Toxicity of silicones

1. Introduction
Understanding the risks to human health of chemicals requires knowledge of their toxicity, comprising knowledge of their harmful effects in humans, in animal experiments and in various in vitro systems plus information about their kinetics and metabolism, i.e. the rates and ways in which substances become dispersed through the body, thus gaining access to tissues remote from their point of entry, how the body affects the substances chemically and physically and how they are cleared from the body.

For substances that have been used for some time, it is usual to find medical information about effects in humans (and sometimes animals) linked to the substances, such as individual case reports, series of cases, possibly formal epidemiological surveys and deliberate trials in people. There will also be large numbers of experiments in animals, in living cells and in other laboratory systems that follow legal or other guidelines and are intended to provide a comprehensive account of the potential risks of exposure of humans to the substances.

The special purpose of much of the work in non-human studies is to show what harmful (toxic) actions may occur after various exposures under circumstances related to the likely exposure of humans, so that risks in man can be predicted and their mechanisms understood. In this way, there will be a good basis for understanding what types of toxicity are most likely to occur under a given circumstance (e.g. type of substance, route of exposure, dose, duration), what clinical and laboratory investigations are most likely to demonstrate their presence and to treat or prevent them, and how to enjoy the benefits of the substances without being harmed by them.

Comparison initially of the potential and subsequently of the demonstrated risks of toxicity and of the corresponding benefits is the basis of decision making about the value of substances and hence of whether, if they are medical products, of permitting their use in humans.

In the case of silicone implants, which have been available in various forms in Britain since about the early 1960s, there is information from manufacturers of the chemical substances used in their manufacture, further information from companies that have produced the finished implants from those substances, and from a variety of case reports, case series and formal surveys. The data range from detailed chemical analyses, toxicity and compatibility tests in animals and various cell and tissue systems, many detailed biochemical and pathological studies to various types of medical investigation and evaluation. Scientific knowledge has advanced over the period of more than 30 years since silicone implants were introduced and the testing requirements of official and professional bodies have also developed over that period. As a result, the types and nature of the toxicity data now available represent a wide range of reports of variable extent and quality, when considered by today's standards. The need is to synthesise conclusions, making appropriate allowance for the diverse nature of the studies considered appropriate at different times, in order to present a conclusion based on the totality of the available knowledge.

This brief overview is based on material already extensively reviewed in previous publications from the Medical Devices Agency (Tinkler et al. 1993, Gott and Tinkler 1994), on detailed reports from manufacturers and on publications in the medical and scientific literature. It is not intended to be a comprehensive account and evaluation of the toxicity of the silicones, which would be a very large document, but to present a concise note on aspects of their toxicity to support the wider assessment of risks provided in the IRG report.

2. Nature of silicones and of the materials used in implants
2.1 Composition of silicone gel breast implants
The types of material used in implants are described in previous reports (Tinkler et al. 1993, Gott and Tinkler 1994). More detailed information about the complex chemistry of the silicones, i.e. the various silicone polymers used, as well as fillers (amorphous fused silica), coatings (e.g. a specific polyurethane) and adhesives, and about their manufacture is provided in published sources and private communications from manufacturers and other groups, e.g. Compton, (1997), Silicones Environmental Health and Safety Council (1995), Lane et al. (1998), Harrison (1998), Barlow (1998), and Eschbach and Schulz (1998).

Breast implants have changed in nature over a period (see Figure 1 of the IRG report). The earlier type comprised a silicone elastomer envelope containing a silica filler with attached Dacron sheeting, and containing a silicone gel. Later products consisted of a similar silicone elastomer envelope, also with Dacron attachments, filled with a silicone gel and sealed with a silicone polymer patch. Table 1, which is based on more detailed information supplied to the IRG in confidence by manufacturers, summarises the nature of chemical ingredients used in the manufacture of silicone gel breast implants.

Table 1: Chemical constituents of silicone gel breast implants

component	typical compounds	factors influencing residues or toxicity
base polymers	dimethyl polysiloxanes; other polysiloxanes	mostly incorporated into polymer; low molecular weight silicones are also included in gel
additional polymers	substituted polysiloxanes	incorporated into polymer to provide specific physical properties
crosslinking agents	substituted polysiloxanes	incorporated into polymer
filler / reinforcer	amorphous, fumed silica or trimethylated silica	incorporated into elastomer
crosslinking catalysts and reaction inhibitors	platinum catalyst; tin catalyst (occasional); peroxide catalyst (rare); organic inhibitors	stable platinum compounds are most commonly used, typically up to 10ppm (0.5mg per implant). These have different properties, particularly in terms of biochemical reactivity, and are much less toxic than platinum compounds used as cytotoxic drugs.
solvents	1, 1, 1-trichloroethane; xylene, acetone; ethatnol, other solvents (occasional)	these organic compounds have low boiling points (up to about 150°C). They are effectively removed during processing for several hours at around 160°C. Residues, where detectable, are typically below 10ppm and would rapidly be cleared by the body
release agent	zinc stearate	Zinc residues are typically below 10ppm

The information supplied to the IRG by manufacturers was comprehensive in some instances and patchy in others, and identification of the exact nature and source of the materials tested was not always possible from the data provided. Although the technologies used to manufacture and characterise elastomers and implants has evolved over a number of years, results demonstrating the application of more recent and more sensitive or specific assay techniques were not supplied by all manufacturers. The use of multiple proprietary names or identification codes rather than an unique designation specific to each substance has also hindered straightforward comparison of different products. It must be recognised that it is technically difficult to characterise complex polymers by other than a mixture of their physical and chemical properties plus an accurate account of the process of polymerisation, including both the catalysts and any enhancers used, as well as the physical features of the process. That information must, however, be available to manufacturers or materials suppliers, since strict control of the conditions of manufacture is essential in maintaining consistency of the product. It is therefore assumed that the materials used in all silicone gel breast implants have actually been tested to the same rigorous standards by the manufacturers of the starting materials, but data confirming this were not available to the IRG.
The general experience has been that these silicone substances are, in reality, a small group of closely related polysubstituted siloxanes, containing simple alkyl groups for cross-linking and other purposes to control their physical properties. They are prepared from a small range of starting materials and are polymerised with a few specific reagents and catalysts to form polymers with specific properties. The gel used inside certain types of implant has an analogous composition. In addition, as already noted, the outer membrane of polyalkylsiloxane elastomer contains an inert filler, amorphous fumed silica, and a polyurethane coating has been applied to some products in the past. The adhesive is a further polyalkylsiloxane product, as is the patch used to seal the injection site in certain types of implant. The Dacron reinforcement has a long history of safe medical use.

Multiple, sophisticated chemical and physical analyses are required to characterise the properties of the raw materials used and to verify their conditions of manufacture. This is especially the case for the polymerisation of the various elastomers, polymers, adhesives and patches used. The analyses carried out on breast implants cover the raw materials (monomers, crosslinking agents and catalysts, adhesives, amorphous fumed silica etc.), and various procedures applied to the final product. The purposes of these analyses and other manufacturing controls are to demonstrate that the different components of breast and other implants consist of the required elastomers and other components, that they have the desired physical properties and that they do not contain undesirable constituents. They confirm, for example, the sterility of the product and that its chemical composition and physical properties conform to standards laid down by the manufacturer in accordamce with internal procedures and the external requirements of international standards, regulatory bodies and professional associations concerned with medical devices and implantable synthetic materials. It is important for the manufacturer to verify that all these critical characteristics meet defined specifications, using standardised methods and appropriate control procedures and samples. Control measures of this sort (sometimes termed Good Manufacturing Practice) are enforced as part of statutory quality management requirements.

2.2 Biological safety testing
In developing an implantable device, many tests of its biological actions will be done, both of individual components and of the intact device itself, or of parts of it.

The intention of the biological tests, many of which are similar to the procedures employed in experimental investigation of the toxicity of other substances with which we come in contact (including medicines, food additives, consumer products etc.), is to reveal whether and how the device or its components can have local effects on tissues where the product is to be implanted, or on distant sites in the body through release of components by the action of body fluids or cells, and their dispersion and possibly their subsequent metabolism in the body.

Many of the toxicity tests are of a general nature, e.g. experiments in animals implanted with a suitable portion of a device and studied over a period by clinical, laboratory and ultimately pathological procedures. The breadth of the investigative procedures will enable many different types of effect to be detected, and the nature of any actions found will help to focus subsequent studies on the particular actions and mechanisms seen.

Other types of investigation are of a more specific nature, because of the special circumstances of implantation of a device into the tissues of the body, in particular the need to study local tolerance and other actions on tissues and cells in the immediate vicinity of the device to see how they may be affected by the local chemical and physical environment produced.

The types of toxicity covered by the procedures employed are now largely carried out according to standardised methods, and in line with 'Good Laboratory Practice' regulations that ensure the completeness of the reported results. Such tests investigate local or systemic toxicity (acute to chronic), effects on reproduction, toxicokinetics, genetic toxicity and carcinogenicity. The experiments are of broad types and so have the ability to reveal actions on all the functional systems of the body, including the immune system, joints and bones, the kidneys, skin etc. It must be accepted that there are differences between the animals or cells used in the toxicity testing and human beings, but the range of the species and cell types used and the breadth of the procedures employed make it unlikely that major types of toxicity will not be detected.

Clinical follow-up of patients treated with implants is the final check on the absence of toxicity and so on the adequacy of the investigative procedures. It is also the route by which the need for new laboratory techniques is revealed if there are confirmed results showing a previously unpredicted type of harm in patients.

The general nature and methodology of the majority of the chemical and physical test procedures and controls are specified by applicable regulatory controls or standards and so are part of the formal specification of each device. They have to be adapted pragmatically to the nature of the components used and their processing, as well as to the availability and proof of adequacy of the test methods. The techniques tend to be adapted over time, as the value of new methods becomes apparent in showing their greater sensitivity or specificity, or their economy, as compared to the procedures initially adopted. Many become laid down in international standards, pharmacopoeial specifications or other official publications.

Similarly, the biological tests represent groups of procedures current in general toxicity testing, as well as others specific to the nature and uses of implants. Many of them, too, have become listed as officially accepted techniques for examining specific actions. They will almost always be applied to explore the toxicity of implants. Other methods may be devised and applied to these devices as scientists in academic or industrial laboratories develop novel procedures to investigate new types of toxicity, or as better alternatives to existing techniques.

Accordingly, the toxicologist concerned to evaluate the toxicity of silicone implants needs to be aware of a broad range of information :-

• what substances are present or might be present in the device, including the principal intended components, residues of the raw materials and substances used in manufacture, such as catalysts, impurities and breakdown products formed in the body
• what are the physical properties of each component of the device
• what are the biological effects of the device on local tissues and cells
• what are the biological effects of the device on distant tissues and cells (systemic effects)
• how does the device change physically and chemically over time after implantation, when it is exposed to the biological activities of the body and to mechanical stress in tissues
• if one substance is tested as representative of a class of closely related analogues, how good is the information that its behaviour in experiments and people is indeed representative of the entire set of compounds
• what are the local and systemic consequences of any such change in its properties and composition with time
• what are the appropriate chemical and physical controls to apply to the raw materials and to each stage of the manufacturing process to prevent toxic and other risks on first implantation and to ensure that deleterious change with time is prevented or minimised to an acceptable level?

Beyond that lies the need to demonstrate by clinical experience, including focused surveys over a period in treated people, that the chemical and physical analyses and toxicity tests have successfully predicted the risk of every foreseeable type of harm on use of the device and so to indicate what are the limits of acceptability in terms of composition, properties and 'dose', i.e. the tolerable quantity of any harmful material potentially present or likely to be formed whilst the device is present in the body.

3. Toxicity of silicones and breast implants
The previous publications by the MDA (Tinkler et al. 1993, Gott and Tinkler 1994) summarise much information across the range of silicone derivatives and other products used in breast implants, as does Compton (1997).

The information supplied about the local and systemic toxicity, genetic toxicity, reproduction toxicity and carcinogenicity testing showed that they were all relatively bland substances in a range of animal and in vitro tests. 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 in 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, including breakdown products of the polymers, 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.

Similarly, the analysis of catalysts used to polymerise the starting monomers has shown that a very small amount of platinum is present in certain implanted elastomers, but it is a chemcially stable form not associated with the well known true immunological sensitisation that does occur on human and animal exposure to certain types of platinum compound.

An important finding is that smooth surfaced silicone elastomers, like many other smooth-surfaced materials implanted in certain species of laboratory animals, may cause local sarcomas to form after a long period. This is a consequence of the physical form of the implant, it does not occur if the same material is implanted in a roughened or particulate or fibrous form, and it is accepted as being a phenomenon specific to rodents; it does not represent a risk to man ("Oppenheimer effect"; see review by Brand, 1994).

The substantiated risks of implants, as shown in laboratory studies, and as borne out by experience in man, 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-containing 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 abnormalities of the immune system in subjects who have received implants. These aspects, however, are further discussed in the IRG report and reviewed in the previous publications from the MDA.

The above points are based on the availability only of limited information from manufacturers, much of it taking the form of summaries or statements rather than fully detailed test results. Information necessary for the complete and systematic characterisation of relevant materials was not made available to the Independent Review Group by all manufacturers, perhaps because it is regarded as commercially confidential (see Section 2.1 above).

4. General conclusions about the results of toxicity testing of 'silicone' implants
The experiments in animals and in other laboratory systems, as well as the much more limited investigation of samples from people treated with implants, have shown only local reactions to certain types of elastomer and gel. Systemic damage and dispersal of implant materials throughout the body appears not to have been well demonstrated, despite various claims, even after rupture of the older gel-filled implants.

5. References
Barlow PG 1998. Toxicological Assessment of Silicone Ingredients.

Brand KG 1994. Do Implanted Medical Devices Cause Cancer? J Biomat Applicat, 8, 325-343.

Compton RA 1997. Silicone manufacturing for Long-term Implants. J Long-term Effects medical Implants, 7, 29-54.

Gott DM, Tinkler JJB. 1994. Silicone Implants and Connective Tissue Disease. Medical Devices Agency, UK Department of Health, London.

Eschbach CS and Schulz CO 1998. Chemical Characterization of Silicone Gel-Filled Breast Prosthesis Materials.

Harrison J 1998. Applied Silicone Corp.- Implant Grade Silicone Testing.

Lane TH, Curtis JM, Klykken PC 1998. Silicone Breast Implants: Composition and Information. Pp 1-27.

Silicones Environmental Health and Safety Council 1995. Summary of the Chemistry and Toxicology of 56 Siloxanes Described in the ITC's 30th Report.

Tinkler JJB, Campbell HJ, Senior JM, Ludgate SM. 1993. Evidence for an association between the implantation of silicones and connective tissue disease. Medical Devices Directorate Report MDD/92/42, UK Department of Health, London.