Biologic properties of eugenol and zinc oxide-eugenol

endodontics Editor: SAMUEL SELTZER, DDS Department of Endodontology School of Dentistry Temple Universit,y 3223 North Broad Street Philadelphia, Pennsylvania 19140

Biologic properties of eugenol and zinc oxide--eugenol A clinically oriented review

Kenneth Markowitz, DDS,(’ Michael Moynihan, DDS, Mintsai Liu, DDS, MA,b and Syngcuk Kim, DDS, PhD,C New York, N.Y.

DIVISION OF ENDODONTICS AND LABORATORY OF ORAL PHYSIOLOGY, SCHOOL OF DENTAL AND ORAL SURGERY, COLUMBIA UNIVERSITY

Eugenokontaining dental materials are frequently used in clinical dentistry. When zinc oxide-eugenol (ZOE) is applied to a dentinal cavity, small quantities of eugenol diffuse through the dentin to the pulp. Low concentrations of eugenol exert anti-inflammatory and local anesthetic effects on the dental pulp. Thus use of ZOE temporary filling may facilitate pulpal healing; on the other hand, high eugenol concentrations are cytotoxic. Direct application of eugenol to pulp tissue may reslult in extensive tissue damage. The ability of ZOE-based endodontic sealers to influence periapical tissue healing is considered in view of eugenol’s anti-inflammatory and toxic properties. (ORAL SURC ORAL MED ORAL PATHOL 1992;73:729-37)

D entists frequently use zinc oxide-eugenol (ZOE) as a temporary filling and as a cement for provisional restorations. Eugenol-soaked pellets are occasionally placed on vital exposed pulps as a sedative dressing. These practices are not always successful or without controversy.’ Both beneficial and harmful effects have been attributed to eugenol.2 To date few studies of eugenol’s physiologic: effects on the dental pulp have been undertaken.

Eugenol and related compounds have a long history of use by dentists.3 Eugenol, thymol, and other essential oils have plleasant smells, germicidal activity and some degree of local anesthetic effects. These com-

aAssistant Clinical Profeissor; also Member, Division of Research and Development, Block Drug, Inc. Jersey City, N.J. bAssistant Professor. CDirector. 7/15/35642

pounds are related to phenol, which is a weakly acidic alcohol. Phenol also has anesthetic effects and was one of the first antiseptics used in surgery. Phenol and the closely related compound cresol are irritating and somewhat caustic to tissue. Eugenol is found in oil of clove, which is primarily used as a spice and food pre- servative. When eugenol is mixed with zinc oxide, a chelation reaction occurs and zinc eugenolate is formed. ZOE is a common constituent of temporary filling, material, cavity base, liners, and root canal sealers. When examined ultrastructurally, ZOE cement consists of grains of zinc oxide embedded in a zinc eugenolate matrix. Because separate zinc eugenolate units are held together by van der Waals forces and particle interlocking, ZOE cements are weak mechanically.4 Products such as IBM (L.D. Caulk, Milford, Del.) are reinforced ZOE cements with improved mechanical properties.

When exposed to aqueous media such as saliva or

729

‘\

730 Mavkowitz et al.

Pulpal Tissue

Fig. “i. After mixing of zinc oxide and eugenol, zinc eugenolate is formed. Water stowiy breaks down zinc eugenolate, allowing free eugenoi to diffuse into the pulp through dentinal tubules.

dentinal fluid, hydrolysis of zinc eugenolate occurs, yielding eugenoi and zinc hydroxide. Eugenol hber- ated from ZOE can diffuse through dentin and into the saliva. Hume5 filled occlusal cavities in extracted human teeth with zinc oxide mixed with tritium- labeled eugenol and found that eugenol was slowly released into the dentin and pulpal fluid. A schematic diagram illustrating the release and dentinal diffusion of eugenol from a ZOE filling is shown in Fig. 1. In the dentin below the filling, concentrations of 10m2 mol/L were reached. Fluid in the pulp space obtained concentrations of 10e4 mol/L. These concentrations were maintained for more than 1 week. The release of eugenol was not markedly affected by the zinc oxide/ eugenol mix ratio. The release of eugenol was affected by the thickness of remaining dentin between the pulp chamber and the ZOE-filled cavity. Meryon et a1.6, 7 found that thick dentin sections provided a better protective barrier than thin sections. Calcium in the dentinal tubules chelates eugenol, limiting its ability to diffuse through dentin. Binding of eugenol to the organic matrix of dentin, especially collagen, also slows diffusion. Modified ZOE cements were also demonstrated to release less eugenol and exert fewer toxic effects. It has been suggested that acid-etched dentin may facilitate diffusion of potentially toxic

amounts of eugenol to the pul~.~ Flume8 considered ZOE paste a good ““control deiivery system” to deposit pharmacologically active but subtoxic levels of eugenol to the pulp,

TOXIC EFFECTS OF ~U~E~OL

Eugenol is bactericidal at relatively high concentrations ( 10m2 to low3 mol/L). Dentin adjacent to a ZOE-filled cavity may be exposed to bactericidal eugenol levels. ZOE fillings act to prevent bacteria! penetration of dentinal cavities9 This clinically important effect was attributed to the ability of ZOE to prevent microleakage of contaminated oral fluids. Direct measurements of leakage suggest that the seal created by ZOE is not particularly tight when compared with other materials.” Thus the antibacterial effects of ZOE fillings may contribute to their clinical effectiveness. Brief exposure to lo-’ mol/L eugenol kills mammalian cells. Prolonged exposure to LOW3 mol/L also kills cells. Hume’s data from these studies show that eugenol concentrations that diffuse through dentin are not cytotoxic. Even lower concentrations, however, can inhibit cell respiration and cell division.” Recent studies tested the ability of phenolic compounds to inhibit enzymes in cultured rat pulp cells. Inhibitory eugenol concentrations were signifi-

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Properties of eugenol 731

cantly higher than concentrations that had anti- inflammatory eflrects. I2 Various biochemical mechanisms have been proposed to explain the cytotoxicity of eugenol. For instance, eugenol can be oxidized by peroxidase enzymes t.o a product that is toxic to rat hepatocytes. I3 Eugenol and related compounds were shown to have a high affinity for plasma membranes because of their lipid solubility. This is hypothesized to contribute tso cell damage.14 Cotmore et a1.t5 reported that eugenol can uncouple oxidative phos- phorylation in mitochondria. These toxic effects of eugenol may explain why direct application of eugenol-soaked cotton pellets to pulp tissue appears to cause an exacerbation of pulpitis symptoms. Direct pulp capping with ZOE evokes mild to more severe pulpal inflammatory response.‘5-17 Watts and Pater- son1* tested the effects of ZOE-containing cements on germ-free rats after sterile pulp exposure. When the ZOE material was sleparated from the exposed pulp by dentin chips, the pulp exhibited minimal inflammatory change 28 days after pulp capping. Placement of the ZOE materia!l in direct contact with the pulp tissue resulted in chronic inflammation and necrosis. Because this test was conducted with a commercial ZOE cement, the possible toxic role of other substances besides zinc oxide and eugenol must be considered. Severe inflalmmatory reactions to ZOE cements applied to deep cavities were reported in human teeth by BrannstrGm and Nyborg.19 These studies highlight an important principle concerning eugenol’s clinical use. Direct (contact between vital tissue and eugenol-containing material can cause damage to tissue.

PULPAL INFLAMMATION

Inflammation is the response of tissues to injury and infection. The dental pulp is subject to bacterial inva- sion from caries and trauma from drilling and other restorative procedures. Inflammation is charcterized by an increase in blood flow, increase in vascular leakage, and sensitization of nerve endings. These responses lead to’ the principal symptoms of inflammation, swelling, and pain. In addition, various blood- borne cells enter inflamed tissue. In most organs inflammation serves a useful function, limiting the extent of damage and initiating healing. In the dental pulp inflammation may lead to a less favorable outcome. The pulp -is enclosed in the rigid confines of the dental hard tissues and lacks collateral circula- tion. This low-compliance environment does not allow the pulp to swell during the inflammatory response.20 Instead, the pulpal tissue pressure increases to an extent that may I.ower pulpal blood flow. Because of this unique functional property, irreversible damage and even pulp death are frequent consequences of deep

caries and traumatic restorative procedures. The fol- lowing sections examine the effects of eugenol on various components of the inflammatory process. This provides a basis for understanding effects that eugenol has on both pulpal and periapical tissue.

ANESTHETIC PROPERTIES OF EUGENOL

The ability of eugenol to allay tooth pain is the main reason it is so widely used in dentistry. Chewing on cloves produces topical anesthesia of the oral mucosa (personal observation). Kozam21 observed that eugenol irreversibly blocked the conduction of action potentials in the frog sciatic nerve. Brodin and Rded22> 23 tested the effect of eugenol and ZOE cement on compound action potentials in the phrenic nerve. At low concentrations eugenol inhibited nerve activity in the reversible manner like a local anesthetic. After exposure to high concentrations of eugenol, nerve conduction was irreversibly blocked, indicating a neurotoxic effect. Eugenol also reduced synaptic transmission at the neuromuscular junction. Ozeki24 found that eugenol slowed nerve conduction in crayfish neurons and made them less excitable. These results are partially explained by the observation made in the same article that eugenol makes the crayfish nerve cell membrane more permeable to potassium ions; this lowered the membrane resistance. These eugenol-treated motor neurons also appeared to release less neurotransmitter. Additional studies such as Ozeki’s, where the effect of eugenol and other drugs are measured at the cellular level, are needed to determine this drug’s mechanisms of action. Trow- bridge et a1.25 found that eugenol liquid and ZOE paste placed into the canine teeth of cats blocked intradental nerve activity (INA) induced by compound 48/80. The reversibility of this effect was not determined. The mechanism by which compound 48/80 induces INA is not known. It is thought to act on sensory nerves indirectly through degranulation of mast cells.26 Zinc oxide mixed with paraffin oil had no effect on INA. Although the depth of cavities used in this study was not stated, it appears that eugenol lib- erated from ZOE paste can diffuse into the pulp in sufficient concentrations to inhibit compound 48/80- induced INA. INA recorded in human teeth corre- lates with the sensation of pain.27 It may be argued that sedation of the pulp is undesirable because it merely masks the symptoms of pulpal inflammation. According to our contemporary view of inflammation, sensory nerve fibers and their function are known to play an important role in the generation of the inflammatory response. Sensory nerves in the dental pulp contain vasoactive peptides such as substance P, calcitonin gene-related peptide, and others.28, 29 These vasoactive peptides are capable of causing vasodila-

932 Markowitz et al. OR~L§rxci ORAL M-ED ORAL PATH~L June 1992

Fig. 2. Eugenol release from a ZOE cement filling can lessen an inflammatory response by suppressing prostaglandin formation and possibly through its depressant effect on sensory nerves.

tion and an increase in tissue pressure in the dental pul~.~O-~~ Stimulation of the inferior alveolar nerve causes a similar increase in pulpal blood flow (PBF).33 Wakasaki et al. 34, 35 found that neuropeptide-containing sensory nerves surround pulpal blood vessels and send processes to the odontoblast and deep dentinal areas. We demonstrated thai ionic agents that stimulate intradental nerve activity such as hyper- tonic sodium chloride and potassium chloride also cause an increase in PBF. 36 Recent work shows that blocking intradental nerve activity with 1% lidocaine solution attenuates the PBF response to KC1 (Markowitz et al., in preparation). In addition, repeated applications of the C fiber stimulant and de- sensitizing agent capsaicin also causes attenuation of the PBF response to KC1 (Pert1 et al., in preparation). These experimental results indicate that the pulpal C fibers are important in the generation of the inflammatory response in the dental pulp. This involvement of sensory nerves in inflammation is due to the dual role played by these fibers. Not only do they relay in- formation to the central nervous system, but they also release vasoactive agents into the peripheral tissue at the site of injury and through the axon reflex into adjacent areas.37 This process of neurogenic inflamma-

tion has been described in many tissues3* The observation that eugenol inhibits nerve activity may be critical in understanding its possible anti-inflammatory effects, because nerve activity and the vascular components of the inflammatory response appear to be related.

UGENQL INFLUENCES OTHER INFLAMMATORY PATHWAYS

Injury such as traumatic cavity preparation trig- gers a number of cellular and biochemical processes. After injury leukocytes emigrate from blood vessels and enter the pulpal connective tissue.39 At high concentrations eugenol stimulates release of superoxide from neutrophils. This increases tissue damage at the site of inflammation. At these same concentrations eugenol was toxic to these cells.40 Eugenol inhibits neutrophil chemotaxis and superoxide anion generation at low (noncytotoxic) concentrations4” In this study eugenol had a more potent effect than other phenolic compounds tested. At low concentrations eugenol may protect tissue from damage by inhibiting neutrophil function and by removing harmful free radicals. In the pulp histologically observed inflammatory reactions were induced in monkey teeth by the

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. Induces cell death. l Inhibits prostaglandins

. Unknown vascular effect. synthesis.

. Inhibits cell growth l Inhibits nerve activity. and respiration. l Inhibits white cell chemotaxis.

Fig. 3. Effects of eugenol on tissue appears to be highly dependent on tissue concentration of eugenol. High concentrations appear to exert cytotoxic effects. Low concentrations are capable of anti-inflammatory activity.

placement of leaky temporary fillings or human car- ious dentin in deep cavities. These treatments expose the pulp to bacterial irritants. Both ZOE and calcium hydroxide paste allowed resolution of the inflammatory response and the formation of reactive dentin. However, removal of bacterial irritants is the most important factor in pulpal healing. The effect of eugenol on leukocyte function may also contribute to the resolution of the inflammatory response.42 Eugenol, like other phenolic compounds, removes free radicals from tissue and inhibits cyclooxygenase.43, 44 Eugenol has been found to act as a competitive inhibitor of prostaglandin H synthase, preventing binding of arachidonic acid to ,the enzyme.45 Oil of clove has been found to be a potent inhibitor of thromboxane formation and platelet aggregation in human blood in vitr6.46 In this stu d y oil of clove inhibited platelet aggregation evokeld by epinephrine and collagen. Plate- let aggregation and hemostasis are an important part of the response to injlury and the initiation of the inflammatory prolcess. Platelets release vasoactive substances when they aggregate at the site of injury. ZOE fillings have been found to reduce markedly prostaglandin E2 (PGEz), thromboxane, and the PGEl metabolite DHK-prastaglandin formation in rat teeth subjected to traumatic cavity preparation.47 In the case of PGE2 and its metabolite, ZOE filling caused the levels to fall to those below that found in normal pulps. Measurement of tritium-labeled eugenol levels in the pulp in this study yielded a level of 1W5 mol/L that is sufficient to cause metabolic impairment.” It should be noted that the cavity prepared in this study involved placing ZOE paste directly in contact with tissue at the tip of the pulp chamber. These same in- vestigators studied the effect of ZOE on leukocyte

chemotaxis and the production of lipoxygenase products.48 Traumatic cavity preparation caused leukocyte migration into the area of the pulp adjacent to the deep cavity. The numbers of polymorphonuclear leukocytes and lymphocytes reached its peak 3 to 4 hours after cavity preparation. In teeth with the deep cavities filled with ZOE paste, a delay of 2 hours was re- quired to reach peak numbers of these inflammatory cells. There was also a rise in the production of leukotrienes after cavity preparation. As was the case with polymorphonuclear neutrophils and lymphocytes, ZOE caused a delay in the time to peak concentrations of leukotrienes compared with unfilled teeth. The effect of ZOE on leukotrienes and inflammatory cell migrat,ion was not as marked as the effect on cyclooxygenase products observed with the same methods.

The results of this group of studies are significant since prostaglandins and leukotrienes are important mediators of the inflammatory process. PGE2 and some leukotrienes increase blood flow and vascular permeability, and at physiologic concentrations sen- sitize nerve endings, resulting in a lowered pain threshold. Ahlberg49 induced prolonged INA responses to heat application by repeated application of heat to cat teeth. Treatment of the cats with the cyclooxygenase-inhibiting drug indomethacin abolished this prolonged response to heat. The results were explained in terms of prostaglandins sensitizing the intradental nerves to become hyperresponsive to heat. It is likely that heat and traumatic drilling initiates sev- eral pathways of the inflammatory process, some of which may be sensitive to eugenol. Fig. 2 shows some of the possible anti-inflammatory effects of eugenol. Aspirin and the nonsteroidal anti-inflammatory drugs

734 Markowitz et al. ORAL %JRC~ ORAL MED OR~PATHOL

June 1992

such as ibuprofen have pharmacologic effects simiiar to eugenol. These drugs also inhibit prostaglandin synthesis and alter leukocyte function.50 These pharmacologic properties of eugenol may modify the tissue response to injury, allowing a less intense inflammatory response to occur.

~RCUL~T~RY EFFECTS OF EUGENOL

To date there are few detailed studies of the effects of eugenol or ZOE on pulpal vasculature and blood Bow. Humejr studied the effects of eugenol on circu- lation in the rabbit ear. Eugenol caused vasodilation and inhibited the response of these vessels to norepi- nephrine and histamine. Hume hypothesized that vasodilation caused by eugenol would result in preven- tion of toxic accumulations of materials and rapid removal of irritants. Hashimoto et a1.47 found that tritium-labeled eugenol released into the pulp rapidly reached the 1 Oe5 mol/L levels within 30 minutes after the filling of a deep cavity with ZOE paste. This level of eugenol in the pulp tissue rapidly declined to basal levels within the subsequent 4 hours. This type of de- cline in concentration is consistent with rapid micro- circulatory removal of eugenol from the pulp tissue, because eugenol release from ZOE paste is known to occur during a long time period when studied in extracted teeth.5 Kim (unpublished observations) observed that eugenol liquid increased PBF and vessel diameter when applied to very deep dentinal cavities. These effects were measured by intravital microscopy.

The special anatomic environment of the dental pulp make an understanding of the vascular effects of eugenol important. Because the pulp is contained in the low-compliance environment of the tooth, many vasodilators produce a biphasic blood flow response (an increase followed by a decrease).20, 52 Neuropep- tides, prostaglandins, bradykinins, and other inflammatory mediators cause vasodilation and leakage of fluid from the vasculature. Because the pulp can not increase in volume like other tissues, inflammatory substances induce a rise in pulp tissue pressure.53 This increase in tissue pressure causes compression of the vasculature, especially the thin-walled pulpal venules.20 Eventually this leads to a drop in PBF. Traumatic procedures, such as full crown preparation without water spray, caused an increase in PBF followed by a later decrease. 54 The eventual decrease in PBF in response to inflammatory mediators is hypothesized to be an important factor leading to pulp necrosis in response to inflammation caused by caries and operative procedures. 55 Our hypothesis is that a large increase in PBF caused by eugenol or ZOE would be undesirable to -the damaged pulp because these changes wou.ld be superimposed on preexisting vascular derrangements. By further increasing PBF,

eugenol-induced vasodilation may cause irreversible vascular changes, leading to pulp necrosis2’, 55 Clearly, direct studies of the vascular effects of eugenol and ZOE paste are needed to determine whether these events occur. The results of these studies should determine whether eugenol and ZOE have undesirable pharmacologic properties or can help preserve pulp vitality by shielding the pulp from hemodynamic perturbations caused by traumatic stimulus. These studies would also provide a physiologic methodology that could be used to test new base- and pulp-capping materials.

CLINICAL IMPLICATIONS OF EUGENOL’S PROPERTIES

The pharmacologic effects of eugenol are likely to be complex and to depend on the free eugenol concentration to which the tissue is exposed. Fig. 3 shows that beneficial pharmacologic responses are most probable when the pulp is exposed to low eugeno! concentrations. These low concentrations can be obtained by eugenol diffusion from a ZOE filling through a layer of intact dentin. Placement of a ZOE filling after excavation of deep caries should exert a sedative and anti-inflammatory effect. Clinically this should be manifested by a decrease in sensitivity of the tooth to cold, hot, and sweets. Alternatively, high concentrations capable of cytotoxic effects can be de- livered to tissues by placing eugenol or ZOE in direct contact with vital tissue. The evidence strongly suggests that direct pulp capping with eugenol-containing materials should be avoided if long-term mainte- nance of pulp vitality is to be achieved. Direct placement of a eugenol-soaked pellet over a vital exposure should be done when an endodontic procedure can be performed within a few days.

Like other drugs, eugenol is not a panacea. The effectiveness of eugenol is limited in the face of severe tissue injury. In some instances deep caries or traumatic tooth preparation may induce irreversible effects not amenable to pharmacologic intervention. Although eugenol may reduce the response to mild trauma, the nature of the pulp’s reaction depends on the severity of the damage. No pharmacologic treatment can mitigate the effect of poor technique. To preserve tooth vitality, there is no substitute for early, conservative, and atraumatic tooth preparation.

USE OF EUGENOL IN ENDODONTIC QBTURATION

Sealers used in endodontic obturation often include ZOE in combination with a wide variety of other in- gredients. Unlike the dental pulp, the periapical tissues are difficult to study directly in vivo. Despite this, various experimental approaches can help us under-

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stand the effects of eu.genol on periapical tissues. As described in the preceding section, eugenol diffusion into the dental pulp from a ZOE filling is limited by an intact dentin barrier. In this relatively dry cavity, free eugenol is released slowly as the eugenolate is hydrolyzed. In contrast, when used as an endodontic sealer, ZOE may be placed into direct contact with inflamed or healthy periapical tissue. This type of “wet” interface between ZOE paste and tissue allows the release of large amounts of eugenol into the apical tissue during a short period of time. At this higher concentration eugenol has been demonstrated to ex- hibit its cytotoxic effects.

The difficulty in assessing the effect of eugenol on periapical tissues is due to the greater importance of cleaning and shaping the canal system. Clinical success in endodontics is due to the elimination of micro- organisms and other antigenic material from the pulp space and their continued exclusion by the endodontic filling. 56 The pharmacologic properties of the sealer are of secondary importance.57 Whether eugenol contributes to the healing process or actually delays healing by causing tissue damage and main- taining the inflammatory reaction remains to be determined. Many stuldies have been conducted to determine the effects of eugenol, and the discrepancy between laboratory studies and clinical results appears to be great. Eugenol, in addition to being antibacterial, may have other beneficial effects.8 Eugenol may inhibit periapical nerve activity, as has been shown in the dental pulp. 22 At greater concentrations eugenol may also be toxic to these apical nerves. Both effects can lessen the perception of pain. Through the inhibition of prostaglandin and leukotriene synthesis, eugenol may assist in the resolution of periapical inflammation. Of great relevance to periapical disease is the contribution of prostaglandins, especially PGE2 in bone resorption. Fibroblasts in apical cysts are believed to synthesize PGE2 under stimulation by lymphocytes. This PGE2 then stimulates osteoclasts to resorb bone.58 These Ieffects of eugenol on neutrophil chemotaxis and free radical removal can also help to promote resolutison of apical inflammation.41 Neutro- phils and the free radicals they release damage tissue as well as kill bacteria. 59 Eugenol has been reported to affect the cell-me.diated immune response. The feeding of eugenol to Iyoung mice had dose-dependent effects on cell-mediated immunity. At low doses sup- pressor T cells were activated. With higher doses helper T cells ‘were activated to the point where eugenol became toxic to these cells.60 Although the relevance of these re;sults to apical pathology is not clear, the pharmacologic modulation of cell immunity is likely to be an area of active investigation.

Experiments with tissues in culture have shown eu-

genol to be highly toxic to human cell lines. If this cytotoxicity were to occur in the periapical tissue, healing may be delayed or inhibited. Studies with gingival fibroblasts found that periodontal dressings with ZOE were more cytotoxic than noneugenol dressings. 61 As a result of such studies, periodontal dressings no longer contain eugenol, because it is thought to delay healing. In another study, also with the use of gingival fibroblasts, Briseiio and Willershausen62 demonstrated cytotoxicity in all the ZOE-based root canal sealers tested. These results are in agreement with studies involving implantation of endodontic sealers into subcutaneous tissue of experimental animals. Such studies demonstrate a severe to moderate inflammatory reaction to eugenol in ZOE-based sealers.63 In another study an experimental sealer without eugenol was compared with a similar eugenol-containing material. The sealer without eugenol showed a higher degree of biocompatibility.64

Although eugenol is believed to be capable of causing persistent inflammation when used in endodontic sealers,65 these products have a most impressive clinical record. Studies on animals have shown that eugenol-based sealers provide adequate sealing char- acteristics yet still display an inflammatory reaction expected from both the tissue culture and implantation studies. ZOE-based sealers were found on histologic examination to cause a greater degree of inflammation than Ca(OH)z when used as dressings for experimentally produced root perforations in dogs. The teeth treated with Ca(OH)2 exhibited a greater degree of healing, whereas the ZOE group displayed a progressive inflammatory reaction that was essen- tially equal to the untreated control group.@j In another study Ca(OH)2 was compared with ZOE as a filling material for the root canal systems of primary teeth in dogs. The results showed that the teeth treated with Ca(OH)2 exhibited a lesser inflammatory reaction at the apex. This was determined by histologic examination and correlated with both clinical and radiographic evaluation, which confirmed an increased amount of bone apposition and a decreased degree of resorption and abscess formation for Ca- (OH)2 treated teeth. It should be noted that in the cleaning and shaping of the canal systems of these teeth, saline solution was used as the irritant. As a result the differences between ZOE and Ca(OH)2 may be due to the greater antibacterial activity of the Ca- (OH)2, because infection in these teeth may have in- fluenced the apical response.67 One interesting point noted by the authors was the type of inflammation caused by each of these agents. Ca(OH)2 caused a more acute inflammatory reaction with a faster resolution, whereas the ZOE displayed a more chronic inflammatory response. Recently ,the long-term his-

736 Markowitz et al.

tologic response to a variety of endodontic sealers was reported by Pascon et al. Endodontic treatment with aseptic technique was performed on primate teeth. A ZOE-based material was demonstrated to provoke a mild inflammatory response at most time intervals studied.68 In human studies comparing different types of filling materials in the healing of apical periodon- titis, no significant difference was found between Kloroperka (gutta-percha dissolved in chloroform), Proco-sol (a ZOE-based cement) and AH-26 (an ep- oxy resin). This study, based on radiographic analysis instead of histologic studies, found healing in almost all cases.57 Although radiographic evidence of healing was eventually seen in almost all cases, this does not mean that no inflammatory reaction oc- curred. Despite the large amount of data that demonstrate the toxic and inflammatory nature of ZOE- based sealers, they appear to be very satisfactory clinically.

In the case of endodontic obturation, a small amount of ZOE at the root apex may have a level of eugenol high enough to be toxic to bacteria and host cells. Surrounding this confined area of cell death, the nearby tissue in the periapical area receives a lower dose of eugenol, where the effect is both anti-inflammatory and analgesic. Thus the effect of eugenol on apical tissue is dependent on the distance from the eugenol source. In addition, it may be argued that such a resorbable material69 that provokes an inflammatory response is capable of causing a proliferative reaction and thereby stimulate healing. The apparent contradiction between these two reactions may be due to the criteria used to judge success in clinical studies as compared with the more scientific studies. The human studies are graded on the basis of patient com- fort and radiographic appearance. In comparison, the animal studies use histologic examination and cell vi- ability.

Even though our knowledge of these materials is far from complete, it is obvious that the amount of root canal sealer exposed to viable soft tissue should be kept to a minimum. In endodontic therapy apical perforations or extrusion of sealer past the apical fo- ramen increases the interface between the ZOE paste and the apical tissue. This allows greater diffusion of eugenol into the apical tissue and possibly interferes with the healing process.

This review of the pulpal and possible apical effects of eugenol suggests that this substance be used con- servatively in clinical practice. On the basis of the results of in vitro studies alone, ZOE may not be accepted as a restorative material.9 Although less toxic than some materials,22 ZOE’s maximal benefit can be obtained by avoiding direct contact with vital tissue. This allows eugenol’s analgesic and anti-

QRAL SURG ORAL MED ORAL PATHOL June 1992

inflammatory effects to predominate over its toxic potential.

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Reprint requests: S. Kim, DDS, PhD Department of Endodontics School of Dental Medicine University of Pennsylvania 4001 Spruce St. Phildelphia, PA 19104

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Biologic properties of eugenol and zinc oxide-eugenol