Download Hypersensitivity to metals in orthodontics

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. A
study of nickel allergy. J Prosthet Dent 1984;52:116-9.
7. Jones TK, Hansen CA, Singer MT, Kessler HP. Dental implications of nickel hypersensitivity. J Prosthet Dent 1996;56:507-9.
8. McDonagh AJG, Wright AL, Cork MJ, Gawkrodger DJ. Nickel
sensitivity: the influence of ear piercing and atopy. Br J Dermatol
1992;126:16-8.
9. Bass JK, Fine H, Cisneros GJ. Nickel hypersensitivity in the
orthodontic patient. Am J Orthod Dentofacial Orthop 1993;103:
280-5.
10. Kerusuo H, Kullaa A, Kerusuo E, Kanerva L, Hensten-Petersen
A. Nickel allergy in adolescents in relation to orthodontic
treatment and piercing of ears. Am J Orthod Dentofacial Orthop
1996;109:148-54.
11. O’Brien WJ. Dental materials: properties and selection. Chicago:
Quintessence; 1989.
12. Skoglund A, Torbjörn E. Hypersensitivity reactions to dental
materials in patients with lichenoid oral mucosal lesions and in
patients with burning syndrome. Scand J Dent Res 1991;99:
320-8.
13. Van Hoogstraten IMW, Andersen KE, Von Blomberg BME,
Boden D, Bruynzeel DP, Burrows D, et al. Reduced frequency of
nickel allergy upon oral nickel contact at an early age. Clin Exp
Immunol 1991;85:441-5.
14. Margarido-Marchese L. Revisão de tema alopecia aguda por
cosmético. Ciladerma. Rev Ibero Latino Am Dermatol 1998;3:
5-15.
15. Magnusson B, Bergman M, Bergman B, Soremark R. Nickel
allergy and nickel-containing dental alloys. Scand J Dent 1982;
90:163-7.
16. Feasby WH, Ecclestone ER, Grainger RM. Nickel sensitivity in
pediatric dental patients. Pediatr Dent 1998;10:127-9.
17. Janson GRP, Dainesi EA, Consolaro A, Woodside G, Freitas
MR. Nickel hypersensitivity reaction before, during, and after
orthodontic therapy. Am J Orthod Dentofacial Orthop 1998;113:
655-60.
18. Bishara SE, Barret RD, Selim MI. Biodegradation of orthodontic
appliances and their effect on the blood level of nickel. J Dent
Res 1993;72:368.
19. Park HY, Shearer TR. In vitro release of nickel and chromium
from simulated orthodontic appliances. Am J Orthod Dentofacial
Orthop 1983;84:156-9.
20. Barret RD, Bishara SE, Quinn JK. Biodegradation of orthodontic
appliances. Part I. Biodegradation of nickel and chromium in
vitro. Am J Orthod Dentofacial Orthop 1993;103:8-14.
21. Valyasevi MA, Maddox DE, Li JTC. Systemic reactions to
allergy skin tests. Ann Allergy Asthma Immunol 1999;83:132-6.
22. Silvennoinen-Kassinen S, Ikäheimo I, Karvonen J, Kauppinen
M, Kallioinen M. Mononuclear cell subsets in the nickel-allergic
64 Menezes et al
23.
24.
25.
26.
27.
reaction in vitro and in vivo. J Allergy Clin Immunol 1992;89:
794-800.
Lisby S, Hansen LH, Skov L, Menné T. Nickel-induced activation of T cells in individuals with negative test patch test to
nickel sulphate. Arch Dermatol Res 1999;291:247-52.
Council on Dental Materials, Instruments and Equipment. Biological effects of nickel-containing dental alloys. J Am Dental
Assoc 1982;104:501-5.
Matasa C. Trend: good bye Ni, welcome Co, Mn. Orthod Mat
Insider 1995;8:1-6.
Tsalen DL, Zaprianov ZK. Atomic absortion spectrometry in
occupational and environmental health practice. Boca Raton
(Fla): CRC Press; 1983.
Suzuki H. Nickel and gold in skin lesions of pearced earlobes
American Journal of Orthodontics and Dentofacial Orthopedics
July 2004
28.
29.
30.
31.
with contact dermatitis. A study using scanning electron microscopy and x-ray microanalysis. Arch Dermatol Res 1998;290:
523-7.
Wolfaardt JF, Peters E. The base metal alloy question in
removable partial dentures—a review of the literature and a
survey of alloys in use in Alberta. J Can Dent Assoc 1992;58:
146-51.
Olumide YM. Contact dermatitis in Nigeria. Contact Dermatitis
1985;12:129-35.
Lenza MA, Moore RN, Cohen DM, Hoffman M. Nickel sensitivity to orthodontic archwires. J Dent Res 1993;72:368.
Vreeburg KJ, Groot K, Von Blomberg M, Scheper RJ. Induction
of immunological tolerance by oral administration of nickel and
chromium. J Dent Res 1984;63:124-8.