III.

BIOCOMPATIBILlTY OF DENTAL RESTORATIVE MATERIALS

Ideally, a dental material that is to be used in the oral cavity should be harmless to all oral tissues gingiva, mucosa, pulp, and bone. Furthermore, it should contain no toxic, leachable, or diffusible substance that can be absorbed into the circulatory system, causing systemic toxic responses, including teratogenic or carcinogenic effects. The material also should be free of agents that could elicit sensitization or an allergic response in a sensitized patient. Rarely, unintended side effects may be caused by dental restorative materials as a result of toxic, irritative, or allergic reactions. They may be local and/or systemic. Local reactions involve the gingiva, mucosal tissues, pulp, and hard tooth tissues, including excessive wear on opposing teeth from restorative materials. Systemic reactions are expressed generally as allergic skin reactions. Side effects may be classified as acute or chronic. In this chapter, the Ad Hoc Subcommittee on the Benefits of Dental Amalgam addresses these biocompatibility issues in relation to all dental posterior restorative materials used to replace missing tooth structure. Only local reactions with regard to dental amalgam are considered. Potential systemic side effects from dental amalgam use are addressed in the report of the Risk Assessment Subcommittee. Standards and Testing The oral environment is especially hostile for dental restorative materials. Saliva has corrosive properties, and bacteria are ever present. This environment demands appropriate biological tests and standards for evaluating any material that is developed and intended to be used in the mouth. Such tests and standards, which have been developed in the past 10 to 15 years, serve as the basis for recommending any dental restorative material (Stanley, 1985; Mjr, 1991). Until a few years ago, almost all national and international dental standards and testing programs focused entirely on physical and chemical properties. The physical and chemical requirements set forth in the specifications for dental materials have been based on published clinical studies and clinical use of the materials; that is, the specifications lag behind materials development. Today, however, dental materials standards require biological testing as well. The science of dental materials now encompasses a knowledge and appreciation of certain biological considerations associated with the selection and use of materials designed for use in the oral cavity (Phillips, 1991). In accordance with existing standards, all dental materials should pass primary tests (screening to indicate cellular response), secondary tests (evaluating tissue responses), and usage tests in animals before being evaluated clinically in humans. Testing programs for dental materials are based on specifications or standards established by national or international standards organizations, such as the American National Standards Institute (ANSI) and International Standards Organization (ISO). The oldest and largest of these programs has been operated continuously by the ADA since the late 1920's. Initial, secondary, and usage tests, described in ADA/ANSI specification #41 have been reviewed by Craig (1989). 1 Evaluation of dental products for safety and efficacy has historically been the purview of both the ADA and the FDA. The U.S. Medical Device Amendments of 1976 were the first regulations that emphasized the need for biological standardization and testing of dental, as well as medical, materials. In accordance with these regulations, all dental materials are reviewed for safety and effectiveness and classified by the FDA as Class I, II, or III, according to risk. Class I materials are those considered to be of low risk in causing adverse reactions and, thus, require only "general controls," such as good manufacturing practices and record-keeping by the producer. Materials in Class II must satisfy the requirements outlined in the current ANSI/ADA specifications. The most extensive testing is required for Class III materials, which includes full safety and efficacy assessments prior to marketing. The FDA regulates the components of dental amalgam and, with the advice of a panel of experts, classifies the alloy component into class II (special

controls) and the USP grade mercury into Class I (general controls). The amalgamated product is not classified.
1

Extensive literature is available on investigations of biological reactions using initial tests, secondary tests, and usage tests (ANSI/ADA, 1979). However, the clinical significance of these tests is unsettled and there is poor correlation between the results of different tests (Mjr et al., 1977; Wennberg et al., 1980). Similar problems in the correlation of laboratory test results have been demonstrated for medical devices (Wilsnack et al., 1973). Biological test methods and some published results have been reviewed by Mjor et al. (1985), but attempts to correlate these data to clinical reports have been unsuccessful. One difficulty in examining these effects is that many reports are self-reports based on subjective recall, rather than precise clinical assessments (Kallus and Mjr, 1991).

In 1984, the FDA established a system for individuals to report side effects of medical devices, including dental restorative materials. This program is intended to record systematically any side effects from medical and dental devices and to establish a database from which their potential adverse effects can be evaluated. These data can then be used to determine the types of regulatory actions that should be taken in the future. Use of this system by the dental profession has been low. In the past few years there has been an increasing demand for safety evaluation and control of dental restorative materials. However, the task is difficult. In general, qualitative and quantitative information about substances released intraorally from dental alloys and other dental materials is meager (Hensten-Pettersen, 1986; Klotzer and Reuling, 1990). Verified diagnoses of side effects are not often established because the mild nature of the reactions are not viewed as justifying more extensive testing involving several medical specialties. Published studies of side effects among patients therefore are mostly inconclusive, especially because much information is based solely on questionnaire surveys among patients and dentists. Questionnaires do not provide objective information on side effects that may be attributable to dental treatments because of varying respondent ability to observe, evaluate, and clearly describe symptoms and because the symptoms could be caused by factors other than dental treatment. Few large-scale studies have been conducted to evaluate systematically the frequency and severity of side effects of restorative materials, and most of the existing clinical citations of side effects are case reports. Although these are important in providing the basis for larger epidemiological studies, only systematic, cross-sectional, and, possibly, longitudinal studies truly can establish the magnitude and nature of side effects associated with restorative materials. A balanced discussion of the biocompatibility of dental amalgam requires consideration of the relative biocompatibility of other restorative materials that potentially could serve as alternatives to amalgam. This chapter includes a review of the biocompatibility of other dental restorative materials as well, focusing on those used for posterior restorations. These include resin-based composites, glass ionomer materials, gold foil and dental casting alloys, ceramics, and other materials. Current standards and testing of dental materials, potential side effects, and biocompatibility are also presented. Side Effects Side effects to dental materials are believed to be rare and, generally, those that have been reported are mild (Kallus and Mjr 1990; Hensten-Pettersen and Jacobsen, 1991). Yet, given the millions of treatments provided, many individuals potentially may be affected. Consideration must be given to the relative biocompatibility of all dental restorative materials. The incidence and severity of side effects of restorative materials have been included as part of a few general studies on dental materials. Two basically different research approaches have been followed, one focusing on the general population and one on defined risk groups. One approach has been to evaluate side effects in dental patients and retrospective dentist reports of clinical experience (Kallus and Mjor, 1991). In these studies, no systemic toxic reactions to dental restorative materials have been reported. Local reactions that have been reported are not severe, the most common being lichenoid reactions in the oral mucosa and skin reactions such as rashes, dermatitis, and eczematous lesions. These reactions depend on the chemical composition of the materials used and their degradation products, absorption, accumulation, and other factors associated with leachable substances from the restoration.

The other approach has been to study personnel (e.g., dental personnel) who handle restorative materials as part of their daily work (Ahlbom et al., 1986; Nylander et al., 1986 and 1989; Ericson and Kallen, 1990; Hensten-Pettesen and Jacobsen, 1990; Munksgard et al., 1990). Studies of dental personnel are presented in the Risk Assessment Subcommittee Report. Local Reactions Lichenoid/white or erosive red lesions in the oral mucosa have been reported in direct topographical relation to dental amalgam, composite, and other restorative materials (Banoczy et al., 1979; Bolewska et al., 1990; Lundstrm, 1984; Lind et al., 1986; Holmstrup, 1991). Hietanen et al. (1987), on the other hand, found no evidence of hypersensitivity to dental restorative materials in patients with oral lichen planus. In part, these local reactions may be allergic in origin (Lied et al., 1986; Lind, 1988; Kaaber, 1991), occurring at the site of exposure or distant from the site of exposure, or they may be toxic in nature (Hensten-Pettesen and Jacobsen, 1991), having a direct, irritating effect at the site of exposure. In either case, the cause often is difficult to ascertain. It must be recognized that toxic reactions are dose dependent, while allergic reactions are virtually dose-independent. Based on published case reports and surveys of adverse reactions, most verified adverse effects of dental materials are allergic reactions (Kaaber, 1990). Dental materials contain components that are common allergens, such as chromium, cobalt, mercury, eugenol, components of resin-based materials, colophonium, and formaldehyde. Direct toxic effects also may occur, for example, from formaldehyde-containing materials (Brodin et al., 1982) and as enhanced tissue responses to methyl methacrylate in formaldehyde-sensitized individuals (Kallus, 1984). However, it is important to keep in mind that the presence of an allergen or a toxic component in a material is not a verification of the reason for a reaction per se. Even in patients with a known hypersensitivity to specific substances, other contributing factors may elicit a reaction. On the other hand, the more potent the allergen or toxic component, the more likely will be the association with adverse reactions. Concentration and length of exposure are two important considerations. As pointed out by Paracelsus more than 400 years ago, dose is a critical factor in toxicology. Many materials, including table salt, water, and mercury, can be toxic if given in sufficiently high concentrations. Even potentially toxic amounts of materials appear to be well managed by normal physiological clearing mechanisms if the amount of exposure per unit time is low. In the oral cavity, concentration versus time is mitigated by the filtering effects of dentin, the smear layer of cutting debris, and/or the base material between the source of the toxin and the pulp (Stanley, 1990). Besides concentration and filtering effects, one must consider a number of procedural influences involved with providing a new restoration. For instance, a composite restoration typically includes mechanical cutting, pressures from placement or curing, drying effects, bacterial exposure, acidetching procedures, enamel and/or dentin bonding, and light-curing steps. Any of these procedures may produce pulpal reactions that are not associated with the filling material itself. Biocompatibility Factors: Local Reactions In Designing Restorative Materials, dental scientists give particular attention to several key factors relating to a material's biocompatibility with the human organism. These include potential tissue responses, leakage of bacteria at the tooth-filling interface, shrinkage of materials, and stress created in the tooth structure from restoration procedures. Tissue Responses. Restorative materials may elicit responses from the pulp, gingiva, and oral mucosa. The pulp may be irritated in a number of ways: by cutting, mechanical procedures involved in preparing the tooth cavity, and the restorative material itself, potential leaching of a material's components, improper placement of the restoration, leakage of bacteria at the margins of the restoration caused by an inadequately placed or incompletely cured material, and agents (e.g., acid) used to prepare the tooth cavity and secure bonding of the restorative material. Severe and prolonged irritation may be irreversible and lead to permanently damaged pulp tissue.

Since the landmark studies of Langeland in the 1950s, knowledge of the biology of the human dental pulp and its capacity to recover from injury has increased tremendously (Langeland, 1957; Stanley, 1984, 1989). Although some restorative materials have been known to cause pulp lesions when placed as far as 1.5 mm from the pulp, most only produce significant and often irreversible lesions when placed less than 1.0 mm, and usually less than 0.5 mm, from human pulp tissue (Stanley, 1991). Appropriate lining agents are useful for preventing severe lesions. Some agents (e.g., calcium hydroxide) act to stimulate formation of secondary dentin, while others (e.g., glass ionomer cement) protect the prepared dentin and enamel from leakage around the restoration and invasion of bacteria into pulpal tissues. Acid etching of dentin during treatment may elicit pulpal effects by increasing the permeability of dental tissues to restorative materials and microbial products. These effects depend largely on the particular acid used and the skill of the practitioner (Stanley, 1988 and 1989). Similar considerations apply to gingival and mucosal tissue. Effects may be temporary in response to the procedure or longer lasting in response to the amount of material placed and agents used. Leakage of Bacteria. The presence of bacteria at the tooth-filling interface and the consequences of the penetration of microorganisms into the dentin and pulp because of leakage around the margins of a restoration have received considerable attention. Some authors believe that infection due to the penetration of microorganisms around the restoration, and especially beneath it, is the greatest threat to the pulp, rather than the toxicity of any restorative material (Brannstrom and Nyborg, 1971; Brannstrom and Vojinovic, 1976; Bergenholtz et al., 1982). Pulpal lesions that become more severe 1 week or more after a dental restoration has been placed may be due to marginal leakage. Severe pulp lesions, in the short term, may be related to the toxicity of the restorative material used. All restorative materials may leach to some extent, and the amount, toxicity, and allergenicity of components that do leach vary considerably (Mjr, 1991). When the pulp becomes devitalized after a restorative procedure, consideration must be given to the combined effects of the mechanical and thermal injury induced during cutting of the tooth substance, the toxicity of the restorative materials, and bacterial action (Qvist and Stoltze, 1982). Shrinkage of Materials. This problem, particularly relevant to composites, may occur when a restorative material is bonded to the surface of a tooth, creating stress as the polymer sets and pulls on the tooth. The larger the cavity and the larger the mass of the restoration, the more extensive the shrinkage can be. Shrinkage may be the cause of postrestoration sensitivity. The degree of bonding and the shrinkage of material will affect the extent of marginal opening that allows bacteria to leak under the material, especially at the critical gingival marginal area, thus potentiating pulpal irritation and even recurrent decay. Eventually, it may be necessary to replace the restoration. Stress from Restoration Procedure. As a restorative material is condensed into a cavity or a restoration is cemented to a tooth, material may be forced into open dentinal tubules and pressure gradients may arise that place force on live tissue. Individuals may demonstrate initial tissue reactions to these procedures, but these generally subside within hours or days after a procedure is completed. Restorative Materials The biocompatibility of specific dental restorative materials is summarized below. Dental Amalgam Because of its extensive use, there is more information available about the biocompatibility of dental amalgam than about any other dental restorative material. Local soft tissue reactions to dental amalgam fillings are addressed in this report. Potential, systemic biological effects are addressed in the report of the Risk Assessment Subcommittee.

Over the years, amalgam has provided excellent clinical service with few documented adverse effects. Mercury from dental amalgam does not seem to contribute to any pulpal responses (Stanley, 1991). Leakage also has not been perceived as a significant problem with amalgam restorations. In fact, corrosion products from amalgam form along the restoration-tooth interface, suppressing the penetration of fluids, debris, and microorganisms (Phillips, 1984) and, over time, improving the adaptation of dental amalgam to the tooth structure. Information pertaining to mucosal diffusion of corrosion products of dental alloys is scarce. Large amalgam particles that are embedded accidentally in the gingiva during placement of a restoration may elicit chronic inflammation, but no, or minimal, tissue effects are observed with smaller particles (H` rsted-Bindslev et al., 1991). Benign pigmentation of the mucosa can occur from embedded amalgam particles, commonly referred to as "amalgam tattoo." An increased content of mercury has been observed in gingival biopsies from areas in close contact with amalgam (Freden et al., 1974). Mercury also has been found in lysosomes of macrophages and fibroblasts of submucous connective tissue of contact lesions. However, mercury also has been identified in normal mucosa and in oral lichen planus lesions with and without any relationship to amalgam (Bolewska et al., 1990). Therefore, it appears mercury is taken up by damaged oral mucosa, but under certain conditions, as yet undefined, it also may be taken up by intact mucosa without causing any clinical or histopathological changes (Holmstrup, 1991). Amalgam restorations, in general, have been considered to be either inert or only mildly irritating to the pulp or body tissues in dogs, rats, and humans (Manley, 1942; Schroff, 1946-47; James and Schour, 1955; Silberkweit et al., 1955; Massler, 1956; Welder et al., 1956). Any pulpal response to amalgam seems to be related mainly to the physical insertion of the amalgam, that is, the pressure of condensation (Stanley, 1991), and is usually of short duration. Skogedal and Mjor (1979) indicate that alloys containing the highest percentages of copper cause slightly more pulpal responses after 1 to 2 months in monkeys than conventional amalgam. In 1962, Swerdlow and Stanley reported extreme degrees of leukocytic accumulation in the pulps of human teeth restored initially with amalgam, which resolved as early as 15 days after the restoration, suggesting that the physical insertion of the amalgam was a contributing factor, rather than the properties of the amalgam itself. They also demonstrated that the pressure of grinding procedures and dehydration can contribute to intensified pulpal responses (Stanley and Swerdlow, 1960). In 1968, Soremark et al., using radioactive mercury (Hg ), showed that mercury reached the pulp in humans by 6 days, if no liner was used, and that the rate of mercury diffusion into enamel and dentin was related inversely to the degree of mineralization of the tooth, which is higher, generally, in older patients. However, Kurosaki and Fusayama (1973) showed that mercury from amalgam in humans and dogs did not reach the pulp; they thus postulated that the mercury does not dissolve, but, rather, penetrates back into the amalgam and reacts further with previously unreacted alloy cores. Stephen and Ingram (1969) reported similar findings, as did van der Linden and van Aken (1973). Only zinc and tin occurred in high concentrations in the dentin beneath the amalgam restorations. Resin-Based Composites Composite materials that are certified or accepted by the ADA are required to pass a variety of tests. However, like amalgam, longitudinal, in viva research on the biocompatibility of composite resins is scant, particularly on those developed for posterior restorations (Bayne,l991). Composite material, however, has been shown to elicit a chronic inflammatory response in viva (Nasjleti et al., 1983), to be cytotoxic in cell culture (Hensten-Pettersen and Helgeland, 1977, 1981; Mjor, 1977; Wennberg and HenstenPettersen, 1981; Kasten et al., 1982), to be potentially allergenic (Nathanson and Lockart, 1979; Kallus et al., 1983; School, 1991), and to inhibit RNA synthesis (Caughman et al., 1990). Composite materials are associated with many organic compounds whose long-term allergenic and toxicity potentials have not been established (Anusavice, 1989). The organic matrix contains, in addition to a variety of different dimethacrylates, a number of reactive chemicals to make the materials optimal as dental restorative materials. These components include initiators, such as benzoyl peroxide or camphorquinones; accelerators, such as toluidines, anilines, aminobenzoic acid, and others, depending on whether the polymerization is chemically or light induced; inhibitors, such
197

as hydroquinonmonomethylether or 2,6 ditertiary butyl-p-cresol; plasticizers, such as dibutylphytlate; and pigments which are metal salts (Munksgaard, 1989). Many of these components are found in household glues and, thus, sensitization and allergic reactions to these components may occur on the basis of dental or other exposures. Chemicals from both the resin (Inoue and Hayashi, 1982) and filler (Soderholm, 1983) components of composite have been shown to leach out from the set material. Degradation and wear of resin-based composites release their components, including the fillers, silanized layer, and polymer matrix. Minute amounts of these materials may be swallowed, exposing components and fragments of restorative material to stomach acids and enzymes. Subsequent dissolution and absorption of ionic species under this condition have just begun to be explored by Freund (1990) and others, and the significance is unknown. Also, minute amounts of formaldehyde may form as a degradation product of resin-based composite materials (ysaed et al., 1988). Incomplete polymerization is an inherent problem with resin-based composites, and it predisposes the material to degradation and leaching into adjacent tissue. Incomplete polymerization occurs when a number of reactive groups do not participate in the polymerization (Ruyter and Svendsen, 1978). In addition, any surface layer exposed to oxygen/air will be polymerized incompletely (Ruyter and Svendsen, 1978; Ferracane and Greener, 1984) and such layers will release an amount of monomer or degradation product from the composite corresponding to the thickness of the unpolymerized layer (ysd et al., 1988). It is important to obtain as complete polymerization as possible through the entire restoration in order to minimize pulpal responses (Stanley, 1984). The level of pulpal response to composite resins is intensified especially in deep cavity preparations when an incomplete curing of the resin permits an even higher concentration of residual unpolymerized monomer to leach into the pulp (Swartz et al., 1983; Visible Light Bonding, 1985). Great strides have been made in the curing and polymerization of resin-based composites, but an ideal system has not yet been obtained. During the past 20 years, pulp and dentin reactions to composite materials have been related more to bacterial leakage than to the toxicity of the material (Brnnstrm and Nyborg, 1971; Bergenholtz et al., 1982; Brnnstrm, 1985; Bergenholtz, 1989; Stanley, 1989). Leakage, adverse pulp reactions, and the development of recurrent caries are associated with polymerization shrinkage of composites and imperfect adhesive bonding of the material to the tooth cavity (Bower, 1991). Thermal stress also increases marginal leakage around composite restorations (Momoi et al., 1990), as does the use of composites with higher viscosity and lower water-sorption values (Cnm, 1989). Although there is less leakage with heat-and-light-treated composite inlays (Wends, 1991; Shortall et al., 1989; Biedem~an, 1989), the problems associated with marginal gaps have not been solved completely (Cheung, 1990). Pulp studies of individual components show slight, but varied responses (Stanley et al., 1979). Early developed composite materials produced severe pulp reactions (Langeland et al., 1966), but most studies of pulp reactions to modem materials show no, or moderate, reactions (Mjr and Wennberg, 1985; Qvist and Thylstrup, 1989), although severe pulp reactions also have been reported (Qvist et al., 1989). A number of factors will affect the result (Qvist and Stoltze, 1982), and it is recommended, generally, that a base, or liner, be used in conjunction with composite restorations. A report on the use of plastic materials as retrograde root fillings revealed slight tissue reactions (Andreasen et al., 1989). Pain/toothache has been reported following the insertion of composite restorations (Boksman and Jordan, 1986; Wilson et al., 1986; Leinfelder, 1991), especially large ones (Qvist and Thylstrup, 1989). Again, a number of factors may affect the pain, such as polymerization shrinkage (which can cause severe strain to develop within the tooth), the effect of acid on the dentin, leakage, and reactions to the materials per se. Gingival reactions following contact with composite materials have not been described. However, inflammatory reactions adjacent to unfilled, cold-cured acrylic resin have been noted, while heat-cured resins are well accepted (Podshodly, 1968). The permeability of the gingival epithelium (Squier, 1973) allows penetration of leachable components and, thus, there is potential for toxic and allergic reactions with composite materials. Lichenoid reactions in the oral mucosa in contact with resin-based

composite materials have been described (Lied, 1988). Such lesions usually heal spontaneously when the restoration is replaced with a different type of restorative material. In addition to toxic components, such as remaining monomer in cold-cured plastics, plaque adhesion to resin-based materials may play a significant role in gingival reactions. It has been demonstrated in vitro and in viva that more plaque attaches to plastic restorative materials than to other materials or enamel (Skjorland, 1973; Sonju and Skjorland, 1976). Plaque at the restoration/tooth junction also contains elevated levels of cariogenic bacteria (Svanberg et al., 1990). The allergic reactions associated with resin-based materials can affect dental personnel working with the materials, as well as patients (Malmgren and Medin, 1981; Hensten-Pettesen and Lyberg, 1986; Munksgaard, 1989; Hensten-Pettesen, 1989;Kaaber, 1990). Documentation and conclusive diagnosis of individual patient reactions are difficult and sometimes confused by confounding factors or multiple allergies (Hensten-Pettesen and Mjor, 1989). A classic problem for usage studies is to isolate the effects of the material of interest from the effects of other materials that are part of the overall procedure. Cavity lines, enamel acid-etch material, and bonding agents are used routinely with composite. In addition, long-term effects of bacterial leakage confound measurements of potential chemical effects of the filling material and may be the primary cause for pulpal responses to composite filling materials (Skogedal and Eriksen, 1976). Excessive acid etching before placing a composite also may cause irritating effects by permitting the ingress of bacteria (Brnnstrm, 1981). The pulpal effects of composite materials and procedures currently are a relatively minor concern for most clinicians, but postoperative sensitivity and loss of vitality associated with posterior composite restorations have been reported (Bowen, 1991). These reports have resulted in a renewed emphasis on careful cavity preparation and careful use of restorative materials and lines (Council on Dental Materials, Instruments and Equipment, 1986; Bales, 1987; O'Hara et al., 1988; Swift, 1989). Glass Ionomer Materials Almost all of the clinical and toxicological information on glass ionomer has been developed on lines, bases, and cements, which were the first widespread clinical applications of this material. Clinical trials have focused mainly on restoration retention and integrity. Smith and Ruse (1986) attempted to identify the mechanisms of potential sensitivity related to glass ionomer use. They measured the pH of cements following mixing and concluded that the initially low pH may produce chemically irritating conditions for the dental pulp. The actual pH depends importantly on manipulation procedures, such as the mixing ratio of components (Mount, 1986). Woolford (1989) also observed that the pH of glass ionomer cements remained very low during the fist hour after setting, noting differences between a variety of commercial products. Brnnstrm et al. (1991) commented that the low pH could occur for a long time and probably complicated the evaluation of other biological properties of glass ionomers. When glass ionomer cements first were introduced, pulpal responses were classified as bland, moderate, and less irritating than with other cements or composite resins. Clinical studies show that such cements may cause early inflammatory reactions on newly prepared dentin, which resolve within a few days. Screening tests in cell cultures indicate that glass ionomers can be cytotoxic and therefore, protective calcium hydroxide liners are recommended when working near the pulp and when the thickness of remaining dentin is not certain (Kawahara et al., 1979; ~1son and Prosser, 1982; Mount, 1988; Draheim, 1988; Muller et al., 1990; Caughman et al., 1990). Liners are recommended particularly when using glass ionomer cements as luting agents for indirect restorative materials since glass ionomer, when used as a luting agent, requires the material to be more viscous and, thus, more irritating. Still, it is thought that the high molecular weight of the polymer liquid, as well as other aspects of its composition (e.g., the use of weaker acids and less toxic monomers), help guard against permeation of the material through the dentinal tubules to the pulp (Kltzer, 1975; Dahl and Tronstad, 1976; Wilson, 1977; Tobias et al., 1978; Beagrie, 1979; Beagrie and Brnnstrm, 1979; Kawahara et al., 1979; Nordenvall et al., 1979; Wilson and Prosser, 1982; Mount, 1984; Van de

Voorde et al., 1988). With a new, visible light-cured composition Kanaoka et al. (1991) did not find adverse responses in cell cultures. A more severe pulp response has been reported with the powder-liquid ratios used for the luting cement (Hensten-Pettersen and Helgeland, 1977; Meryon et al., 1983). Both the proximity of the pulp and treatment of the bacterial layer covering the tooth will affect this response. Numerous in vitro cytotoxicity studies have shown that fresh-mined glass ionomer cements cause more damage than set cements; the longer the set before placing them in contact with cell cultures, the less the effect on cell cultures. Also, the more powder that is incorporated into the mix, the less toxic the mix will be to the cell cultures (Dahl and Tronstad, 1976; Hensten-Pettersen and Helgeland, 1977; Mjr et al., 1977; Tobias et al., 1978; Kawahara et al., 1979; Cooper, 1980; Meryon et al., 1983; Hume and Mount, 1988). As with other materials, hydraulic pressure and etching during placement of the restoration may cause irritation of the pulp. Undue reactions in gingival tissue related to the use of glass ionomer cements, however, have not been reported from clinical practice. It is thought that the relatively good adhesion of this material accounts for its high biocompatibility. Leakage appears to be largely prevented and, thus, invasion of bacteria at the tooth-filling interface is minimized. Leaching of component materials may be advantageous for glass ionomers. When glass ionomers are used as a luting agent or a restorative material, fluoride is released slowly, thereby inhibiting caries formation at the margins of and beneath restorations. The mechanism of action is not clear. DeSchepper et al. (1989a, 1989b) concluded that the effect might come as much from the hydrogen ion concentration as from the fluoride ion release. Levels of hydrogen and fluoride ion release are not constant. Hydrogen ion release is related primarily to the setting reaction of traditional formulations. Fluoride ion release is related to the degree of solubilization and diffusion of the glass particle components. The level of release decreases with time (Cooley and McCourt, 1991). Early human clinical trials by Plant and Jones (1976) in Class I sites in premolars resulted in no sensitivity, but there was irritation in 5 percent of the pulps. In that study, clearly there was adequate remaining dentin thickness to provide a substantial barrier to any potential chemical insults. Nordenvall et al. (1979) compared glass ionomer to composite in contralateral tooth pairs (same tooth type at opposite sides of the mouth) Gold foil and reported that, in cases in which pulpal inflammation was present, bacteria also were present in the restored site. Browne et al. (1983) reported a high correlation of pulpal inflammation with bacterial microleakage. They concluded that any potential chemical irritation was of only minor importance. Plant et al. (1988) evaluated a range of cementing media for inflammation and sensitivity. They detected at least some cases of bacterial microleakage for all materials. Even though there was pulpal inflammation detected in 15 of 37 teeth after extraction, there was no sensitivity reported by any of the patients at any time. This is further evidence that sensitivity should not be used as a measure of biological activity. Osborne and Berry (1986, 1990) have been monitoring glass ionomer filling materials as Class III and V restorations for 3 years. There have been no reports of any sensitivity at any recall time. In a study designed to evaluate the effects of immediate finishing of glass ionomer restorations (Matis et al., 1988), there were no reports of sensitivity problems. Powell et al. (1990) examined 108 Class V abrasion/erosion lesions restored with glass ionomer filling materials. Sensitivity was examined in detail, distinguishing hot and cold sensitivity as well as evaluating the effects of patient age and tooth site. Posterior teeth were more sensitive to cold. Younger patients showed more preoperative and postoperative sensitivity. Most teeth, but not all, became less sensitive by being restored Sensitivity appeared to be worse at cervical margins. All of the conclusions of this study correlate well with the hypothesis that the mechanism of fluid flow in dentinal tubules is the main cause of sensitivity. Gold Foil and Dental Casting Alloys Gold foil Gold foil is a stable and relatively insoluble restorative material. In extremely rare circumstances (estimated at 1:1 million), patients sensitized to gold may react to gold restorations. These reactions include burning sensations of the oral mucous membrane in contact with the gold alloy, lichenoid

lesions, and general systemic reactions (Pregert et al., 1979; Holland-Moritz et al., 1980; Castelain and Castelain, 1987). The insertion of gold foil may result in pulpal reactions, but these are generally thought to be caused by the forces of condensation (Swerdlow and Stanley, 1962; Thomas et al., 1969; Stanley, 1984), thermal conductivity, cavity preparation, dehydration of the cavity, and micro leakage. Dowden and Langeland (1983) reported, however, that pulpal inflammation, destruction of odontoblasts, and hemorrhage were attributable to the toxicity of gold. Casting alloys Gold alloys and other alloys used in cast dental restorations and solders contain a number of elements, either intentionally added or as impurities. Allergic reactions have been described for many of these metals, including palladium (Phlelepeit and Legrum, 1986), nickel (Council on Dental Materials, 1982; Henstein-Pettersen et al., 1984; Femandez et al., 1986), chromium (Hildebrand, 1985), and cobalt (de Melo et al., 1983; Hildebrand, 1985). Approximately 10 percent of women and 1 percent of men are sensitive to nickel (Merck Index, 1983). The extensive use of base metal casting alloys containing nickel for fixed restorations has been of major concem to the dental profession, but relatively few case reports substantiate this concern (Kalkwarf, 1984; Hensten-Pettersen, 1984; Femandez et al., 1986, Lamster et al., 1987). Allergy to gold-based restorations is reported more commonly than allergic reactions to nickel-containing dental alloys (Tomell, 1962; Elgart and Higdon, 1971; Schof et al., 1971; Young, 1974; Klaschka, 1975; Fenton and Jeffry, 1978; Fregert et al., 1979; Holland-Moritz et al., 1980; Izumi, 1982). Palladium-based alloys have been reported as causative agents in cases of stomatitis (van Loon et al., 1984), oral lichenoid reactions (Downey, 1989), and disseminated urticaria (van Joost and Roesyanto-Mahadi, 15 90). Palladium allergy seems to occur in patients who are sensitive also to nickel (van Ketel and Niebber, 1981; Nakayama, 1982; van Loon et al., 1984, 1986; Stenman and Bergman, 1989; Augthun et al., 1990), but not consistently (Castelain and Castelain, 1987). Studies of T-lymphocyte levels in patients exposed to amalgam and nickel-containing alloys (Eggleston, 1984) and of the effect of fixed prosthodontic restorations made of silver-palladium alloys on serum immunoglobulins IgA, IgG, and IgM (Vitsentzos et al., 1988) are inconclusive. All casting alloys, except unalloyed titanium, seem to have a potential for eliciting adverse reactions in individual hypersensitive patients. Chromium/cobalt alloys have an excellent history of biocompatibility, although there are some reports of tissue sensitivity in a very limited population (Merck Index, 1983). More extensive studies have been performed in patients before and after replacement of amalgam restorations with gold-based inlays. These studies found no significant effects on blood cells, erythrocyte components, electrolyte balance, liver function, inflammatory activity, immune stimulation, tissue damage, and kidney function (Molin, 1990). No evidence of toxicity or tissue reaction has been shown to alloys with a low gold content. Only limited data have been generated on the biological response to high-copper casting alloys. Removable partial dentures made of base metal alloys have the potential of eliciting adverse reactions in patients allergic to cobalt, chromium, or nickel, but the incidence is uncertain. Patients with denture stomatitis related to the metal part of the prosthesis, and who have been patch-tested for contact allergy to nickel, cobalt, and chromium, often react to two, or all three, of the metals (Re, 1960; Brencllinger and Tarsitano, 1970; Levantine, 1974; Wood, 1974; Kaaber et al., 1979). Elevated cobalt and chromium levels have been observed in the saliva and tongue scrapings of patients with cobalt-chromium removable partial dentures (Stenman, 1982; de Melo et al., 1983), but the significance is unknown. Toxic metals, such as beryllium and cadmium, also may be present in dental alloys, but no adverse effects have been reported in patients. Indium, the most common substitute for zinc, does not appear to have adverse biological effects (Merck Index, 1983). Likewise, there appear to be no adverse

effects from alloys containing iron, molybdenum, manganese, or gallium. Titanium, the metal of choice for metallic implants, and alloys of titanium are biocompatible (Norman, 1991). For the most part, metal ions, when placed on culture media, present an inhibited zone with various organisms (e.g., they show cytotoxicity or cell damage). These metals include chromium, cobalt, copper, mercury, nickel, tin, and zinc, all of which are used in dentistry. However, these metals are not found in dental restorations as metal ions, but as "eliminated structures." In addition, the alloying of these metals reduces their potential for ion production. Ceramics The relative incidence of biological side effects of dental ceramics compared with other restorative materials is considered to be low. In general, conventional dental ceramics are considered to be the most inert of all materials used for dental restorations. Ceramic restorative materials are not known to cause biological reactions, except for wear on the opposing dentition and/or restorations. No longterm data on the biocompatibility of these restorations are available (Roulet and Herder, 1991). Additional Materials Used in the Restoration of Teeth The fabrication of indirect cast restorations of alloys, fused and CAD/CAM prepared ceramic restorations, and in direct composites involves many separate procedures that bring the oral tissues into contact temporarily with a wide variety of materials. These materials include impression materials, tissue retraction cord and astringents, and plastic or metal temporary restoration materials. Other materials, such as luting agents (cements), last as long as the restoration itself. For all cemented restorations, pulp, dentin, and, to some degree, gingival reactions may be more dependent on the luting cement than on the material used to make the restoration. The biological response varies with the type of luting agent used and the methods of handling. Pulpal response to luting agents also may be related to hydraulic pressures produced during cementation. Most of these materials are subject to the same biocompatibility standards as the posterior restorative materials discussed above; however, the scope of the discussion in this report is limited to materials used in the long-term replacement of missing tooth structure. Summary and Conclusion Many of the biocompatibility considerations pertaining to dental restorative materials are sized in Table 1. All materials in current use are considered acceptable, in terms of their biocompatibility with local tissues, when properly handled and placed. Adverse systemic reactions are believed to be rare and self-limiting and tend to be of an allergenic nature. Local reactions have been documented in a small percentage of individuals, and systemic toxic reactions have been reported in the scientific literature. Table 1. Summary of Biocompatibility Considerations of Dental Restorative Materials Restorative Material
Dental Amalgam: local reactions2

Biocompatibility Consideration
No adverse pulpal responses from mercury Corrosion may limit marginal leakage, but in the long-term may lead to breakdown of marginal integrity, especially with low-copper amalgams Innocuous to gingival tissues Lichenoid reasons reported Thermal conduction to pulp

Resin-Base Composites

Few documented systemic adverse effects Very little research on systemic biocompatibility Associated with many organic compounds, the effects of which are not known

Incomplete polymerization leading to degradation, teaching, and imperfect bonding Predisposed to polymerization shrinkage Associated with adverse local pulpal and dentin reactions, development of recurrent caries, and pain May lead to increased plaque adhesion, which can cause elevated levels of dental disease-causing bacteria and local reasons Lichenoid reactions reported

Glass lonomer Cements

Few documented systemic adverse effects Early pulpal reactions, although less than with cements or composite resins, and with rapid recovery Composition guards against permeation of material through the dentinal tubules to the pulp When used as luting agent, liners are advocated Hydraulic pressure and etching during placement may irritate the pulp No undue reactions reported in gingival tissue Good adhesion, minimal leakage at margins, high biocompatibility Leaching of component materials offers opportunity for slow release of fluoride

Gold Foil and Cast Alloys

Inert; sensitivities are rare Potential pulpal reactions due to condensation Rare allergic reactions to alloy metals

Ceramics

No known reactions except wear on opposing dentition and restoration No long-term data on biocompatibilility