LOCAL AND SYSTEMIC RESPONSES TO DENTAL COMPOSITES AND GLASS IONOMERS HAROLD R. STANLEY

Department of Oral Diagnostic Sciences College of Dentistry University of Florida Gainesville, Florida 32610 Adv Dent Res 6:55-64, September, 1992 Abstract—For many years, the dental profession worked mainly with rather inert restorative materials that had a limited contact with vital tissue, and the opportunity for local and systemic complications was minimal. However, conditions have changed in recent years where the two leading nonmercury-containing materials, resin composites and glassionomer cements, are chemically active compounds and can have detrimental effects on pulp tissue. With the advent of light-curing techniques with incremental layering, resin component formulae that were formerly found to be quite irritating to the pulp have become less so with the elimination of the need for matrices and pressure for good adaptation to be gained. As experience revealed the deficiencies and dangers of ultraviolet-light-curing techniques, visiblelight-curing systems were developed that provided greater depth of cure, a higher degree of polymerization with less shrinkage with incremental layers, and less porosity. When glass-ionomer cements (GICs) were first introduced, with just one acid (poly acrylic), pulpal responses were classified as bland. With the addition of many more acids to enhance certain characteristics and reduce the setting time, GICs have become more irritating, especially when used as luting agents in areas where the remaining dentin thickness is 0.5 mm or less. Gold foil and amalgam are inert and innocuous restorative materials but require pressure for condensation which creates an exaggerated inflammatory response. This presentation emphasizes the pulpal responses and side-effects of these non-mercury-containing restorative materials and how to keep them within an acceptable range of biocompatibility. Despite the lack of any substantial appearance of soft tissue and systemic responses to resin composites and GICs, the results of a survey of recent literature are included.

This manuscript is published as part of the proceedings of the NIH Technology Assessment Conference on Effects and Sideeffects of Dental Restorative Materials, August 26-28, 1991, National Institutes of Health, Bethesda, Maryland, and did not undergo the customary journal peer-review process.

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deally, a dental material that is to be used in the oral cavity should be harmless to the pulp and the soft tissues, should contain no toxic diffusible substance that can be absorbed into the circulatory system to cause a systemic toxic response, should be free of potentially sensitizing agents that could lead to an allergic response, and should have no carcinogenic potential (Phillips, 1991).

LOCAL (PULP AND SOFT TISSUE) SIDE-EFFECTS Pulp Responses For many years, the dental profession worked mainly with rather inert restorative materials that had a limited contact with vital tissue, and the opportunity for local or systemic complications was minimal. However, conditions have changed in recent years, where dental materials, such as resin composite restorations, are chemically active compounds which can have detrimental effects on pulp tissue. Our knowledge of the biology of the human dental pulp and its capacity to recover from injury is now considerable as compared with the early 1950's. In the '50's and '60's, pulp studies evaluated the degree of trauma due to cutting procedures and the toxicity of restorative materials, with little regard for the detailed structure of the tooth. However, it was appreciated that dentin was tubular and permeable and that the area of the experimental cavity should not be lined by reparative dentin which could nullify the response, unless the reparative dentin possessed many tubules. Although some restorative materials have been known to cause pulpal lesions when placed in dentin as far as 1.5 mm from the pulp, the majority produce significant and irreversible lesions only when placed in cavities with a remaining dentin thickness (RDT) of less than 1.0 mm, and mainly less than 0.5 mm in humans. In smaller animals, the inner third of the tooth is considered the crucial area. Yet most of these severe lesions could be prevented with the use of appropriate lining agents. In the '50's and '60's, little was known about the smear layer. We appreciated that dry-cutting produced burn lesions which were not acceptable. However, the work of Ostrum (1963) demonstrated that, when cavity preparations in rats were cut with air-cooling alone, only 10% of the animals developed a partial paralysis following the application of botulin toxin to the cavity preparations, as compared with 80% being affected when the cavities were prepared with an airwater spray. This protection was no doubt due to the creation of a smear layer by the air-alone cutting technique. Evidently, the acidic nature of the originally conceived formulae for chemically self-curing resin composites in their fresh state altered or destroyed the smear layer, resulting in severe lesions. Also, etching and conditioning agents, such as 37-50% solutions of phosphoric acid applied to dentin for up to two minutes, increased the permeability of dentin and

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created even more severe lesions if followed by resin composite restorative materials. Pressure itself also had an effect on pulpal responses. No matter how much water or coolant was applied to neutralize factional heat, increased applied pressure produced exaggerated pulpal responses. This increased pressure was related not only to cutting procedures but also to the use of matrices to obtain maximum adaptation of silicate cements and self-curing resin composites to cavity walls, the condensation of conventional amalgam and cohesive gold, and the luting of crowns and inlays. Matrix pressure forces the toxic ingredients of the selfcuring resin composite restorations—the phosphoric acid of silicate cements and acids within luting cements—through the shortest dentinal tubules and into the pulp. Thus, the recommendation that appropriate lining agents, such as calcium hydroxide (CH), be used before placement of resin composites or the carrying out pf luting procedures was adopted (Myers et aL, 1976; Stanley, 1985).

Resin Composites For decades, the dental profession has sought an esthetic material to replace the traditional amalgam alloy for stressbearing restorations which would survive the rigors of a wet field, rapid temperature changes, abrasion from food and enamel, as well as the disruptive action of a slightly basic saliva, and regurgitated stomach fluids which are highly acidic (Status Report on Posterior Composites, 1983; Lee, 1985). Advances in polymer chemistry and more precise analyses of the mode of failure of this type of material encouraged researchers to pursue formulations that would meet this challenge (Lee, 1985). The history of the precursors of the current composite restorative materials extends back about 150 years, when the German chemist Joseph Redtenbacher discovered acrylic acid. Acrylic resin was first developed as a denture-base material in Germany in 1935 (Jones, 1987). Shortly thereafter, poly (methyl methacrylate) resin was used for indirect fillings (Paffenbarger and Rupp, 1974), and then, in the late 1930's, direct resin restorative materials began to appear (Lee, 1985). Although the German scientists continued to improve these resins during and after World War II, they still possessed significant deficiencies that led to pronounced discoloration, a high coefficient of thermal expansion, a large polymerization shrinkage, and excessive marginal leakage which could lead to recurrent caries (Paffenbarger and Rupp, 1974). By 1970, there had been numerous attempts to evaluate the pulpal response to unfilled acrylic resin restorations, some studies relying solely on clinical assessment, whereas others used detailed histologic methods. Some histologic studies reported limited pulp responses, whereas others found mild, moderate, or severe responses. Moreover, the outcome of the reported responses was considered reversible by some investigators and irreversible by others. The fact that several different evaluation methods had been used to study unfilled resins contributed to the confusion (Suarez et aL, 1970). Although the addition of mineral fillers to the direct filling resins began in the early 1950's, resin composites of the 1960's and 1970's still presented significant toxicity problems. Most

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of the initially filled resin composites, if not properly lined, still caused foci of chronic pulpitis, which persisted for an indefinite time even in cavities of ordinary depth. As long as pulpal fluids could come into contact with the composite material via patent tubules, chronic irritation continued. These chemically selfcured resiii composites maintained their potential for irritating the pulp, because they still required the use of matrix pressure to enhance adaptation to the cavity walls during polymerization (Stanley etaL, 1967; Myers etaL, 1976). The introduction of Bis-GMA (bisphenoi A-glycidyl methacrylate) composite systems following the work of Bowen in 1956 is a history in dental evolution in itself (Jqnes, 1987). This development revolutionized restorative materials. His resin was really a compromise between epoxy and methacrylate resins (Paffenbarger and Rupp, 1974; Simonson et aL, 1985). After Buonocore (1970) reported on the safety of polymerizing a pit-and-fissure sealant with ultraviolet light (UYL), the concept was extended to restorative materials. However, excessive pulpal responses continued to occur, indicating that the resin composites were incompletely cured, despite extended UVL curing times, repeated exposures to UVL, and incremental layering of the resin composite. The work of Myers et aL (1976) showed considerable improvement with the UVL curing system, but not enough to make it acceptable. It is important to obtain as complete polymerization as possible through the entire restoration to minimize pulpal responses (Stanley, 1984). The level of the pulpal response to resin composites is especially intensified in deep cavity preparations when an incomplete curing of the resin permits an even higher concentration of residual unpolymerized monomer to get close to the pulp (Visible light-activated resins—depth of cure, 1983; Visible Light Bonding, 1985). As experience revealed the deficiencies and dangers of UVL curing techniques, visible-light-curing (VLC) systems were developed that would provide a greater depth of cure, less porosity, and more wear-resistant resin composite restorations. The incandescent lamps maintained a more constant energy output and reduced curing problems from changes in light intensity (Visible Light Bonding, 1985). The cure times were shorter, from 40 to 60 seconds vs. several minutes for chemically cured resins. Generally, VLC resins were more color-stable than chemically set materials, because there were fewer residual tertiary amine accelerators, the major cause for color shift in aging composites (Visible Light Bonding, 1985; Lee, 1985). Young's modulus of elasticity, with most self-cured material, reaches only a fraction of its final value about 10 minutes after being mixed, while the VLC composites approach 24-hour values after only 10 minutes (Lambrechts et aL, 1987). Although the visible-light source is better controlled than with the older UVL systems, variations in intensity still occur, and the effective wavelength is not always constant. It became prudent practice to use exposure times longer than—even double—those recommended by the manufacturer. These materials cannot be overcured by light but certainly can be undercured (Davis and Mayhew, 1986). Even with VLC resins, however, working time is not infinite. Ambient light from the operatory will initiate a viscosity change and some

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surface polymerization in as little as 90 seconds with some materials (Lee, 1985). Also, the degree of polymerization decreases as the distance increases from the surface nearest the curing unit (Lambrechts et al, 1987). No matter what kinds of lamps (ultraviolet or incandescent) are offered to the profession, there is not enough energy to cure a large filling in one application; it must be cured incrementally in layers (Lee, 1985). Despite all the advantages that have been espoused for VLC systems, the ideal situation has not yet been attained. However, with the forthcoming of the light-curing techniques with incremental layering, resin composite formulae that were formerly quite irritating to the pulp have become less so, with the elimination of the need for matrices and pressure to gain acceptable adaptation. Only when the recently developed dualcure resin cements are not adequately cured with visible light do significant pulp lesions appear, but not as severe as with matrix-utilized chemical self-cure resin restorations of the past (Pameijer and Stanley, 1992). Glass-ionomer Cements (GIC)

When GICs were first introduced as restorative materials, the pulpal responses were classified as bland, moderate, and less irritating than responses to silicate cement, zinc phosphate cement, and resin composites. Nevertheless, several investigators recommended using CH when near the pulp (Kawahara et al, 1979; Wilson and Prosser, 1982; Mount, 1988; Draheim, 1988). The blandness of the GICs was thought to be due to the fact that they avoided the stronger acids and toxic monomers. Polyacrylic acid and related polyacids are much weaker than phosphoric acid, and, as polymers, they possess higher molecular weights that supposedly limit their diffusion to the pulp through the dentinal tubules (Klotzer, 1975; Dahl and Tronstad, 1976; Wilson, 1977; Tobias et al, 1978; Beagrie, 1979; Beagrie and Brannstrom, 1979; Kawahara et al, 1979; Nordenvall et al, 1979; Wilson and Prosser, 1982; Mount, 1984; Van de Voorde et al, 1988). Later, other acids were added. Itaconic acid increased the reactivity of the polyacrylic acid on the glass and lowered the viscosity. Tartaric acid extended the working time of the cement and sharpened the set. In addition, maleic, mesaconic, and similar unsaturated acids were added (Wilson, 1977). In some GIC formulations, the glass powder was blended with a polyacrylic powder, and the cement was formed by the mixing of this powder blend with water or a diluted tartaric acid solution. The elimination of the viscous polyacid solution from the system yielded a more satisfactory mix that was fluid and easily workable (Wilson and Prosser, 1982). These formulations leave little to no unreacted anhydrous polymaleic acid (Wilson et al, 1977; Hume and Mount, 1988). Smith and Ruse (1986) compared the initial acidity of GICs with that of zinc polycarboxylate and zinc phosphate cements and found a general rise in pH for all cements during the first 15 minutes. The liquids in the zinc phosphate and zinc polycarboxylate cements reacted rapidly with the zinc oxide powder, causing the pH to rise above 2.0 after one minute of mixing. However, the initial reactions of the GICs were

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slower, being close to a pH of 2.0 at five minutes, and a pH of only 3.0 after 10 minutes, especially when used as luting agents. It should be pointed out that when GICs are used as luting agents, a number of problems may develop. When Pameijer and Stanley (1984) permitted an anhydrous GIC to harden under continuous pressure, pulpal abscesses and intense hemorrhage occurred when the RDT was 0.5 mm or less. When this study was repeated with a full-crown technique (Pameijer et al., 1991), those specimens with average RDTs less than 1.0 mm showed slight pulpal responses and no abscess formations or intense hemorrhage. However, the lesions persisted, even after 60 days. GICs, regardless of the mixing technique used, appear to be pulp irritants only when used as luting agents. Therefore, it has been recommended that CH be dabbed only onto those areas of crown preparations whenever the clinican feels he/she is close to the pulp (less than 1.0 mm) before the luting procedure is carried out. This treatment will provide the needed pulpal protection without decreasing the overall adhesion benefits of the GIC (Stanley, 1992). Surface Contaminants, Smear Layer Removal, Etching, and Permeability

Etching procedures are now used with both resin composite systems and GICs. Before a resin composite or a GIC restorative material is placed, surface contaminants must be eliminated to permit the ionic exchange of the dental material with the tooth structure to occur. However, excessive acid conditioning can remove the smear layer and dentinal tubular plugs, funnel the orifices of the tubules, and deplete the number of surface ions necessary for adequate chemical bonding (Hotz et al, 1911; Mount, 1988;Pashley, 1990). Brannstrom (1981) believes that etching not only allows the ingress of bacteria, but also allows the excessive outward flow of dentinal fluid into the cavity, which possibly contributes to creating a biofilm that will interfere with adhesion. With the realization that only the surface of the dentin needs to be changed for bonding to be improved, either by removal or modification of the smear layer, investigators have developed conditioning agents with weaker acids of lower concentrations, shorter time intervals, and with passive (no rubbing) application to clean the surface. To enhance bonding with a resin composite system, a primer or adhesion promoter or booster is applied to the dentin to improve wettability. A quick-setting visiblelight-cured low-viscosity (unfilled) resin is then applied which infiltrates the smear layer, if left, and the outermost orifices of the demineralized dentinal tubules to create the so-called hybrid layer or reinforced resin layer. When cured, this layer plugs the tubules and apparently prevents the toxic components' penetration to the pulp (Stanley, 1992; Nakabayashi, 1992). Future studies may show that the use of liners and bases may be de-emphasized. Amalgam

Amalgam restorations have generally been considered to be either inert or only mildly irritating to the pulp or bodily tissues in dogs, rats, and humans (Manley, 1942; Schroff, 1946; James and Schour, 1955; Silberkweit et al, 1955; Massler, 1956;

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Weideretah, 1956). DixonandRickert(1933)implantedrootcanal-obturating materials into the subdermal and muscle tissues of rabbits and found copper amalgam the most irritating, followed (in decreasing severity) by copper, balsam, rosin, and silver amalgam. Mitchell (1959), using small cylinders of conventional amalgam placed in the supramuscular connective tissue of rats, produced early (2-4 days) moderate reactions that decreased some by 16 days and especially by four weeks. However, copper amalgam produced indisputably severe reactions. Swerdlow and Stanley (1962) reported the results of a human study with amalgam condensed with either hand or low-speed mechanical condensers. A frequent characteristic histopathologic feature in the amalgam-restored teeth was a dense accumulation of neutrophilic leukocytes between the predentin and the odontoblast layer. The quantity of neutrophils was, in several instances, sufficient to lift the odontoblastic layer away from the predentin and press it into the deeper pulpal tissues. Such lesions represented extreme degrees of neutrophilic accumulation and not the conversion of necrotic tissue to abscess formation. Because the pulpal responses of the short-term amalgam specimens were so much greater than those of the zinc oxide-eugenol (ZOE) control specimens, it was suggested that the physical insertion of the amalgam was amajorcontributingfactorresponsible for the greater responses rather than the toxic, chemical, or thermal properties of the amalgam itself. Despite the increased pulpal responses from amalgam initially as compared with ZOE, definite resolution was found as early as after 15 days. It has been shown that the factor of load or application of force in grinding procedures themselves can contribute to an intensification of the pulpal response, even though frictional heat was neutralized with adequate coolants (Stanley and Swerdlow, 1960). Soremark et ah (1968) showed that radioactive Hg197 had reached the pulp in humans by six days, which was the shortest observation period used, if no cavity liner was used. They found that areas in the dentin near the amalgam had a high Hg content, and that the rate of diffusion into enamel and dentin was inversely related to the degree of mineralization. In general, this implied that the enamel and dentin, which were more mineralized in older patients, permitted less penetration of mercury ions. The penetration rate was even lower if the water component in enamel and dentin was reduced, as in a non-vital tooth. They made no comment as to whether the factor of condensation of amalgam accelerated the diffusion of Hg into the pulp. However, Kurosaki and Fusayama (1973), in contrast, showed that Hg from amalgam restorations in humans and dogs did not reach the pulp. In fact, it did not even penetrate dentin which had been demineralized intentionally before placement of the amalgam. They also claimed that the discoloration of the tooth was due to ions other than Hg in the amalgam. They postulated that, as the 72-phase corrodes, Hg does not leach out as does Sn, but instead re-penetrates the amalgam and reacts further with previously unreacted alloy cores. Stephen and Ingram (1969) reported similar findings. Van der Linden and van Aken (1973), studying human teeth, also found no Hg in the more radiopaque dentin beneath the amalgam restoration. Previously, it had been thought that this

layer was made prominent because of Hg diffusion. Instead, only zinc and tin occurred in high concentrations in the dentin beneath the amalgam restoration. These findings were confirmed by Halse (1975) using human teeth. Although Skogedal and Mjor (1979) indicated that an amalgam alloy with the highest percentage of copper caused the most pronounced pulp responses after 1-2 months in monkeys compared with conventional amalgam, they admitted that samples with high-copper amalgam had extremely thin RDTs, which may have been a contributing factor. Since they did not develop average RDT values for each category, one cannot be certain that the high-copper amalgam was truly more toxic. However, as mentioned earlier, "old time" copper amalgams were highly toxic to connective tissue as compared with conventional amalgam (Mitchell, 1959). In reviews of the literature, Hg itself does not seem to contribute to any pulpal response. Pulpal response to amalgam placement seems to be related mainly to pressure of condensation. The pulpal reactions from the insertion of the cohesive and compacted gold are also due to the pressures of condensation, whether with hand instruments or with mechanical pneumatic instruments. The reactions develop only when the condensation occurs over freshly cut dentinal tubules, not lined with pre-operatively formed reparative dentin induced from previous episodes of disease or restorative procedures (Swerdlow and Stanley, 1962; Thomas et ah, 1969; Stanley, 1984). Pulpal Responses to Cast Metals, Porcelain, and Ceramics

The pulp responses to inlays of cast metals, porcelain, and ceramics are determined by the type of luting agent utilized, not by the ingredients of the restorations. Again, the pulpal responses are related to the hydraulic pressures involved and not to the biocompatibility of the above materials.

Microleakage The consequences of the penetration of micro-organisms through marginal microleakage have received considerable attention. Brannstrom and his co-workers believe that infection due to the penetration of micro-organisms from marginal leakage around the restoration is the greatest threat to the pulp, rather than the toxicity of the restorative material (Brannstrom andNyborg, 1971; Brannstrom and Vojinovic, 1976). Pulpal lesions increasing in intensity after a post-operative time interval longer than one week may be due to marginal leakage micro-organisms, but to attribute severe pulpal lesions in short-term experiments to micro-organisms and their byproducts without relating the lesions to the potential toxicity of restorative materials is questionable. Bergenholtz (1982) has pointed out that, although microorganisms may contribute to the pulpal responses beneath restorations, they appear to be unable to sustain a long-standing irritation to the pulp. The dentin permeability to noxious bacterial agents decreases with time, even under continual bacterial provocation, allowing the pulp to heal (unless recurrent caries develops due to a clinically defective restoration). This may partially explain why pulps remain vital in most restored teeth. Consequently, when pulp devitalization occurs following

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a restorative procedure, it apparently results from the combined effect of the mechanical injury induced during cutting of the tooth substance, the toxicity of the restorative materials, and the bacterial action. Obviously, there is a relationship between the presence of micro-organisms and the degree of pulpal response. Microorganisms can definitely intensify the pulpal response. Unfortunately, the present enthusiasm for the Brannstrom concept has reached a point where many now believe that no restorative material has a toxic potential or capability. Although it is doubtful that marginal leakage will ever be completely eliminated, it certainly can be controlled. When the leakage is extreme, due to a defective restoration detected by clinical examination, recurrent caries can occur. No one would question the importance of invading micro-organisms in such circumstances. But how important, clinically, is marginal leakage of a lesser degree? Further research is needed to identify the specific effects of microbial activity associated with microleakage (Phillips, 1991). All the parameters have been established to guide the dentist in his effort to provide the best treatment to preserve pulp vitality. The rationale and understanding are there. They only need to be put to use.

SYSTEMIC RESPONSES As mentioned by Mjor (1991), the main reason why risk/ benefit analyses for soft-tissue and systemic responses have not received particular attention in the evaluation of dental restorative treatment is that the side-effects occur so infrequently and, when present, are not severe and are usually easily treatable. Therefore, few large-scale studies have been carried out to evaluate the frequency and severity of side-effects of restorative materials. The smaller the risk, the larger the population needed for study in order to determine the risk level (Wendel, 1969). Mjor (1991) emphasized that most verified adverse effects of dental materials are allergic reactions, because many dental materials contain components which are known to be common allergens, e.g., chromium, cobalt, mercury, eugenol, components of resin-based materials, colophonium, and formaldehyde. Minute amounts of formaldehyde may form as a degradation product of unreacted monomers in dentures made from resin-based composite materials (0ysaed et ai, 1988a,b), and formaldehyde-sensitized individuals may develop enhanced tissue responses (Kallus, 1984). The allergic reactions associated with resin-based materials affect not only patients but especially dental personnel working with such materials (Malmgren and Medin, 1981; HenstenPettersen andLyberg, 1986; Munksgaard, 1989; Munksgaard et al., 1990; Hensten-Pettersen, 1989; Kanerva et al., 1989; Mjor, 1991). Resin-based composite materials consist, by definition, of at least 50 wt% inorganic fillers, usually quartz or glass, and an organic matrix composed primarily of polymeric dimethacrylates. The organic matrix contains, in addition to a variety of different dimethacrylates, a number of reactive chemicals to make the materials more acceptable as dental restoratives. These components are comprised of initiators, such as benzoyl peroxide or camphorquinone, accelerators, toluidines, anilines, aminobenzoic acid, and other components,

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depending upon whether the polymerization is chemically- or light-induced, inhibitors, such as hydroquinonemonomethylether or 2,6 di-tertiary butyl-p-cresol, plasticizers such as dibutylphthalate, and pigments which are metal salts (Munksgaard, 1989; Mjor, 1991). The polymerization of composite materials is never complete, i.e., a number of reactive groups do not participate in polymerization. The incomplete polymerization of a resin restorative material is an inherent problem and predisposes to material degradation. In addition, any surface layer exposed to oxygen/air will be incompletely polymerized, including those resin molecules lining porosities within the bulk material. Degradation and wear of the materials will release the components of the resin-based materials, and these may cause reactions both locally and systemically (Ruyter and Svendsen, 1978). Slavin and Ducomb (1989) concisely described the problem of allergic contact dermatitis, which is seen quite commonly by primary physicians. The flow of such patients can only be expected to continue, since new chemicals that can serve as potent sensitizers are continuously coming into use. Workplaces are important arenas for the development of the disorder; in fact, allergic contact dermatitis now ranks as the most common occupational disease. The disease can cause great discomfort and is frequently disabling. Moreover, the chronicity of an undiagnosed case may make the patient extremely depressed. The interval between exposure to the causative agent and the occurrence of clinical manifestations is usually from 12 to 48 hours, although it may be as short as four hours or as long as 72. The incubation period may be as short as 2-3 days (poison ivy) or as long as several years (for a weak sensitizer such as chromate). The location of the patient's dermatitis usually occurs where the body surface makes direct contact with the allergen. In some cases, however, the relation is not quite as straightforward (e.g., contact dermatitis of the eyelids is frequently caused by nail polish or hand cream). A skin condition frequently confused with allergic contact dermatitis is "primary irritant dermatitis", the skin reaction caused by a simple chemical or physical insult to the skin, such as "dishpan hands". A prior sensitizing exposure is unnecessary (Slavin and Ducomb, 1989). A toxic reaction (primary irritant dermatitis) is dose-dependent, while allergic reactions are virtually dose-independent (Mjor, 1991). The oral mucosa can manifest a localized form of allergic contact dermatitis, called allergic contact stomatitis (stomatitis venenata). The condition is infrequently seen, because of the circumstances attending oral exposure: the brief duration of surface contact with many materials, the diluting action of saliva, and the rapid dispersal of antigen by the extensive oral vascularization. Chemicals that may produce allergic contact stomatitis on a short-term basis can be found in mouthwashes, dentifrices, and topical medications such as lozenges and cough drops. They can cause burning, swelling, and ulcerations. Clinically, the reaction can resemble gingivitis, which can progress to erosions or ulcers. A peri-oral rash may also be present. Allergic contact stomatitis is by far the most common adverse reaction to dental materials. The adverse reactions

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may be local or of a contact-type lesion, but reactions distant from the material site are also manifested (itching on the palms of the hands or limbs). The long-term reactions are dependent on composition of the materials, the toxic components, degradation products, absorption, accumulation, and other factors associated with leachable substances from the materials (Mjor, 1991). Although restorative materials may contain toxic components, they are present in such small amounts that adverse reactions are unlikely. Leachable components present themselves in the saliva regardless of the type of restoration, but the amount, toxicity, and allergenicity of the components vary considerably. The exposure to the oral environment is minimal for luting cements, and toxic reactions are, therefore, quite unusual (Yamauchi et aL, 1987; Platzer and Roth, 1989; Mjor, 1991). Lichenoid reactions representing a long-term effect in the oral mucous membrane adjacent to amalgam and resin-based resin composite materials occur more often than do other longterm side-effects (Bolewska et aL, 1990; Ishii et aL, 1987). In patients in whom the contact area of the lesion opposed the amalgam, there was a significantly greater proportion of patients sensitive to mercury. If removal of a dental material results in spontaneous healing of a local lesion, it is often considered a verification of an association between the material and the lesion (Lind, 1988; Mjor, 1991). The most definitive diagnostic test for allergic contact dermatitis or stomatitis is patch-testing, which can be thought of as creating the disease in miniature. The idea is to apply the suspected allergen to the skin with the intent to produce a small area of allergic contact dermatitis. The test generally takes from 48 to 96 hours, although a reaction may appear after 24 hours (Slavin and Ducomb, 1989). Documentation and conclusive diagnosis of individual patients' reactions are difficult and sometimes confused by confounding factors or multiple allergies (Hensten-Pettersen and Mjor, 1989). In 1985, the US Food & Drug Administration received about 37,000 reports of adverse drug reactions of all types in a country with a population exceeding 240 million people. Two percent involved deaths (nearly half in patients over age 59), and 21% required hospitalization. About 70% of the reports involved toxic reactions to the usual prescribed doses of drugs (Food and Drug Administration, 1987). Medline, National Library of Medicine (NLM), provides a database of bibliographic citations and abstracts from more than 3600 journals worldwide, including almost 500 dental journals. Besides Medline, users have access to more than 20 other NLM databases with more than 10 million references. Since Medline holds the world's largest repository of computerized dental information, the system allows dentists to scan selected topics of interest (NIDR Research Digest, 1991). An investigator can formulate a search of the repository by using multiple key words. Recently, this author instigated a search for local (soft tissue) and systemic side-effects of dental restorative materials, using the following key words: allergic, toxic, side-reactions and adverse reactions to resin composites, glass-ionomer

cements, and specific bonding agents. The search covered the years 1980 through 1990 and included all languages, animal reports, and human reports from age 13 to 64 years. The search revealed 394 citations, of which only 21 had some relevance to the problem of human systemic effects. Even if this figure was multiplied 10-fold, it would still represent a sparse number of instances. The scarcity of references supports the statements of Mjor (1991) and Wendel (1969) as to why there is so little effort to counteract the problem. Only one reference mentioned glass-ionomer cements. Certainly there are more relevant references, but these could not be detected from the language of the titles.

RESULTS OF RECENT MEDLINE SEARCH Baker et aL (1988) demonstrated that the free residual methyl methacrylate monomer in autopolymerized acrylic dentures or appliances, used particularly in children, can cause allergic reactions which seldom occur when correctly-heat-cured dentures and appliances are used. They recommended that autopolymerized appliances and dentures should be immersed in water for 24 hours before being worn. Two other references to similar allergic oral mucosal reactions to dental materials have been published (Sawakuma et aL, 1982; Drygas and Malenta, 1983). Personnel and patients in orthodontics and pedodontics have the highest incidence of side-effects, amounting to half the personnel and 1:100 for patients. An allergic contact dermatitis from the monomers of bonding agents frequently involves the distal parts of the fingers and the palmar aspects of the fingertips (Fredericks, 1981; Malmgren and Medin, 1981; Davidson et aL, 1982; Munksgaard et aL, 1990; Afsahl et aL, 1988; Mjor, 1991). Similar cases of allergic contact dermatitis have been reported in industry where workers were involved in electronic assembly operations that utilize polyethylene glycol dimethacrylate as an anaerobic sealant (MathiasandMaibach, 1984). Similar conditions can develop from artificial acrylic fingernails and the acrylic glues, wellknown to be allergic contact sensitizers, necessary for cementation (Kechijian, 1990; Shelley and Shelley, 1984; Malten, 1984). Allergies to the polyether in the latex rubber gloves worn by the dentist were reported (March, 1988). Although few gingival reactions following contact with composite materials have been described (van Dijken et aL, 1987), the permeability of the gingival epithelium (Squier, 1973) allows for penetration of leachable components, and thus the potential for toxic and allergenic reactions exists. When the amounts of gingival inflammation (crevicular exudate) resulting from contact with resin composite surfaces were compared with those from intact and enamel surfaces after seven days of no oral hygiene, there were no differences between the different brands of one-year-old resin composite restorations, but much less gingival inflammation against intact surfaces and enamel. However, inflammatory reactions adjacent to unfilled cold-cured acrylic resin have been described, while heat-cured resins are well-accepted (Phodshadley, 1969). The effect of cement dust on periodontal tissues has been described (Schneider and Schworer, 1982). Under extremely rare conditions (1:1 million), patients

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sensitized to gold may react to gold restorations with burning sensations of the oral mucosa in contact with the gold alloy, lichenoid lesions, as well as generalized systemic reactions (Mjor, 1991). Wilson's disease is a rare genetic disorder in which copper accumulates in tissue. Its victims must adhere to a strict dietary regimen yielding less than 2 mg of copper per day (McGuiness et ai, 1987). Some thought should be given to such patients when the placement of multiple copper-containing amalgam restorations is being considered; resin composite restorations would probably be preferred. Some individuals may suffer pulmonary aspiration resulting from a diminished gag reflex produced by the local anesthetic action of the eugenol contained in the smoke of clove cigarettes (J Am Med Assoc, 1988). One reference reported on oral burns and potential airway obstruction (requiring tracheotomy) following the use of black copper cement (pH 0.8) for fixation of dental splints for the treatment of fractured jaws (Aveling and Von Arx, 1981). Such obstruction can be avoided by application of a liberal amount of vaseline to the lips and gingiva (Frost, 1982). One reference described an iatrogenic oral ulceration following restorative treatment with an acid-etch material (Gutteridge, 1984). Cotton-wool-roll isolation of cavities was used, since the subgingival extension of the cavities made rubber dam placement difficult. At the end of the 90-minute appointment, it was noted that the gingiva over the labial aspect was pale, friable, and tended to slough if touched. The white sloughing ulcer that developed corresponded to the cotton wool roll used for moisture control. It appeared that the etchant solution (50% phosphoric acid) was absorbed into the cotton wool roll and held in contact with the already-desiccated tissues for an extended time. The tissue damage also involved bone, resulting in sequestration over a period of 14 weeks. Ibsen and Neville (1974), quoted by Gutteridge (1984), stated that a chemical burn resembling an aphthous ulcer may result if acid remains in contact with epithelium for five minutes or more. As Mjor (1991) has emphasized, no extensive study has been carried out to determine the incidence and severity of side-effects of restorative materials per se, but they have been included as part of a few studies on dental materials in general. Two basically different approaches have been used: one focusing on the general population and the other on defined risk groups. In a study by Kallus and Mjor (1991), 137 clinicians cared for 13,325 patients receiving 15,820 appointments and treatments. Only 24 subjective side-effects of dental materials were reported (seven acute and 15 long-standing). The clinical symptoms of "acute effects" were burning sensations in the mouth, swelling, mucosal ulcerations, and, in some cases, itching on the palms of the hands or limbs. The "long-term effects" were a lichenoid type of reaction adjacent to the exposure site in the mouth. None of the 24 cases was related to composite restorations or ionomer cements. Eight were related to the long-term effects of amalgam. In another study (Mjor, 1991), 31 clinicians were asked to recollect and record all cases of side-effects they had experienced

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in their entire clinical practice. A total of 113 side-effects was remembered, 26 involving amalgam. No glass-ionomer cements were mentioned; however, few restorations may have been inserted at that time.

SUMMARY AND CONCLUSIONS Ideally, a dental material should be harmless to the pulp and soft tissues. For many years, dentistry worked mainly with rather inert restorative materials (amalgam and gold); however, in recent years, some dental materials, such as resin composite restorations, are chemically active compounds which can have detrimental effects not only on pulp tissue but on adjacent oral mucosa as well. Visible-light-curing systems and the use of bonding agents have greatly reduced the toxicity level of resin composite restorations in terms of pulpal responses. However, the potential for side-effects on local adjacent soft tissues and systemic responses can occasionally occur when these materials are improperly used. Glass-ionomer cements appear to be bland to the pulp when used as restorative materials, but when used as luting agents, they can induce increased pulpal responses. This applies to other luting agents as well when used for all cast metals, porcelain, and ceramics. The response to amalgam restorations appears to be due to the pressure of condensation rather than to the chemistry of the alloy formula. The pulpal responses occur quickly and resolve rapidly. Mercury by itself does not appear to reach the pulp through dentin and does not contribute to the pulpal lesions. Similar findings occur with impacted gold restorations. Microleakage is an added factor that must be taken into consideration in evaluations of the degree of pulpal response from any restorative procedure, especially with time intervals greater than one week. Local soft-tissue and systemic responses are exceedingly rare, except in the utilization of bonding agents by personnel in the specialties of orthodontics and pedodontics. During the period from 1980 through 1990, Medline, which catalogues nearly 500 dental journals, revealed only 21 citations which had some relevance to local soft-tissue and systemic effects. This result supports the findings of Mjor (1991) and Wendel (1969) that the lack of risk/benefit analyses is due to the sparsity of cases, the minimal degree of damage, and the easy treatability of the lesion. Despite the scarcity of adverse reactions in dentistry, we must always stay on the alert for such events because of the ever-changing formulae and the addition of new chemicals to dental products that can serve as potential irritants and sensitizing agents. REFERENCES Afsahl SP, Sydiskis RJ, Davidson WM (1988). Protection by latex or vinyl gloves against cytotoxicity of direct bonding adhesives. Am J OrthodDentofac Orthop 93:47-50. Aveling W, Von Arx DP (1981). Oral burns and potential airway obstruction following the use of black copper cement (letter). Anaesthesia 36:718.

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Baker S, Brooks SC, Walker DM (1988). The release of residual monomeric methyl methacrylate from acrylic appliances in the human mouth: as assay for monomer in saliva. J Dent Res 61:1295-1299. Beagrie GS (1979). Pulp irritation and silicate cement. / Can DentAssoc 45:67-70. Beagrie GA, Brannstrom M (1979). Pulpal response to cavity treatment with microbicidal solution and silicate restorations in monkeys. / Can Dent Assoc 43:239-243. Bergenholtz G (1982). Relationship between bacterial contamination of dentin and restorative success. In: Rowe N, editor. Proceedings of Symposium on Dental Pulp: Reaction to restorative materials in the presence or absence of infection. Ann Arbor (MI): University of Michigan, 93107. Bolewska J, Hansen HJ, Holmstrup P, Pindborg JJ, Stangerup M (1990). Oral mucosal lesions related to silver amalgam restorations. Oral Surg Oral Med Oral Pathol 70:55-58. Brannstrom M (1981). Dentin and pulp in restorative dentistry. Nacka (Sweden): Dental Therapeutics. Brannstrom M, Nyborg H (1971). The presence of bacteria in cavities filled with silicate cement and composite resin materials. Swed Dent J 64:149-155. Brannstrom M, Vojinovic O (1976). Response of the dental pulp to invasion of bacteria around three filling materials. J Dent Child 43:83-89. Buonocore M (1970). Adhesive sealing of pits and fissures for caries prevention with use of ultraviolet light. J Am Dent Assoc 80:324-328. Dahl BL, Tronstad L (1976). Biological tests of an experimental glass ionomer (silicopolyacrylate) cement. JOralRehabil 3:19-24. Davidson WM, Sheinis EM, Shepherd SR (1982). Tissue reaction to orthodontic adhesives. Am J Orthod 82:502507. Davis RD, Mayhew RW (1986). A clinical comparison of 3 anterior restorative resins after three years. / Am Dent Assoc 112:659-663. Dixon CM, Rickert UG (1933). Tissue tolerance to foreign materials. / Am Dent Assoc 20:1458. Draheim RN (1988). Cavity bases, liners, and varnishes: a clinical perspective. Am J Dent 1:63-66. Drygas E, Malenta E (1983). A case of polyvalent allergy to materials used in dentistry. Czas Stomatol 36:631-633. FoodandDrugAdministration(1987). "OTBriefs". Oncology Times, June 1,29. Fredericks HE (1981). Mutagenic potential of orthodontic bonding materials. Am J Orthod 80:316-324. Frost PM (1982). Oral burns and potential airway obstruction following the use of black copper cement (letter). Anesthesia 37:98. Gutteridge DL (1984). Iatrogenic oral ulceration following restorative treatment with an acid-etch material. BrDentJ 156:403-404. Halse A (1975). Metals in dentinal tubules beneath amalgam fillings in human teeth. Arch OralBiol 20:87-88. Hensten-Pettersen A (1989). Replacement of restorations based on material allergies. In: Anusavice KJ, editor.

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Quality evaluation of dental restorations. Chicago (IL): Quintessence, 357-371. Hensten-Pettersen A, Lyberg T (1986). Contact allergy to constituents of dental materials (abstract). / Dent Res 65:789. Hensten-Pettersen A,MjorIA(1989). Plastyfllinger: Biologiske egenskaper. In: Asmussen E, Budtz-J0rgensen E, editors. Nordisk Klinisk odontologi, Chapter 7B. Copenhagen (Denmark): Forlaget for faglitteratur, 7B-II-1-10. Hotz P, McLean JW, Seed J, Wilson AD (1977). The bonding of glass ionomer cements to metal and tooth substrates. Br Dent J 142:41-47. Hume WR, Mount GJ (1988). In vitro studies on the potential for pulpal cytotoxicity of glass-ionomer cements. / Dent fos 67:915-918. Ibsen RL, Neville K (1974). Adhesive restorative dentistry. Philadelphia: Saunders, 46. Ishii K, Kinoshita K, Ozaki M, Ichiki K, Fukamoto S, Yoshida Y, Horibe T, Okamoto Y, Naruse S, Ichiki S (1987). The primary irritant testing to the human skin of gallium alloy. Fukuoka Shika Daigaku Gakki Zasshi 14:96-102. James VE, Schour I (1955). Early dentinal and pulpal changes following cavity preparation and filling materials in dogs. Oral Surg Oral Med Oral Pathol 8:1305. Jones DW (1988). The future of biomaterials. / Can Dent Assoc 54:162-173.

Journal of the American Medical Association (1988). Evaluation of the health hazard of clove cigarettes. Report of the Council on Scientific Affairs, American Medical Association. J Am Med Assoc 260:3641-3644. Kallus T (1984). Enhanced tissue response to denture base polymers in formaldehyde-sensitized guinea pigs. JProsthet Dent 52:292-299. Kallus T, Mjor IA (1991). Incidence of adverse effects of dental materials. Scand J Dent Res 99:236-240. Kanerva L, Estlander T, Jolanki R (1989). Allergic contact dermatitis from dental composite resins due to aromatic epoxy acrylates and aliphatic acrylates. Contact Dermatitis 20:201-211. Kawahara H, Imanishi Y, Oshima H (1979). Biological evaluation on glass-ionomer cement. J Dent Res 58:10801086. Kechijian P (1990). Danger of acrylic fingernails. Questions and Answers. / Am Dent Assoc 263:458. Klotzer WT (1975). Pulp reactions to a glass ionomer cement (abstract). / Dent Res 54:678. Kurosaki N, Fusayama T (1973). Penetration of elements from amalgam into dentin. J Dent Res 52:309-317. Lambrechts P, Braem M, Vanherle G (1987). Evaluation of clinical performance for posterior composite resins and dentin adhesives. OperDent 12:53-78. Lee H (1985). Visible light cured biomaterials. SAMPE J (May-June): 18-21. Lind P (1988). Oral lichenoid reactions related to composite restorations. Ada Odontol Scand 46:63-65. Malmgren O, Medin L (1981). Hypersensitivity reaction caused by bonding materials used in orthodontic care. Tandlakartidn 73:544-546.

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Pameijer CH, Stanley HR, Ecker G (1991). Biocompatibility of a glass ionomer luting agent. Part II: crown cementation. Am JDent 4:134-142. Pameijer CH, Stanley HR (1992). Pulp reactions to resin cements. Am J Dent 5:81-87. Pashley DH (1990). Clinical considerations of microleakage. JEndod 16:70-77. Phillips RW (1991). Science of dental materials. 8th ed. Philadelphia: W.B. Saunders Co., 65. Phodshodly AG (1969). Gingival response to pontics. / Prosthet Dent 19:51. PlatzerU, Roth KF (1989). Hotly debated: Ketac-Cem and its secondary effects. Zahndrztl Mitt 79:2464, 2471-2472. Ruyter IE, SvendsenS (1978). Remaining methacrylate groups in composite restorative materials. Acta Odontol Scand 36:75-82. Sawakuma M, Taniguchi K, Imamura M, Kow Y, Kitamura K (1982). Oral mucosa reactions to new dental restorative materials. Fukuoka Shika Daigaku Gakki Zasshi 9:1-8. Schneider HG, Schworer H (1982). Effect of cement dust on periodontal conditions. Z Arztl Fort-bild 76:357-360. Shelley ED, Shelley WB (1984). Chronic dermatitis simulating small-plaque parapsoriasis due to cyanoacrylate adhesive used on fingernails. J Am MedAssoc 252:2455-2456. Shroff FR (1946). Effects of filling materials on the dental pulp. NZDent 742:99,145. Shroff FR (1947). Effects of filling materials on the dental pulp. NZ Dent J 43:35. Silberkweit M, Massler M, Schour I, Weinmann JP (1955). Effects of filling materials on the pulp of the rat incisor. / Dent Res 34:854. Simonson RJ, Phillips RW, Faunce FR, Goldstein RE, Dennison JD,LeinfelderKF(1985). Visible light bonding. JAmDent Assoc 111:720-734. Skogedal O, Mjor IA (1979). Pulpal response to dental amalgams. Scand J Dent Res 87:346-350. Slavin RG, Ducomb DF (1989). Allergic contact dermatitis. Hosp Pract (April 30):39-51. Smith DC, Ruse ND (1986). Acidity of glass ionomer cements during setting and its relation to pulp sensitivity. J Am Dent Assoc 112:654-657. Soremark R, Wing K, Olsson K, Goldin J (1968). Penetration of metallic ions from restorations in teeth. J Prosthet Dent 20:531-539. Squier CA (1973). The permeability of keratinized and nonkeratinized oral epithelium to horseradish peroxidase. Ultrastruct Res 43:160. Stanley HR (1984). Pulpal responses. In: Burns RC, Cohen S, editors. Pathways of the Pulp, 3rd ed., Chap. 14. St. Louis (MO): C.V. Mosby, 465-489. Stanley HR (1985). Toxicity testing of dental materials. Boca Raton (FL): CRC Press, Inc. Stanley HR (1989). The relationship of bacterial penetration and pulpal lesions. In: Anusavice KJ, editor. Quality Evaluation of Dental Restorations: Criteria for Placement and Replacement. Chicago (IL): Quintessence Publishing Co., 303-323. Stanley HR (1992). Pulpal considerations of adhesive materials.

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van de Voorde A, Gerdts GJ, Murchison DF (1988). Clinical uses of glass iiihomer cement, A literature review. Quint Int 19:53-61. van der Linden LWJ, van Aken J (1973). The origin of localized increased radiopacity in the dentin. Oral Surg Oral Med Oral Pathol 35:862-871. van Dijken JW, Sjostrom S, Wing K (1987). Development of gingivitis around different types of composite resin. / Clin Periodontol 14:257-260. Visible light-activated resins—depth of cure (1983). / Am Dent Assoc 106:634. Visible light bonding: A review for the clinician (1985). J Am Dent Assoc 111:720-734. Weider SR, Schour I, Mohammed CI (1956). Reparative dentine following cavity preparation and fillings in rat molar. Oral Surg Oral Med Oral Pathol 9:221. Wendel HA (1969). Adverse drug effect and the controlled clinical trial. Pharmacol Clin 2:58-62. Wilson AD (1977). The development of glass-ionomercements. Dent Update (Oct):401-412. Wilson AD, Crisp S, Lewis BG, McLean JW (1977). Experimental luting agents based on the GICs. Br Dent J 142:117-122. Wilson AD, Prosser HJ (1982). Biocompatibility of the glass ionomer cement. / Dent Assoc S Afr 37:872-879. Yamauchi M, Takigawa H, Segawa M, Kano S, Kawano J (1987). Clinical study on the effect of temporary cements to marginal gingiva. Nippon Holetsu Shika Gakkai Zasshi 31:901-906.

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