3.2.1 United Kingdom
In September 2010, in parallel with the tests conducted by Afssaps, the MHRA commissioned a first series of tests1314 to evaluate the toxicity of PIP silicone breast implants and then completed this evaluation in 2012 by a second series of tests1415,89. All these tests were conducted under in vitro conditions by comparison with implants filled with medical grade silicone gel.
The following series of tests was performed:
- Comparative composition of PIP implants and implants with medical grade silicone gel - Genotoxicity tests (in vitro Ames assay: bacterial reverse mutation)
- Evaluation of cytotoxicity (in vitro test on fibroblast cultures) , - Skin irritation test (in vitro test on the EpiSkin model)
The results concerning implant composition, such as those of tests commissioned by the French authorities, showed that concentration levels of low molecular weight D4-D6 siloxanes were significantly higher (10 times or more) in PIP implants than in medical grade silicone implants, and that these levels varied from one batch to another.
PIP silicone implants do not contain major levels of organic or inorganic impurities. Platinum levels (catalyst used in the polymerisation of the gel) in PIP silicone gel implants are lower than in medical grade silicone implants. A very low level of caesium was detected in PIP implants unlike in medical grade silicone implants.
Moreover, low molecular weight siloxanes were assayed in the milk of a woman with ruptured PIP implants. The quantity detected was much lower than that found in commercial cow's milk.
Concerning the toxicological data, the MHRA concluded that the in vitro evaluation of the toxicity of the gel demonstrated no genotoxicity or cytotoxicity, supporting the French results.
In addition, the PIP implants tested were considered to be non-irritant according to an in vitro skin irritation test on the EpiSkin skin model.
Finally, the MHRA1314 and NHS89 reports point out that the presence of these siloxanes is not a significant health risk for subjects with implants even in the case of the complete rupture of the implant. Siloxanes are not genotoxic and do not cause skin or eye irritation or allergic sensitisation
1314 Summary report on tests performed on extracts of silicone gel filler material from PIP silicone breast implants, Sept. 2012
1415 Chemical analysis summary, composition and toxicity of PIP silicone, November 2012
or induce acute toxicity. D4 siloxanes were shown to reduce female fertility in rats under exposure conditions corresponding to the inhalation of 300 ppm or more. However, this is not considered to represent a risk for human health.
In view of all these results, the MHRA and NHS concluded that PIP silicone breast implants differ from medical grade silicone by a higher concentration of siloxanes. This does not represent a risk to human health.
3.2.2 Australia
The Australian authority carried out several series of tests and analyses from 2010 until the last update in February 20131516.
Overall, the TGA commissioned the following tests:
Chemical and physicochemical analysis of the composition of the gel and shell
Mechanical tests according to standard EN ISO 14607 for evaluating the tensile strength of the shell and cohesiveness of the gel
An in vitro test to evaluate the cytotoxicity of the filling gel according to ISO 10993-5
Transdermal irritancy test according to ISO 10993-10: 2010
Visual inspection and mechanical testing of explants The results of these tests showed:
The absence of volatile organic compounds among a selection of compounds (10 different batches) and trace metals
The presence of D4-D6 siloxanes in implants in proportions broadly consistent with the results obtained by Afssaps and unrelated to the year of manufacture
The compliance of PIP implants tested according to the requirements of the standard on mechanical tests (15 samples from 13 different batches)
Negative results on cytotoxicity for all the implants tested (8 samples from 5 different batches)
Negative results in intradermal irritation tests in rabbits when the same series of tests was performed by two different laboratories (7 batches)
Visual examination of explants showed damage to the shell, a lack of cohesiveness and a change of colour for certain products and the mean elongation at break of explanted PIP breast implant shells was about 35% lower than for non-implanted samples of smooth and textured shells.
This latter observation was expected, since it had already been reported for breast implants produced by other manufacturers 16,1717, 18.
TGA results on explants therefore confirmed the previously published scientific data: the mechanical resistance properties of silicone breast implants deteriorate after implantation in the human body.
The report published in April 20121112 by the Australian Department of Health concluded that the tests conducted by the TGA did not identify any specific safety issue with PIP implants. In particular, although the presence of low molecular weight siloxanes is a marker of non-
1516 http://www.tga.gov.au/safety/alerts-device-breast-implants-pip-130211-testing.htm
1617 Brandon HJ, Young VL, Jerina KL, Wolf CJ, "Analysis of explanted silicone/silica composite breast implants" Advanced Composites Letters 9 (2000) 115
1718 Marotta JS, Goldberg EP, Habal MB, Amery DP, Martin PJ, Urbaniak DJ, Widenhouse CW. "Silicone gel breast implant failure: evaluation of properties of shells and gels for explanted prostheses and meta-analysis of literature rupture data". Ann Plast Surg 49 (2002) 227
compliance, this does not pose a safety problem. Finally, they underlined the differences with the French results for the intradermal irritation test and elongation at break test.
3.2.3 Discussion and summary of the French and international toxicological data All the tests performed in France, the UK and Australia led to the same conclusions that these implants do not result in any significant risk to human health and in particular have no cytotoxicity or genotoxicity.
The physicochemical tests gave concordant results demonstrating in particular the heterogeneity of batches of PIP implants and the presence of higher levels of siloxanes (D4-D6) compared to other breast implants and in particular those manufactured according to the CE marking dossier.
These low molecular weight molecules are therefore markers of the non-compliance of these implants, leading in particular to their fragility and tendency to bleed, although they are not considered to constitute a significant health risk. There are no other organic or inorganic impurities in PIP implants.
One of the two conflicting results concerned the in vivo intradermal irritation test performed according to ISO 10993-10 which gave negative results in the Australian tests whereas the gel was slightly to moderately irritant in the tests performed in France. The French results are corroborated by the reports of inflammatory reactions. Moreover, these discrepancies may be partly explained by the known variability between batches.
4 . C o n c l u s i o n i n 2 0 1 3 a n d A N S M a c t i o n p l a n
French and international medical device vigilance reports and the physicochemical and toxicological data on PIP implants are concordant.
Follow-up recommendations for women vary according to the country. The French authorities have recommended that as a precautionary and non-urgent measure, the women concerned should be offered the explantation of their implants even if there is no clinical sign of damage to the implant.
In parallel with the ongoing work of the SCENIHR1213 and the other countries, ANSM continues to pursue a plan involving specific actions and increased surveillance of breast implants in France.
1 . The adverse device incident reports with PIP implants will continue to be subject to specific monitoring, including periodic updates which will now be published three times a year.
2 . Surgeons will be asked to repeatedly inform their patients about the need for monitoring: an assessment of explantations has shown that implant failures or other adverse events were fortuitously detected after preventive explantation (no clinical alert sign) in 21% of these women. It is now estimated that more than half the women with PIP implants have been explanted. However the other women should be further informed about the importance of clinical and radiological follow-up and reminded about the preventive explantation option.
3 . Surveillance of all other silicone breast implants, as well as for PIP implants which were withdrawn from the market in 2010, has been stepped up: in particular the Agency has implemented an inspection programme to control all the implants sold in France. In addition, work is under way to facilitate the setting up of a register for the follow-up of the patients concerned.
The ANSM continues to monitor any new data and will take into account any finding, including from the next review conducted by the SCENIHR, which may make it necessary to update the follow-up recommendations for women with PIP implants.
A P P E N D I X
H i s t o r y o f r e c o m m e n d a t i o n s f o r t h e f o l l o w - u p o f w o m e n w i t h P I P b r e a s t i m p l a n t s .
Follow-up recommendations for women with PIP silicone gel breast implants have been reviewed and updated each time new information has been obtained since the health policy decision of March 20101.
30 March 2010: Afssaps recommendations
Within the framework of follow-up of women with these implants, Afssaps asked surgeons to make an appointment with women in whom they have implanted PIP silicone gel implants in order to give them this information and prescribe an ultrasound scan to check the implant within a maximum timeframe of six months.
28 September 2010: Updating of Afssaps recommendations
In September 2010, Afssaps recommended as a precautionary measure, to increase the frequency of follow-up of women with PIP implants so that each may have a clinical examination with an ultrasound scan during a period of less than 6 months. It was also recommended that if an implant rupture was detected or suspected during these examinations, both this implant and the second breast implant should be explanted. Finally, it was stated that the next contact between the surgeon and patient would provide an occasion to discuss possible explantation even in the absence of any clinical evidence of deterioration of the implant.
15 April 2011: Updating of Afassaps recommendations
In April 2011, after publishing the results of additional tests, Afssaps maintained its previous recommendations and specified that according to vigilance data, a clinical examination and ultrasound scan every 6 months should target both breast and axillary lymph node regions, and that the implant should be explanted if gel-bleed of the gel was suspected. It was also recommended after explantation of an implant showing unusual signs of inflammation, to take a histological and immunohistochemical specimen on the capsule.
30 November 2011: Updating of Afssaps recommendations
In November 2011, following the case of anaplastic large-cell lymphoma occurring in the breast of a patient with PIP implants, Afssaps reiterated and clarified its recommendations of April 2011, namely:
- Patients should routinely undergo a clinical examination and ultrasound scan every 6 months, targeting the breast and axillary lymph node areas during each of these examinations;
- Any rupture, suspected rupture or gel-bleed from an implant should lead to the explantation of both this implant and the second breast implant.
- "Anaplastic large-cell lymphoma of the breast should be considered in particular in the case of persistent periprosthetic serous effusion occurring after implantation surgery as well as in certain cases presenting capsular contracture or masses close to the serous effusion".
- Afssaps asked professionals to advise patients and discuss with them the possibility of explantation even if they present no clinical evidence of deterioration of the prosthesis. This choice should be made after evaluation with the surgeon of the individual risk/benefit ratio including the risk of complications inherent to the procedure.
23 December 2011: Updated recommendations of the Ministry of Health intending to reinforce those issued by Afssaps and recommendations of the experts convened by INCa
The following instructions were sent to regional health agencies by the DGS and DGOS:
- Women with breast implants should check the brand of their implant on the implant card they were given. If they have no such card, they should contact their surgeon or the institution where the implantation was done.
- Patients with PIP implants should consult their surgeon. They will then be proposed preventive explantation, even if they present no clinical sign of deterioration of the implant. If they do not wish to have their implant removed, they should have a follow-up ultrasound scan every 6 months, targeting breast and axillary lymph node areas.
- Any rupture, suspected rupture or gel-bleed from an implant should lead to its explantation, as well as the second breast implant.
- Prior to explantation, for whatever reason, an imaging assessment (including a mammography and a breast and axillary ultrasound scan) must be available.
- To ensure that any woman who wishes to have her implants removed can do so, ministry officials have requested that all Regional Public Health Agencies (ARS) set up, from the beginning of January, a hotline for women with PIP breast implants who may have difficulties reaching a healthcare professional in order to propose a list of institutions able to treat them.
- Health care facilities and health professionals were informed at the same time about this decision and the new recommendations.
- Any costs associated with explantation, including the hospital stay, will be covered by national health insurance. In the case of women who have had reconstructive surgery after breast cancer, the implantation of a new implant will also be reimbursed.