tubes need blocking to prevent protein adsorption

VA79 Vargas, A

Shedding of silicone particles from inflated breast implants

PlasReconSurg 64:252-253

particles containing Si-C bonds by IR on implant

V078

Voronkov, M. et al The Siloxane-Bond

*1444

Consultants Bureau (Plenum), NY pl48 at room temp., in homogeneous medium, hydrolysis goes if trace catalyst present (HC1, or piperidine, etc.) for D3,Me6Si20 p. 85 ultrasound accelerates SiO cleavage

V082

Vondraeek P. and Gent A.

Slow decomposition of silicone rubber

JApplPolymSci 27:4517-4523 sol content slowly increases in wet air (after extraction), NH3

accelerates this hydrolysis, also stress relaxation, ref 4 to human body induced changes?

WE70-dc Wetters, J.

Mammary problems

DC memo to Burdick et al., Feb. 4, 1970 normal gel has 100 ppm K (cf. Mc87-dc)

WE83

Weiss, S. et al.

Long-lived oxidants generated by human

neutrophils

Science 222:625-628

superoxide, H202, HOC1, hydroxyl radical, chloramines formed

WI83

WUflmgseder, P et al.

Tissue reations ...

Minerva Chirugia 38, 877 gel bleed

W093

Wolf, L. et al

Human immune response to pdms: screening studies in a breast implant population

FASEB Journal 7:1266-1268 (1993) says Ab to pdms (IgG), but looks like Ab to albumin

YU93

Yu-min Chen et al.

Silicone fluid-induced pulmonary embolism Am Rev Respir Dis 147:1299-1302 3 new cases, one death, review of other cases, one fibrosis

ZH87a

Zhuravlev, L.

Concentration of hydroxyl groups on the surface of amorphous silicas Langmuir 3:316-318

all a-Si02’s have c. same OH surface cone of c. 4.9 OH’s per square nm; surface H20 lost at 175 C, leaving silanols.

ZI92

Zimmer, M

Teratology Studies

DEPOS

FR94D

Frank, Curt

June 27,1994

hard to remove low molecular weight cyclies LA94D

Lake, Robt. (Ph.D. PSU 1970, microbiology, now at Lorillard)

vol 1, April 20

pl43 impaired phagocytosis of MPh affects whole cell network

pl60 DC worked with Beecham to develop silicone adjuvant

p219 D4 stimulated MPh directly —> interferon

D6 and L6 —> eosinophilia

p225 eosinophilia —> immune complex disease, autoimmunity June 13,1996

EXHIBIT C

1. Andrews, J.; “Cellular Behavior to Injected Silicone Fluid: A Preliminary Report,”

Plast.Recon.Surg.,

38(6):581 (1966).

2. Ben-Hur, N.; Ballantyne, D.; Rees, T.; and Seidman, I.; “Local and Systemic Effects of Dimethylpolysiloxane Fluid in Mice,”

Plast.Recon.Surg,

39(4):423 (1967).

3. Failes, J.; Faulbom, J.; Erb, P.; “The Phagocytosis of Silicone Oils of Different Viscosities by Peritoneal Macrophages in the Mouse,”

KMn.Mbl.Augenheilk,

184:450 (1984).

4. Pfleiderer, B.; Moore, J.; Ackerman, J.L.; Garrido, L.; “Study of the Aging Process of PDMS Implants In Vivo and Ex Vivo by Nuclear Magnetic Resonance Spectroscopy and Imaging,”

Polymer Preprints,

33(l):767-768 (1992).

5. Garrido, L.; Pfeiderer, B.; Papisov, M.; Ackerman, J.L.; “In Vivo Degradation

*1445

of Silicones,”

Magnetic Resonance in Medicine,

29(6):839-843 (1993).

6. Pfleiderer, B.; Ackerman, J.L.; “In Vivo Localized Proton NMR Spectroscopy of Silicone,”

Magnetic Resonance in Medicine,

839-843 (1993).

7. Pfleiderer, B.; Ackerman

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