Research and analysis

Poly Implant Prosthèse (PIP) implants: toxicology testing

Published 18 December 2014

Overview

On 29 March 2010, the French medical device regulatory authority (AFSSAPS) informed MHRA that it had suspended the marketing, distribution, export and use of silicone gel filled breast implants manufactured by Poly Implant Prosthèse (PIP), a French breast implant manufacturer.

Following an inspection of the PIP manufacturing plant, AFSSAPS had established that breast implants manufactured since 2001 had been filled with a silicone gel with a composition different from that approved.

On 31 March 2010, MHRA issued a medical device alert advising UK clinicians not to implant these devices.

Initial toxicology testing

In April 2010, AFSSAPS initiated testing of affected implants to look at the genotoxicity (potential for cancer), cellular toxicity and irritation to biological tissues. In addition, mechanical testing of the implant shell was carried out.

At the end of June 2010, AFSSAPS told the MHRA of delays to their product testing. MHRA decided to commission a specific series of tests on PIP silicone. These were the Ames tests that measure the genotoxic activity of chemicals. The results of these tests were uniformly negative, as were other subsequent tests of PIP silicone for genotoxicity conducted elsewhere.

To facilitate the Ames tests, organic extracts of the silicone within PIP breast implants were prepared of the silicone within PIP breast implants. Analysis of these organic extracts did not raise any concerns regarding risks to human health.

See the results of the UK testing.

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.

Expert group review

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 presented to the PIP expert group on 6 January 2012. The information seen by the group is in Annex D of their interim report.

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 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.

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:

• whether and in what way PIP breast implant silicone differs from medical-grade silicone
• whether and inter-batch variation with regard to the composition of PIP breast implant silicone exists

The final report of the expert group was published on 18 June 2012.

They concluded 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 PIP implants, and that these vary between batches.

The presence of these siloxanes is not considered to constitute a significant health risk, 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.

They concluded that there are no other organic impurities in PIP implants. There are also 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).

The group’s other relevant conclusions were that:

• 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 5 years, it seems increasingly unlikely that testing of further samples will reveal any cause for concern

Additional MHRA tests

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.

The Ames test: reverse mutation in five histidine-requiring strains of Salmonella typhimurium Evaluation of in vitro cytotoxicity on Balb/c 3T3 fibroblasts using the Neutral Red Uptake assay An assessment of in vitro skin irritation using EpiSkin™

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.

See the comparative analysis of silicone implant samples and the chemical analysis summary.

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.

See the full final report this test or the summary document.

The reports contain a small number of redactions necessary to protect personal and commercially confidential information.

Final European safety report about PIP silicone breast implants

The European Commission’s Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) report gives their final opinion following a public consultation on their preliminary report which was published in October 2013. The report highlights that:

• there is no reliable evidence that ruptured PIP implants create a greater health risk than a ruptured silicone breast implant from another manufacturer
• the decision to remove an intact PIP implant should be based on an individual assessment of the woman’s condition by her surgeon or other treating physician after consultation
• there are currently no convincing medical, toxicological or other data to justify removal of intact PIP implants

These findings support the findings of the report of NHS Medical Director for England Professor Sir Bruce Keogh’s Expert Group on PIP breast implants which was published on 18 June 2012.

Gathering information from implanting centres

The expert group asked MHRA to contact all the major implanting centres in the NHS and 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

MHRA received information on around 240,000 implants given to 130,000 women and detailed findings from 5,600 explant operations.

The main findings from this analysis were:

• PIP implants are 2 to 6 times more likely to rupture or leak silicone than other implants, and this is apparent after 5 years
• the failure rate for PIP implants is estimated on the basis of reported adverse events at 1.2% at 5 years, rising to 3.1% at 10 years - this compares with a failure rate for other brands of silicone gel implant of 0.2 to 0.4% at 5 years and 0.5 to 1.1% at 10 years
• PIP implants are 3 to 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 5 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
• 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