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Date: Wednesday, 15 July 1998 10:06

Subject: Part THREE - Silicone Gel Breast Implants - British Study

6.3 Neurological disorders

A number of researchers have suggested that silicone gel breast implants may be the cause of a variety of neurological effects or of a multiple sclerosis-like syndrome. The available literature and unpublished data were reviewed by the Practice Committee of the American Academy of Neurology in 1997. The Committee concluded that the existing studies came from the weakest of their three possible categories of evidence and did not support any association or causal relationship between silicone gel breast implants and neurological disorders. They recognised that well conducted observational studies were needed to examine this issue.

Two observational studies were published in April 1998. Both were epidemiological studies, one from Denmark (Winther et al., 1998) using their national register and the other from Sweden (Nyren et al., 1998) based on their national discharge register. The controls were women undergoing breast reduction surgery. There was no statistically significant difference in the occurrence of neurological disorders between the study group and the control group. However both groups had more cases than were expected although this was not statistically different from the historical data on the general population. 6.4 Hormonal disorders The possibility that some low molecular weight silicones may possess oestrogenic activity and act in an analogous manner to environmental oestrogens has been raised. At present there are no data to support these putative actions. There is as yet no consensus on which chemicals act as environmental oestrogens and major research efforts are underway to validate a methodology to identify such compounds and assess their effects.

24 Silicone gel breast implants: Report of the IRG, 1998 6.5 Effects on children of women with breast implants There is understandable concern among women, and resultant media interest, in the possible effects of silicone gel breast implants on the health of their children. A number of women with silicone gel breast implants have reported that their children have developed swallowing difficulties, irritability, non-specific skin rashes, fatigue and a range of other symptoms similar to those that occur in some women with silicone gel breast implants. The IRG considered the papers published on these issues. The majority of the papers report individual case studies and there are no epidemiological cohort or case control studies comparing the symptoms of children born to women who have an implant with children of women who do not have an implant. The IRG examined papers relating to swallowing difficulties, to autoantibodies in children of women with an implant, and to T-lymphocyte responses to silica. They also examined relevant studies in animals and looked at whether there was any evidence of silicone being present in breast milk. The IRG concluded that the published literature does not substantiate the claims that there are significant, clinically apparent, effects in children of women who have had an implant. While immunological abnormalities have been reported in some of these children, the methodological problems associated with the published studies mean that this cannot be interpreted as a clear effect of the presence of the implant. There is no evidence that the incidence of immunological abnormalities is any greater than in the general childhood population. Because of the presence of silicone in many forms, the exposure of children born to women with an implant is no greater than that to which they are exposed from other sources of silicone in the diet and in the environment. See Website for a detailed discussion of the effects on children of women with breast implants. www.silicone-review.gov.uk/children 6.6 Silicone toxicity Understanding the risks to human health of chemicals requires knowledge of their toxicity. The IRG considered evidence reviewed in previous publications, detailed reports from manufacturers and publications in the medical and scientific literature. The information supplied about the local and systemic toxicity, genetic toxicity, reproductive toxicity and carcinogenicity showed that silicones were relatively bland substances. There was little local reaction, except to older smooth-surfaced implants, which tended to excite local scarring and contraction over a period in animal studies. There has been no evidence of sensitisation of animals to implants or extracts of them, pathological changes in the tissues of the immune system in animals have not been seen after implantation of implant materials, nor were alterations found in specific tests of immune function in animals exposed to certain silicones. Tests looking with reliable, validated analytical techniques for the dissemination of silicones from implants in the body have shown either no dissemination, or the presence of only very small amounts at distant sites following rupture of gel-filled implants, or after deliberate injection of the gel. The substantiated risks of implants, as shown in experiments in animals and in other laboratory studies, and as borne out by the much more limited investigation of samples from women with implants, are local inflammatory and scarring reactions, and local infection, as around any foreign body in the tissues. If a silicone fluid is released from a ruptured gel implant, the inflammatory and fibrotic reaction will affect a wider area. There does not appear to be any evidence of a conventional or validated type of systemic reaction, or of abnorm-alities of the immune system, in women who have received implants, but these aspects are further discussed in this report and previous publications (Tinkler et al., 1993; Gott and Tinkler, 1994). The overall pattern of the findings in the toxicity tests, both the general studies of systemic actions and the experiments examining local actions, has been consistent with conventional forms of toxic responses. There has been no clinical, laboratory or pathological indication of unusual or unique types of reaction. The IRG concluded that the relevant studies have shown only local reactions to silicones. Systemic damage and dispersal of silicone polymers W

28 Silicone gel breast implants: Report of the IRG, 1998 Having reviewed all the available evidence, the IRG have reached a number of conclusions.

1. There is no histopathological or conclusive immunological evidence for an abnormal immune response to silicone from breast implants in tissue.
2. There is no epidemiological evidence for any link between silicone gel breast implants and any established connective tissue disease. If there is a risk of connective tissue disease, it is too small to be quantified. The IRG cannot justify recommending further epidemiological studies to investigate this hypothesis.

3. Good evidence for the existence of atypical connective tissue disease or undefined conditions such as 'silicone poisoning' is lacking. It is possible that other conditions such as low grade chronic infection may account for some of the non-specific illnesses noted in some women with silicone gel breast implants.

4. The overall biological response to silicone is consistent with conventional forms of response to foreign materials, rather than an unusual toxic reaction.

5. There is no evidence that children of women with breast implants are at increased risk of connective tissue disease.

6. The IRG recognised that there were issues such as the precise incidence of rupture where the scientific data were incomplete so that rigorous conclusions could not be drawn. 7 Overall Conclusions from the Scientific Evidence Silicone gel breast implants: Report of the IRG, 1998 26

27 Silicone gel breast implants: Report of the IRG, 1998 8 Conclusions and Recommendations

The IRG recognises the physical and psychological benefits of breast implantation but at the same time is aware that many women are concerned about the effects of the procedure. The IRG also recognises that there is some risk associated with the use of any implant. On the basis of information available, the IRG concludes that risks to patients associated with the use of silicone gel breast implants are no greater than for other implants. It is, however, important to ensure that women are able to make informed decisions by providing clear and comprehensive information about potential advantages and disadvantages of particular products and treatments. Two major areas of concern were brought to the attention of the IRG by women giving oral and written evidence. These were:

Poor quality of information available to assist women in making informed decisions about breast implant surgery inadequate follow-up which makes it impossible to establish the true incidence of any short- and long-term complications. The IRG makes recommendations to address these areas of concern.8.1 Provision of adequate information before consultation The IRG was concerned that some organisations promote breast augmentation as a simple procedure and do not provide adequate information to women. Women have difficulty in obtaining reliable information about breast implant surgery. Information may be gathered from friends who have had similar surgery or from advertisements in the media. However, these sources give no information about the quality of the products, the service, or the follow-up care. Women who are contemplating breast implantation should see their GP and obtain the names of surgeons who are on the General Medical Council (GMC) Specialist Register.

The IRG recommends that all patients undergoing cosmetic breast Augmentation surgery should be able to obtain, free of charge, from a designated body, comprehensive information about the benefits and risks of such surgery. This should be accompanied by a checklist of topics (see Figure 2) which should be covered when the possibility of an operation is discussed.

The IRG recommends that advertisements in all media promoting breast implant surgery should include a statement indicating that anyone contemplating this type of surgery can obtain information about the operation and its risks from a designated body. 28 Silicone gel breast implants: Report of the IRG, 1998 8.2 Provision of adequate information at the consultation The IRG's work has shown that women are frequently given inadequate information about the operation and any possible problems associated with it. They may be pressurised into going ahead with the operation before they have considered fully the advantages and disadvantages. They may not be given full information about the possible short- and long-term medical and financial implications of the operation. The IRG believes that women should be given comprehensive information about the surgery and about any short- and long-term risks connected with silicone gel breast implants. 8.3 Post-operative care The IRG considered the need for women to be given comprehensive information about post-operative care and possible associated problems. The IRG agreed that:

* women should receive instructions about immediate and continuing

aftercare including advice on physical activity, pain management, time off work and what circumstances might indicate the need to seek medical advice

* women should be informed of the type, manufacturer and batch number of their implants and told to keep this information. They should be given an explanation of why this may be important

* women should be informed that a letter will be sent to their GP giving details of the operation. The purpose of the letter should be explained; should women develop problems associated with surgery in the short- or long-term, the GP will need to be aware of previous surgery since it may be related to the prevailing condition.

* women should be followed-up for a minimum of one year with the option of longer follow-up at the woman's request

* women should be given advice about how to recognise signs of rupture and told to return for a follow-up appointment if they suspect this may have occurred

* women should be told that if capsular contracture occurs, they should make an appointment with the surgeon as soon as possible.

The IRG recommends that all women undergoing or proposing to undergo cosmetic breast augmentation surgery should be offered the following:

1. an initial appointment with the surgeon carrying out the operation

2. an opportunity to discuss the checklist of issues with that surgeon. Figure 2 contains a list of issues that should be included in any checklist

3. information on the likely financial implications of breast implant surgery including the fact that further treatment and expenditure may be necessary at some time in the future. These costs may include not only initial consultations and operation but also regular follow- up, screening for rupture if this is thought to have occurred, explantation and reimplantation

4. a 'cooling off' period of several days between the initial consultation with the surgeon and the operation

5. a guarantee that any deposit or payment for the operation will be fully refunded if for any reason the woman changes her mind, even at the very last moment, and cancels the operation

6. an assurance that they will not come into direct contact with a representative of a particular manufacturer prior to agreeing to surgery.

29 Silicone gel breast implants: Report of the IRG, 1998 n n The experience of the surgeon in performing this operation (together with information on whether on the GMC Specialist Register, and whether a member of the British Association of Plastic Surgeons/British Association of Aesthetic Plastic Surgeons)

* * The types of implants generally available, the advantages and disadvantages of each and the reason for the individual decision

* * Cosmetic effects of the operation including:

l position of pocket

l position of implants

l appearance of scar

* * Information on the possible immediate post-operative effects including:

l bruising

l pain

l swelling

l bleeding

l infection

l nipple sensitivity

l likely recovery time

* * Information on longer term, local effects including:

l wrinkles, folds

l capsule formation

l gel bleed

l rupture linked to the expected lifetime of the implant, the incidence of rupture, screening for rupture, what it means if rupture occurs, symptoms that may be noted if rupture occurs, and what actions need to be taken under these circumstances

* * Follow-up, including:

l minimum follow-up of one year

l further follow-up at woman's request or on development of certain symptoms n n Possible association between silicone and generalised illness such as connective tissue disease or autoimmune effects or a new connective tissue disease-like syndrome. There is no evidence for a significant association over and above the normal risk n n Breast cancer. There is no evidence for an association with either breast cancer or any other malignancy

* * Effect on breast cancer detection and screening. Women with breast implants should continue to be screened. Breast screening arrangements are not affected by the presence of an implant. However, women should inform those carrying out the screening of the presence of an implant so that screening techniques can be modified appropriately

* * Effect on the children of women with breast implants. There is no

evidence for an increase of illness in children of women with silicone gel breast implants

* * Effect on breast feeding. There is no interference with the ability to breast feed

* * Information on financial implications:

l the initial consultation

l operation

l follow-up

l possible screening for rupture, possible explantation and re-implantation

* * Letter to the GP. Letter will be sent to GP giving details of the operation. Explanation of this action

* * The National Breast Implant Registry

l details of implant and procedure

l option to participate in future follow-up Suggested checklist of issues to be discussed with women considering breast implantation

30 Silicone gel breast implants: Report of the IRG, 1998 8.5 Consent for the operation The IRG's concerns about adequate information for women focused on the important issue of consent to treatment. In 1993, the Department of Health defined consent in the following way:

"Consent is the voluntary and continuing permission of the patient to receive a particular treatment based on an adequate knowledge of the purpose, nature and likely risks of the treatment including the likelihood of its success and any alternatives to it. Permission given under any unfair or undue pressure is not consent".

Consent to medical treatment may be oral or written, express or implied. For the purposes of surgery it is usual to obtain written consent from the patient except in an emergency. One matter of concern is that it appears from the evidence presented to the IRG that there is no uniformity in the approach taken to counselling of women, and that in some instances women are given far too little information about what to expect as normal both in the immediate post-operation period and in the long-term. One of two civil actions might be available in circumstances when consent is deficient. These are the actions for trespass to the person (assault and battery) and the action for negligence.

Trespass to the person Assault and battery are forms of the civil action of trespass to the person. They are also crimes, though it would be very unusual for criminal proceedings to be brought against a doctor who treated a patient without consent. Assault (putting a person in fear of immediate battery), usually accompanies battery as a matter of course. in medical cases, battery may be committed if the individual:

* is treated against his or her will

* consents to one treatment but receives another or an additional treatment

* is given treatment without being told that this will happen

* is treated under duress agrees to treatment after being provided deliberately with information that is wrong. A hypothetical example might be the case of a woman who has consented to a mastectomy, and at the same time reconstruction with a silicone gel implant is performed without her consent to that procedure having been obtained before surgery.

If the individual consents to a particular treatment but this was without having received appropriate information beforehand, this is described in legal terms as 'negligence'. In the United Kingdom, the general rule is that a patient is entitled to receive information concerning the material risks associated with the treatment. The nature and extent of that information is currently determined by the Bolam test. This means that a doctor would not be found to be negligent even if a woman claimed that she was given insufficient information about certain risks, if the doctor had acted, in good faith, on the basis of responsible, currently held medical opinion. In breast surgery, as in many other areas of care, medical opinion can be divided. Despite this, the IRG is strongly of the opinion that doctors should give women comprehensive information about the risks and benefits of silicone Gel breast implants. See Website for a detailed discussion on Consent. www.silicone-review.gov.uk/consent

The IRG recommends that a specific consent form be developed which incorporates, as an integral part, the checklist of issues (see Figure 2). The consent form should confirm that the different types of implant available have been discussed with the surgeon and the type agreed, and that all subjects on the checklist have been discussed to the woman's satisfaction along with any other concerns that the woman wishes to address. This consent form should be signed by the surgeon and the woman. One copy should be kept by the surgeon in the notes, and one copy kept by the woman. According to the Bolam test, as long as the doctor is found to have acted in accordance with a responsible body of medical opinion, there can be no finding of negligence. W

8.6 Regulation of private clinics

The IRG was concerned about varying standards of quality assurance among the variety of organisations offering breast implant surgery.

The IRG recommends that measures should be introduced to ensure that proper standards of care are implemented in clinics carrying out breast implantation within the private sector. In particular, a quality assurance system, including the sending of a routine letter to the woman's GP and clinical audit procedures should be standard practice within such clinics.8.7 National Breast Implant Registry There has been a National Breast Implant Registry since 1993. Currently the Registry is voluntary and women can decide whether to have their details included. The purposes of the Registry are to identify information about short-term complications such as rupture, and to provide a source of data for future research studies on the long-term effects of breast implants. It is only by having access to a comprehensive systematically collected database that concerns about the possible effects of breast implants can be investigated. The IRG emphasised the value of a Registry for this purpose. If the Registry is to be used for future research which will benefit all women with breast implants, it is essential to have information included on the Registry about all implant procedures carried out in both the NHS and the independent sector. The IRG gave careful consideration to the issues of confidentiality and to the use of information on the Registry for research purposes. It was agreed that the principles of confidentiality should continue to be maintained in relation to this information. See Website for detailed information on the National Breast Implant Registry. www.silicone-review.gov.uk/registry

The IRG recommends that prospective registration of details of each breast implant and explant operation on the National Breast Implant Registry should be compulsory. In addition all women should be given the opportunity to participate in long term follow-up projects with the full understanding that they may be contacted in the future to provide information to facilitate research. It should be explained to the woman that the Registry will be used to gather accurate data on the outcomes associated with silicone gel breast implants, including the incidence of rupture.W

8.8 Adverse incidents

It is essential to have information about the clinical performance of implants during use to be able to assess and monitor their safety and suitability in the long-term. Information about adverse incidents can provide an early indication of a problem with a product and the IRG recognised the value of the Medical Devices Agency (MDA) adverse incident reporting system. Under this system a report is made to the MDA about any suspected problems with poorly designed or malfunctioning medical products. Similar systems exist elsewhere such as the FDA's Medical Device Reporting scheme in the USA and the Vigilance reporting system set up under the European Directives. The IRG emphasises the importance of using the adverse incident reporting system to ensure that any problems are recognised as quickly as possible. See Website for further information about adverse incidents. www.silicone-review.gov.uk/incident

The IRG recommends that all clinicians should report breast implant related adverse incidents to the Medical Devices Agency Adverse Incident Centre. The MDA should provide guidance to clinicians on which incidents should be reported.8.9 Future research The IRG is concerned that future research should enable women with silicone gel breast implants, clinicians, manufacturers and scientists to work together to ensure the highest levels of confidence in the use of silicone gel breast implants. The IRG therefore make the following recommendations about future areas of research.

The IRG recommends that a small steering group be set up to prioritise, plan and monitor the following programme of research. Priorities should include:

Research into the true incidence of rupture

Rsearch into the aetiology of symptoms exhibited by a number of women who have had implants, in particular to elucidate the role, if any, of sub-clinical infection. The IRG recommends that the steering group should also consider the need to validate the results of other studies, such as those by Ellis et al.

The IRG concluded that the publications of Tenenbaum et al., and Smalley et al., were not conclusive and are open to legitimate scientific criticisms. However, in view of concerns expressed by women's groups, the IRG recommends that there would be scientific merit in determining whether the results of these studies can be reproduced by independent laboratories.

Although there is currently no justification for routine regular breast investigation to detect rupture, the IRG recommends that this subject should be kept under review and the decision revisited in the light of possible new information and technical advances relating to imaging techniques used in the detection of rupture.

33 Silicone gel breast implants: Report of the IRG, 1998 Annex 1

Members of the Independent Review Group Professor R D Sturrock, The McLeod/Arthritis Research Campaign Professor of Rheumatology, University of Glasgow (Chairman) Professor J R Batchelor, Emeritus Professor of Immunology, Imperial College of Science, Technology and Medicine on the Campus of Hammersmith Hospital Mrs V Harpwood, Senior Lecturer, Cardiff Law School, University of Cardiff Professor D R London, Emeritus Professor of Medicine, University of Birmingham; Registrar of the Royal College of Physicians Mr T M Milward, Consultant Plastic Surgeon, Leicester Royal Infirmary Professor A J Silman, Arthritis Research Campaign Professor of Rheumatic Disease Epidemiology, University of Manchester Medical School Professor J P Sloane, Professor of Pathology, University of Liverpool Secretariat provided by the Medical Devices Agency

Mr G A Crosbie

Dr D M Gott

Dr S M Ludgate

Mr J J B Tinkler

At their first meeting, members of the Independent Review Group were asked to declare any existing relevant interests. Mr Milward stated that he had resumed the use of silicone gel breast implants in line with the conclusions of the previous Independent Expert Advisory Group. Professor Silman stated that he had summarised the findings of previous epidemiological studies in scientific publications on the epidemiology of connective tissue disease.Advisors to the Independent Review Group Dr A J Darby, Consultant Histopathologist, Robert James and Agnes Hunt Orthopaedic Hospital, Oswestry Professor A D Dayan, Professor of Toxicology, St Bartholomew's Hospital, London Mr J Denton, Research Scientist, Department of Pathological Science, University of Manchester Dr M Field, Senior Lecturer, Department of Rheumatology, University of Glasgow Professor A J Freemont, Professor of Pathological Science, University of Manchester Dr C Gemmell, Reader in Medical Microbiology, University of Glasgow Professor R I Lechler, Professor of Immunology, Imperial College of Science, Technology and Medicine on the Campus of Hammersmith Hospital Professor F D Lee, Professor of Pathology, Glasgow Royal Infirmary Dr D E Woolley, Reader in Cell Biology, University of Manchester

34 Silicone gel breast implants: Report of the IRG, 1998 Annex 2

Oral Evidence considered by the Independent Review Group Mr P Balen Freeth Cartwright Hunt Dickens (Solicitors)

Ms N Bazire National Breast Implant Registry

Ms M Cameron Silicone Support UK (Women's Group)

Mrs A Clwyd Member of Parliament

Ms E Coomber Survivors of Silicone (Women's Group)

Professor R Garry Tulane University, USA

Ms S Green

Ms M Heasman Breast Implant Information Service (Women's Group)

Mr R Levy Leigh Day and Co. (Solicitors)

Dr S Myhill General Practitioner and Allergist

Mr M Notaras British Association of Cosmetic Surgeons

Dr P O'Leary International Association of Prosthesis Manufacturers: McGhan

Dr B Purkait International Association of Prosthesis Manufacturers: Mentor

Dr P Shakespeare National Breast Implant Registry

Professor D R Shanklin University of Tennessee, USA

Professor D Sharpe British Association of Plastic Surgeons and British

Association of Aesthetic Plastic Surgeons

Professor D R Uhlmann University of Arizona, USA (Nominated by former manufacturers)

Ms R Urion Survivors of Silicone (Women's Group)

35 Silicone gel breast implants: Report of the IRG, 1998 References cited in text Croft, P; Schollum, J. and Silman, A. (1994) Population study of tender point counts and pain as evidence of fibromyalgia. British Medical Journal. 309: 696 - 699.

Ellis, T. M; Hardt, N. S; Campbell, L; Piacentini, D. A; and Atkinson, M. (1997) Cellular immune reactivities in women with silicone breast implants:

A preliminary investigation Annals of allergy, asthma and immunology. 79: 151 -154.

Gott, D. M; and Tinkler, J. J. B. (1994) Silicone Implants and Connective Tissue Disease: evaluation of evidence for an association between the implantation of silicones and connective tissue disease. Medical Devices Agency, Department of Health: London.

Nyren, O. McLaughlin, J. K; Yin, L. Josefsson, S; Engqvist, M; Hakelius, L; Blot, W. J; and Adami, H. O. (1998) Neurology. 50: 956 - 962.

Smalley, D. L; Shanklin, D. R; Hall, M. F; Stevens, M. V; and Hanissian, A. (1995) Immunologic stimulation of T-lymphocytes by silica after use of silicone mammary implants. FASEB Journal. 9: 424 - 427.

Smalley, D. L; Levine, J. J; Shanklin, D. R; Hall, M. F; and Stevens, M. V. (1996/1997) Lymphocyte response to silica among offspring of silicone breast implant recipients. Immunobiolology. 196: 567 - 574.

Tenenbaum, S. A; Rice, J. C; Espinoza, L. R; Cuéllar, M. L; Plymale, D. R; Sander, D. M; Williamson, I. I; Haislip, A. M; Gluck, O. S; Tesser, J. R. P; Nogy, L; Sribrny, K. M; Bevan, J. A; and Garry, R. F. (1997) Use of antipolymer antibody assay in recipients of silicone breast implants. Lancet; 349: 449 - 454.

Tinkler, J. J. B; Campbell, H. J; Senior, J. M.; and Ludgate, S. M. (1993) Evidence of an association between the implantation of silicones and connective tissue disease. Medical Devices Directorate Report MDD/92/42 Department of Health: London. Winther, J. F; Bach, F. W; Friis, S; Blot, W. J; Mallemkjer, L. Kjellar, K; Hagsted, C; McLaughlin, J. K; and Olsen, J. H. (1998) Neurology. 50: 951 - 955.

Young, V. L; Nemecek, J. R; Phelan. D. L. and Schorr, M. W. (1995) HLA typing in women with breast implants. Plastic & Reconstructive Surgery. 96: 1497 - 1519.

See Website for a full list of references considered by the IRG.

www.silicone-review.gov.uk/reference W

36 Silicone gel breast implants: Report of the IRG, 1998 Glossary

Adjuvant: a substance which enhances antibody production.

Antibody: a protein that is manufactured by certain lymphocytes (types of white blood cell) which reacts with a specific antigen in the body.

Antigen: a substance that can trigger an immune response resulting in the production of an antibody as part of the body's defense against disease.

Autoantibody: an antibody which reacts with the individual's own tissues because it recognises these as foreign antigens.

Autoimmune reaction: a response arising from and directed against the individual's own tissues.

Axillary lymph nodes: a group of glands in the armpit.

Brachial plexus: a group of nerves in the armpit which supply the arm.

Capsular contracture: shrinkage of the fibrous capsule, noticeable as an apparent hardening of the breast.

Capsulotomy: the creation of an opening through the scar tissue forming around the breast implant, by application of external pressure. Fibrous capsule: a wall of scar tissue around the breast implant.

Gel bleed: diffusion of small molecules of the liquid component of silicone gel through the intact shell.

Haematoma: a mass of extra-vascular clotted or partially clotted blood, confined within a tissue or space.

Polydimethylsiloxanes (PDMS): polymers of dimethylsiloxane, referred to throughout this report as silicone.Staphylococcus epidermidis: a bacterium which exists as part of the normal skin microflora causing no ill effects unless introduced into the human body.

Subclinical: this denotes the presence of a condition without obvious symptoms; may be an early stage in the evolution of a disease.

Systematic review: an exercise which aims to review all relevant published studies in the scientific literature on a specific topic, evaluates their quality and the results obtained with the aim of reaching an overall conclusion.

T-lymphocyte: a particular type of long-lived white blood cell.

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Silicone Gel Breast Implants The Report of the Independent Review Group