The MHRA publishes a review of the products.
“Morag E. Saunders
Jeremy J. B. Tinkler
Medical Devices Agency
July 2001
REVIEW OF THE BIOLOGICAL SAFETY OF POLYURETHANE-COATED BREAST IMPLANTS
Summary
Polyurethane-coated breast implants were the subject of two advisory notices by the
Medical Devices Agency, in 1994 and 1996. These highlighted reports from the
literature which suggested that degradation of the polyurethane coating occurred over
time producing the potentially carcinogenic 2,4-toluenediamine (2,4-TDA). The UK
Department of Health’s Committee on Carcinogenicity (COC) had advised, in 1991
and 1994, that the breakdown of the polyurethane over a period of several years,
leading to the presence of 2,4-TDA in the tissues surrounding breast implants, gave
rise to a small, unquantifiable, carcinogenic risk. Specifically, the COC concluded
that:
- 2,4-toluenediamine (2,4-TDA) should be regarded as a probable genotoxic carcinogen;
- there is evidence that small amounts of 2,4-TDA can be released from polyurethane foam in vitro and in vivo;
- direct evidence exists that 2,4-TDA is released from polyurethane coated breast implants in vivo in women. This leads to the presence of 2,4-TDA in the tissues surrounding the implant. These tissues can metabolise 2,4- TDA and there is therefore a potential carcinogenic risk from this release;
- information on the breakdown of implanted polyurethane foam in human tissues suggests that breakdown occurs over a period of several years;
- there were no data on the possible release of harmful substances other than 2,4-TDA from implanted polyurethane foam either in vitro or in vivo.
A review of more recent data has now been carried out by MDA. This has revealed the following new findings:
- DNA damage has been shown in animals following oral administration of
2,4-TDA, but not following implantation of polyurethane foam disks; - 2,4-TDA has been identified in the urine, wound drainage fluid and, for up to 2 years after implantation, bound to plasma components, of women with polyurethane-coated breast implants.
Recent evidence is thus consistent with the conclusions reached by the COC in 1991 and 1994.
The results of studies on the rate of degradation have been used as a basis for quantitative risk assessments. Three separate estimates concluded that the lifetime cancer risk resulting from the implantation of polyurethane-coated breast implants to be in the region of 1 in a million and thus of minimal toxicological risk. However, risk assessments of this sort are not consistent with UK scientific policy that exposure to genotoxic carcinogens should be eliminated wherever possible and, where it cannot be avoided, should be reduced to a level as low as is reasonably practicable.
Moreover, the European Medical Devices Directive requires that any residual risks be outweighed by benefit to the patient. Thus, in assessing the suitability of polyurethane-coated breast implants, it is necessary to take into consideration both the avoidability of the risk and any benefit arising from the use of the product.
The principle benefit claimed for this type of implant, in comparison with other breast implants, is a reduction in the rate of capsular contracture. While there is evidence to support this claim, uncertainties exist over the degree and persistence of the benefit and it is not possible to conclude that the benefits claimed for polyurethane-coated breast implants can only be achieved through the use of this particular coating material.
It is concluded that there remains insufficient evidence for benefits arising exclusively from the use of the polyurethane coating applied to these breast implants to justify exposure to the carcinogenic risk, albeit very small, associated with its breakdown in situ.
Policy in the UK should therefore remain that polyurethane-coated breast implants should not be implanted, but that the removal existing implants is not indicated.
Background
A polyurethane foam coating was developed for silicone gel breast implants in the
1980s because it was felt that the open texture of the foam would modify the
alignment of cells in the fibrous capsule surrounding an implant and thus reduce the
incidence of capsular contracture. Two models of polyurethane-coated breast
implants (Même and Replicon) were developed in the USA, using a commercially
available polyesterurethane foam. Following concerns that degradation of this
particular polyurethane could lead to the release of a carcinogenic breakdown product, the original American manufacturer voluntarily withdrew the products from the market in 1991. Similar products were subsequently re-introduced to the European
market by other manufacturers but very few were used in this country before all
manufacturers ceased supply to the UK at the instigation of the Department of Health
in 1993.
As part of an on going process, the Medical Devices Agency (MDA) continues to
monitor the safety of materials used in the manufacture of breast implants available in the UK. Recent controversy over silicone-filled implants and the events surrounding Trilucent. breast implants, prompted MDA to review available data on a number of these product types including two hydrogel-filled breast implants. Although polyesterurethane-coated implants, are not currently available in the UK. The
manufacturer has indicated a wish to place these implants back on the UK market,
pointing out that two extant Safety Notices published by MDA warning against their
use represent a technical barrier to trade which, if unjustified, would run counter to European single market legislation.
Assessments in 1991 and 1994
Two previous reviews of the carcenogenicity of polyurethane-coated breast implants
have been carried out by the MDA in 1991 and 1994 and both reports were submitted
to the Committee on Carcinogenicity (COC) for review. In 1991, concerns were
raised over the degradation potential for of polyurethane and the release of 2,4-and
2,6-toluinediamine (TDA) and the fact that 2,4-TDA is a known rodent carcinogen
which has been shown to be released from polyesterurethane in vitro following
hydrolysis.
The 1994 report strengthened the view that 2,4-toluenediamine (2,4-TDA) is
produced from the degradation of polyurethane breast implants in vitro. Further
evidence was presented which showed that 2,4-TDA is produced from the degradation
of polyurethane breast implants in vivo. However, there was insufficient data
available at the time to comment on the rate of degradation of polyurethane.
The 1994 report was submitted to the COC, who concluded that 2,4-TDA should be
regarded as a probable genotoxic carcinogen when administered orally. They
considered that direct evidence existed that 2,4-TDA was released form polyurethane-
coated breast implants in vivo in women which led to the presence of 2,4-TDA in the
tissues surrounding the implant. These tissues could metabolise 2,4-TDA and there
was therefore a potential carcinogenic risk from this release. The information on the breakdown of implanted polyurethane foam in humans suggested that breakdown
occurred over a period of several years. Overall, the COC considered that
polyurethane was not a suitable material for implantation as it presented a small, but unquantifiable carcinogenic risk.
The conclusions of the COC were published in the 1991 and 1994 Annual Reports of
the Committees on Toxicity, Mutagenicity, Carcinogenicity of Chemicals in Food,
Consumer products and the Environment. In addition, the implications of the findings
lead to the issue of two Safety Notices (SAB(94)39, September 1994 and SN 9620,
July 1996) by the MDA.
Situation at Present
At present polyurethane-coated breast implants are CE-marked (through the German
Notified Body, MDC) and distributed in Germany, Italy and Spain. In the light of the
1994 COC opinion and the two Safety Notices, the manufacturer (Polytech Silimed)
has indicated that the product will not be marketed in the UK but has pointed out that this situation runs counter to European free market legislation. The manufacturer claims that new evidence is now available in support of the safety of polyurethane-covered breast implants. In particular, that the amount of 2,4-TDA released does not pose a carcinogenic risk. Polytech Silimed is keen to have the situation regarding the UK market reviewed and has supplied the MDA with further information in support of their claim that there is no risk of cancer from these breast implants. The company pointed out that this information has become available since the MDA review of 1994 and that it has not so far been taken into account. This paper presents a review of the literature supplied by Polymed Silitech in support of their claim that these implants do not pose a safety threat. Other relevant publications obtained through a literature search carried out by MDA are also considered.
Structure of Polyurethane
The polyurethane used in the manufacture of breast implants is a polyesterurethane
manufactured from polyethylene glycol adipate (PEGA) and toluene diisocyanate
(TDI). The latter comprises of a mixture of 2,4-TDI and 2,6-TDI isomers in a 4:1
ratio. TDI is unstable in aqueous environments and reacts to form the equivalent
toluenediamine (TDA) isomers.
All polyurethanes are to a greater or lesser degree susceptible to hydrolysis of the
urethane bond with production of low molecular weight fragments. The polyesterurethanes are also susceptible to hydrolysis of the ester linkages with an
initial production of low molecular weight fragments and, ultimately, the components
of the polyester diol. The ether linkages in polyetherurethanes are more resistant to hydrolytic cleavage and are essentially hydrolytically stable.
New Data In Vitro Studies
A study conducted by LPU (1996) on the behalf of Polytech Silimed investigated the
release of TDA under physiological conditions. Samples of the polyurethane coating
of breast implants were extracted over a period of 30 days at 37oC both in the
presence and absence of papain. The extraction medium was exchanged every two
days for 60 days and the levels of 2,4-TDA and 2,6-TDA measured in each solution.
Both sterilised and non-sterilised material was tested for the release of 2,4-TDA and 2,6-TDA. Sterile and non-sterile samples were also incubated in papain for 14 days
without changing the papain solution and in saline for 30 and 60 days only.
No detectable levels of either 2,4-TDA or 2,6-TDA were found in the extracts from
either the sterile or non-sterile samples treated with papain when the extract solution was changed every two days over the 60-day incubation period. The quantity of TDA released within two days was considered to be below the analytical limit for 2,4- and 2,6-TDA. In samples incubated in papain over 14 days with no change of solution or in a sodium chloride solution, over 30 and 60 days, up to 245 ppb of 2,4-TDA and 246 ppb of 2,6-TDA were released from both the sterile and non-sterile material.
From their data based on a total weight of 8 g of polyurethane incubated with 0.9%
salt solution for 60 days, a total quantity of approximately 1.5 µg/ml 2,4-TDA and 2.3 µg/ml 2,6-TDA were recovered. Extrapolated over a year, this gives a total quantity released of 9 µg/ml 2,4-TDA and 13.8 µg/ml 2,6 TDA. Linear release rates were assumed making the release of 1-2 µg/ml 2,4-TDA equivalent to approximately 0.02-0.03 µg/ml per day. The authors compared these values with the dose levels used in the studies carried out by the National Cancer Institute where rats and mice were fed substantially higher dose levels. They suggested that the release rates determined for 2,4-TDA were relatively low and this may be the reason why no effects were seen in carcinogenicity and genotoxicity studies where polyurethane foam or extracts of foam were used in the relevant test systems. This suggestion is of limited validity, since a quantitative comparison of in vitro and in vivo studies is of questionable relevance.
The findings of the Polytech Silimed/LPU Report are in marked contrast to those of
Szycher and Siciliano (1991) who previously examined the hydrolysis of washed
polyurethane foam over 30 days in an aqueous solution of papain. They found that
2,4-TDA and 2,6-TDA were released only within the first 4 days of incubation.
The in vitro biodegradation of polyurethane foam was also discussed by Lubbers
(1997) who reviewed several reports where separation of the polyurethane coating of
implants was observed. The chemical hydrolysis and/or chemical breakdown of the
polyurethane coating were considered to be of more importance. Many of the studies
referred to in this text were discussed in the 1994 MDA report. In summary, TDA
was released from foam samples incubated in NaOH at 37oC. No TDA was extracted
from samples incubated in normal saline but trace quantities of 2, 4-dimethyl-6-t-
butyphenol were washed out after incubation in methanol (Daka and Chawla 1993).
Battich and Williams (1989) also detected TDA after incubation in NaOH. Amin et al. (1993) were unable to extract TDAs from foam incubated in either methyl tert-
butyl ether or aqueous buffer extracts. Only incubation of foam or foam extracts in
either strong mineral acid or base resulted in TDA release. On the other hand, Benoit (1993) showed that polyurethane foam released 2,6-TDA, 2,4- and 2,6-TDI and
toluene isocyanate (TIA) following incubation in Ringer’s solution at 37 oC for
periods of 6 to 36 days. The investigations of Szycher and Sicillano (1991) who
found that 2,4-TDA was released only within in the first four days after enzymatic
digestion were also discussed. As mentioned above, this finding is in contrast to those found in the LPU investigation (see above). The degradation of polyurethane-coated implants has also been reported by Sinclair et al. (1993) and by Brorson et al. (1991).
The report by Lubbers concluded that ‘although several studies showed that that
biodegradation of polyurethane occurred and that in some cases TDA had been
detected in urine, there was no clinical or epidemiological proof that breast implants cause cancer in any way’. The risk benefit analysis concluded that ‘the great advantage of the polyurethane-coated breast implants is the low frequency of capsular contracture and that the negative side effects do not exceed those of other breast implants’.
An extensive search of the literature found few recent reports (post 1994) directly
related to the breakdown of polyurethane used to coat breast implants and the release of 2,4-TDA. However a number of studies on the breakdown of polyurethane foam in
general were found. In vitro biodegradation studies on polyesterurethane synthesised
with radio-labelled toluene diisocyanate (TDI) (Santerre et al. 1994) were carried out using cholesterol esterase (CE) and Horseradish peroxidase (HRP). High
performance liquid chromatography (HPLC) analysis of the products showed that the
bulk of the TDI remained covalently bound within the cleaved chain segments of the
original polymer and not released as pure toluene diamine. Further studies (Wang et
al. 1997) with poly(ester)urea-urethanes synthesised with radio-labelled TDI and
incubated with CE generated a number of biodegradation products. TDA, was not
detected by chromatographic separation although two products were identified which
were TDA derivatives (secondary aromatic diamine) substituted with end units of the
polyester segment at N and N’ positions of TDA. The authors suggest that there could
be a stabilisation of the urethane and urea linkages within the TDI segments of the
polyurethanes.
Summary of In Vitro Data
For the most part, the in vitro studies support the view that small amounts of 2,4-TDA are released from polyurethane following various treatments. In many cases, the amounts of 2,4-TDA released were low. In two of the more recent studies, TDA was
not detected.
In Vivo Studies
Luu et al. (1998) described a physiological based pharmacokinetic model to simulate
the fate of low dose exposure of 2,4-TDA leached from polyurethane foam-covered
implants. They used their model to assess the potential health risk to humans. Rats
were given 0.52 mg/kg 2,4-TDA by iv bolus, orally or 0.021 g by implantation. The
concentration of 2,4-TDA was measured in five tissue compartments (kidney, gastro-
intestinal tract, liver, fat, muscle) as well as in plasma and urine. Based on a
polyurethane foam mass of 4.87 g the results were extrapolated to determine values
for implant simulation in rats and humans and low dose ingestion in the rat. From
their results the authors predicted an excess lifetime average daily dose in humans of 11.93 x 10-6 mg/kg/day with an increased risk of breast (and liver) cancer of 1 in 400,000.
The results of the Luu study have been criticised for over-estimation of the dose of
polyurethane, incorrect measurement of the breakdown products and the scaling
factor used (Kulig 1998). Their estimate of risk (1 in 400,000) was considered to be
greatly over estimated. However correcting for the greater weight of the implant used in the study (4.87 g cf 2.7 g), the estimated exposure value is approximately equal to that of the FDA (1991) and Hester et al. (1997) (i.e. 1 in 1,000,000).
Bradley at al. (1994a) investigated the subchronic immunotoxicological potential of
the principal constituents of silicone (fluid, gel and elastomer) breast implants and of polyurethane. The silicone fluid and gel were injected subcutaneously and disks
(6mm) of the silicone elastomer and the polyurethane were implanted subcutaneously
into B6C3F1 mice. Immunotoxicological and host resistance studies were carried out
after 10 days. They found no treatment-related deaths or overt signs of toxicity.
None of the tested materials had notable effects on body or organ weights,
erythrocytes or leukocytes in the blood or blood chemistries. The tested silicones did not alter the distribution of B cells and T cells in the spleen, but some perturbations in the levels of CD4+CD8+ and CD4-CD8- T cells were seen in the polyurethane-treated mice. The antibody response to sheep erythrocytes was not markedly altered nor were the proliferative responses to concanavalin A, phytohemagglutinin, lipopolysaccharide or allogeneic cells. Reticuloendothelial function was normal but polyurethane evoked an enhance phagocytosis of Covaspheres by adherent peritoneal cells. Natural killer cell activity and serum complement were not altered. All of the materials showed some protection to a challenge with Listeria monocytogenes that killed 40–58% of vehicle control mice. Host resistance to Streptococcus pneumoniae or the B16F10 tumour was not affected. The results suggested perturbation of T cell differentiation in mice implanted with a polyurethane disk.
In a similar long-term, 180 day exposure study Bradley et al. 1994b showed the only
consistent effect of exposure to silicone materials or polyurethane was a modest
depression of natural killer cell activity. No indication is given in either study as to the anticipated levels of polyurethane exposure or of the form of the polyurethane.
Delcos et al. (1995) assessed the extent of DNA damage in rats fed 2,4-TDA under
conditions that result in tumour induction and in rats implanted with Microthane
polyesterurethane foam (67 mg/kg or 267 mg/kg). Time and dose dependent adducts were found in the DNA from the liver and mammary glands of rats fed 10, 40, 80 or
180 ppm 2,4-TDA for up to 6 weeks. In the rats fed 40 or 180 ppm 2,4-TDA, DNA
adducts were detectable in liver and mammary tissue for 26 – 43 weeks after the
termination of treatment. No adducts were detected in T lymphocytes isolated from
the spleens of rats fed 40 or 180 ppm 2,4-TDA nor was there an increase in mutations
at the hprt locus in these lymphocytes. This indicates the potential for 2,4-TDA to
cause genotoxic effects in vivo.
In the implantation groups, no DNA damage was observed in the liver, mammary
glands or T-lymphocytes of rats up to 42 weeks post implantation (67 mg/kg) or in the liver and mammary glands of rat implanted with 267 mg/kg polyesterurethane foam.
The authors calculated that a 50 kg woman with 2 implants would receive 54 mg
polyurethane foam per kg body weight. They were unable to detect 2,4-TDA-related
damage in rats treated with 67 or 268 mg foam per kg body weight and pointed out
that rat bioassay data indicated that a dose of 4.7 mg 2,4-TDA/kg/day was sufficient
to induce tumours in rats.
While the results showed the development of DNA adducts as a result of systemic
exposure in rats fed 2,4-TDA, the tissues immediately surrounding implants did not
appear to have been analysed for adducts. The levels of 2,4-TDA used in the study
corresponded to time-weighted average doses used to demonstrate tumourigenicity
(US Department of Health, Education and Welfare bioassay for 2,4-TDA). While
2,4-TDA was capable of damaging DNA, the authors concluded that the polyurethane
foam implants presented a minimal risk of genotoxicity through release and
subsequent metabolic activation of 2,4-TDA.
Summary of In Vivo Data
Recent in vivo data suggest that polyurethane does not cause immunoreactivity in a rat model. Of greater importance is the identification of DNA adducts in the liver and mammary tissues of rats fed 2,4-TDA, although no DNA damage was observed in rats
implanted with ployurethane foam disks for 42 weeks.
Clinical Studies
A number of clinical studies relevant to the safety of polyesterurethane breast
implants have been carried out. These have included studies on the levels of 2,4-TDA
released from the polyesterurethane coating, systemic effects relating to implantation and the occurrence of capsular contraction.
Exposure Assessment
At the request of the FDA, Bristol-Myers Squibb carried out a study to determine
whether the polyurethane foam covering silicone breast implants could release the
known animal carcinogen 2,4-TDA. The results of this study were published in a
report by Hester et al. (1997). The initial results were described in an interim report by Ford et al. (1993) and referred to in paragraph 48 of the 1994 MDA report which was reviewed by COC.
The urine and blood serum of 61 women with polyurethane-covered implants and 61
women without implants were tested for the presence of TDA. The study reported
that tiny amounts (parts per trillion) of TDA were found in the urine of 80% of the
women in the study with breast implants. Smaller amounts of free TDA were found
in the urine of 13% of the women without implants. No free TDA was found in the
blood of the women with polyurethane implants.
As noted in the 1994 MDA report, the study showed that 2,4 TDA is released from
polyurethane foam in vivo. Hester et al. (1997) and the FDA used the results of this
study to estimate the lifetime average daily dose of 5.06 x 10-6 mg per kg per day
TDA resulting from the breakdown of the foam. To this they applied the cancer
potency factor (0.21 mg/kg/day) previously used by the FDA which gave an estimate
for the upper limit of excess lifetime risk resulting from the implants of 1.1 x 10-6. This represents a theoretical lifetime risk of about 1 in 1 million. The report concluded that while the polyurethane foam coating of the implants degrades, the risk of cancer in humans from exposure to TDA is negligible.
Sepia et al. (1995) also measured levels of TDA in vivo in six patients implanted with polyurethane-covered breast implants. They monitored levels of TDA in blood, urine and wound drainage. They reported that following acid hydrolysis of urine samples elevated amounts of TDAs were found in post-operative test samples. High levels of TDAs were found in the wound drainage samples which showed a sharp drop over the first four days. The levels of 2,4-TDA and 2,6-TDA in plasma rose after an initial lag period of 20-30 days, remaining elevated for up to 2 years. TDA released from total plasma proteins under acid conditions were not released under mild base treatment. When the plasma proteins were precipitated in ethanol, redissolved and treated with a mild base, TDA was still not released. Protein was however released after acid hydrolysis of the precipitated samples. The levels of TDA released from globulin and albumin fractions subjected to acid hydrolyis both in the presence and absence of precipitation in ethanol was similar.
This paper gives further evidence of the presence of polyurethane degradation
products in the urine and plasma of implanted patients for a period of up to two years. The TDA-derivatives appeared to be covalently bound to plasma proteins. The
lifetime risk of cancer was assessed on the basis of protein adducts. A post-operative level of 4.4 ng 2,4-TDA/ml plasma was calculated which is equivalent to 10.56 µg 2,4-TDA in a 60 kg subject with a plasma volume of 2,400 ml. The kinetics of globulin adducts were considered to be the same as those for plasma and an adduct level of 352 ng was calculated which was used to calculate a daily dose of 70.4 µg
2,4-TDA. This figure was compared with the dose used in the risk assessment carried
out by the Canadian Medical Association (1991) who calculated that a 236 ng (0.236
µg) TDA would be released per day from two implants containing 2.7 g polyurethane.
Hester et al. (1997) measured free TDA in the serum and urine of implant patients
while Sepia et al. (1995) measured the level of bound TDA. The results are indicative of continued degradation of the polyurethane coating on the implants. Both papers
concluded that no free 2,4-TDA was present in the circulation. The estimated valueor annual exposure calculated from available data and averaged over 6 years
assuming linear degradation suggested a value in the range of 28 – 41.4 mg. These are similar to the figures reported by Sepia (1995).
De Lorenzi et al. (1995) reported on an HPLC method for the determination of
urinary content of 2,4- and 2,6-TDAs in patients with polyurethane breast implants.
Urine was collected from 6 patients at several time points over a period of 8 months to 8 years. The urine was analysed using reverse phase HPLC with fluorescence
detection for the simultaneous determination of 2,4- and 2,6-TDAs following
liquid/liquid extraction and derivitisation. Most of the samples analysed were
negative for TDA with the exception of the urine from one patient in which a
detectable level of 2,6-TDA was found. The limit of sensitivity of the technique was
given as 15 ng/ml urine.
Tissue Response and Clinical Outcome
Other studies have been reported which describe the histological reactions associated
with implantation of polyurethane-coated breast implants. Handel et al. (1995)
reported on a follow-up study of patients which involved 1655 breast implants over a
period of 15 years. The study was designed in order to overcome the inconsistencies
and incomplete data records that existed for implant patients. A comparison of
various breast implant types, including polyurethane, was made and a number of
criteria were assessed (e.g. capsular contracture, surface texture, implant position, skin wrinkling, skin rash) by various statistical methods. In the short term, the risk of capsular contracture was similar for textured and polyurethane-covered implants but less for smooth implants. On the other hand, the polyurethane-covered implants significantly reduced capsular contracture over the entire follow-up period. However, a higher incidence of skin rash and to a lesser extent skin wrinkling was associated with these implants compared the majority of the other implant types (Siltex, smooth implants). Biocel implants showed a much greater frequency of skin wrinkling than the polyurethane-covered implants. The polyurethane-covered implants were shown to be superior to both smooth and textured silicone implants in terms of reducing the risk of capsular contracture.
The literature review carried out by Lübbers (1997) and supplied by Polytech Silimed
set out to clarify whether the aim to decrease capsular contracture without increasing other side effects had been achieved with polyurethane foam-covered breast implants. The review compared the risk of infection in relation various types of implants (smooth, textured, polyurethane-coated). From the papers reviewed, they concluded that the risk of infection was no greater with polyurethane-covered implants. However, some reports linked polyurethane-covered implants to the appearance of an inflammatory response including a rash. A number of studies, both in rats and humans, were discussed and it was concluded that use of polyurethane-covered implants reduced the occurrence of capsular contracture compared to other implant types. All of the literature reviewed pre-dated the MDA report of 1994.
Vázquez (1999) reported on a series of 407 patients with polyurethane-covered
implants carried out over a period of 10 years. Of the 811 single implants inserted, 24 were of the Même National White type, 6 were the Replicon surgitex model and 781 were Silimed. Only 0.49 % of the total implants inserted showed capsular
contracture.
Light microscopic analysis showed the capsule could be divided into five layers
according to histological composition. The inner layers were composed of
macrophages, foreign body giant cells and inflammatory cells and the outer layers
consisted of fibrous connective tissue. The capsules showed a lower concentration of
collagenous fibres compared to other types of implants. Enzymatic degradation of
capsules showed the presence of polyurethane remnants confirming that the
polyurethane is digested in the capsule. Light microscopic examination and
immunological typing of the capsule showed the presence of a chronic inflammatory
cell infiltrate.
A number of papers report associations between polyurethane-coated breast implants
and cellular reactions. Luke et al. (1997) studied capsular tissue from 86 cases in
order to characterise the relationship between capsular findings and the type of
implant used. Cellular reactions were associated with all implant types examined but
were most prominent in capsules associated with polyurethane-coated implants. The
cellular reaction consisted of vacuolated macrophages, chronic granulomatous
inflammation and large numbers of multinucleated giant cells, some containing
asteroid bodies. In addition, particulate material identified as polyurethane by FTIR microscopy was found in all cases where polyurethane-coated devices were
implanted. A pseudoepithelium was seen at the inner capsular surface (synovial
metaplasia). Immunohistochemical studies suggested the pseudoepithelia were of
macrophage/histiocytic origin.
In a single case study, Raso and Greene (1995) also reported on synovial metaplasia
in the periprosthetic capsule. The synovial metaplasia was considered to develop in
response to the polyurethane-coated implant and was implicated in reducing capsular
contracture and increasing host acceptance of implantable biomaterials. It was
suggested that a synovium-lined periprosthetic capsule lubricates the luminal cavity
and could theoretically reduce friction at the prostheses-capsular interface.
A report by Wang et al. (1998) describes the development of two cases of late
haematomas after breast reconstruction with polyurethane-coated implants. The exact
origin of this adverse effect was not explained, but may have been due to the highly
vascular inflammatory response associated with the polyurethane coating of the breast implants. It was suggested that the extensive inflammatory and foreign body reaction seen with polyurethane-coated implants prevents fibroblasts being laid down in the
regular fashion as seen with other implants, giving a softer capsule less likely to
contract. However, disruption of the vascular component of the reaction could have
lead to the late bleeding observed.
A comparison of systemic and rheumatic disease manifestations was reported by
Bulpitt et al. (1998). From 250 patient cases, they randomly chose 25 patients with
polyurethane-coated breast implants and compared these with 25 patients with non-
polyurethane-coated breast implants. Patients with the polyurethane-coated breast
implants showed a shorter time between implantation and symptom onset. A possible
association with a higher incidence of mucocutaneous lesions (rash, photosensitivity, oral ulcer) was suggested.
In a population-based case-control study, Brinton et al. (1996) showed the relative
risk of breast cancer was reduced with a prior implant when compared to the controls. This rate persisted with increasing interval since surgery and was lower for both
localised and distant tumours.
Summary of Clinical Studies
Clinical studies have indicated the presence of 2,4-TDA in the urine, wound drainage
fluid and blood (bound to plasma components). In one study, 2,4-TDA was detected
in the urine and plasma for up to 2 years post-implantation, confirming continued
polyurethane degradation.
A reduction in capsular contracture with polyurethane-coated implants compared to
other types of implant has been reported. However other contra-indications have been
reported including, skin rash and skin wrinkling, chronic inflammatory reactions
associated with the capsule and the presence of granulomatous reactions composed of
cells containing particles of polyurethane indicating breakdown of the implants. The
inflamatory changes may be related to the effect on capsular contracture.
Discussion
The information supplied by Polytech Silimed has been reviewed along with other
relevant data from the literature. The majority of the data supplied by Polytech
Silimed had previously been considered by the UK Medical Devices Agency (MDA)
and was discussed in their 1994 report to the UK Government’s expert advisory
group, the Committee on Carcinogenicity (COC). In particular, the data reported by
Hester et al (1997) had already been considered by the COC and the literature survey
carried out by Lübbers (1997) included many of the studies previously reviewed.
MDA carried out an extensive literature search and a number of additional papers
were identified and reviewed that were relevant to an assessment of toxicity or
exposure in relation to polyurethane-coated breast implants.
The nature of the degradation products depends on the original formulation of the
polyurethane foam. It has been established, from in vitro studies carried out under
various conditions, that 2,4-TDA is released from the particular polyurethane foam
chosen for use in the Polytech Silimed implant. The release of 2,4-TDA was found to
be dependent on the extract medium used although the timing of release was not
always consistent.
While it is widely agreed that 2,4-TDA is released from polyurethane implants in
vivo, not all workers have been able to detect the presence of TDAs. Two papers
concluded that no free 2,4-TDA was present in the circulation and one study was able
to detect TDAs in the urine of only one out of six patients with polyurethane breast
implants. The fact remains, however 2,4-TDA has been detected in the urine and
bound to plasma components in implanted women and the release of 2,4-TDA from
the breakdown of polyurethane foam has been demonstrated under in vitro, in vivo
and clinical conditions. This evidence for the breakdown of the polyurethane foam
covering the implants cannot be ignored.
The Critical Issues Are:
- Whether the levels present in women with polyurethane implants represent a
significant toxicological risk, and - Whether the residual risk is acceptable when considered in relation to any
benefits to patients arising from the presence of the polyesterurethane foam.
MDA policy in addressing these questions arises from guidance provided by the UK
Government’s expert committees on Carcinogenicity (COC) and Mutagenicity
(COM), the European Medical Devices Directive (93/42/EEC), and the international
standards ISO/DIS 10993-17 (1999) and EN ISO 14971 (2000).
Following their review of the 1994 MDA report, the COC concluded that 2,4-TDA
should be regarded as a possible human carcinogen There was evidence that small
amounts of 2,4-TDA could be released from polyurethane in vitro and indirect
evidence of breakdown in vivo in rats. At the time, the quantity and identity of the
breakdown products had not been established and the possible effects on local tissues were not known. In addition, no information on the breakdown of implanted
polyurethane foam in human tissues was available. The more recent observation of
DNA adducts in the liver and mammary gland in rats fed 2,4-TDA confirms that 2,4 TDA is genotoxic in vivo. Evidence of the presence of 2,4-TDA in women with
polyurethane breast implants is also now available.
While it is accepted that the amount of 2,4-TDA released from an implant, and thus
the risk, decreases over time, the absence of data on local tissue levels of 2,4-TDA
was of particular concern to the COC, since these tissues were felt to be at greatest risk. More recently reported changes in the structure of the polyurethane coating and the presence of fragments of the foam support the COC’s view, based on the 1994
MDA report, that there is complete break down of the polyurethane. No further data
could be found in the literature from which to estimate the rate of degradation of the polyurethane coating in vivo or which address local tissue levels of 2,4-TDA after implantation.
While no reports exist of tumour development as a direct result of the implantation of polyurethane-coated breast implants, this cannot be used to discount the risk of
carcinogenesis, as any tumours might arise several years after implantation. It is
unlikely that data on human cancer incidence will ever provide any useful insight into the carcinogenic risk arising from polyurethane-coated breast implants.
Three quantitative estimates of the lifetime risk of cancer arising as a result of the implantation of polyurethane coated breast implants have been reported. These
assessments reach a consensus that the risk is in the region of 1:1,000,000. A number of risk assessment models characterise a risk of this order as negligible and a case can be made for considering any risk of this magnitude to be tolerable. The magnitude of a risk, however, is not the only factor that needs to be taken into account in determining its acceptability. In order to be confident that a risk is “so low that it is not worth bothering about”, it is also necessary to consider the nature of the hazard, the balance of risks and benefits and whether the risk is avoidable or undertaken voluntarily (EN ISO 14971).
In assessing the nature of the hazard, the critical concern is that we are dealing with exposure to a genotoxic carcinogen. A precautionary approach is adopted in public policy in the UK for such risks (COM, 2001). It is considered prudent to assume that there is a linear, non-threshold dose response to in vivo mutagens. For risk management purposes in the UK, it is assumed that any exposure to such chemicals results in some damage to DNA and thus an increased risk of mutation leading, in
turn, to an increased risk, albeit possibly very small, of adverse health effects. The COM recognises specific exceptions to this rule, in situations where thresholds can be identified for mutagenicity, but considerable mechanistic data are available to justify these exceptions. No such data are available with respect to 2,4-TDA.
The consequence of scientific policy in the UK is that a tolerable exposure limit to a genotoxic carcinogen or in vivo mutagen cannot be established. Instead, a risk
management policy is adopted whereby exposure to such compounds is eliminated
wherever feasible and, where it cannot be eliminated, is reduced to a level “as low as reasonably practicable” (ALARP). In the absence of convincing reassuring data, the observation that DNA adducts are formed in vivo on exposure to 2,4-TDA, requires
that this approach must be adopted in the UK in the case of polyurethane-coated
breast implants.
In many other countries, however, including the USA, a quantitative risk estimate is
considered an acceptable basis for the risk assessment of genotoxic carcinogens.
Indeed, ISO/DIS 10993-17 allows either approach to be selected, based on the
prevailing regulatory scientific policy. A strong case can thus be made for
compliance of a purely quantitative risk assessment with ISO/DIS 10993-17.
Although this draft standard is intended to become a harmonised European standard,
it cannot be assumed that the quantitative risk assessment option will remain available to those who wish to use the standard to claim compliance with the Medical Device Directive. This is an issue that has yet to be considered by the relevant European Standards Technical Committee and the European Commission.
EN ISO 14971 and ISO/DIS 10993-17 require that any residual risk, unless it can be
classified as negligible (i.e. “so low that it is not worth bothering about”), must be outweighed by the benefit obtained from exposure to it. The risk arising from
exposure to an in vivo mutagen cannot be considered by the UK Department of Health
to be negligible, so it is necessary to look for further justification for the use of the product. Such justification must come in the form of evidence for a desirable clinical outcome that cannot be achieved by other means.
A number of reports on the cellular reactions associated with Polyurethane-coated
breast implants have been cited. In most cases, the implants have been associated
with a normal inflammatory response, characterised by synovial metaplasia which, it
has been suggested, could have a favourable influence on the rate of capsular
contracture. A slight immunological effect has been seen in animals implanted with
polyurethane, with effects noted on T cell differentiation and natural killer cell
activity. While the significance of these findings is not clear, and some adverse
clinical reactions of potential concern have been reported (such as late haematoma or granulomatous reactions), the overall pathological response is acceptable and similar to that seen with other silicone gel breast implants.
Several clinical studies have indicated the superiority of polyurethane-coated breast implants in reducing the occurrence or onset of capsular contracture, compared with
smooth and, in some cases, textured silicone implants. While this association is
commonly acknowledged, more prospective data are needed before the benefit of
polyurethane-coated implants can be irrefutably demonstrated. In view of the
assumption that the coating will degrade completely over time and the limitations of
available clinical data, uncertainty exists over the long-term effects of the
polyurethane coating on the rate of capsular contracture. Doubts have also been raised anecdotally by plastic surgeons, as to whether a significant difference in contracture rate exists between polyurethane-coated breast implants and those with a textured silicone surface.
Even if the benefit of polyurethane-coated implants is accepted, EN ISO 14971 and
ISO/DIS 10993-17 both require that, before the benefit associated with a device can
be considered relevant to a risk assessment, a test of feasibility of risk reduction is required. It is necessary to determine whether the risk can be reduced further at
reasonable cost. In this case the risk can be eliminated by omitting the coating or
using another coating material. Alternative products, with textured envelopes
constructed only of silicone elastomer, are available that also claim to reduce the
incidence of capsular contracture. No information has been reviewed to address the issue of whether it is possible to manufacture foam with similar physical properties to the one used by Polytech Silimed from a material that is resistant to degradation or that breaks down into non-carcinogenic compounds. From the information available
it is thus not possible to conclude that the use of polyester urethane foam is essential to reduce the incidence of capsular contracture to the desired extent.
Conformity of polyurethane-coated breast implants with ISO/DIS 10993-17 depends
on which risk management option is selected for dealing with genotoxic carcinogens.
The quantitative risk assessment approach favoured in the USA leads to the
conclusion that the risk of cancer arising is around one in a million and thus tolerable. By this method, the product should be considered suitable for use. In the UK, however, public policy rules out this option and suitability for use must be judged on the basis that the risk is outweighed by benefit and reduced to a level that is as low as reasonably practicable. Since some doubt remains over the benefit of the coating and alternatives are available that do not give rise to any carcinogenic hazard, the residual carcinogenic risk, albeit small, cannot be justified.
There is therefore no reason to alter the advice given by MDA in 1994 and 1996 that
polyurethane-coated breast implants should not be implanted in the UK. Recent
evidence is also consistent with the advice that any risk arising from leaving existing polyurethane-coated breast implants in place is likely to be low when balanced against the small risks associated with explantation. Removal of existing polyurethane-coated breast implants is not therefore indicated.
Conclusions
The following conclusions can be drawn:
- polyesterurethane foam can break down in situ to form the genotoxic carcinogen 2, 4-TDA;
- recent evidence is consistent with the conclusions reached by the COC in 1991
or 1994 that:- 2,4-toluenediamine (2,4-TDA) should be regarded as a probable genotoxic
carcinogen; - there is evidence that small amounts of 2,4-TDA can be released from
polyurethane foam in vitro and in vivo; - direct evidence exists that 2,4-TDA is released from polyurethane coated
breast implants in vivo in women. This leads to the presence of 2,4-TDA
in the tissues surrounding the implant. These tissues can metabolise 2,4-
TDA and there is therefore a potential carcinogenic risk from this release; - information on the breakdown of implanted polyurethane foam in human
tissues suggests that breakdown occurs over a period of several years; - there were no data on the possible release of harmful substances other
than 2,4-TDA from implanted polyurethane foam either in vitro or in vivo;
- 2,4-toluenediamine (2,4-TDA) should be regarded as a probable genotoxic
- no evidence has come to light to indicate that the 1994 COC conclusions need to
be reassessed; - he risk of cancer arising from the implantation of polyurethane foam-coated
breast implants has been estimated to be in the region of 1:1,000,000. While
risks of this magnitude are often considered to be negligible, this sort of risk
assessment model is not considered appropriate for application to genotoxic
carcinogens by the UK Department of Health; - there is no scientific reason to alter the advice published in 1994 and 1996 by the UK Department of Health, based on the COC conclusions, which was:
Polyurethane-coated breast implants pose an unquantifiable (but prabably low) carcinogenic risk. Since suitable alternative products are available, these devices should not be implanted.
The integrity of the silicone shell of the implants is unaffected by the breakdown of the polyurethane foam coating.
The available data show that the amount of 2,4-TDA released decreases with time but suggest that the majority of the exposure occurs during the first 3-4 years post-implantation. There are insufficient data to quantify the rate of degradation with certainty. Since polyurethane-coated breast implants were withdrawn from the UK market in 1991, it is unlikely that explantation of these prostheses will significantly reduce exposure to 2,4-TDA. Although unquantifiable, the risk from leaving polyurethane breast prostheses implanted since 1991 in situ is likely to be low when balanced against the small risks associated with explantation. Any decision to explant must remain a matter of clinical judgement, taking into account the
wishes and condition of the patient.
- there is insufficient evidence to demonstrate conclusively the long-term benefit
of polyurethane-coated implants over other products currently available; - the necessity of using the particular polyesterurethane foam applied to breast
implants to achieve the benefits claimed has not been demonstrated;
In summary, there is insufficient evidence for benefits arising exclusively from the
use of the polyurethane coating to justify exposure to the carcinogenic risk, albeit very
small, associated with its breakdown in situ. Any use of polyurethane-coated breast
implants in the UK thus remains counter to the risk management policy applied by the
Department of Health to non-threshold risks.
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