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MHRA toxicology testing in 2010
At the end of June 2010, AFSSAPS told the MHRA of delays to their product testing. The MHRA recognised the concerns of implanted women and so decided to commission some limited testing to obtain an early indication of genotoxicity .
In July 2010, the MHRA agreed with the relevant experts on the Committee on the Safety of Devices to commission one specific series of tests on PIP silicone. These were Ames tests that measure the genotoxic activity of chemicals.. It was considered that these would give some important information on whether there were potential health risks associated with the filler material.
To facilitate the conduct of the Ames tests, organic extracts were prepared of the silicone within PIP breast implants. Analysis of these organic extracts (4419Kb) did not raise any concerns regarding risks to human health.
In early September 2010 the MHRA was therefore able to announce results of the UK testing (26Kb), with no evidence of safety issues associated with the filler material.
Analyses of the silicone contained in PIP breast implants indicates that the material does not pose a long-term risk to human health. None of the chemicals listed will cause harm at the levels found within PIP breast implants and many are used routinely in various consumer products.
MHRA information collection on breast implant rupture - early January 2012
On 31 December 2011 the Secretary of State for Health asked the NHS Medical Director to launch a review into the PIP breast implant situation by leading an expert group. This was in response to the French government announcement on 23 December 2011 that it was recommending that all women who had been implanted with PIP breast implants should have them removed as a preventative measure.
On 4 January 2012 the expert group requested a rapid collection of data from implanting centres of readily available information on the rupture rates of PIP breast implants and three other common makes of silicone gel filled breast implant.
This information was collated on 5 January 2012 and presented to the PIP expert group on 6 January 2012. The information seen by the group is presented at Annex D of their Interim report (external link).
The expert group considered the information gathered and concluded that the statistical evidence on the rate of ruptures for PIP implants compared with other implants was incomplete and the risks could not be assessed accurately. It therefore recommended the collection of additional information to enable the group reach a more informed view.
Toxicology testing – January 2012 and onwards
The Expert Group Interim report (external link) noted that the standard toxicological tests carried out in the UK, France and Australia showed no evidence of cytotoxicity or genotoxicity .However, the Expert Group requested further chemical and toxicological testing to establish whether, and to what extent, the silicone gel used in PIP breast implants may be associated with increased health hazards compared with conventional ‘medical grade’ silicone.
The MHRA set up a toxicology and chemistry expert group to establish whether, and to what extent, ‘industrial grade’ silicone used in PIP breast implants may be associated with increased health hazards compared with conventional ‘medical grade’ silicone.
Tests carried out under this group's advice were designed to establish:
(a) whether and in what way PIP breast implant silicone differs from ‘medical grade’ silicone, and
(b) whether there exists inter-batch variation with regard to the composition of PIP breast implant silicone.
If there was evidence for inter-batch variation we would also establish whether there exists intra-batch variation in PIP breast implant silicone
The final report of the Expert Group (external link) was published on 18 June 2012.
Their conclusions concerning the additional chemical and toxicological testing results from the above programme available to them at the time were that:
- Chemical analyses of further batches of the silicone used in PIP implants and other silicone breast implants shows that there are higher levels of siloxanes in the former, and that these vary between batches. The presence of these siloxanes is not considered to constitute a significant risk to health, even in the event of a complete rupture of a PIP implant. Apart from this, there is no significant variation between batches, and no significant differences between PIP and other implants.
- In particular, there are no other organic impurities in PIP implants.
- There were no significant inorganic impurities in any batch. The levels of platinum in the silicone of PIP implants are lower than in medical grade silicone. A very low level of caesium was found in PIP implant silicone (not considered to be of significance to health).
Other relevant conclusions were:
- rigorous world-wide chemical and toxicological analyses of a wide variety of PIP implants have not shown any evidence of significant risk to human health
- there is no reason to believe that further testing will change this conclusion, given the results of the chemical analysis and the number of batches that have now been tested world-wide, which have all reached a similar conclusion
- in the light of the findings from the chemical analysis, that there is little variation in chemical composition between batches of PIP implants made over a period of five years, it seems increasingly unlikely that testing of further samples will reveal any cause for concern.
A more detailed analysis of the chemical and toxicological testing data is contained on pages 6-8 and13 of the final report (external link). The interim report that provided the further toxicology testing information upon which the expert group drew its conclusions is provided here (8938Kb) with a small number of redactions necessary to protect personal (on pages 1,2 and 32) and commercially confidential information (on pages 3, 9,10, 24-31).
The MHRA commissioned additional tests of the silicone gel material from batches of PIP breast implants to look for toxicological properties of genotoxicity, cellular cytotoxicity and skin irritation. These assessments were all conducted using well-established and fully validated in vitro test methods. Five different batches of PIP breast implant (and 1 control implant of ‘medical grade’ silicone) were selected for analysis, and in each case both aqueous and organic extracts of implant silicone were tested. In all tests both aqueous and organic extracts of all batches of implant silicone were uniformly negative.
The final reports of these additional tests are provided below. The final report for the chemical analysis is also provided below and a summary document is also available, Chemical Analysis Summary (175Kb).
A single sample of breast milk obtained from a lactating donor with a ruptured PIP breast implant was also tested for the presence of total silicon. Although the method used has not been fully optimised and validated, normal, commercially available semi-skimmed cows’ milk was found to contain considerably higher levels of total silicon than the sample of breast milk. The final report is provided, Determination of Total Silicon in Milk (2286Kb). A summary document for this test is also provided, Silicon in Breast Milk Summary (143Kb)
The reports contain a small number of redactions necessary to protect personal and commercially confidential information.
List of 2012 PIP test reports:
- Chemical analysis: Comparative Analysis of Silicone Implant Samples (9139Kb)
- Determination of Total Silicon in Milk (2286Kb)
- The Ames test : Reverse mutation in five histidine-requiring strains of Salmonella typhimurium (51208Kb)
- Evaluation of in vitro cytotoxicity on Balb/c 3T3 fibroblasts using the Neutral Red Uptake assay (7774Kb)
- An assessment of in vitro skin irritation using EpiSkin™ (4363Kb)
MHRA information collection on clinical findings at breast implant explantation – January to May 2012
The expert group requested the MHRA to contact all the major implanting centres, both in the NHS and in the private sector, to ask them to complete a questionnaire seeking information for both PIP and other brands on:
- the total number of women who received implants each year over the period 2001-2011
- the reasons for explantation, and the clinical findings at explantation, of all explantations carried out over the same period
- the reasons for explantation and the detailed clinical findings at explantation for all PIP breast implants removed from February to May 2012.
In response to this request the MHRA received information on some 240,000 implants given to 130,000 women and detailed findings from 5,600 explant operations.
The main findings from this analysis are:
- PIP implants are 2-6 times more likely to fail than other implants, and this is apparent after five years.
- the failure rate for PIP implants is estimated on the basis of these reported adverse events at 1.2% at five years, rising to 3.1% at 10 years. This compares with a failure rate for other brands of silicone gel implant of 0.2 - 0.4% at 5 years and 0.5 - 1.1% at 10 years. However, the true underlying failure rate, including 'silent' ruptures, will be greater than this.
- PIP implants are 3-5 times more likely than other implants to result in local clinical signs. The rate of explants with local clinical signs is 0.8% at five years rising to 2.1% at 10 years
- PIP implants are not associated with higher risks of other clinical problems such as capsular contraction, haematoma or cancer.
The main conclusions in the expert report include:
- PIP implants are significantly more likely to rupture or leak silicone than other implants, by a factor of around 2-6, and this difference is detectable within five years of implantation.
- in a proportion of cases, failure of the PIP implant results in local reactions but these are readily detected by outward clinical signs – ‘silent’ ruptures (ruptures which come to light only on explantation) are not generally associated with these local reactions.
The final report (external link) contains a more detailed presentation of the clinical findings on pages 8-12 of the main document and on pages 5-14 of Volume 2: Appendix II: Data analysis (external link). The data in Appendix II are summarised data. In the interests of completeness and transparency we provide below the full set of detailed data that were used in compiling the tables in the final report.
PIP background data - Excel file (314Kb)