OLD DOC - Additional Information on Polyurethane Mammary Implant & Cancer Risk

[Guest guest]

DEPARTMENT OF HEALTH & HUMAN SERVICES

Date:

From Deputy Director, DSRD (HFZ-410)

Subject: Additional Information on Polyurethane

Mammary Implant & Cancer Risk

to Director, Office of Device Evaluation

Through: Director, DSRD

This memorandum is an addendum of my April 3, 1989 and

May 31, 1990 technical reviews on the same subject.

Our previous reviews did not provide the precise

chemical nature of polyurethane (PU) foam used in the

implant because at that time we were unable to obtain

such information from the manufacturer. Through our

review of several masterfiles from both device

manufacturer and foam manufacturer and communication

with the foam manufacturer and Device EIR, we now can

reasonably document the exact nature of the PU-foam

used in breast implants. This has allowed us to review

and compare two previously published results of animal

studies on similar PU-foams obtained from different

sources.

The PU-Foam

The stock foam used in the mammary implant is actually

made by Scotfoam Corporation of Eddystone,

Pennsylvania and sold to the manufacturer as precut

washed individual pieces through vendors (either

Wilshire foam or by Sirod Corporation of California).

The cleaning, packaging, and some testing are also

done by the vendor. The foams are cleaned for class 10

laundry by ABA cleaning services for Wilshire foam or

by Prudential overall supply (class 100 laundry) using

unknown detergents and supplied to the device

manufacturer. The PU mother stock used is designated

as SIP 100 PPI Z MA, which refers to reticulated

Industrial foam with 80-110 open pores per linear

inch. This is a polyester polyurethane made by using

saturated polyester resins (Adipic acid and diethylenc

Glycol. mixture made by Iriolex Chemical Company),

Toluene diisocyanate (Dow chemical: Voranate T-80 - an

80:20 mixture of isomers of Tol), N-ethylmorpholine

(Texacat NEM) and catalysts such as n-cetyl, N,

N-dimenthylamine in isoproponal (Louza or Airproduct)

and N-methyldicyelohexylamine (Polycat-12), and

commercial surfacant mixtures.

A recent study performed in the preformed foam

characterized the product as a “cross-linked

polyesterurethane made from diol-terminated

polyadipate oligotners containing small amounts of the

corresponding amines and amine-isocyaaates. "

The foam is made in large industrial quantities and

the end process involves quick burning for opening of

the pore. The major application of the foam is for use

in the air and oil filters. Although the designation

MA indicates for medical applications, no special

steps or precautions in the manufacturing is involved.

The Two Carcinogenicity Studies

Two published studies has been reported by Heuper from

The National Cancer Institute (1961 and 1964).

Although the studies are old, results are still valid

because these are the only available bioassay results

using this type of polyesterpolyurethane foam. The

foams used in the first study was obtained from Hobay

Chemical and the second study used foam made at NCI

laboratory. The chemical formulation provided by the

author indicates that the PU-foam used in these

studies is similar, if not identical, to the foam used

for breast implants. These studies used Bethesda black

rats implanted with shredded or intact PU foams and

several routes of administration.

The results of these studies are positive. Without

going through the details it can be briefly reported

that a significant increase in adenocarcinomas were

noted in both studies (8/30 and 6/70). For

clarification purposes, several aspects of these

results need further comments.

Firstly, the shredded PU implants produced tumors,

which indicate that no solid-state phenomenon were

involved, as such event requires continuous smooth

surfaces (generally 0.5 cm.). Carcinogenicity of any

solid film under this size is generally taken to be

indicative of chemical effect. Furthermore, the tumor

types involved in this study included adenocarcinomas,

(in addition to local sarcomas), which has never been

associated with solid-state carcinogenesis.

Secondly, the author indicated that the PU material

was partially resorbed. Collectively, these two

observations strongly indicate that PU is acting as a

straight-forward chemical carcinogen. In the

discussion section, the author commented on the

unsuitability of PU foam as an implant in cosmetic

surgery. It is remarkable that these comments were

made in the sixties when the constituent TDI (or TDA)

was not known to be a carcinogen.

Manufacturer Sponsored Bioassay of PU-foam

The masterfile submitted to FDA by Surgitek (device

manufacturer) contained an interim report from Dr.

Woodward which indicates that a contract for bioassay

was initiated by the company (90 rat study) on June

23, 1987. I was informed that this study has been

terminated at 9 months (1 month after the interval

report). However, I was unable to obtain either the

original protocol or a final report of this study. I

have requested OC to follow-up this study through

Bioresearch Monitoring Staff (memo attached). The

interim report does not contain any reviewable data

but contains a set of conclusionary findings. Two of

the reported findings are:

a. Within the connective tissue infiltrating the PU,

collections of foamy macrophages containing PAS

positive deposits are frequent. This non-hemosiderin

pigment may represent a PU breakdown product.

b. The polyurethane film implants decreased in size at

least 50% between two to eight months, although the

film is recoverable at eight months. This finding is

strong evidence for the local degradation of the

porous PU film.

Conclusion

1. The two reported positive bioassay results

correlates very well with our previous conclusion of

potential carcinogenicity of PU-foam due to hydrolytic

release of TDA. The composition of PU-foam used in

mammary implant is similar to the PU-foam tested in

the bioassays. It is now reasonable to assume that IDA

generated tram the PU-foam may be the etiologie agent

producing the adenocarcinomas in rats (chemical as

opposed to solid-state carcinogenesis).

2. The interim report from the sponsor’s testing

indicates that PU-foam (as used in breast implants) is

resorbed in the animal model. The resorption rate in

the biologic system can now be assumed to be 50% at

six months. This information is consistent with data

on the loss of mechanical strength of PU-foam in water

and certainly of relevance to patient complaint

reports provided in our previous memo.

3. As these reports are consistent with in vitro

analytic data demonstrating release of TDA from

various experimental conditions (Batish et al, Guidion

et al, (OST in-house results), our previous

conclusions regarding the carcinogenicity of PU-coated

breast implants were correct.

It may be restated again in the words of Dr. Huper as

“Polyurethane foams of different chemical composition

are pluripotential carcinogens capable of eliciting

cancers in various tissues and organs”. Consequently

PU-foam is not an appropriate material for use PU

breast implants.

Recommendation

Based on the information we possess, we believe PU

mammary implants are sold at the rate of 50-60

thousand units per year, which translates to about

75-80 patients implanted per day. Since polyurethane

has been shown to contribute very little to the

functioning of breast implants, an additional delay in

the resolution of this important safety issue is not

justified. I strongly recommend that we proceed with

the CDRH Risk Assessment Committee meeting in a timely

manner.

Nimual K. Hishra D.V.M, Ph.D.

FDA00054916

[Guest guest]

No wonder Dr. Guidoin found polyester fibers in my breast implant tissue. I

hope that this will not stop me from getting well.

Love you all.....Lea

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~```

Additional Information on Polyurethane

> Mammary Implant & Cancer Risk

> to Director, Office of Device Evaluation

>

> Through: Director, DSRD

>

> This memorandum is an addendum of my April 3, 1989 and

> May 31, 1990 technical reviews on the same subject.

>

> Our previous reviews did not provide the precise

> chemical nature of polyurethane (PU) foam used in the

> implant because at that time we were unable to obtain

> such information from the manufacturer. Through our

> review of several masterfiles from both device

> manufacturer and foam manufacturer and communication

> with the foam manufacturer and Device EIR, we now can

> reasonably document the exact nature of the PU-foam

> used in breast implants. This has allowed us to review

> and compare two previously published results of animal

> studies on similar PU-foams obtained from different

> sources.

>

> The PU-Foam

>

> The stock foam used in the mammary implant is actually

> made by Scotfoam Corporation of Eddystone,

> Pennsylvania and sold to the manufacturer as precut

> washed individual pieces through vendors (either

> Wilshire foam or by Sirod Corporation of California).

>

> The cleaning, packaging, and some testing are also

> done by the vendor. The foams are cleaned for class 10

> laundry by ABA cleaning services for Wilshire foam or

> by Prudential overall supply (class 100 laundry) using

> unknown detergents and supplied to the device

> manufacturer. The PU mother stock used is designated

> as SIP 100 PPI Z MA, which refers to reticulated

> Industrial foam with 80-110 open pores per linear

> inch. This is a polyester polyurethane made by using

> saturated polyester resins (Adipic acid and diethylenc

> Glycol. mixture made by Iriolex Chemical Company),

> Toluene diisocyanate (Dow chemical: Voranate T-80 - an

> 80:20 mixture of isomers of Tol), N-ethylmorpholine

> (Texacat NEM) and catalysts such as n-cetyl, N,

> N-dimenthylamine in isoproponal (Louza or Airproduct)

> and N-methyldicyelohexylamine (Polycat-12), and

> commercial surfacant mixtures.

>

> A recent study performed in the preformed foam

> characterized the product as a " cross-linked

> polyesterurethane made from diol-terminated

> polyadipate oligotners containing small amounts of the

> corresponding amines and amine-isocyaaates. "

>

> The foam is made in large industrial quantities and

> the end process involves quick burning for opening of

> the pore. The major application of the foam is for use

> in the air and oil filters. Although the designation

> MA indicates for medical applications, no special

> steps or precautions in the manufacturing is involved.

>

> The Two Carcinogenicity Studies

>

> Two published studies has been reported by Heuper from

> The National Cancer Institute (1961 and 1964).

>

> Although the studies are old, results are still valid

> because these are the only available bioassay results

> using this type of polyesterpolyurethane foam. The

> foams used in the first study was obtained from Hobay

> Chemical and the second study used foam made at NCI

> laboratory. The chemical formulation provided by the

> author indicates that the PU-foam used in these

> studies is similar, if not identical, to the foam used

> for breast implants. These studies used Bethesda black

> rats implanted with shredded or intact PU foams and

> several routes of administration.

>

> The results of these studies are positive. Without

> going through the details it can be briefly reported

> that a significant increase in adenocarcinomas were

> noted in both studies (8/30 and 6/70). For

> clarification purposes, several aspects of these

> results need further comments.

>

> Firstly, the shredded PU implants produced tumors,

> which indicate that no solid-state phenomenon were

> involved, as such event requires continuous smooth

> surfaces (generally 0.5 cm.). Carcinogenicity of any

> solid film under this size is generally taken to be

> indicative of chemical effect. Furthermore, the tumor

> types involved in this study included adenocarcinomas,

> (in addition to local sarcomas), which has never been

> associated with solid-state carcinogenesis.

>

> Secondly, the author indicated that the PU material

> was partially resorbed. Collectively, these two

> observations strongly indicate that PU is acting as a

> straight-forward chemical carcinogen. In the

> discussion section, the author commented on the

> unsuitability of PU foam as an implant in cosmetic

> surgery. It is remarkable that these comments were

> made in the sixties when the constituent TDI (or TDA)

> was not known to be a carcinogen.

>

> Manufacturer Sponsored Bioassay of PU-foam

>

> The masterfile submitted to FDA by Surgitek (device

> manufacturer) contained an interim report from Dr.

> Woodward which indicates that a contract for bioassay

> was initiated by the company (90 rat study) on June

> 23, 1987. I was informed that this study has been

> terminated at 9 months (1 month after the interval

> report). However, I was unable to obtain either the

> original protocol or a final report of this study. I

> have requested OC to follow-up this study through

> Bioresearch Monitoring Staff (memo attached). The

> interim report does not contain any reviewable data

> but contains a set of conclusionary findings. Two of

> the reported findings are:

>

> a. Within the connective tissue infiltrating the PU,

> collections of foamy macrophages containing PAS

> positive deposits are frequent. This non-hemosiderin

> pigment may represent a PU breakdown product.

>

> b. The polyurethane film implants decreased in size at

> least 50% between two to eight months, although the

> film is recoverable at eight months. This finding is

> strong evidence for the local degradation of the

> porous PU film.

>

> Conclusion

>

> 1. The two reported positive bioassay results

> correlates very well with our previous conclusion of

> potential carcinogenicity of PU-foam due to hydrolytic

> release of TDA. The composition of PU-foam used in

> mammary implant is similar to the PU-foam tested in

> the bioassays. It is now reasonable to assume that IDA

> generated tram the PU-foam may be the etiologie agent

> producing the adenocarcinomas in rats (chemical as

> opposed to solid-state carcinogenesis).

>

> 2. The interim report from the sponsor's testing

> indicates that PU-foam (as used in breast implants) is

> resorbed in the animal model. The resorption rate in

> the biologic system can now be assumed to be 50% at

> six months. This information is consistent with data

> on the loss of mechanical strength of PU-foam in water

> and certainly of relevance to patient complaint

> reports provided in our previous memo.

>

> 3. As these reports are consistent with in vitro

> analytic data demonstrating release of TDA from

> various experimental conditions (Batish et al, Guidion

> et al, (OST in-house results), our previous

> conclusions regarding the carcinogenicity of PU-coated

> breast implants were correct.

>

> It may be restated again in the words of Dr. Huper as

> " Polyurethane foams of different chemical composition

> are pluripotential carcinogens capable of eliciting

> cancers in various tissues and organs " . Consequently

> PU-foam is not an appropriate material for use PU

> breast implants.

>

> Recommendation

>

> Based on the information we possess, we believe PU

> mammary implants are sold at the rate of 50-60

> thousand units per year, which translates to about

> 75-80 patients implanted per day. Since polyurethane

> has been shown to contribute very little to the

> functioning of breast implants, an additional delay in

> the resolution of this important safety issue is not

> justified. I strongly recommend that we proceed with

> the CDRH Risk Assessment Committee meeting in a timely

> manner.

>

> Nimual K. Hishra D.V.M, Ph.D.

>

> FDA00054916

>

>

>

>

>

> Opinions expressed are NOT meant to take the place of advice given by

> licensed health care professionals. Consult your physician or licensed

> health care professional before commencing any medical treatment.

>

> " Do not let either the medical authorities or the politicians mislead you.

> Find out what the facts are, and make your own decisions about how to live

> a happy life and how to work for a better world. " - Linus ing,

> two-time Nobel Prize Winner (1954, Chemistry; 1963, Peace)

>

>