Journal of Dental Research http://jdr.sagepub.com/
The Effect of Eugenol on Oral Mucous Membranes George Kozam and Gary M. Mantell J DENT RES 1978 57: 954 DOI: 10.1177/00220345780570110901 The online version of this article can be found at: http://jdr.sagepub.com/content/57/11/954
Published by: http://www.sagepublications.com
On behalf of: International and American Associations for Dental Research
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The Effect of Eugenol on Oral Mucous Membranes GEORGE KOZAM and GARY M. MANTELL* College of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newvark, New Jersey 07103.
Eugenol, in the 100 percent concentration in commercial use, was applied to a circumscribed area, 3 mm in diameter, of rat labial mucosa for I minute. Reaction periods of 15 minutes, 1, 2, 4 and 6 hours were then permitted. Using routine histological procedures for processing the experimental tissues, it was observed that eugenol caused denaturation of cytoplasmic proteins and loss of staining capacity of epithelium, loss of cell boundaries, swelling and cell necrosis. In addition, vesicle formation, edema in the corium, and striated muscle dissolution were observed.
J Dent Res 57(11-12):954-957, Nov.-Dec. 1978
Introduction. Eugenol, 4 allyl-2-methoxyphenol, is an old and revered dental remedy which has been used empirically for oral pathoses for decades. That it has deleterious effects if misused has been reported (1-7), but its value as an anodyne and, to some extent, as an antiseptic, has kept it in use, especially in endodo-atic and periodontic therapy. It has become clear, however, that even as a component of periodontal packs it still retains its activity for some time and that its effects may be harmful. The paucity of controlled experiments on its effects on oral mucous membranes or even on vital pulpal tissue impelled the authors to determine the pathological effects of this medicament on oral epithelium and its subjacent tissues. Accordingly, both light and electron microscopic studies were made. The light microscopic findings are being reported at this time. Received for publication November 30, 1977 Accepted for publication May 4, 1978 *In partial fulfillment of the requirements for the degree of Master of Science, College of Medicine and Dentistry, Newark, N.J. Present address: Department of Anatomy, Fairleigh Dickinson University, School of Dentistry, Hackensack, N.J. Address reprint requests to: Dr. George Kozam, College of Medicine and Dentistry of New Jersey, 100 Bergen Street, Newark, New Jersey 07103. 954
Materials and methods.
White rats (Sprague-Dawley)* weighing between 500 and 600 grams were anesthetized by means of an intramuscular injection of Ketamine HCl** (100 mg/kg body weight) supported by an injection of Xylazine*** (20 mg/kg body weight). This combination produced a sustained period of anesthesia, without respiratory difficulties, during which the experimental procedures could be performed. The mouth was stabilized in an open position and the lower lip extended by thumb and forefinger as a shortened medicine dropper (aperture 3 mm. in diameter) was applied to the mucous membrane of its central region. In order to produce a standardized acute effect, 100 percent eugenol**** was used. This was introduced by means of a capillary pipette into the lumen of the medicine dropper by an aide and permitted to act on the epithelium for a period of one minute. The test site was then gently swabbed with a soft cotton pledget lowered by means of the fine forceps through the medicine dropper lumen. The site was then cleansed with physiologic saline (though immiscible with eugenol) introduced and then withdrawn through the medicine dropper to remove physically as much of the test substance as possible. Reaction times of fifteen minutes and one, two, four and six hours were employed after which the animal was sacrificed by the intracardiac injection of nembutal and the lower lip excised. The central mucosal region and its surrounding area
*Marland Farms, Hewitt, N.J. **Ketaset, manufactured by Bristol Laboratories, Syracuse, N.Y. * * * Rompun, manufactured by Chemogro, Division of Bay Chem. Corp., Kansas City, Missouri ****Manufactured by Sultan Chemists, Jersey City, N.J.
Downloaded from jdr.sagepub.com at CARLETON UNIV on November 28, 2014 For personal use only. No other uses without permission.
ZVol 57No. 11-12
EUGENOL EFFLCTS ON MUCOSA
were immersed in l0% formalin. All specimens were processed using standard histological procedures, sectioned at six microns, and stained with hematoxylin and eosin. Fifty-five animals were used in this study; 40 rats were studied with 100 percent eugenol. 5 were absolute controls and, as a further precaution against artifacts, 10 animals were exposed to a mock application in which the medicine dropper was positioned on the lip mucosa for 1 minute without the introduction of a test substance.
Results. The results of our investigation of the effects of eugenol as compared with our controlled studies (Fig. A) confirm the view that it has a severe destructive effect on when topically applied, and the concentrations available for clinical use. All animals eugenol on the labial mucosa demonstrated epithelial changes and, if the reaction period was long enough, inflammation and tissue destruction. One hundred percent eugenol in a 15-minute reaction period resulted in an apparent denaturation of the cytoplasm with resultant decrease in the staining capacity of the outer epithelial layers (Fig. B). When a reaction period of one hour was employed, the loss of staining capacity extended deeper into the epithelium together with a general swelling of cells and the presence of hyperchromic nuclear material (Fig. C). Additionally, a loss of clarity of nuclear and cellular membranes (Fig. D) was also ob-
oral mucosa especially in commercially subjected to
IFig. A. Normal histological architecture of rat labial mucosa from pressure control by application of medicine dropper. 400X.
955
served. These are all signs of early cell necrosis. Moreover, dark staining intracytoplasmic bodies were observed in the cytoplasm of the swollen cells. Examination of the affected region near a normal area appears to indicate that these were keratohyaline granules, now more easily seen because of the loss of staining capacity of cellular proteins. Binucleate cells were also observed in a greater frequency than noted in untreated oral epithelium. The 2-hour reaction time with 100% eugenol produced either intra-epithelial or sub-epithelial vesicle formation together with edema in the corium. The 4-hour reaction period (Fig. E) presented vesicle formation observable with the naked eye in addition to all the microscopic findings noted above with engorged capillaries and inflammatory cells-the typical inflammatory reaction. The six-hour reaction period (Fig. F) produced obvious gross vesicle formation, tissue swelling, and microscopic findings which demonstrated striated muscle fibers, widely separated by edema fluid, undergoing dissolution (arrow). Inflammatory cell infiltration was observed throughout the treated area.
Discussion. Sternberg (8) and Silvers (9) found that inflammation with a sensation of burning and redness of the oral mucosa, ultimately leading to the formation of vesicles, resulted from surgical dressings containing eugenol. This finding led these authors to counsel against the use of eugenol dressings.
Labial epithelium following 100% Fig. B. eugenol application and a reaction period of 15 minutes. Note cellular edema, decrease of staining capacity, hazy cell boundaries and presence of intracytoplasmic granules. 400X.
Downloaded from jdr.sagepub.com at CARLETON UNIV on November 28, 2014 For personal use only. No other uses without permission.
J Dee & MANTELL KOZ-AM D96 kt NoM E R es beVr-DeceberDember 19 78 956
Fig. C. - Labial epithelium following application of 100l eugenol and a reaction period of 1 hour; margin of experimental area showing normal and affected cells. 240X.
Labial epithelium following 100% F ig. D. eugenol and a reaction period of 1 hour. Note cellular swelling and nuclear clumping and loss of clear cellular boundaries. Keratolhyaline granules present. 240X.
.~t *~~~~~
6[ ^ - yr*g-*4**s* 4"
F
'
oe .r
4$ te@ 4
Fig. E. - Labial epithelium following application of 100% eugenol and a reaction period of 4 hours. Note well-formed vesicle and inflammatory cell infiltration. 160X.
Fig. F. Corial region subjacent to basement membrane followino application of 100% eugenol and a reaction period of 6 hours. Observe corial edema, dissolution of striated miuscle fibers (arrow) and inflammatory cell infiltration. 400X.
Although the exact mode of action of topically applied eugenol is not well known, it appears from our observations that it enters the cell and acts to denature the cytoplasmic and nuclear proteins with the resultant loss of physiological function and staining capacity. Undergoing degeneration, the cells swell and finally disintegrate. It appears to us that in the process of cell necrosis, the loss of staining capacity unmasks, or makes more easily visible, the keratohyaline granules previously observed with difficulty. Because the hematoxylin and eosin staining procedure requires the use of alcohol, we discarded the possibility that these particles might be ingested globules of the test substance. It is interesting, however, to obser-ve the junction of the lesional area with the normal epithelium in Fig. C, i.e., that the stratum granulo-
sum, with many condensed keratohyaline granules, becomes widened by the cellular edema giving the appearance of keratohyaline granules deeper and more dispersed than they would normally be. We must also comment on the degree of destructiveness of 100% eugenol to mucosal surfaces since even an application time of one minute followed by as much removal of residue as possible results in a severe reaction in a six-hour period. Apparently, sufficient amounts of it, having penetrated the outer layers, continue their passage and destructiveness inward. We have observed instances of intraepidermal vesicle formation, although in most cases the basement membrane appeared to dissolve with later formation of sub-epidermal vesicle formation, submucosal edema and engorged capillaries. Of signifi-
Downloaded from jdr.sagepub.com at CARLETON UNIV on November 28, 2014 For personal use only. No other uses without permission.
Vol. 57No. 11-12
EUGENOL EFFECTS ON MUCOSA
cance was the observation that the effect of eugenol in 1 00% concentration was so strong as to induce striated muscle fiber degeneration and dissolution. The cells of the stratum germinativum appeared to be able to resist, for a time, the effects of eugenol more than the superficial cells. This layer seemed to act as a final barrier to the action of eugenol. It is apparent from our observations that the effect of eugenol is more penetrating and destructive than previously thought. Its initial effect in the concentrations studied (clinically used concentrations are 90 to 100% as obtained commercially) is clearly cytotoxic. There occurs subsequently an acute inflammatory response in the corium which demonstrates all the features of that process. The longer lasting effects and the character and role of the healing process are under investigation in our laboratory at this time. These reactions were not observed in either absolute controls or mock treatment animals.
Summary and conclusions. The topical application of eugenol to rat labial mucosa in 100 percent concentration initially induces epithelial degeneration and necrosis in the epithelium and then vesiculation and an inflammatory response in the corium. It must be concluded that eugenol is injurious to labial mucous membranes and should not be used in any packs, or other capacities in which it might contact soft oral membranes.
957
Acknowledgments. The authors express sincere appreciation to Dr. Jerome Bartholomew for technical assistance contributed in a phase of this study References 1. BERNIER, J. L. and KAPLAN, H.: The Repair of Gingival Tissue After Surgical Intervention. J. Amer. Dent. Assoc., 35:697-705, 1947. 2. WAERHAUG, J. and LOE, H.: Tissue Reaction to Gingivectomy Pack. Oral Surg., 10:923-937,
1957. 3. LOE, H.: Tissue Reaction to a New Gingivectomy Pack. Oral Surg., 14:1305-13, 196 1. 4. RATEITSCHAK, K. H.; GRAFF, H.; and GULDENER, P.: Periodontal Pack Without Eugenol. J. Periodont., 35:290-297, 1964. 5. GURNEY, B. F.: Eugenol: Utility Versus Toxicity. Oral Hyg., 55:74-82, 1965. 6. GUGLANI, L. M. and ALLEN, F.: Connective Tissue Reactions to Implants of Periodontal Packs. JPeriodont., 36:279-282, 1965. 7. BANDMANN, H. J. and DOHN, W.: Die Epicutantestung. Verlag, J. F. Berman, Miinchen, 1967. P. 148. 8. STERNBERG, L.: Contact Dermatitis. Cases Caused by Oil of Cloves and Oil of Camomile Tea (Anthemis Cotula). J. Allerg., 8:185-186, 1937. 9. SILVERS, S. H.: Stomatitis and Dermatitis Venanata with Purpura, Resulting from Oil of Cloves and Oil of Cassia. Dent. Items, 61: 649-651, 1939.
ANNOUNCEMENT
International Symposium on Phenytoin-Induced Teratology and Gingival Pathology. May 25-26, 1979, Chapel Hill, North Carolina, U.S.A. In this symposium, clinicians and basic scientists in various disciplines will present their recent research relating to the orofacial manifestations associated with chronic phenytoin therapy. The main conference topics will be "drug metabolism and disposition", "teratology", and "gingival overgrowth". A panel discussion will encourage audience participation. For information and pre-registration packet, contact: Dr. Thomas M. Hassell, Department of Periodontics, School of Dentistry, University of North Carolina, Chapel Hill, NC 275 14 U.S.A. Downloaded from jdr.sagepub.com at CARLETON UNIV on November 28, 2014 For personal use only. No other uses without permission.
The Effect of Eugenol on Oral Mucous Membranes George Kozam and Gary M. Mantell J DENT RES 1978 57: 954 DOI: 10.1177/00220345780570110901 The online version of this article can be found at: http://jdr.sagepub.com/content/57/11/954
Published by: http://www.sagepublications.com
On behalf of: International and American Associations for Dental Research
Additional services and information for Journal of Dental Research can be found at: Email Alerts: http://jdr.sagepub.com/cgi/alerts Subscriptions: http://jdr.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Citations: http://jdr.sagepub.com/content/57/11/954.refs.html
>> Version of Record - Nov 1, 1978 What is This?
Downloaded from jdr.sagepub.com at CARLETON UNIV on November 28, 2014 For personal use only. No other uses without permission.
._
The Effect of Eugenol on Oral Mucous Membranes GEORGE KOZAM and GARY M. MANTELL* College of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newvark, New Jersey 07103.
Eugenol, in the 100 percent concentration in commercial use, was applied to a circumscribed area, 3 mm in diameter, of rat labial mucosa for I minute. Reaction periods of 15 minutes, 1, 2, 4 and 6 hours were then permitted. Using routine histological procedures for processing the experimental tissues, it was observed that eugenol caused denaturation of cytoplasmic proteins and loss of staining capacity of epithelium, loss of cell boundaries, swelling and cell necrosis. In addition, vesicle formation, edema in the corium, and striated muscle dissolution were observed.
J Dent Res 57(11-12):954-957, Nov.-Dec. 1978
Introduction. Eugenol, 4 allyl-2-methoxyphenol, is an old and revered dental remedy which has been used empirically for oral pathoses for decades. That it has deleterious effects if misused has been reported (1-7), but its value as an anodyne and, to some extent, as an antiseptic, has kept it in use, especially in endodo-atic and periodontic therapy. It has become clear, however, that even as a component of periodontal packs it still retains its activity for some time and that its effects may be harmful. The paucity of controlled experiments on its effects on oral mucous membranes or even on vital pulpal tissue impelled the authors to determine the pathological effects of this medicament on oral epithelium and its subjacent tissues. Accordingly, both light and electron microscopic studies were made. The light microscopic findings are being reported at this time. Received for publication November 30, 1977 Accepted for publication May 4, 1978 *In partial fulfillment of the requirements for the degree of Master of Science, College of Medicine and Dentistry, Newark, N.J. Present address: Department of Anatomy, Fairleigh Dickinson University, School of Dentistry, Hackensack, N.J. Address reprint requests to: Dr. George Kozam, College of Medicine and Dentistry of New Jersey, 100 Bergen Street, Newark, New Jersey 07103. 954
Materials and methods.
White rats (Sprague-Dawley)* weighing between 500 and 600 grams were anesthetized by means of an intramuscular injection of Ketamine HCl** (100 mg/kg body weight) supported by an injection of Xylazine*** (20 mg/kg body weight). This combination produced a sustained period of anesthesia, without respiratory difficulties, during which the experimental procedures could be performed. The mouth was stabilized in an open position and the lower lip extended by thumb and forefinger as a shortened medicine dropper (aperture 3 mm. in diameter) was applied to the mucous membrane of its central region. In order to produce a standardized acute effect, 100 percent eugenol**** was used. This was introduced by means of a capillary pipette into the lumen of the medicine dropper by an aide and permitted to act on the epithelium for a period of one minute. The test site was then gently swabbed with a soft cotton pledget lowered by means of the fine forceps through the medicine dropper lumen. The site was then cleansed with physiologic saline (though immiscible with eugenol) introduced and then withdrawn through the medicine dropper to remove physically as much of the test substance as possible. Reaction times of fifteen minutes and one, two, four and six hours were employed after which the animal was sacrificed by the intracardiac injection of nembutal and the lower lip excised. The central mucosal region and its surrounding area
*Marland Farms, Hewitt, N.J. **Ketaset, manufactured by Bristol Laboratories, Syracuse, N.Y. * * * Rompun, manufactured by Chemogro, Division of Bay Chem. Corp., Kansas City, Missouri ****Manufactured by Sultan Chemists, Jersey City, N.J.
Downloaded from jdr.sagepub.com at CARLETON UNIV on November 28, 2014 For personal use only. No other uses without permission.
ZVol 57No. 11-12
EUGENOL EFFLCTS ON MUCOSA
were immersed in l0% formalin. All specimens were processed using standard histological procedures, sectioned at six microns, and stained with hematoxylin and eosin. Fifty-five animals were used in this study; 40 rats were studied with 100 percent eugenol. 5 were absolute controls and, as a further precaution against artifacts, 10 animals were exposed to a mock application in which the medicine dropper was positioned on the lip mucosa for 1 minute without the introduction of a test substance.
Results. The results of our investigation of the effects of eugenol as compared with our controlled studies (Fig. A) confirm the view that it has a severe destructive effect on when topically applied, and the concentrations available for clinical use. All animals eugenol on the labial mucosa demonstrated epithelial changes and, if the reaction period was long enough, inflammation and tissue destruction. One hundred percent eugenol in a 15-minute reaction period resulted in an apparent denaturation of the cytoplasm with resultant decrease in the staining capacity of the outer epithelial layers (Fig. B). When a reaction period of one hour was employed, the loss of staining capacity extended deeper into the epithelium together with a general swelling of cells and the presence of hyperchromic nuclear material (Fig. C). Additionally, a loss of clarity of nuclear and cellular membranes (Fig. D) was also ob-
oral mucosa especially in commercially subjected to
IFig. A. Normal histological architecture of rat labial mucosa from pressure control by application of medicine dropper. 400X.
955
served. These are all signs of early cell necrosis. Moreover, dark staining intracytoplasmic bodies were observed in the cytoplasm of the swollen cells. Examination of the affected region near a normal area appears to indicate that these were keratohyaline granules, now more easily seen because of the loss of staining capacity of cellular proteins. Binucleate cells were also observed in a greater frequency than noted in untreated oral epithelium. The 2-hour reaction time with 100% eugenol produced either intra-epithelial or sub-epithelial vesicle formation together with edema in the corium. The 4-hour reaction period (Fig. E) presented vesicle formation observable with the naked eye in addition to all the microscopic findings noted above with engorged capillaries and inflammatory cells-the typical inflammatory reaction. The six-hour reaction period (Fig. F) produced obvious gross vesicle formation, tissue swelling, and microscopic findings which demonstrated striated muscle fibers, widely separated by edema fluid, undergoing dissolution (arrow). Inflammatory cell infiltration was observed throughout the treated area.
Discussion. Sternberg (8) and Silvers (9) found that inflammation with a sensation of burning and redness of the oral mucosa, ultimately leading to the formation of vesicles, resulted from surgical dressings containing eugenol. This finding led these authors to counsel against the use of eugenol dressings.
Labial epithelium following 100% Fig. B. eugenol application and a reaction period of 15 minutes. Note cellular edema, decrease of staining capacity, hazy cell boundaries and presence of intracytoplasmic granules. 400X.
Downloaded from jdr.sagepub.com at CARLETON UNIV on November 28, 2014 For personal use only. No other uses without permission.
J Dee & MANTELL KOZ-AM D96 kt NoM E R es beVr-DeceberDember 19 78 956
Fig. C. - Labial epithelium following application of 100l eugenol and a reaction period of 1 hour; margin of experimental area showing normal and affected cells. 240X.
Labial epithelium following 100% F ig. D. eugenol and a reaction period of 1 hour. Note cellular swelling and nuclear clumping and loss of clear cellular boundaries. Keratolhyaline granules present. 240X.
.~t *~~~~~
6[ ^ - yr*g-*4**s* 4"
F
'
oe .r
4$ te@ 4
Fig. E. - Labial epithelium following application of 100% eugenol and a reaction period of 4 hours. Note well-formed vesicle and inflammatory cell infiltration. 160X.
Fig. F. Corial region subjacent to basement membrane followino application of 100% eugenol and a reaction period of 6 hours. Observe corial edema, dissolution of striated miuscle fibers (arrow) and inflammatory cell infiltration. 400X.
Although the exact mode of action of topically applied eugenol is not well known, it appears from our observations that it enters the cell and acts to denature the cytoplasmic and nuclear proteins with the resultant loss of physiological function and staining capacity. Undergoing degeneration, the cells swell and finally disintegrate. It appears to us that in the process of cell necrosis, the loss of staining capacity unmasks, or makes more easily visible, the keratohyaline granules previously observed with difficulty. Because the hematoxylin and eosin staining procedure requires the use of alcohol, we discarded the possibility that these particles might be ingested globules of the test substance. It is interesting, however, to obser-ve the junction of the lesional area with the normal epithelium in Fig. C, i.e., that the stratum granulo-
sum, with many condensed keratohyaline granules, becomes widened by the cellular edema giving the appearance of keratohyaline granules deeper and more dispersed than they would normally be. We must also comment on the degree of destructiveness of 100% eugenol to mucosal surfaces since even an application time of one minute followed by as much removal of residue as possible results in a severe reaction in a six-hour period. Apparently, sufficient amounts of it, having penetrated the outer layers, continue their passage and destructiveness inward. We have observed instances of intraepidermal vesicle formation, although in most cases the basement membrane appeared to dissolve with later formation of sub-epidermal vesicle formation, submucosal edema and engorged capillaries. Of signifi-
Downloaded from jdr.sagepub.com at CARLETON UNIV on November 28, 2014 For personal use only. No other uses without permission.
Vol. 57No. 11-12
EUGENOL EFFECTS ON MUCOSA
cance was the observation that the effect of eugenol in 1 00% concentration was so strong as to induce striated muscle fiber degeneration and dissolution. The cells of the stratum germinativum appeared to be able to resist, for a time, the effects of eugenol more than the superficial cells. This layer seemed to act as a final barrier to the action of eugenol. It is apparent from our observations that the effect of eugenol is more penetrating and destructive than previously thought. Its initial effect in the concentrations studied (clinically used concentrations are 90 to 100% as obtained commercially) is clearly cytotoxic. There occurs subsequently an acute inflammatory response in the corium which demonstrates all the features of that process. The longer lasting effects and the character and role of the healing process are under investigation in our laboratory at this time. These reactions were not observed in either absolute controls or mock treatment animals.
Summary and conclusions. The topical application of eugenol to rat labial mucosa in 100 percent concentration initially induces epithelial degeneration and necrosis in the epithelium and then vesiculation and an inflammatory response in the corium. It must be concluded that eugenol is injurious to labial mucous membranes and should not be used in any packs, or other capacities in which it might contact soft oral membranes.
957
Acknowledgments. The authors express sincere appreciation to Dr. Jerome Bartholomew for technical assistance contributed in a phase of this study References 1. BERNIER, J. L. and KAPLAN, H.: The Repair of Gingival Tissue After Surgical Intervention. J. Amer. Dent. Assoc., 35:697-705, 1947. 2. WAERHAUG, J. and LOE, H.: Tissue Reaction to Gingivectomy Pack. Oral Surg., 10:923-937,
1957. 3. LOE, H.: Tissue Reaction to a New Gingivectomy Pack. Oral Surg., 14:1305-13, 196 1. 4. RATEITSCHAK, K. H.; GRAFF, H.; and GULDENER, P.: Periodontal Pack Without Eugenol. J. Periodont., 35:290-297, 1964. 5. GURNEY, B. F.: Eugenol: Utility Versus Toxicity. Oral Hyg., 55:74-82, 1965. 6. GUGLANI, L. M. and ALLEN, F.: Connective Tissue Reactions to Implants of Periodontal Packs. JPeriodont., 36:279-282, 1965. 7. BANDMANN, H. J. and DOHN, W.: Die Epicutantestung. Verlag, J. F. Berman, Miinchen, 1967. P. 148. 8. STERNBERG, L.: Contact Dermatitis. Cases Caused by Oil of Cloves and Oil of Camomile Tea (Anthemis Cotula). J. Allerg., 8:185-186, 1937. 9. SILVERS, S. H.: Stomatitis and Dermatitis Venanata with Purpura, Resulting from Oil of Cloves and Oil of Cassia. Dent. Items, 61: 649-651, 1939.
ANNOUNCEMENT
International Symposium on Phenytoin-Induced Teratology and Gingival Pathology. May 25-26, 1979, Chapel Hill, North Carolina, U.S.A. In this symposium, clinicians and basic scientists in various disciplines will present their recent research relating to the orofacial manifestations associated with chronic phenytoin therapy. The main conference topics will be "drug metabolism and disposition", "teratology", and "gingival overgrowth". A panel discussion will encourage audience participation. For information and pre-registration packet, contact: Dr. Thomas M. Hassell, Department of Periodontics, School of Dentistry, University of North Carolina, Chapel Hill, NC 275 14 U.S.A. Downloaded from jdr.sagepub.com at CARLETON UNIV on November 28, 2014 For personal use only. No other uses without permission.
