Tooth filling materials Dental amalgams & alternative materials

5. What are the possible health effects of alternative tooth filling materials?

• 5.1 How toxic are the different components of alternative materials ?
• 5.2 What are the possible negative effects on health associated with alternative materials ?

5.1 How toxic are the different components of alternative materials ?

The SCENIHR opinion states:

3.4. Alternatives

3.4.1. Classification of alternatives according to chemical composition

Increasing use is made of tooth-coloured materials in restorative dentistry. Currently, most attention is focused on direct restorative materials, such as composites, glass ionomer cement, compomers, giomers and sealants, and less on indirect materials, such as dental porcelain. The reason is that the use of indirect materials is costly and time consuming (in terms of procedure) even though these materials show excellent biocompatibility properties and durability, particularly a high resistance to wear and distortion.

A composite is generally defined as a material composed of two or more distinct phases (O’Brien 2002). Dental composites consist of a polymerisable resin base containing a ceramic filler. They may be classified in a number of ways, the normal method being based on the size, distribution, and volume percentage of the ceramic particles. With respect to their size, this classification yields the so-called macrofill, midifill, minifill, microfill and nanofill composites. Macrofill composites contain ceramic particles ranging in size form 10-100 µm, midifill in the range from 1-10 µm, minifill in the range from 0.1-1 µm, microfill in the range from 0.01-1 µm and nanofill in the range from 0.005-0.01 µm. Hybrid composites contain a mix of two particles size fraction of fillers, e.g. midi-hybrids consist of mix of microfillers and midifillers, mini-hybrids or micro-hybrids consist of a mix of microfillers and minifillers and nanohybrids consist of a mix of nanofillers and minifillers.

Filler loading varies significantly between the different composite materials. For example in a macrofill and hybrid composite, the filler material occupies 50-80% of the composite by weight, while in a microfill composite the filler loading is limited to about 35-50% by weight.

Currently, almost all composites are supplied as a pre-packed single-paste system, the curing of the resins occurring by light activation. Different types of commercially available curing units have different light intensities and utilise different light sources. Light-curing units use halogen-based, light-emitting diode (LED), plasma-arc, or laser technology. The energy levels range from 300 to more than 3,000 milliwatts/cm².

Glass ionomer cements were introduced in 1972 by Wilson and Kent (1972) and may be considered as a combination of silicate and polyacrylate cement system. Glass ionomer cements bind to dental hard tissues. Polyalkenoate chains enter the molecular surface of dental apatite, replacing phosphate ions, which leads to the development of an ion- enriched layer of cement that is firmly attached to the tooth (Wilson et al. 1983). In addition to the original concept of glass ionomer cement, certain resin modified cements are now used in order to improve functionality.

Compomers were introduced in the 1990’s and combine some of the benefits of composites and glass-ionomer cements. However, compomers do not bond to hard dental tissue. Giomers have been recently introduced and feature the hybridization of glass-ionomer and composite resins. They contain an adhesive promoting monomer and a bonding polymer catalyst, which allow bonding to hard tooth tissues.

Sealants are flowable resins and high viscous glass ionomers that are applied to seal pits and fissures in permanent teeth in order to prevent the occurrence of caries.

3.4.2. Chemical characterisation of alternative materials

3.4.2.1. Composites

Dental composites are composed of a wide variety of components with different chemical composition (O’Brien 2002, Powers and Wataha 2007, Roeters and de Kloet 1998). There is inadequate data on the composition and leachables of these materials, which is sometimes reflected in the material safety data sheets (MSDS) (Henriks-Eckerman and Kanerva, 1997)

Filler material

The filler materials are of inorganic composition, such as silica glass (SiO₂), alumina glass (Al₂O₃), and combinations of glass and sodium fluoride. Silica glass is made of beach sand and ordinary glass, but also of crystalline quartz, pyrolytic silica and specially engineered aluminium silicates (e.g. barium, strontium or lithium aluminium silicate glass). Alumina glass is made of crystalline corundum, while sodium-calcium-alumina- fluorosilicate glass is an example of a combination glass. A combination glass has to be considered as an engineered mixture of various glasses, which can serve as a source of fluoride ions. The radiopacity of composites is obtained by the addition of barium, strontium, lithium or ytterbium fluoride (YF3) to the filler particles.

Matrix material

The matrix is of organic composition. A large group of different aromatic and diacrylate monomers and oligomers is used, such as bisphenol A-glycidylmethacrylate (Bis-GMA), ethoxylated bisphenol A-methacrylate (Bis-EMA), triethyleneglycoldimethacrylate (TEGDMA) and urethane dimethacrylate (UDMA).

Filler particle incorporation

Coating of the filler particles with silane coupling agents (such as trialkoxysilane) ensures covalent coupling between filler and resin matrix. The carbon-carbon bond on silane molecules binds to the filler particles as well as resin monomer during polymerization of the composite.

Composite curing

Chemical agents (self or auto-cure) or, most commonly, light energy (ultraviolet or visible light) ensures polymerization of dental composites. Dual curing, i.e. a combination of chemical and light curing is also possible. For most composite systems in current use, visible light polymerization at 470 ± 20 nm wavelength is used. Depending on the curing method, various polymerisation initiators and accelerators are required.

Initiators for chemical curing are usually benzoyl peroxide and benzene sulphinic acid which initiate polymerisation in the presence of an aromatic tertiary amine. For light curing systems, camphorquinone is normally used in conjunction with an aliphatic tertiary amine as accelerator.

Additional components

Inorganic oxides and organic compounds are pigments that are added to create a range of various composite shades.

Bonding to enamel and dentine

Bonding of the composite material to hard tooth tissues is achieved by use of a bonding system may that incorporates etchants, primers and resins. Chemical etching solutions, such as phosphoric acid, citric acid, and maleic acid are used to demineralise the tooth surface and increase the surface area. Subsequently, after rinsing and drying, a primer solution, composed of a low viscosity resin such as hydroxyethylmethacrylate may be applied to obtain optimal wetting of the surface for the bonding agent. In addition to water based primers, use is also made of acetone based primers, and primers without the addition of resins. Final bonding of the composite material is achieved by the application of a very thin resin layer. Classical bonding agents are composed of unfilled resin of similar composition as the resin matrix of the composite material. Newer bonding systems are composed of two components, one consisting of a resin and the other containing ethanol and a catalyst. Currently, there is a trend to simplify the bonding procedure by combining the etchant and primer and by supplying primer and bonding as one component.

3.4.2.2. Glass ionomer cements

In the original form, the powder component of these cements is a sodium-calcium- alumino-fluoro-silicate glass. The liquid component is composed of polyacrylic acid and tartaric acid. When the powder and liquid are mixed together, a three phase acid-base reaction occurs, involving calcium and aluminium ions leaching as the acid attacks the glass particles, hydrogel formation as the polyacrylic acid molecules crosslink, and polyalkenoate salt gelation as the polyalkenoate salt captures un-reacted glass.

In the resin modified cements, methacrylate monomers have been added to improve functionality with respect to higher strength and water resistance. The materials have been further modified by the addition of photo initiators so that light-curing can occur, but they maintain their ability to set by an acid-base reaction. The setting of resin modified glass ionomer cement is identical to the polymerization of composite resin. During this process, free radical species are generated.

3.4.2.3. Compomers

The main components of compomers are polymerisable dimethacrylate resins, such as urethane dimethacrylate and TCB, which is a reaction product of butane tetracarboxylic acid and hydroxyethylmethacrylate, and ion-leachable glass filler particles such as strontium fluorosilicate glass. The glass particles are partially silanised to achieve bonding with the resin matrix. The setting reaction is based on free radical polymerization using photoinitiators. During the setting reaction HEMA is released while fluoride release occurs after setting. Since compomers do not bind to enamel and dentine directly, a specific priming and bonding system has had to be developed, which includes the use of a tooth conditioner (34% phosphoric acid) and a light curing adhesive consisting of di- and trimethacrylate resins, functionalized amorphous silicon dioxide, dipentaerythritol penta acrylate monophosphate, photoinitiators, stabilizers, cetylamine hydrofluoride and acetone.

3.4.2.4. Giomers

Giomers are based on the technology of a reaction between fluoride containing glass and a liquid polyacid. The reacted glass particles are mixed with resin such as urethane dimethacrylate and hydroxyethylmethacrylate, and a catalyst to initiate polymerization. Bonding of the material is achieved through the use of self-etching primers that modify the smear layer and allow the penetration of the bonding agent into the dentine. The bonding agent releases fluoride. This group of materials may be used for restoration of small cavities, and also for pit and fissure sealing.

3.4.3. Toxicology of components of alternative materials

Clearly these alternative restorative materials are complex chemically, with many different components, setting reaction mechanisms and opportunities to interact with tissues of the individuals in whom they are placed. However, characteristics of exposure are very difficult to determine, bearing in mind that volumes of the materials used are very small, the residence time within the body of chemicals that take part in setting reactions is usually very short and the chemical and toxicological profiles of the set material are usually very different to those of the starting materials. In evaluating the possibilities for adverse effects arising from the clinical use of these materials, it is necessary to consider the evidence about the inherent toxicity of the chemicals used and the performance and behaviour of the restorations over time. Of interest to most investigations here have been the monomers used in polymerisation reactions, which may remain unreacted and therefore present in the set material, the acids used in various phases of the setting and etching processes and ions released from glasses. An extensive evaluation of the acute and chronic toxicity of materials used in various alternatives to dental amalgam was published by IARC (1999).

3.4.3.1. Short-term release of monomers during polymerisation

Unbound monomers and/or additives are eluted within the first hours of placement in the tooth cavity. The very nature of the polymerisation processes, that involve the absorption of light energy by the material, which will vary with depth within the restoration, and the subsequent conversion of monomer molecules into cross-linked macromolecules, inevitably means that some monomer molecules do not have the opportunity to take part because of diffusion limitations. The completeness of the polymerisation process is reflected by the degree of conversion. Between 15 and 50% of the methacrylate groups may remain un-reacted according to Ferracane (1994). Improvements in the material formulations has resulted in increasingly superior degrees of conversion in recent years and currently only 1.5 - 5% of groups should remain un-reacted. However, this is may be enough to contribute to major cytotoxic effects in vitro (Stanislawski et al. 1999). The effects may also be dependent on dentine permeability and residual dentine thickness (Bouillaguet et al. 1998) since dentine may absorb unbound monomers and therefore contributes to decrease the cytotoxicity of the material. This is not directly under the control of the dental surgeon although the formation of reactionary dentine may be stimulated by preparative steps. Dentine permeability may also be modified by calcium phosphate precipitation in the lumen of the tubules leading to sclerotic dentine formation. It has also been shown that the surface of composite resins exposed to oxygen during curing produces a non-polymerized surface layer rich in formaldehyde, which by itself is an additional factor of cell toxicity (Schmalz 1998).

Monomers have been identified in dental composites eluates by gas and liquid chromatography/mass spectrometry. A considerable concentration of the co-monomer triethyleneglycoldimethacrylate and minor concentrations of the basic monomers Bis- GMA and UDMA as well as the co-monomer HDDMA have been detected with these methods (Geurtsen 1998, Spahl et al. 1998). TEGDMA and the photostabiliser 2-hydro-4- methoxybenzophenone (HMBP) are cytotoxic and inhibit cell growth (Geurtsen and Leyhausen 2001). The intracellular glutathione level may be decreased by 85% by TEGDMA (Stanislawski et al. 1999, Stanislawski et al 2000, Stanislawski et al 2003, Engelmann et al. 2001, Engelmann et al 2002).

An in vitro evaluation of the cytotoxicity of 35 dental resin composite monomers and additives indicated moderate to severe cytotoxic effects (Geurtsen et al. 1998). The effects vary according to the material tested, but also they are strongly depending on the cells used for testing. For example, human periodontal ligament and pulp fibroblasts are more sensitive than 3T3 and gingival fibroblasts (Geurtsen et al. 1998). With the exception of a very few reports, there is a general consensus that resin-containing restorative materials are cytotoxic (Geurtsen et al 1998, Geurtsen 2000, Schmalz 1998), greater effects generally been seen at early intervals after preparation.

3.4.3.2. Leachable substances generated by erosion and degradation

Leachable components are released due to degradation or erosion over time, the leaching process being determined not only by the degradation process itself but also diffusivity through the material. Chemical degradation is caused by hydrolysis or enzymatic catalysis. Non-specific esterases, human saliva derived esterase and pseudocholinesterase may catalyze the biodegradation of composite resins (Geurtsen 2000, Jaffer et al. 2002, Finer et al. 2004). Incubated in vitro with cholesterol esterase, the composites may release 2,2-bis [4(2,3-hydroxypropoxy)- phenyl]propane (bis-HPPP) and TEGDMA for up to 32 days, the amount depending on the matrix/filler ratio (Shajii and Santerre, 1999).

It is also assumed that bonds in the pendant side chains of the macromolecule are attacked through the effect of thermal, mechanical and photochemical factors.

Water or other solvents may diffuse into the polymer, facilitating the release of degradation products, including oligomers and monomers. The leaching process is influenced by size and polarity and by hydrophilic and lipophilic characteristics of the released components (Geurtsen 1998). Softening of the Bis-GMA matrix allows the solvents to penetrate more easily and expand the polymer network, a process that facilitates the long-term diffusion of unbound monomers (Finer and Santerre 2004). Differences in the toxicity of monomers leached out in the short-term and long-term are not yet documented.

3.4.3.3. Release of ions

Many of the alternative materials release ions such as fluoride, strontium and aluminium ions. The fluoride is expected to be beneficial and reduce the development of secondary caries. Presumably, the fluoride content of toothpastes and nutriments reload the material so that the resins or resin modified glass ionomer cements do not become porous. Other ions are implicated in the colour of the restorative material, and these metal elements may interfere with the biocompatibility of the resin because they are implicated in the Fenton reaction producing reactive oxygen species that are cytotoxic. The concentration of fluoride and strontium is considered to be too low to produce cytotoxicity. In contrast, however, copper, aluminium and iron may be present in toxic concentrations. The cytotoxic cascade has been shown to be enhanced by metals such as aluminium and iron present in various amounts in some of these materials (Stanislawski et al. 1999, Stanislawski et al.2000, Stanislawski et al.2003).

3.4.3.4. Toxicity of composite resin monomers

Only limited toxicity data for the monomers used for in dental composite systems are available. Major differences in the degrees of cytotoxicity of various composite materials have been found (Schedle et al. 1998, Franz et al. 2003, Franz et al. 2007). Most tested materials showed only mild cytotoxicity comparable to amalgam or less than amalgam but there were a few exceptions. Most of the available toxicity data have been generated in in-vitro systems that focus on genetic toxicity of the compounds in standard test systems such as the Ames- test, and on cytotoxicity in gingival fibroblasts. TEGDMA, UDMA and HEMA have all been shown to be positive in the COMET assay indicating induction of DNA-damage in mammalian cells. HEMA, BisGMA and TEGDMA also induced gene mutations in mammalian cells by a clastogenic mechanism.

The monomers also caused cytotoxicity in cultured cells with ED50 in the low millimolar to submillimolar concentrations (Kleinsasser et al. 2006, Schweikl et al. 2005, Schweikl and Schmalz 1996a, Schweikl and Schmalz 1997, Schweikl et al. 1998a, Schweikl et al. 1996b, Schweikl et al. 1998b, Schweikl et al. 2006). In an in vitro embryotoxicity screening study, BisGMA induced effects at low, non-cytotoxic concentrations suggesting a potential for embryotoxicity or teratogenicity (Schwengberg et al. 2005).

The limited data on these monomers in experimental animals include studies on absorption, distribution, metabolism and elimination (ADME) on HEMA and TEGDMA after oral application of radiolabelled compounds. A rapid absorption of these compounds from the gastrointestinal tract and rapid catabolism by physiological pathways to carbon dioxide, which is exhaled (Reichl et al. 2001a, Reichl et al. 2002a, Reichl et al. 2002b, Reichl et al. 2001b, Reichl et al. 2002c).

No direct data on toxic effects of resin monomers in animals are available from publicly accessible sources. However, since the materials used as a basis for resin generation are derivatives of methacrylic acids and glycidyl ethers, the well studied toxicology of methacrylate and its esters may be used as a basis for structure activity relationships to predict major toxicities.

Methylmethacrylate, as a relevant resin monomer, is rapidly absorbed after oral administration in experimental animals and is rapidly catabolised by physiological pathways to carbon dioxide. The major toxic effects of methylmethacrylate in animals are skin irritation and dermal sensitization. In repeated dose-inhalation studies, local effects on respiratory tissue were noted after methylmethacrylate inhalation. Neurotoxicity and liver toxicity were observed as systemic effects after inhalation of methylmethacrylate in rats and in mice to concentrations above 3000 ppm for 14 weeks. For developmental toxicity of methylmethacrylate a NOAEC > 2000 ppm was observed. Methylmethacrylate is also clastogenic at toxic concentrations (EU-RAR 2002).

A detailed overview of the toxicity of glycidyl ethers compounds is available (Gardiner et al. 1992), although it is based mainly on unpublished study reports. Skin irritation and sensitization were the major toxicities observed. In addition, positive effects in genetic toxicity testing were seen with many glycidyl ethers at comparatively high concentrations.

3.4.4. Exposure

As noted earlier there are very limited data on exposure levels to the components of alternative dental restorative materials. Unlike the situation with amalgam, there are no obvious markers for exposure. Moreover, there are significant limitations to the determination of these exposure levels. The molecules used in any setting reaction, whether that is a polymerisation or an acid - base reaction, are by definition chemically reactive with a potential to exert toxic effects in humans. However, the reaction involves a small amount of material and usually takes place very quickly, following which many of these molecules have been irreversibly changed into far less reactive species or trapped within a solid mass with very limited capacity to diffuse and leach out. It is therefore expected that there will be a low but detectable level of exposure to many of these molecules during placement of the restoration. This is followed by a very much reduced level, possibly an infinitesimally low level, during the lifetime of the restoration. It is difficult to see how such low levels could be measured in a clinical setting.

The monomers used in dental resin-based materials are volatile and it is usually possible to smell them in dental clinics. The exposure of dental personnel to airborne methacrylates was studied during the placing of composite resin restorations in six dental clinics in Finland by Henriks-Eckermann et al. (2001). Both area and personal sampling were performed, and special attention was paid to measurement of short-term emissions from the patient's mouth. The median concentration of HEMA was 0.004 mg/m³ close to the dental nurse's work-desk and 0.003 mg/m³ in the breathing zone of the nurse with a maximum concentration of 0.033 mg/m³. Above the patient's mouth the concentration of 2-HEMA was about 0.01 mg/m³ during both working stages, i.e., during application of adhesive and composite resins and during finishing and polishing of the fillings. Maximum concentrations of 3-5 times higher than median concentrations were also measured. TEGDMA was released into the air during the removal of old composite resin restorations (0.05 mg/m³) but only to a minor extent during finishing and polishing procedures. The results showed that, except for short-term emissions from the patient's mouth, the exposure of dental personnel to methacrylates is very low. Measures to reduce exposure were discussed, as the airborne concentrations of methacrylates should be kept as low as possible in order to reduce the risk of hypersensitivity. Except for the data from this paper, there seems to be very limited information about the actual level of exposure to volatile monomers in a clinical situation.

Polymerised resin based materials contain various amounts of residual monomers and polymerisation additives that may leach from restorations. The release may remain on a high level for some days (Polydorou et al. 2007). In addition, as noted above, chemical, microbiological and wear impacts are observed over time, and occlusal or approximal degradation of composites restorations occurs (Groger et al. 2006, Söderholm 2003). Most information on the release of material components is based on laboratory models with solvents such as ethanol, water, saline, artificial saliva or culture media. Gas chromatography and mass spectrometry of the solutes from composites, compomers and resin based glass-ionomers have demonstrated the presence of a number of organic leachables such as monomers, co-monomers, initiators, stabilizers, decomposition products and contaminants Some of them have been identified as the low viscosity monomers EDGMA, TEGDMA and HEMA together with initiator and co-initiators such as hydroquinone, camphorquinone, and DMABEE and an ultraviolet absorber, Tinuvin P (Lygre et al. 1999, Michelsen et al. 2003). Attempts at quantification have shown that elution from different materials differs significantly (Michelsen et al. 2006) and the data are contradictory. Bis-GMA, Bis-EMA, UDMA and various additives have been shown to leach (Rogalewicz et al. 2006), although others have failed to demonstrate BisGMA and UDMA in aqueous extracts, even though TEGDMA-based composites released high amounts of monomers (Moharamzadeh et al. 2007).

It is reasonable to assume that similar leaching reactions take place in patients, depending on the composition of the material, the effectiveness of the polymerisation process and the chemical impact of the oral environment, although limited information is available on the concentration of components from amalgam alternatives in patient saliva or other body fluids. There are some exceptions, such as acrylic monomers from soft liners and phthalates from denture base materials (Lygre et al. 1993, Lygre 2002). In addition, bisphenol A has been indicated in leachables from composites and sealants (Olea et al. 1996, Sasaki et al. 2005).

3.4.5. Potential adverse effects in patients

On the basis of the above comments on the composition of the alternatives to amalgam, the possible exposure levels associated with their components and known in vitro data on their toxicity, a general assessment of potential adverse effects in patients may be made.

3.4.5.1. General

The components released from dental restorative materials comprise a long list of xenobiotic organic substances and metallic elements (Schmalz 2005, Wataha and Schmalz 2005). The components are subject to oral mucosal, pulpal and gastrointestinal absorption, and, for aerosols, pulmonary absorption, the passive diffusion through cell membranes being guided by factors such as the concentration gradient, molecular size, polarity, lipophilicity, and hydrophilicity.

Toxic effects after inadvertent contact with chemicals associated with restorative dentistry may appear as acute soft tissue injuries among dental patients. Local chronic reactions of irritation, or of combined irritation and hypersensitivity, appear as lichenoid reactions of the gingiva or mucosa. It is generally accepted that the amount of potentially toxic substances absorbed from alternatives to amalgam is too small to cause systemic reactions by dose dependent mechanisms in target organs. However, this statement does not deny that adverse reactions may occur, elicited by minute quantities of released substances, including allergies and genotoxicity. Of these, only allergy has been confirmed among dental patients.

The cytotoxicity and genotoxicity of substances leached from resin based materials and metallic elements have been the subject of extensive studies using cell culture techniques and bacterial mutation test (Ames test). Substances such as TEGDMA and HEMA cause gene mutations in vitro. Studies on the intracellular biochemical mechanisms have clarified various effects such as cell membrane damage, inhibition of enzyme activities, protein or nucleic acid synthesis etc. (Schweikl et al. 2006). At present, the clinical relevance of these in vitro studies is uncertain.

The release of Bisphenol A from Bis-GMA based materials such as fissure sealants and composites into saliva has been of special interest because of its potential estrogenic effect (Joskow et al. 2006). The concentration of released Bis-GMA from certain types of sealants has been reported to be within the range at which estrogen receptor-mediated effects were seen in rodents (Schmalz et al. 1999). However, the release from resin based restoratives is much lower. The conversion of Bis-GMA to Bis-MA is minimal in resin based materials if pure base monomers are used (Arenholt-Bindslev and Kanerva 2005). However, the minute concentration in resin based amalgam alternatives is not considered to be a problem.

It must be noted that there are other alternatives to amalgams in addition to these resin and cement based materials. These primarily include gold alloys and ceramics used for indirect restorations. These, however, do not represent clinically relevant options for the treatment of the vast majority of teeth and are only used when direct restorations are contra-indicated. Although idiosyncratic responses may be encountered with most materials (Ahlgren et al. 2002), and there may be exposure even to gold from such restorations (Ahlgren et al. 2007), there are very few indications that such materials have the potential for adverse effects and they are not considered further in this Opinion.

3.4.5.2. Allergy

Potential allergens among amalgam alternatives

There is limited possibility to predict the allergenic potential for a foreign substance on the basis of chemical composition using Quantitative Structure-Activity Relationship (QSAR) analysis. However, experimental testing such as the Guinea Pig Maximisation Tests or the murine Local Lymph Node Assay, and empirical results after years of testing substances causing allergies, have given some leads: the strongest allergens are often low molecular weight, aromatic, lipid soluble substances, or otherwise chemically active substances that react with proteins. Metal and metal salts are also high ranking haptens. On this basis, monomers, cross-linking agents, chemicals associated with the polymerisation process, and degradation products, all associated with resin based materials, are important candidates for allergic responses among users of these alternatives, including dental patients and professionals. A short list of allergens relevant to resin based amalgam alternatives is presented in Table 3.

Although an allergic reaction may be provoked by haptens derived from dental materials, the sensitisation process may be caused by substances unrelated to dentistry. Plastics are met with in everyday life and in occupations such as construction work and printing. For anatomical reasons both the allergic sensitisation and the allergic response are more easily obtained on skin than in the oral tissues. Epidermal tests are therefore adequate also for observations of intraoral adverse effects. A positive patch test is an indication of a causal relationship between the substance and the suspected allergic reaction, but does not provide definitive evidence without other criteria of causality, which often cannot be performed for practical and ethical reasons.

Table 3. Some allergens in resin based amalgam alternatives

(primers, bonding agents, composites, glass ionomers, resin modified glass-ionomers, compomers etc).

Methacrylate monomers

• 2-hydroxy ethyl methacrylate
• Triethylene glycol dimethacrylate
• Pyromelilitic acid dimethylmethacrylate
• Bisphenol-A glycidyl methacrylate
• Urethane dimethacrylate
• Bis-phenol-A polyethylene glycol diether dimethacrylate
• Ethylene glycol dimethacrylate (EGMDA)

Other substances

• Benzoyl peroxide, camphoroquinone (initiators)
• Tertiary aromatic amine (activator)
• Methylhydroquinone (inhibitor)
• 2-hydroxy-4-methoxy benzophenones, (UV absorber)
• 2-(2-hydroxy-5 methylphenyl) benzotriazole (Tinuvin P)

3.4.5.3. The role of bacteria

The presence of bacteria located at the interface between composite materials and dental tissues may be important (Hansel et al. 1998). EGDMA and TEGDMA promote the proliferation of cariogenic microorganisms such as Lactobacillus acidophilus and Streptococcus sobrinus; TEGDMA stimulates the growth of S mutans and S salivarius in a pH dependent manner (Khalichi et al. 2004). This provides one explanation for caries that develops beneath restorations of resin-containing materials. In addition, bacterial exotoxins have harmful effects on pulp cells after diffusion throughout dentine tubules.

It is also important to note that effects on dental pulp associated with restorations may be caused by bacterial contamination rather than the materials themselves (Bergenholtz et al. 1982, Bergenholtz 2000). This is still a matter of controversy and a few reports still consider that the pulp reaction to adhesive systems is generally minimal (Murray et al.2002, Murray et al. 2003). Improvements of resin-containing materials and bonding agents and techniques have reduced the significance of shrinkage and gaps at the interface, which may be less than 1µm (Hashimoto et al. 2004). However this is still a large gap for many microorganisms such as lactobacilli that are less than 0.1µm in diameter, and therefore the microbial parameter cannot be ignored.

Source & ©: SCENIHR,  The safety of dental amalgam and alternative dental restoration materials for patients and users (2008), 3.4 Alternatives, p.36

5.2 What are the possible negative effects on health associated with alternative materials ?

The SCENIHR opinion states:

3.4.6. Epidemiological and clinical evidence concerning adverse effects of alternatives in patients

3.4.6.1. Case reports

Several cases of confirmed allergic reactions caused by tooth coloured restorative materials have been published. For example, an early case report described a female patient who developed a rash and hives on her chest, arms and legs after treatment with a composite (Nathanson and Lockhart 1979). Patch testing indicated that Bis-GMA was the provoking agent, whereas the sensitisation might have taken place by contact with a cross-reacting epoxy product. Patch tests also indicated Bis-GMA in a case of peri-oral erythema and crusting of cheeks following the application of a bonding agent for composite and glass ionomer fillings (Carmichael et al. 1997). Moreover, stomatitis and peri-oral dermatitis was attributed to Bis-GMA in a filling material (Kanerva and Alanko 1998). Local lichenoid reactions similar to those described for amalgam, have also been attributed to composite fillings. In one case patch testing indicated EGDMA as the allergen (Auzeerie et al. 2002), other cases indicated formaldehyde derived from the resin (Lind 1988). Ulcerating gingivitis localised to composite fillings was explained as a delayed reaction to the UV-absorber Tinuvin P (Björkner and Niklasson 1979).

3.4.6.2. Reports from adverse reaction registry units

In the years 1999-2002 the Norwegian Dental Biomaterials Adverse Reaction Unit received an increasing number of reports of adverse reactions associated with composite materials, although these were still outnumbered by reactions to amalgam and other alloys (Lygre et al. 2003, Vamnes et al. 2004). Swedish data showed a similar tendency. Patch testing of referred patients demonstrated positive reactions to methacrylates and additives relevant to resin based materials, although the most frequent allergens were nickel, gold, cobalt, palladium, mercury, and chromium. A survey by the UK registry indicated that the number of adverse reactions caused by resin based materials, amalgam alternatives included, was about 14 % of the total number of patient reactions (Scott et al. 2004).

Since all dental materials pose a potential risk to patients and members of the dental team, the post-market monitoring of adverse reactions caused by dental materials should be considered essential. Van Noort et al. (2004) reviewed the current status of post- market monitoring of adverse reactions to dental materials and highlights some of the issues that arise in trying to establish an evidence base on the characteristics of adverse reactions to dental materials. Norway, Sweden and the UK have sought to monitor adverse reactions to dental materials systematically and proactively in an effort to add to the evidence base on the safety of dental materials. Their experience in undertaking post-market surveillance was combined. The Norwegian, Swedish and the UK projects had received 1268 reports over 11 years, 848 reports over 5.5 years and 1117 reports over 3 years, respectively, relating to adverse reactions seen or experienced by dental personnel and patients. There are no harmonized criteria for what can be classified as an adverse reaction related to dental materials. Under-reporting was a recognised problem and lack of awareness and lack of clarity as to what constitutes an adverse reaction may be contributory factors. A pro-active reporting system takes a considerable time to become established, but can generate a lot of potentially useful information. Van Noort et al. (2004) concluded that there is a need to raise the awareness among dental professionals of the potential for adverse reactions due to dental materials and to develop an internationally accepted system of data gathering that can produce the evidence that reflect the extent, severity and incidence of adverse reactions to dental materials

3.4.6.3. Reports from dermatological units

A Finnish multicentre study based on dental screening allergens on 4000 patients concluded that methacrylates, particularly HEMA, were responsible for 2.8 % of reactions, which were otherwise dominated by metal salts (Kanerva et al. 2001). A Swedish investigation showed positive patch tests to methacrylate allergens in 2.3 % of the patients (Goon et al.2006). The most common of these allergens was HEMA, followed by EDGMA, TEGDMA, and MMA. Simultaneous positive reactions were frequent. Only one patient reacted to Bis-GMA, whereas reactions to HEMA alone were seen in most patients. Data from Israel after testing of patients with oral manifestations such as cheilitis, burning mouth, lichenoids, and orofacial granulomatosis also ranked HEMA as the most frequent dental allergen after the metal salts (Khamaysi et al. 2006).

3.4.6.4. Questionnaire studies

A few attempts have been made to estimate the incidence of adverse effects of dental materials among dental patients. However, no studies have focussed specifically on alternatives to amalgam. After about 10 000 dental treatments, one fifth of which were composite restorations, 22 adverse reactions were observed, none of them being related to tooth coloured restorative materials. Thirty-one dentists, representing a collective practice time 387 years, recollected 70 cases of adverse effects, of which two were attributed to temporary resin based and denture base materials, and 5 to copper cement, but none to alternatives to amalgam (Kallus and Mjø¸r 1991).

Other questionnaire studies have aimed at obtaining incidence rates of materials related side effects in dental specialty practices such as paedodontics, orthodontics, and prosthodontics. Data from paedodontics indicated one reaction in 2400 patients, but only a minimal part was attributed to alternatives to amalgam (Jacobsen et al. 1991). Orthodontics and prosthodontics do not regularly include the placement of restorative amalgam alternatives, but resin based materials of similar composition are used. In orthodontics, only one of 41 000 patients showed an intra-oral reaction to an orthodontic composite, but 9 others reacted to resin based removable appliances, retention appliances, activators, and polymeric brackets (Jacobsen and Hensten-Pettersen 2003). However, some of these appliances are often made by chemically polymerised methacrylates, containing relatively higher concentration of potentially allergenic residual monomers as compared to well-cured restorative composites. Questionnaire data from prosthodontics could be interpreted to indicate a reaction rate of one per 600 patients for resin-based prosthodontic materials (Hensten-Pettersen and Jacobsen 1991).

3.4.6.5. General Comments

Case reports and reports from dermatological units highlight the possibility of adverse effects related to identified dental materials. Information from these sources is helpful in a field where these events are infrequent. The adverse reaction registry units in some countries contribute data on the relative frequency of the different adverse reactions, including those to amalgam alternatives. However, since participation by dental personnel is voluntary, the amount of under-reporting of patient reactions is unknown. The existing epidemiological studies offer an impression of the different materials related adverse effects as perceived by dental personnel. However, none of these studies are well suited as a basis for estimation of the prevalence of reactions caused by specific allergens associated with amalgam alternatives or other materials.

In spite of these drawbacks, an attempt to rationalise the risk of materials related adverse effects in dentistry on the basis of published reports has appeared recently (Schedle et al. 2007). Large variations were found, ranging between 1:10 000 and 1:100 for dental patients. A recent FDI-report also points to the fact that the vast majority of patients have encountered no adverse reactions, but dentists were advised to be aware of the possibility of reactions to resin based materials (Fan and Meyer 2007). The importance of satisfactory curing of these materials was specifically underlined. It is assumed that the most frequent potential allergens associated with resin based amalgam alternatives are found in Table 3.

3.4.7. Epidemiological and clinical evidence concerning adverse effects of alternatives in dental personnel

The potential for adverse effects to alternative restorative materials amongst dental personnel is widely recognised (Hume and Gerzina 1996). Most of the evidence of adverse effects takes the form of case reports, findings from surveys (Örtengren 2000) and reports from national reporting systems (van Noort et al. 2004). Given the extent of the use of alternative restorative materials, hundred of millions of restorations annually, and the possibility that <7% of dental personnel may report skin symptoms when working (Örtengren 2000), it is surprising that the reported incidence of adverse effects to alternative restorative materials is low (van Noort et al. 2004). The prevalence of verified allergic contact dermatitis amongst dental personnel (<1%) is much lower than the prevalence of self-reported skin symptoms (<7%) (Örtengren 2000).

Most of the adverse reactions reported take the form of contact dermatitis, which in severe cases may be associated with paresthesia of the finger tips (Kanerva et al. 1998). Reactions around the eyes, generalised skin itching and bronchial problems have been reported, but these are rare (Hume and Gerzina 1996).

HEMA appears to be a common sensitizer, although a small minority of dental personnel may have positive patch-tests to BisGMA and/or TEGDMA (Kanerva et al. 2001). It is relevant that relatively low molecular weight resin monomers, including HEMA and TEGDMA take only a few minutes to diffuse through latex gloves of the type worn by dental personnel, while higher molecular weight monomers, such as BisGMA, take a little longer to pass through the relatively thin latex of treatment gloves (Jensen et al. 1991, Munksgaard 1992). These findings emphasise the importance of a “no-touch” technique when handling resin-based restorative materials, even when wearing gloves. This approach to the handling of resin-based restorative materials is highlighted in manufacturers’ directions for use.

Regarding the lower incidence of allergic responses to resin-containing alternative restorative materials in patients relative to dental personnel, Kallus and Mjör (1991) and Hensten-Pettersen and Jacobsen (1991) suggest that this may be related to the fact that the principal exposure of dental personnel is to methacrylates as monomers during the handling of uncured materials. Adverse effects of alternative restorative materials in dental personnel may, as a consequence, be minimised by the avoidance of contact with, in particular, low molecular weight monomer during the handling and placement of uncured materials. The effects may be further reduced by the use of effective face protection, water cooling and suction, as appropriate, in all operative procedures involving both cured and uncured resin-based materials and associated systems.

Between 1995 and 1998, 174 dental personnel were referred as patients to the Department of Occupational and Environmental Dermatology, Stockholm (Wrangsjö et al.2001). After clinical examination, 131 were patch tested with the Swedish standard series and 109 with a dental screening series. Furthermore, 137 were tested for IgE- mediated allergy to natural rubber latex. Hand eczema was diagnosed in 109/174 (63%), 73 (67%) being classified as irritant contact dermatitis and 36 (33%) as allergic. Further diagnoses included other eczemas, urticaria, rosacea, psoriasis, tinea pedis, bullous pemphigoid or no skin disease. 77/131 (59%) had positive reactions to substances in the standard series and 44/109 (40%) to substances exclusive to the dental series. 24/109 (22%) patients had positive reactions to (meth)acrylates, the majority with reactions to several test preparations. Reactions to HEMA, EGDMA and MMA were most frequent. Nine of the 24 were positive only to (meth)acrylates, the remaining 15 also had reactions to allergens in the standard series. Irritant hand dermatitis was the dominant diagnosis. Contact allergy to (meth)acrylate was seen in 22% of the patch tested patients, with reactions to 3 predominant test substances. In one third of these cases the (meth)acrylate allergy was seen together with atopy and/or further contact allergies.

Also less severe allergic skin reactions among dental personnel have been diagnosed as caused by methacrylates, secondary in frequency only to chemicals related to natural rubber latex (Alanko et al. 2004). Hand dermatoses, together with eye-, nose-, and airways reactions are consistent findings among dental personnel, although the role played by amalgam alternatives is undecided (Sinclair and Thomson 2004, Andreasson et al. 2001).

The Finnish Register of Occupational Diseases diagnosed 24 cases of occupational asthma or rhinitis caused by methacrylates during the years 1990-98 .The incidence rate of occupational respiratory disease was considered greater than in the whole population (Piirilö et al. 2002)

Preventive actions such as change in hygiene factors, use of no-touch techniques when working with methacrylates, less use of latex and awareness of risk factors seems to keep the prevalence of skin and respiratory symptoms low among dental personnel (Schedle et al. 2007).

3.4.8. Potential adverse effects of ancillary items and equipment

3.4.8.1. Photopolymerisation energy sources

Light sources are used to activate photoinitiators, by absorption of photons, in order to initiate polymerisation in many restorative materials (Small 2001). The applied energy depends on the light source used. Photoinitiator activation occurs at specific wavelengths. The most common photoinitiator is camphoroquinone, the activity of which peaks between 470 and 480 nm. The main advantages of light-cured composites compared to chemically cured products are based on the fact that mixing of components in the clinic is not required, resulting principally in less porosity and increased strength.

Types of curing lamps

Dental curing systems use light sources such as quartz-tungsten-halogen lamps (QTH), light-emitting diodes (LEDs), xenon-plasma arcs and lasers. The lamps are discussed here in the conventional order of lowest to highest intensity, although this has changed recently since some of the LED lamps now claim to have much higher energy output than the QTH lamps.

LED dental curing lamps, using a solid-state, electronic process emit radiation only in the blue part of the visible spectrum, between 435 and 495 nm and do not require filters. The irradiance of 13 products measured in the 400 to 515 nm range varied from 454 - 1456 mW/cm² (Bruzell and Wellendorf 2007). Some LED lamps marketed in 2007 claim irradiance values up to 3000 mW/cm².

QTH lamps with halogen inside quartz bulbs generate light through the heating of a tungsten filament to high temperatures. A small percentage (less than 1 %) of the energy is given off as light, most of the energy being in the form of heat. A drawback of halogen bulbs is that the generation of heat causes a degradation of the components of the curing unit over time. The result can be a decline in the irradiance, which compromises the curing ability of the unit. The light is filtered to remove heat and all wavelengths except those in the violet-blue range (400-515 nm). The irradiance varies from 366 to 1360 mW/cm², depending on the product.

Plasma-arc lights are made up of two electrodes in a xenon-filled bulb. The plasma is heated to several thousand degrees Celsius and gives off light (less than 1 percent of the energy) and heat. The high intensity white light is filtered to remove heat and to allow blue light (400-500 nm) to be emitted.

Lasers can emit light at specific wavelengths as a result of the excitation of atoms of suitable gases/liquids/solids to specific energy levels. Argon lasers currently available emit at 488 nm and have the highest energy output of the dental curing units, up to 5 W. Lasers are reported to require less time to adequately polymerise composites although these units are large, expensive and not widely used.

Light-curing of composites

The dental curing lights initiate polymerization of resin-based dental restorative materials by transmission of light through a fibre optic tip into to the material. For maximum curing, a radiant energy influx of about 16 J/cm² is required for a 2 mm thick layer of resin. This can be delivered by a 40 second exposure from a lamp emitting 400 mW/cm² or by using higher intensity energy output and shorter exposure times. Curing depths equivalent to that of a 500 mW/cm² QTH lamp have been demonstrated using an exposure time of 10 seconds with certain PAC lamps and 5 seconds with an argon laser (Rawls and Esquivel-Upshaw 2003).

Hazards

The light intensity and energy output may be hazardous per se. The light emitted by curing lamps can cause retinal damage if a person looks directly at the beam. Laser light sources require the use of special protective glasses.

Exposure of the eyes

The eyes of the lamp operators are at risk from acute and cumulative effects, mainly due to back-reflection of the blue light. Exposure to intense visible light radiation sources in a dental clinic necessitates the use of eye protective filters to avoid blue-light photochemical retinal damage. Bruzell et al. (2007) measured the visible light transmittance of protective filters; nine of the 18 tested filters had adequate filtering capacity.

Exposure of the eyes of patients and professional persons with ocular diseases

Most manufacturers state in the instructions for use that the exposure to light from dental curing units should be avoided in persons who have undergone cataract surgery, with other cataract problems or who have other types of impaired eyesight.

Exposure of skin

The visible light wavelengths and intensity of the dental curing lights do not appear to cause damage to healthy skin. The quartz-halogen lamps may emit some radiation in the UV-region. Chadwick et al. (1994) assessed the level of UVA-I (340 to 400 nm) emitted from three commonly used QTH-radiation sources and assessed the level of protection afforded by six brands of surgical gloves. It was concluded that the risk of initiating adverse dermatological consequences as a result of exposure to UVA-I, is minimal in normal usage. Irradiation with a QTH dental curing light on human stratified epithelium in heterotransplanted skin on nude mice showed that 72 hours after exposure, there was epithelial hyperplasia and reduced reactivity for OKT6 cells. After 4 min of exposure OKT6 positive cells were completely absent from the epithelium after 72 hours. The results indicated that emission from dental light curing units can affect Langerhans cells and could thus modify the local immunological response (Bonding et al. 1987). There does not seem to be any scientific studies on the possibility of adverse reactions in the oral mucosa after exposure to high intensity visible blue light.

Exposure of teeth

The curing lamps with high energy output intensity may cause local thermal emission. Laboratory studies show temperature rises, at 3 mm distance from the light source, from

4.1°C to 12.9°C, and from 17.4°C to 46.4°C for LED and QTH lamps, respectively (Yap and Soh 2003). In vitro studies with thermocouples placed in pulp chambers of extracted teeth show a moderate rise in pulpal temperature. In a vital tooth this does not seem to be a problem, possibly due to the effects of the blood circulation. However, the recent introduction of the high-intensity LED-lights might change this situation.

Light as cofactor in photobiological reactions

Most manufacturers state in the instructions for use that dental curing lights should not be used in patients with a history of photobiological reactions - or who are currently on photosensitising medication, including 8-methoxypsoralen or dimethylchlorotetracycline. Phototoxic and photoallergic reactions are potential problems, but there does not seem to be any case reports on this issue. The dose or output from the high intensity lights are in the same range of what is used for dermatological skin testing of photobiological reactions. Phototoxic or photoallergic reactions have not been documented in the context of oral medicine. The possibility of photo-related reactions should be taken into account in evaluation of dermatological conditions in dental personnel.

Electromagnetic compatibility (LED, QTH)

The instructions for use for some QTH and LED lights warn that the devices must not be used in patients, or by users, with heart pacemaker implants, who have been advised to be cautious about their exposure to small electrical devices. A 59-year-old male with Parkinson’s disease had stimulator electrodes implanted in the brain. During curing of composites with a LED curing unit the patient felt immediate headache which he associated with the use of the curing light. Although the cause-and-effect relationship was questionable, an incidence report was submitted to the Norwegian Board of Health (Vangstein 2003).

Cross-contamination

The routines for infection control procedures as written in the instructions for use for the dental curing light units vary greatly. Some have no recommendations, one states that it should be sterilized before using it the first time, many have elaborate descriptions for cleaning and disinfection procedures.

Ineffective treatment/inferior quality of restoration

Most of the dental curing lights have an integrated photometer to check that the energy output is sufficient for the intended use. Others recommend the use of a separate photometer or to use a device for checking that the depth of cure for the various composites is sufficient. The latter method checks both the quality of the light source and the quality of the composite material. This is an important aspect, since the resin-based materials have a limited shelf life. It is also an issue with some of the very light shades of tooth-coloured resin-based materials that use phenyl propanedione as photo-activator, which requires radiation in the lower part of the spectrum of lower wavelengths than does camphorquinone (absorption peak at about 390 nm).

Overall risk assessment

There are inherent problems in the assessment of adverse effects of light exposure from dental curing lamps. Spectral characteristics vary among the different products, tissues treat radiation differently and the repair mechanisms for photo-induced damage may mask any adverse effect.

The dental curing lights, when used according to the manufacturer’s instructions and with proper eye protection, seem to be safe for use in most patients and users. However, the potential for adverse reactions to occur are definitely present and the manufacturer’s cautionary statements about not using them in specific situations should be heeded (Bruzell Roll et al. 2004).

3.4.8.2. Glove use

The wearing of gloves, often of latex, but increasingly of non-latex alternatives, has become routine in the everyday dental practice. Although not advised, should alternative resin-based filling materials be handled during use, low molecular weight components may quickly pass through the glove (Jensen et al. 1991, Munksgaard 1992) and will remain in contact with the moist skin of the clinician until the gloves are removed and the hands washed at the conclusion of the treatment. With practitioners who are sensitive to such constituents, or in the presence of skin conditions, cuts or abrasions, an adverse reaction may occur. Such reactions may be avoided by strict adherence to the no-touch techniques recommended by manufacturers of alternative restorative materials.

3.4.9. General Observations on Efficacy of Alternatives

The general observations on the efficacy of amalgam restorations (Section 3.3.10) may be reinforced here. Alternatives to amalgam have been in clinical use for well over 30 years. They have not only addressed the issues on the aesthetics of amalgams but have facilitated a radical change in the concepts of restorative dentistry through the introduction of more minimally invasive techniques and the associated retention of more tooth substance when treating caries. This has been achieved through the use of tooth coloured materials that are themselves adhesive to tooth substances or that can achieve adhesion through the use of intermediary agents. It is recognised that their use may be technique sensitive and that the procedures for their placement may take longer and therefore be more expensive. It is also true that they may be more susceptible to secondary caries and, in some situations, have less longevity than amalgams. In general therefore these tooth coloured alternatives offer an effective modality for the treatment of dental caries in most situations.

3.4.10. Conclusions on Alternatives

We note that the materials used as alternatives to dental amalgam for direct restorations are usually very complex chemically, and are not without certain clinical limitations or toxicological hazards. They frequently contain a variety of organic substances and they undergo chemical reactions within the tooth cavity and adjacent soft tissues during placement. It should not be assumed that non-mercury containing alternatives are free from any concerns about adverse effects (Goldberg 2007).

With respect to those materials that incorporate polymerisable resins, it is known that some of the monomers involved in their intra-oral placement and polymerisation are highly cytotoxic to pulp and gingival cells in vitro and there is also evidence that some of them are mutagenic, although it is far from clear whether this has any clinical significance. Some of these substances are irritants when used by themselves in various situations and the occupational hazards associated with their use are similar to those hazards found in the printing and automotive industries. Allergies to a few of these substances have been reported, both in patients and in dental personnel. We note that the full chemical specification of these alternative restorative materials is not always divulged and it may be difficult to ascertain exactly what they contain. In the absence of data, it may not be possible to provide a scientifically sound statement on the safety of individual products. It is also noted, however, that there are very limited scientific data available concerning exposure of patients and dental personnel to these substances. Nevertheless, these alternative materials have now been in clinical use for well over thirty years, and this use has revealed little evidence of clinically significant adverse events. The commercially available materials have either changed substantially or been improved considerably during this time, with reduced bioavailability of harmful components through improved polymerisation processes. It is recognised that many of the new forms of these alternative materials lack long-term clinical data and as such, need to be monitored for possible risks to patients and dental personnel.

As a separate issue, it should be borne in mind that these photo-polymerisable systems require activation and that the powerful light sources now used for this purpose may constitute an additional risk for adverse effects, both to patients and dental personnel. Eye protection is extremely important.

Source & ©: SCENIHR,  The safety of dental amalgam and alternative dental restoration materials for patients and users (2008), 3.4.6 Epidemiological and clinical evidence concerning adverse effects of alternatives in patients, p.44