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ORIGINAL ARTICLE Hypersensitivity to metals in orthodontics Luciane M. Menezes, DDS, PhD,a Luis C. Campos, MD,b Catia C. Quintão, DDS, PhD,c and Ana M. Bolognese, DDS, PhDd Porto Alegre and Rio de Janeiro, Brazil To study the incidence of hypersensitivity to orthodontic metals, patch tests were carried out before and 2 months after the placement of orthodontic appliances in 38 patients (17 male, 21 female). The tested substances were cobalt chloride, copper sulfate, potassium dichromate, iron sulfate, manganese chloride, molybdenum salt, nickel sulfate, and titanium oxide. Eight strips containing the test substances were positioned on the patients’ backs. They were removed after 48 hours and assessed by a dermatologist at 48 and 72 hours after antigen application. The obtained data were analyzed by the chi-square test and McNemar’s chi-square test. Statistically significant positive reactions were observed for nickel sulfate (21.1%), potassium dichromate (21.1%), and manganese chloride (7.9%); reactions to nickel sulfate had the greatest intensity. No differences were observed between the reactions before and after placement of the orthodontic appliances; this indicates that they did not sensitize the patients or affect their tolerance to these metals during the study period. No statistical difference was observed regarding sex for any evaluated substance, although a greater tendency to positivity to nickel sulfate was observed among female patients and to potassium dichromate in male patients. (Am J Orthod Dentofacial Orthop 2004;126:58-64) T here is increasing concern with the biocompatibility of dental materials; this might be due to a real increase in the frequency of allergic reactions to the materials or to an increase in awareness of adverse effects from these materials.1 Some metals commonly used in dental practice are known allergens,2 including nickel, cobalt, and chromium.3 Nickel is known to trigger more allergic reactions than all other metals combined.4 The literature includes some studies in which patch tests were used to evaluate the hypersensitivity reactions to nickel. Prystowsky et al5 evaluated a sample of 1158 adult volunteers and found that 5.8% had a positive reaction to 2.5% nickel sulfate (9% in women and 0.9% in men). There was a strong correlation between pierced ears, ear lesions, and areas of contact with jewelry. Among patients referred for clinical a Senior professor of orthodontics, Pontifical Catholic University of Rio Grande do Sul-PUCRS, Porto Alegre, Brazil. b Dermatologist, Department of Internal Medicine, Pontifical Catholic University of Rio Grande do Sul-PUCRS, Porto Alegre, Brazil. c Senior professor of orthodontics, State University of Rio de Janeiro-UFRJ. d Head of orthodontics, Federal University of Rio de Janeiro-UFRJ, Rio de Janeiro. This article is based on a thesis submitted by Dr Menezes in partial fulfillment of the degree of PhD, Division of Orthodontics, Faculty of Dentistry, Federal University of Rio de Janeiro/Brazil. Reprints requests to: Dr Luciane Macedo de Menezes, Rua Vicente da Fontoura, 2199/402, Santa Cecı́lia, Porto Alegre/RS CEP: 90.640-003, Brazil; e-mail, [email protected]. Financial support was received from Pronex/MEC. Submitted, March 2003; revised and accepted, May 2003. 0889-5406/$30.00 Copyright © 2004 by the American Association of Orthodontists. doi:10.1016/j.ajodo.2003.05.014 58 evaluation of contact dermatitis, 11% had a positive reaction to nickel.5 Blanco-Dalmau et al6 conducted a patch test to 5% nickel sulfate in 403 people (121 male, 282 female). The incidence of positive reaction in the study sample was 28.5%, with a remarkable difference between the sexes (31.9% of female subjects, compared with 20.7% of male subjects). El Agroudi et al2 evaluated 106 subjects (50 male, 56 female) for nickel sensitivity with patch tests. From the entire sample, 97 attended follow-up; 10.3% of these had positive outcomes (14.28% of the men, 6.25% of the women). The number of patients with positive results was not enough to explain the association with sex or age. Nevertheless, children and women had more positive responses to the test, which might be attributed to their having less keratinized skin. Stenman and Bergman1 performed patch tests in 151 patients (119 female, 32 male) with reported hypersensitivity to the components of dental materials or trinkets. Positive response to metals was observed in 42 patients (28% of the sample), whereas reaction to organic components was observed in 7 patients (4.6%). A positive reaction to nickel was found in 21 patients (14%), including 20 women and 1 man. Jones et al7 attempted to determine the incidence of nickel hypersensitivity with a patch tests in 100 patients (50 men, 50 women). The authors investigated the relationship between sex, age, and previous report of allergy to jewelry with hypersensitivity to this metal and found alterations in blood pressure, pulse, or temperature among patients with nickel hypersensitivity. Furthermore, by placing a removable appliance, the American Journal of Orthodontics and Dentofacial Orthopedics Volume 126, Number 1 Menezes et al 59 Fig 1. Stages of patch test: A, cleaning selected area with alcohol-soaked cotton; B, test substance being placed over strip; C, pads and strips in position on patient’s back; D, E, outlining areas with skin-marking pencil for reading of results. authors observed that nickel-hypersensitive patients were prone to demonstrate signs of hypersensitivity, at both the area of contact and distant areas. The authors found an incidence of hypersensitivity to nickel with the patch test of 20% for women and 2% for men. Contact with nickel by susceptible subjects can yield a wide range of hypersensitivity reactions,5 and it is one of the most common causes of contact dermatitis, especially among women.7-9 Epidemiologic data demonstrate that the number of people with sensitivity to nickel has increased to approximately 20%.6,7,9,10 Many materials used in dentistry can alter biologic activity when in contact with living tissue.11 However, relatively few studies have analyzed the organic response to other metals used in orthodontic appliances. The aim of this study was to evaluate hypersensitivity reactions to 8 metals used in orthodontic appliances (cobalt, copper, chromium, iron, manganese, molybdenum, nickel, and titanium) with patch tests, before and 2 months after placement of fixed orthodontic appliances, in a group of 38 patients. MATERIAL AND METHODS A total of 55 patients in need of orthodontic treatment were selected from the postgraduate ortho- dontic clinics for evaluation of hypersensitivity to 8 antigens. From this initial sample, 38 patients were included in the final sample (17 male, 21 female), aged 9 to 25 years. Patch tests were carried out before treatment and 2 months after placement of the fixed orthodontic appliances. All procedures related to the evaluation of hypersensitivity were supervised by a dermatologist. All patients or their guardians received information on the patch tests. Those who agreed to enroll in the study signed the consent form, which explained the test substances and the risks. The patients or their guardians completed a questionnaire especially designed for this study, which collected identification data for each patient as well as medical history, including clinical reports of allergy. Patch tests were done on the back,10,12,13 including the scapular and infrascapular areas, because it provides enough skin area to carry out many tests simultaneously.14 These test areas were previously examined by the dermatologist to ensure that the skin was normal12 with intact epithelium.7,13 The selected areas were cleaned with alcohol-soaked cotton (Fig 1, A). The test substances were 2% cobalt chloride, 5% copper sulfate, 0.5% potassium dichromate, 2% iron 60 Menezes et al American Journal of Orthodontics and Dentofacial Orthopedics July 2004 Fig 2. Reading of patch tests, according to result, score, reaction, and examples observed in study sample. sulfate, 1% manganese chloride, 1% molybdenum salt, 5% nickel sulfate, and 1% titanium oxide, which are some components of bands and brackets used in orthodontic practice. Two pieces of sterile, hypoallergenic, microporous adhesive tape,2 approximately 15 cm long, were prepared for each patient. Eight test strips were positioned, 4 on each piece of tape, 3 cm apart. The test substances were always applied in the same sequence and position (Fig 1, B and C). The pieces of adhesive with the test strips were then placed on each patient’s back and kept in contact with the skin for 48 hours,5,6,10,12,14-17 after which they were removed, and the skin was evaluated by the dermatologist. The patients were instructed to avoid moisture on the test area during the 48-hour study period2,6 and physical efforts or activities that might cause them to sweat or hurt the area. The patients were also instructed not to remove the material during this period, except in cases of extreme itch or pain,6 local irritation, intense discomfort, or fever.17 The first evaluation was carried out by the derma- tologist 48 hours after application of the patch test. The adhesive tape strips were removed, the residues cleaned off with alcohol,2 and the test areas outlined5 with a skin-marking pencil (Fig 1, D and E). To eliminate possible reading errors, such as temporary irritation caused by removing the adhesive strips,17 the test areas were read again 30 minutes later. After reading, the patients were discharged and instructed to avoid direct exposure to sunlight for approximately 1 hour. They were scheduled for follow-up appointments 24 hours later. The third and final evaluation was carried out 72 hours after placing the adhesive strips, and the results were then recorded on the forms. The purpose of the third evaluation was to distinguish doubtful reactions from mild positive results. In cases of true allergic reactions, an increase in the intensity of the response was expected. The tests were read according to International Research Contact Dermatitis Group guidelines: results were correlated with scores as shown in Figure 2. Scores 0 and 1 were considered negative, and scores 2, 3, and 4 were considered positive. In cases of high- Menezes et al 61 American Journal of Orthodontics and Dentofacial Orthopedics Volume 126, Number 1 Table I. Result of patch test, before and after placement of appliance, according to obtained score Percentage distribution of positivity for test substances, before and after placement of appliance, according to sex Table II. Score (no. patients) Substance Period Negative (0, 1) Positive (2-4) Cobalt Before After Before After Before After Before After Before After Before After Before After Before After 38 38 38 38 30 28 38 38 35 37 38 37 30 30 36 38 0 0 0 0 8 10 0 0 3 1 0 1 8 8 2 0 Copper Chromium Iron Manganese Molybdenium Nickel Titanium intensity positive reaction, topical treatment was initiated to relieve the symptoms, according to each case. After the first patch test had been carried out, patients were referred for placement of orthodontic appliances. Two months later, the patch tests were repeated on the patients with the same methodology. The results were evaluated with the chi-square and McNemar’s chi-square tests. RESULTS Results of the patch test of the 8 evaluated antigens (Tables I and II) demonstrated positive outcomes (scores 2-4) in the first evaluation for some substances, such as manganese (3 patients, 7.9%), chromium (8 patients, 21.1%), nickel (8 patients, 21.1%), and titanium (2 patients, 5.3%). Reactions to the 3 first substances (manganese, chromium, and nickel) were regarded as statistically significant. The other evaluated substances showed negative results (scores 0 and 1); that is, without cutaneous reaction or with doubtful reaction. Regarding the intensity of reaction, the first evaluation showed that nickel was the only substance to elicit more severe responses: 3 patients with a score of 3 and 1 patient with a score of 4 (Tables III and IV). Chromium, manganese, and nickel produced positive reactions in the 2 evaluated periods, both before and after placement of the appliance (chi-square test, Table II). These 3 substances were statistically evaluated with McNemar’s chi-square test. Nickel and chromium showed a tendency toward increase in positivity after placement of the appliance (Tables IV and V). For Sex (%) Substance Period Female Male Total (%) Cobalt Before After Before After Before After Before After Before After Before After Before After Before After 0.0 0.0 0.0 0.0 14.3 19.0 0.0 0.0 14.3 4.8 0.0 0.0 28.6 33.3 0.0 0.0 0.0 0.0 0.0 0.0 29.4 35.3 0.0 0.0 0.0 0.0 0.0 5.9 11.8 11.8 11.8 0.0 0.0 0.0 0.0 0.0 21.1 26.3 0.0 0.0 7.9 2.6 0.0 2.6 21.1 23.7 5.3 0.0 Copper Chromium Iron Manganese Molybdenium Nickel Titanium P (chi-square test) ** ** ** ** .426* .293* ** ** .238* 1.000* ** .447* .257* .148* .193* ** *P value for comparison between sexes. **Test could not be carried out because of absence of positivity. Distribution of data according to score of intensity of reaction to substances chromium, manganese, and nickel, before and after placement of orthodontic appliance Table III. Score Substance Period 0 1 2 3 4 Chromium Before After Before After Before After 19 16 33 34 26 21 11 12 2 3 4 8 8 9 3 1 4 6 0 1 0 0 3 1 0 0 0 0 1 2 Manganese Nickel Data are numbers of patients. Results of patch test carried out with nickel, before and after placement of orthodontic appliance, highlighting positive results Table IV. Results - before Results - after Negative (0, 1) Positive (2-4) Total Negative (0, 1) Positive (2–4) Total 27 2 29 3 6 9 30 8 38 Data are number of patients. McNemar’s chi-square test: P ⫽ 1.000. manganese, the inverse was observed, with a decrease in positivity in this period (Table VI). These outcomes were not statistically significant. Regarding the evaluation before placing the appli- 62 Menezes et al American Journal of Orthodontics and Dentofacial Orthopedics July 2004 Table V. Results of patch test carried out with chromium, before and after placement of orthodontic appliance, highlighting positive results Results - before Results - after Negative (0, 1) Positive (2-4) Total Negative (0, 1) Positive (2-4) Total 25 3 28 5 5 10 30 8 38 Data are number of patients. McNemar’s chi-square test: P ⫽ .727. Results of patch test carried out with manganese, before and after placement of orthodontic appliance, highlighting positive results Table VI. Results - before Results - after Negative (0, 1) Positive (2-4) Total Negative (0, 1) Positive (2-4) Total 35 2 37 0 1 1 35 3 38 Data are number of patients. McNemar’s chi-square test: P ⫽ .500. ance according to sex (Table II), no statistically significant differences were seen between men and women (chi-square test). A greater tendency toward positivity to chromium was observed among male patients (29.4%) than female patients (14.3%). There was a trend toward a higher positivity among female patients for manganese (14.3%, compared with 0% for male patients) and nickel (28.6%, compared with 11.8% for male patients). DISCUSSION Recently, there has been increasing concern about the biocompatibility of dental materials.1 There is special interest in the study of the reactions secondary to the use of certain metals in orthodontics, because they are known allergens.2 Austenitic stainless steel contains 18% chromium and 8% nickel.10,12,18-20 These metals are known worldwide as the most sensitizing agents.19 Other metals are also present in orthodontic appliances in different proportions. Thus, this study examined reactions to cobalt chloride, copper sulfate, potassium dichromate, iron sulfate, manganese chloride, molybdenum salt, and nickel sulfate (compounds in the orthodontic braces and bands used in this study), as well as titanium oxide, which has recently been used in the fabrication of brackets. The patch test is a routine and safe means of evaluating the response of cutaneous tissue to different substances.6,21 The tests were applied to 38 patients (17 male, 21 female, aged 9-25 years), before and 2 months after placing orthodontic appliances. The high sensitivity rates to chromium and nickel found in this study (21.1%), as shown in Table II, agree with the findings in the literature—that nickel is one of the most sensitizing agents worldwide.9,22,23 Chromium is the second most frequent metal to cause contact dermatitis.19 Contact with nickel is part of modern life, and, because of its widespread presence, reactions to nickel have been seen much more frequently in the general population, not only in nickel workers.24 The studies of Jones et al,7 McDonagh et al,8 Bass et al,9 and Kerusuo et al10 reported incidences of sensitivity to nickel very similar to that found in the present study, which was 21.1%. Nickel was the only substance to provoke severe responses (Table III, Fig 2). This result agrees with the proposal that several metals might trigger allergies, yet none can compare with nickel for the extent and proportion of problems produced.25 The outcomes in the literature regarding hypersensitivity to nickel are quite variable, with a relatively high distribution in the population and higher frequency among female subjects; this was also noticed in this study: women were affected almost twice as often as men (Table II). According to Tsalen and Zaprianov,26 sensitivity to nickel is 3 to 5 times more common in women than in men. The studies carried out by Prystowsky et al,5 Jones et al,7 and Kerusuo et al10 showed this difference to be up to 10 times greater among female subjects. This is probably associated with the use of earrings5-8,10,16,27 and other jewelry.5,6,28 Some of these objects are covered by a chromium foil and a sublayer of nickel, which is 100 times thicker than the overlayer of chromium. Similarly, some jewelry is made of a thin layer of gold. The lack of continuity in the layer of chromium or gold allows for the dissolution of the underlying nickel by transpiration, bringing about dermatitis in subjects with hypersensitivity to this metal.24 According to Suzuki,27 small metallic fragments (gold, silver, copper, or nickel) remain within the ear skin, even after the removal of pierced earrings and thus cause prolonged irritation and several cutaneous reactions, such as contact dermatitis. No male patient in the present sample had a pierced ear or a report of contact allergy; 18 of 21 female patients had pierced ears, and 4 reported allergies to earrings and trinkets. Contact with such accessories usually starts earlier among girls than boys, with a longer exposure time. This might explain the difference observed between the sexes, with a higher prevalence for women. Olumide29 carried out a study in Nigeria, where the use of trinkets is similar for men and women, and found no differences in the prevalence of sensitiv- Menezes et al 63 American Journal of Orthodontics and Dentofacial Orthopedics Volume 126, Number 1 ity to nickel. The use of earrings or trinkets by men is much less frequent in other countries where sensitivity studies were done; this might explain the smaller number of positive reactions observed for male subjects; this was also seen in this study. Chromium, manganese, and nickel caused positive reactions in both study periods (Tables I and II). These results were not statistically significant, indicating that the orthodontic appliances did not sensitize the patients to nickel or any other metal; this agrees with the findings of Kerusuo et al10 and Janson et al.17 Yet these outcomes do not agree with those reported by Bass et al9 and Lenza et al,30 who claimed that orthodontic treatment can induce sensitivity to nickel. Our results also disagree with those of Vreeburg et al,31 who studied oral administration of nickel-chromium in animals and found induced partial tolerance to both. Thus, the hypothesis that the use of orthodontic appliances might be beneficial also could not be demonstrated in the present study. In addition to an understanding of the physical, mechanical, and chemical properties of dental materials, orthodontists should also know the biological responses triggered by these materials in live tissues. Many materials used in dentistry can affect biologic activity.11 CONCLUSIONS This study produced the following findings: 1. Statistically significant positive reactions to nickel sulfate (21.1%), potassium dichromate (21.1%), and manganese chloride (7.9%) occurred. The reactions to nickel sulfate were the most intense. 2. No statistically significant difference in relation to the use of orthodontic appliances (before and after) was found, indicating that the appliance did not sensitize the patients or affect tolerance to these metals during the study period. 3. No statistical difference was observed in relation to sex for any evaluated substance. Yet greater tendencies were observed among the female patients for positivity to nickel sulfate and among the male patients for potassium dichromate. We thank Professor Ronir Raggio Luiz, Federal University of Rio de Janeiro, for statistical analysis and Dr Orlando Chevitarese, Professor Emeritus, Federal University of Rio de Janeiro, for providing an example of a competent, restless, dedicated, and serious researcher. REFERENCES 1. Stenman E, Bergman M. Hypersensitivity reactions to dental materials in a referred group of patients. Scand J Dent Res 1989;97:76-83. 2. El Agroudi AMM, El Motayam KM, Awad HA. Allergic reaction to nickel. Egyptian Dent J 1986;32:101-7. 3. Munksgaard EC. Toxicology versus allergy in restorative dentistry. Adv Dent Res 1992;6:17-21. 4. Moffa JP, Beck WD, Hoke AW. Allergic response to nickel containing dental alloys. J Dent Res 1977;56:78. 5. Prystowsky SD, Allen AM, Smith RW, Noomura JH, Odom RB, Akers WA. Allergic contact hypersensitivity to nickel, neomycin, ethylenediamine and benzocaine. Arch Dermatol 1979;115: 959-62. 6. Blanco-Dalmau L, Carrasquillo-Alberty H, Silva-Parra J. 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