History: the assessment of health effects attributed to silicone gel breast implants

Introduction
Silicone gel breast implants were invented by the plastic surgeons Cronin and Gerow in the early 1960s. They were developed into a commercial product by Dow Corning in 1962. Other manufacturers introduced breast implants in the late 1960s. Since then a few major changes have been introduced into the design of breast implants (see Figure 1 of the IRG report).

From the 1980s onwards, these suggestions have been made concerning possible health effects arising from silicone gel breast implants and several investgations into these theories have been carried out. In Section 1.2 of its report, the IRG note concern at the apparent selectivity of some reviews of the evidence. The true situation in relation a particular subject can only be ascertained through an informed and carefully balanced assessment of the full extent of the pertinent evidence. A distinction can therefore be drawn between those analyses that set out to support a particular point of view and those that use systematic techniques to obtain relevant data and adopt a weight of evidence approach to evaluating the evidence and reaching conclusions. An assessment displaying the latter characteristics can be termed a systematic review, defined by the IRG as an exercise which aims to review all relevant published studies in the scientific literature on a specific topic and evaluates their quality and the results obtained with the aim of reaching an overall conclusion.

This section summarises the history of systematic reviews, particularly those carried out in the UK.

Reviews of carcinogenicity
In the mid to late 1980s an animal study showed that silicone gel implants could cause cancer in rats. This was considered by the Committee on Carcinogenicity (COC), an advisory committee of the UK Department of Health comprising experts appointed by the Chief Medical Officer. The COC concluded that the cancers seen were caused by a well described mechanism which was only relevant to these test animals.

In 1989 the polyurethane foam covering used on some implants was shown to degrade in extreme laboratory conditions. This released a chemical known to cause cancer in animals. Although it was not possible to demonstrate this breakdown in humans, these implants were withdrawn by the manufacturers. Subsequent work has established that this breakdown can occur in animals and humans. Analysis of this information suggested that the risk of cancer would be less than the risks of surgery to remove the implants. This subject was also considered by the COC in 1991 and 1994 and their advice was brought to the attention of surgeons by MDA advisory notices.

US regulatory action 1990-92
In 1990, the Food and Drug Administration (FDA) in the USA requested technical data from breast implants manufacturers to support continued marketing approval. Breast implants were previously approved for use in the USA on the basis that they had been on the market prior to implementation of regulations in 1976. In late 1991 an FDA advisory panel reviewed the data submitted and recommended that manufacturers needed to collect additional data on silicone gel breast implants before approval could be given, but that the products should remain on the market whilst these data were collected. In January 1992 the FDA called for a moratorium on the use of silicone gel breast implants while the advisory panel reviewed new information from case reports of connective tissue disease and data on silicone bleed in some early models. In April 1992 the FDA restricted the use of silicone gel breast implants to clinical trials with, initially, a limited number of indications (i.e. reconstruction, congenital abnormality and replacement of ruptured implants). It was envisaged that this would be extended to augmentation in later studies.

UK review, 1991-93
In response to concern over case reports appearing in the scientific literature, a review of evidence for the putative links between silicone gel breast implants and connective tissue diseases was initiated by the Medical Devices Directorate (MDD) of the UK Department of Health in 1991. (MDD became an Agency, MDA, in 1994.) Early in 1992, this information was studied by an Independent Expert Advisory Group (IEAG) convened by the Department of Health. The MDD report (Tinkler et al., 1993), which incorporated the views of the IEAG, reached the following conclusions:

Immunological studies in animals, although limited in scope have demonstrated that:

• silicones have not been shown to stimulate a specific antibody response;
• silicones are unlikely to stimulate cell mediated immunity under clinical use conditions. In the presence of potent adjuvants, minimal effects have been observed.
• silicones can act as adjuvants to enhance the immune response to co-administered antigen. The response obtained is transient and minimal;
• silicones have no adverse effect on host-resistance to infection.

Animal studies thus provide no immunological reason for concern over the use of silicone gels in implants. Even under forcing conditions using Freund's complete adjuvant, responses to the silicones have been minimal and of questionable significance.

Of the many reports of connective tissue disease co-existing with breast augmentation, the disease most commonly indicated has been systemic sclerosis (scleroderma). In total at the time of the IEAG reviews three cases of localised scleroderma and eleven cases of systemic scleroderma have been adequately reported in women with breast prostheses and there have been three reports of scleroderma in women who have had silicone injections. Although one series of patients examined showed a significantly higher prevalence of the disease than expected, overall there is no indication that the incidence of systemic sclerosis in women with breast implants is any higher than in the general population.

In April, 1992, the IEAG concluded that there was no evidence of an increased risk of connective tissue disease in patients who had undergone silicone gel breast implantation and that there was no scientific case for changing practice or policy in the UK in respect of breast implantation. These conclusions were brought to the attention of medical practitioners in a letter from the Department of Health's Chief Medical Officer (Calman, 1993).

In view of the anxieties that had been raised, however, the IEAG recommended that some form of surveillance action was required for patient reassurance. A Breast Implant Registry was set up at the Wessex Centre for Plastic and Maxillofacial Surgery at Odstock Hospital in Salisbury, and became fully operational in July 1993. It was anticipated that the information contained in the Registry would form the basis for future research projects into aspects of breast implants or possible breast implant associated morbidity.

Canadian review, 1992
The conclusions of an Independent Advisory Committee on Silicone Gel Filled Implants set up by the Canadian Department of National Health and Welfare were summarised by Baines et al. (1992). This committee recognised the need for more accurate data on rupture rates and commented that, whilst a number of biological problems have been reported (for example, capsule development, capsular contracture, silicone infiltration of lymph nodes, development of granulomas and possible systemic distribution of silicone), neither the frequency nor the health impact of these are known and their relationship to possible associated disease states is undefined. Associations with auto-immune diseases were based solely on case reports and a lack of diagnostic criteria for some of the claimed diseases was noted. The deficiencies in these case reports were outlined and it was concluded that there was insufficient evidence that specific diseases occur more frequently in women with implants and that the available evidence did not point to a health crisis. Whilst reassuring, the absence of evidence on auto-immune disease was not felt to be definitive and the need for additional research was acknowledged, not only in respect of the major components but also for manufacturing residues.

American Medical Association review, 1993
The conclusions of an American Medical Association Task Force were summarised in a paper by their Council on Scientific Affairs (1993). The paper described the US Food and Drug Administration (FDA) proceedings and reported the conclusion of the FDA General and Plastic Surgery Devices Panel that sufficient data do not exist to establish a statistically valid relationship between silicone gel breast implants and systemic disease. The Panel had advised that implants should only be available through clinical trials, with access for reconstruction to be maintained but with limited access for augmentation. Whilst agreeing in principle with their conclusions, the Council on Scientific Affairs raised several concerns. These revolved around the tardiness of the FDA in considering these devices, the deficiencies and missed opportunities seen in manufacturers data, the quality of media coverage and the inadequacy of the planned clinical trials. They characterised the FDA hearings as having an excessive emphasis on evidence based on anecdotal opinion rather than on scientifically proven data. The Council recommended support for a patient registry, acknowledgement of the right of women to make an informed choice of implants both for augmentation and reconstruction, further education of physicians on the data (which they noted did not warrant the current level of anxiety), the continued availability of silicone gel breast implants both for augmentation and reconstruction, and changes in and monitoring of the FDA decision making processes.

UK review, 1994
In 1994, in response to the growing level of public concern following the legal action in the USA, the UK IEAG was again asked to advise on an updated review of the possibility that silicone gel breast implants caused connective tissue diseases. A second comprehensive analysis, reviewing scientific papers written on this subject until August 1994, was published by MDA in December 1994 (Gott and Tinkler). Again, this review incorporated the comments and views of the IEAG. The conclusion reached by the 1994 report was that there continued to be no results from any clinical or scientific studies demonstrating an increase in the incidence of connective tissue disease in implanted patients, compared with the unimplanted population as a whole. This conclusion was fully endorsed by all members of the IEAG.

French review, 1996
Following the regulatory action in the USA in 1992, restrictions on the availability of silicone gel breast implants were introduced in France. The French Ministry of Health commissioned a report from the Agence Nationale pour le Developpement de l'Evaluation Medicale (ANDEM), which was published in 1996. The conclusions of this report with regard to any proposed association with connective tissue disease were consistent with those reached by the UK IEAG. In addition, the ANDEM report provided a valuable assessment of the short-term risks of breast implants.

References
Agence Nationale pour le Développement de l'Evaluation Médicale; Les implants mammaires remplis de gel de silicone. ISBN 2-910653-24-2; ANDEM, Paris (1996)

Baines C J, Arseneau J, Davis P, Smith D C; Summary of the report on silicone-gel-filled breast implants. Can Med Assoc J. 147: 1141-1146 (1992).

Committees on Toxicity, Mutagenicity and Carcinogenicity of Cemicals in Food, Consimer Products and the Environment. 1994 Annual Report. ISBN 0 11 321912 1; p36; HMSO London (1995)

Council on Scientific Affairs, American Medical Association; Silicone gel breast implants. JAMA 270: 2602-6 (1993).

Calman K C; Silicone gel breast implants. Professional Letter PL/CMO(93)2, UK Department of Health, 79 Whitehall, London (25 March, 1993).

Gott DM and Tinkler JJB, Silicone Implants and Connective Tissue Disease: Evaluation of evidence for an association between the implantation of silicones and connective tissue disease, Medical Devices Agency Report, London (1994).

Tinkler J J B, Campbell H J, Senior J M and Ludgate S M; Evidence for an association between the implantation of silicones and connective tissue disease. MDD Report MDD/92/42, UK Department of Health, 14 Russell Square, London (1993).