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Tooth Bleaching—a Critical Review of the Biological Aspects

Article  in  Critical reviews in oral biology and medicine: an official publication of the American Association of Oral Biologists · February 2003
DOI: 10.1177/154411130301400406 · Source: PubMed

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TOOTH BLEACHING—A CRITICAL REVIEW
OF THE BIOLOGICAL ASPECTS
J.E. Dahl*
NIOM-Scandinavian Institute of Dental Materials, Kirkeveien 71B, PO Box 70, N-1305 Haslum, Norway; *corresponding author, [email protected]

U. Pallesen
Institute of Odontology, Faculty of Health Sciences, University of Copenhagen, Denmark

ABSTRACT: Present tooth-bleaching techniques are based upon hydrogen peroxide as the active agent. It is applied directly,
or produced in a chemical reaction from sodium perborate or carbamide peroxide. More than 90% immediate success has been
reported for intracoronal bleaching of non-vital teeth, and in the period of 1-8 years' observation time, from 10 to 40% of the ini-
tially successfully treated teeth needed re-treatment. Cervical root resorption is a possible consequence of internal bleaching and
is more frequently observed in teeth treated with the thermo-catalytic procedure. When the external tooth-bleaching technique
is used, the first subjective change in tooth color may be observed after 2-4 nights of tooth bleaching, and more than 90% satis-
factory results have been reported. Tooth sensitivity is a common side-effect of external tooth bleaching observed in 15%-78%
of the patients, but clinical studies addressing the risk of other adverse effects are lacking. Direct contact with hydrogen perox-
ide induced genotoxic effects in bacteria and cultured cells, whereas the effect was reduced or abolished in the presence of
metabolizing enzymes. Several tumor-promoting studies, including the hamster cheek pouch model, indicated that hydrogen
peroxide might act as a promoter. Multiple exposures of hydrogen peroxide have resulted in localized effects on the gastric
mucosa, decreased food consumption, reduced weight gain, and blood chemistry changes in mice and rats. Our risk assessment
revealed that a sufficient safety level was not reached in certain clinical situations of external tooth bleaching, such as bleach-
ing one tooth arch with 35% carbamide peroxide, using several applications per day of 22% carbamide peroxide, and bleaching
both arches simultaneously with 22% carbamide peroxide. The recommendation is to avoid using concentrations higher than
10% carbamide peroxide when one performs external bleaching. We advocate a selective use of external tooth bleaching based
on high ethical standards and professional judgment.

Key words. Enamel, esthetics, ethics, toxicology.

(I) Introduction (II) History of Bleaching

T ooth discoloration varies in etiology, appearance, localiza-

tion, severity, and adherence to tooth structure. It may be
classified as intrinsic, extrinsic, and a combination of both
Bleaching of discolored, pulpless teeth was first described in
1864 (Truman, 1864), and a variety of medicaments such as chlo-
ride, sodium hypochlorite, sodium perborate, and hydrogen
(Hattab et al., 1999). Intrinsic discoloration is caused by incorpo- peroxide has been used, alone, in combination, and with and
ration of chromatogenic material into dentin and enamel during without heat activation (Howell, 1980). The "walking bleach"
odontogenesis or after eruption. Exposure to high levels of fluo- technique that was introduced in 1961 involved placement of a
ride, tetracycline administration, inherited developmental disor- mixture of sodium perborate and water into the pulp chamber
ders, and trauma to the developing tooth may result in pre-erup- that was sealed off between the patient's visits to the clinician
tive discoloration. After eruption of the tooth, aging, pulp necro- (Spasser, 1961). The method was later modified and water
sis, and iatrogenesis are the main causes of intrinsic discol- replaced by 30-35% hydrogen peroxide, to improve the whiten-
oration. Coffee, tea, red wine, carrots, oranges, and tobacco give ing effect (Nutting and Poe, 1963). The observation that car-
rise to extrinsic stain (Hattab et al., 1999; Watts and Addy, 2001). bamide peroxide caused lightening of the teeth was made in the
Wear of the tooth structure, deposition of secondary dentin due late 1960s by an orthodontist who had prescribed an antiseptic
to aging (Watts and Addy, 2001) or as a consequence of pulp containing 10% carbamide peroxide to be used in a tray for the
inflammation, and dentin sclerosis affect the light-transmitting treatment of gingivitis (Haywood, 1991). The observation was
properties of teeth, resulting in a gradual darkening of the teeth. communicated to other colleagues and must be regarded as the
Scaling and polishing of the teeth remove many extrinsic beginning of the night guard bleaching era. More than 20 years
stains. For more stubborn extrinsic discoloration and intrin- later, the method describing the use of 10% carbamide peroxide
sic stain, various bleaching techniques may be attempted. in a mouth guard to be worn overnight for lightening tooth
Tooth bleaching can be performed externally, termed night color was published (Haywood and Heymann, 1989).
guard vital bleaching or vital tooth bleaching, or intracoro-
nally in root-filled teeth, called non-vital tooth bleaching. The (III) Medicaments
aims of the present paper are to review critically the litera- Tooth bleaching today is based upon hydrogen peroxide (CAS
ture on the biological aspects of tooth bleaching, including No 7722-84-1) as the active agent. Hydrogen peroxide may be
efficacy and side-effects of such treatments. In addition, the applied directly, or produced in a chemical reaction from sodi-
safety of vital tooth bleaching is especially addressed. um perborate (CAS No. 7632-04-4) (Hägg, 1969) or carbamide

292 Crit Rev Oral Biol Med 14(4):292-304 (2003)

peroxide (CAS No. 124-43-6) (Budavari et al., 1989) (Fig. 1).
Hydrogen peroxide acts as a strong oxidizing agent through the
formation of free radicals (Gregus and Klaassen, 1995), reactive
oxygen molecules, and hydrogen peroxide anions (Cotton and
Wilkinson, 1972) (Fig. 1). These reactive molecules attack the
long-chained, dark-colored chromophore molecules and split
them into smaller, less colored, and more diffusible molecules.
Carbamide peroxide also yields urea (Budavari et al., 1989) that
theoretically can be further decomposed to carbon dioxide and
ammonia. It is unclear, however, how much ammonia is formed
during tooth bleaching with carbamide peroxide. The high pH
of ammonia facilitates the bleaching procedure (Sun, 2000). This
can be explained by the fact that, in a basic solution, lower acti-
vation energy is required for the formation of free radicals from
hydrogen peroxide, and the reaction rate is higher, resulting in
an improved yield compared with an acidic environment
(Cotton and Wilkinson, 1972). The outcome of the bleaching
procedure depends mainly on the concentration of the bleach-
ing agent, the ability of the agent to reach the chromophore mol-
ecules, and the duration and number of times the agent is in
contact with chromophore molecules.
Figure 1. The formation of hydrogen peroxide from sodium perbo-
(IV) Non-vital Tooth Bleaching rate (Eq. 1) (Hägg, 1969) and from carbamide peroxide (Eq. 2)
(Budavari et al., 1989). Hydrogen peroxide forms free radicals like
(IV-1) METHODS hydroxyl and perhydroxyl radicals, and superoxide anions (Eq. 3a)
(Gregus and Klaassen, 1995), reactive oxygen molecules that are
Intracoronal bleaching is a conservative alternative to the more unstable and transformed to oxygen (Eq. 3b) (Cotton and Wilkinson,
invasive esthetic treatment of non-vital discolored teeth. 1972), and hydrogen peroxide anions (Eq. 3c) (Cotton and
Careful examination is necessary, since the method requires Wilkinson, 1972).
healthy periodontal tissues and a root canal that is properly
obturated to prevent the bleaching agent from reaching the
periapical tissues (Baratieri et al., 1995). Both
hydrogen peroxide and sodium perborate
have been used, and various heat sources
have been applied to speed up the reaction
and improve the bleaching effect (Howell,
1980). A combination of sodium perborate
and water (Spasser, 1961; Holmstrup et al.,
1988) or hydrogen peroxide (Nutting and
Poe, 1963) has been used in the "walking
bleach" technique. The medicament is placed
in the pulp chamber, sealed, left for 3-7 days,
and is thereafter replaced regularly until
acceptable lightening is achieved. If the tooth
has not responded satisfactorily after 2-3
treatments, the "walking bleach" technique
can be supplemented with an in-office
bleaching procedure (Baratieri et al., 1995).
The treatment may continue until an accept-
able result is obtained (Fig. 2). A modification
of the method that reduces the number of in-
office appointments has been suggested
(Liebenberg, 1997; Caughman et al., 1999). Figure 2. Non-vital tooth bleaching of a discolored tooth in a 21-year-old woman. The
Access to the pulp chamber is gained by tooth had been endodontically treated 6 yrs earlier due to trauma. A slight discoloration,
removal of the coronal restoration and the which subsequently became more intense, was visible immediately after the endodontic
coronal part of the root filling. The remaining treatment. (A) Tooth #11 with a dark blue discoloration. (B) The result after 3 wks of inter-
root filling is sealed off with glass-ionomer nal bleaching with sodium perborate suspended in water and a weekly change of bleach-
ing agent. (C) 5 yrs after internal bleaching. Only slight discoloration is visible, and no re-
cement. The patient places the bleaching
treatment was necessary. (D) 10 yrs after internal bleaching. Recurrence of the discol-
agent, usually 10% carbamide peroxide, oration is visible, and the patient needed re-treatment. The relapse after 10 yrs, however,
intracoronally at regular intervals and covers was not as severe as the discoloration before bleaching, and the tooth could be re-
the lingual aspect of the tooth with a plastic bleached to a satisfying result. Although intercoronal bleaching does not have—as do
splint. In this method, the pulp chamber is most other treatments—indefinite durability, the long-term aesthetic and biological results
left unsealed during the weeks of treatment. of this treatment are considered to be of high quality.

14(4):292-304 (2003) Crit Rev Oral Biol Med 293

 obtained with sodium perborate in water (53% recovered) (Ho
and Goerig, 1989). Artificially stained extracted teeth were used
for comparison of the outcome of the "walking bleach" method
(sodium perborate in 35% hydrogen peroxide), the thermo-cat-
alytic method (heating a pellet soaked with 35% hydrogen per-
oxide), and a combination of the two methods (Freccia et al.,
1982). No difference was observed between the bleaching
methods used. The immediate results after intracoronal bleach-
ing with 10% carbamide peroxide were better than those with
sodium perborate in 30% hydrogen peroxide (Vachon et al.,
1998). The final outcome after 3 treatments over 14 days was
beneficial with sodium perborate in 30% hydrogen peroxide,
but none of the teeth attained their initial shade (Vachon et al.,
1998). The conclusion of the above in vitro studies was that
sodium perborate in water, sodium perborate in 3 and 30%
hydrogen peroxide, and 10% carbamide peroxide were efficient
for internal bleaching of non-vital teeth. It must be taken into
consideration, however, that the conclusion is based on artifi-
cially stained teeth and that the clinical situation may give dif-
ferent results.
(IV-3) ESTHETIC RESULTS
The evaluation of the esthetic outcome of a bleaching treatment
is subjective, and the patient's opinion may differ from that of
the dental surgeon (Glockner et al., 1999). In addition, different
terms and definitions of the outcomes have been applied which
make comparisons between studies difficult (Friedman et al.,
Figure 3. External root resorption after internal bleaching of teeth 1988; Holmstrup et al., 1988; Glockner et al., 1999). Immediate
#11 and #21. Both teeth had been endodontically treated due to
treatment success has usually been defined as no or slight devi-
caries 14 yrs earlier. No history of trauma was reported. Two years
after endodontic treatment, both teeth were internally bleached by ation in color between the treated and non-treated teeth. More
sodium perborate and 3% hydrogen peroxide. Due to an unsatisfac- than 90% immediate success has been reported with the ther-
tory bleaching result after 3 wks, the treatment was supplemented mo-catalytic method (Howell, 1980) or the conventional "walk-
with in-office bleaching with 30% hydrogen peroxide and heat two ing bleach" procedure (Holmstrup et al., 1988). The failure rate
times for 30 min each, with an interval of one week. External root may be useful in determing the long-term esthetic results of
resorption was diagnosed 12 yrs later. internal bleaching. Failure, however, has not been defined in
the different long-term studies (Brown, 1965; Friedman et al.,
1988; Holmstrup et al., 1988; Glockner et al., 1999), but the intu-
itive definition is "teeth that need to be re-treated". The need for
re-treatment increased with the observation time, i.e., 10% after
If the seal of the root-filling leaks, contamination of the peri- 1 to 2 years (Friedman et al., 1988), 20-25% after 3 to 5 years
apical tissue may lead to endodontic treatment failure, the (Brown, 1965; Holmstrup et al., 1988), and 40% failure in teeth
residual bleaching agent will be ingested due to insufficient observed up to 8 years (Friedman et al., 1988). In a more recent
rinse of the sticky gel, and intracoronal dentin will be subject to study, a 7% failure rate was reported after 5 years, but the
discoloration from pigments in foods or beverages. The chair majority of cases in this study were defined as ideal for bleach-
time saved with this bleaching method does not compensate ing (no other filling than the palatinal endodontic opening)
for the adverse biological consequences. (Glockner et al., 1999). A study of endodontically treated, inter-
nally bleached tetracycline-stained teeth that were followed for
(IV-2) EFFICACY 3-15 years showed that four out of 20 patients needed re-treat-
The efficacy of the different medicaments used for internal ment (Abou-Rass, 1998). At present, no study has provided a
tooth bleaching has been evaluated in vitro on artificially good predictor for the long-term outcome of internal bleaching.
stained teeth. After 14 days (Rotstein et al., 1991c) and one year It appears that teeth with multiple fillings are not ideal candi-
(Rotstein et al., 1993), there was no difference in the shade of the dates for the procedure (Howell, 1980; Glockner et al., 1999).
teeth bleached with sodium perborate in 30% hydrogen perox-
ide, sodium perborate in 3% hydrogen peroxide, or sodium (IV-4) ADVERSE EFFECTS
perborate in water. Concurring results were found in a study Cervical root resorption (Fig. 3) is an inflammatory-mediated
with sodium perborate mixed with 30% hydrogen peroxide or external resorption of the root, which can be seen after trauma
water and evaluated after 7, 14, and 21 days of treatment (Ari and following intracoronal bleaching (Friedman et al., 1988). A
and Üngör, 2002). Increased lightening of the teeth was review of published case reports on cervical root resorption
observed with longer bleaching time, but otherwise no differ- revealed 22 such cases following intracoronal bleaching (Table
ence was reported. The results with sodium perborate in 30% 1). Table 1 summarizes the results of 4 follow-up studies. Fifty-
hydrogen peroxide (93% of the artificially stained and bleached eight bleached (30% H2O2 and heated) pulpless teeth were fol-
teeth recovered their initial shade) were better than those lowed for 1-8 years, and 4 cases (7%) of external root resorption

294 Crit Rev Oral Biol Med 14(4):292-304 (2003)

TABLE 1
Internal Tooth Bleaching and Cervical Root Resorption

Bleaching Observation No. of No. of Cervical

Type of Study Procedure Time Patients Teeth Trauma Resorption Reference

Case report WBa 2 teeth 2 teeth all teeth Latcham, 1986, 1991
Case report WBb 1 tooth 1 tooth all teeth Goon et al., 1986
Case report WB+TCc 18 teeth 15 teeth all teeth Harrington and Natkin, 1979;
Lado et al., 1983; Cvek and
Lindvall, 1985; Gimlin and
Schindler, 1990; Al-Nazhan, 1991
Follow-upd WBe 3-15 yrs 20 112 No 0% Abou-Rass, 1998
Follow-upd WBf 4 yrs 31 248 No 0% Anitua et al., 1990
Follow-up WBg 3 yrs 86 95 96% 0% Holmstrup et al., 1988
Follow-up WB, TC, WB+TCh 1-8 yrs 46 58 38%i 6.9% Friedman et al., 1988

a WB = "walking bleach" technique with H2O2.

b WB = "walking bleach" technique with NaBO3 + 30% H2O2.
c WB+TC = "walking bleach" technique (NaBO3 + 30% H2O2) combined with thermo catalytic treatment.
d Tetracycline-discolored, intentionally endodontically treated teeth.
e WB = "walking bleach" technique with NaBO3 + 30% H2O2 replaced once a week.
f WB = "walking bleach" technique with NaBO3 + oxygen-water (conc. not given).
g WB = "walking bleach" technique with NaBO3 replaced every 10-15 days.
h WB = "walking bleach" technique with 30% H2O2 (cervical resorption, 5.0%); TC = thermo catalytic treatment with 30% H2O2 and heat (cervical resorp-
tion, 7.6%); WB+TC = combination of the two previously mentioned techniques (cervical resorption, 8.0%).
i No history of trauma in teeth with cervical resorption.

were observed (Friedman et al., 1988). Another 95 teeth exam- with cervical defects of the cementum constitutes a risk factor
ined three years after treatment by the "walking bleach" tech- for the development of cervical resorption. In addition, efficacy
nique (sodium perborate in water) revealed no cervical resorp- studies have shown that 30% hydrogen peroxide was not essen-
tion (Holmstrup et al., 1988). In a four-year follow-up of 250 tial to the attainment of an acceptable treatment outcome.
teeth with severe tetracycline discoloration, with sodium perbo- Tooth crown fracture has also been observed after intra-
rate in oxygen-water as the bleaching agent, no evidence of coronal bleaching (Grevstad, 1981), most probably due to
external resorption was found (Anitua et al., 1990). An analo- extensive removal of the intracoronal dentin. In addition, intra-
gous study comprised of 112 teeth bleached with a paste of sodi- coronal bleaching with 30% hydrogen peroxide has been found
um perborate in 30% hydrogen peroxide and observed for 3-15 to reduce the micro-hardness of dentin and enamel (Lewinstein
years reported no external root resorption (Abou-Rass, 1998). et al., 1994) and weaken the mechanical properties of the dentin
A high concentration of hydrogen peroxide in combination (Chng et al., 2002).
with heating seemed to promote cervical root resorption
(Friedman et al., 1988; Baratieri et al., 1995), in line with obser- (V) External Tooth Bleaching
vations made in animal experiments (Madison and Walton,
1990; Rotstein et al., 1991b; Heller et al., 1992). The underlying
mechanism for this effect is unclear, but it has been suggested
(V-1) METHODS
that the bleaching agent reaches the periodontal tissue through Vital tooth bleaching can be performed at home and in-office.
the dentinal tubules and initiates an inflammatory reaction Four different approaches for tooth whitening have been rec-
(Cvek and Lindvall, 1985). It has also been speculated that the ognized and reviewed by Barghi (1998): (1) dentist-adminis-
peroxide, by diffusing through the dentinal tubules, denatures tered bleaching—the use of a high concentration of hydrogen
the dentin, which then becomes an immunologically different peroxide (from 35 to 50%) or carbamide peroxide (from 35 to
tissue and is attacked as a foreign body (Lado et al., 1983). 40%), often supplemented with a heat source; (2) dentist-super-
Frequently, the resorption was diagnosed several years after the vised bleaching—by means of a bleaching tray loaded with
bleaching (Lado et al., 1983; Friedmann et al., 1988). In vitro stud- high concentrations of carbamide peroxide (from 35 to 40%)
ies using extracted teeth showed that hydrogen peroxide placed that is placed in the patient's mouth for 30 min to 2 hrs while
in the pulp chamber penetrated the dentin (Rotstein, 1991) and the patient is in the dental office; (3) dentist-provided bleach-
that heat increased the penetration (Rotstein et al., 1991d). The ing—known as "at-home" or "night-guard" bleaching and
penetration has been found, in vitro, to be higher in teeth with administered by the patient applying from 5 to 22% solution of
cervical defects of the cementum (Rotstein et al., 1991a). carbamide peroxide in a custom-made tray; and (4) over-the-
Hydrogen peroxide also increased dentin permeability (Heling counter products, often based on carbamide peroxide or hydro-
et al., 1995), and that may enhance the effects of hydrogen per- gen peroxide of various concentrations and placed in a pre-fab-
oxide following repeated exposures. Based on the cited litera- ricated tray, or by the recently introduced strips (Gerlach, 2000),
ture, the use of a thermo-catalytic bleaching procedure in teeth both to be adjusted by the user.

14(4):292-304 (2003) Crit Rev Oral Biol Med 295

 of the 38 patients experienced some lightening of
the treated teeth (Haywood et al., 1994). The
patients were followed up by mailed question-
naires, and 74% of the 26 respondents and 62% of
the 23 respondents experienced no or slight
reversal in color after 1.5 and 3 years, respective-
ly. A follow-up of 30 patients whose teeth were
bleached with 10% carbamide peroxide revealed
that 43% perceived their tooth color as stable 10
yrs after bleaching (Ritter et al., 2002). Another
clinical trial examined the effects of the use of
Figure 4. External at-home bleaching of discolored teeth in a 13-year-old girl diag- 10% carbamide peroxide nightly for 2 wks, and
nosed with amelogenesis imperfecta. (A) Before treatment, an intense yellowish dis-
coloration of all teeth was visible. Pigments from foods and beverages had penetra-
found, on an average, that the teeth were eight
ted the hypomineralized enamel. (B) The result after dentist-guided at-home bleach- shade units lighter on the Vita shade guide, cali-
ing of the maxillary anterior teeth (#14, 13, 12, 11, 21, 22, 23, 24) with 10% car- brated according to lightness value (Swift et al.,
bamide peroxide twice daily for 30 min each and for two consecutive weeks. The yel- 1999). Two years' follow-up revealed that the
lowish discoloration was eliminated in the bleached teeth. teeth, on average, darkened two units on this
shade guide, and that the regression occurred
during the first 6 months after bleaching. No
patients found it necessary to re-bleach their
teeth. Use of 20% carbamide peroxide resulted in
lighter teeth than with 7.5% hydrogen peroxide
when evaluated immediately after termination
of a 14-day at-home bleaching procedure
(Mokhlis et al., 2000). However, no difference
between the two treatments with regard to tooth
lightness was observed 10 wks later. In a small
study which compared bleaching strips and 10%
carbamide peroxide in trays, it was claimed that
the bleaching strips were more efficient (Sagel et
al., 2002), but others have not confirmed this
finding, and there are no long-term follow-up
data on this issue.

(V-3) LOCAL SIDE-EFFECTS

Tooth sensitivity
Tooth sensitivity is a common side-effect of
Figure 5. External in-office bleaching of teeth #11 and #21 in a 52-year-old woman. external tooth bleaching (Tam, 1999b) (Table 2).
(A) Both teeth had become discolored in the mesial part after restoration of small Class Data from various studies of 10% carbamide per-
II cavities with composite resin material 20 years previously. This is a known side- oxide indicate that from 15 to 65% of the patients
effect of some of the first-introduced composite materials. Replacement of the restora- reported increased tooth sensitivity (Haywood et
tions with a new composite material did not remove the discoloration located in the
al., 1994; Schulte et al., 1994; Leonard et al., 1997;
surrounding dentin and enamel. (B) The result after external in-office bleaching with
35% hydrogen peroxide and heat (from two light-curing units) twice and for 30 min Tam, 1999a). Higher incidence of tooth sensitivi-
each with an interval of one week. Although the restorations were not removed dur- ty (from 67 to 78%) was reported after in-office
ing treatment, an acceptable result was obtained. (C) The result 4 yrs after bleaching. bleaching with hydrogen peroxide in combina-
Only slight relapse was visible. (D) 8 yrs after bleaching. A moderate recurrence of tion with heat (Cohen and Chase, 1979;
discoloration is visible, but the patient did not need re-treatment. Nathanson and Parra, 1987). Tooth sensitivity
normally persists for up to 4 days after the cessa-
tion of bleaching treatment (Cohen and Chase,
1979; Schulte et al., 1994), but a longer duration of
(V-2) EFFICACY AND ESTHETIC RESULTS up to 39 days has been reported (Leonard et al., 1997; Tam,
Data on the efficacy and duration of external tooth bleaching 1999a). In a clinical study that compared two different brands
are mostly related to case presentations, and only a few clinical of 10% carbamide peroxide bleaching agent, 55% of the 64
studies are available for review. It is generally advocated that patients reported tooth sensitivity and/or gingival irritation,
most teeth are susceptible to bleaching (Figs. 4, 5), provided and 20% of those who experienced side-effects terminated the
that the treatment is carried out for a sufficiently long time treatment due to discomfort (Leonard et al., 1997).
(Haywood, 1996; Goldstein, 1997; Heymann, 1997; Dunn, 1998; The mechanisms that would account for the tooth sensitiv-
Leonard, 1998). The first subjective change in tooth color was ity after external tooth bleaching have not yet been fully estab-
observed after 2-4 nights of tooth bleaching with 10% car- lished. In vitro experiments have shown that peroxide pene-
bamide peroxide (Tam, 1999a). In a clinical study of night- trated enamel and dentin and entered the pulp chamber
guard vital bleaching for 6 wks (10% carbamide peroxide), 92% (Thitinanthapan et al., 1999), and that the penetration of

296 Crit Rev Oral Biol Med 14(4):292-304 (2003)

TABLE 2
External Tooth Bleaching and Hypersensitivity Reactions

Incidence of
Type of Duration No. of Treated No. of Untreated Hypersensitivity
Treatment Bleaching Procedure of Study Patients Controls Reactions Reference

In-office 30% H2O2 + heat, 3 visits 30 days 19 0 78% Cohen and Chase, 1979
of 30 min during 3 wks
In-office 35% H2O2 + heat, 2-6 visits nia 15 0 67% Nathanson and Parra, 1987
of 30 min
At-home 10% carbamide peroxide, 28 days 28 0 15%b Schulte et al., 1994
2 hrs or overnight
At-home 10% carbamide peroxide, 14 days 24 0 64% Tam, 1999a
overnight
At-home 10% carbamide peroxide, 6 wks 37 0 38% Leonard et al., 1997
day or night
At-home 10% carbamide peroxide, 6 wks 38 0 52% Leonard et al., 1997
6-8 hrs/day with
solution changes
At-home 10% carbamide peroxide, 6 wks 27 0 78%c Leonard et al., 1997
day + night or day with
solution changes
a ni = no information given.
b These patients terminated the study due to hypersensitivity, and there is no information about hypersensitivity reactions in the patients who completed the
treatment.
c The duration of symptoms was also longer in this group where the solution was changed compared with the group treated daytime or night time without
the solution being changed.

restored teeth was higher than that of intact teeth (Gökay et al., days after the treatment (Seale et al., 1981). In another study,
2000). The amount of peroxide detected in the pulp chamber 1 5 - , 30-, and 45-minute treatments with hydrogen peroxide
was related to the concentration of hydrogen peroxide in the and heat were applied 4 times at two-week intervals, and the
preparations applied (Gökay et al., 2000), and also varied dogs were killed at 13, 62, and 92 days following the last treat-
among different brands of bleaching agents with the same ment (Seale and Wilson, 1985). Histological examination of the
declared concentration of carbamide peroxide (Thitinanthapan pulp of the bleached teeth revealed pathological changes in
et al., 1999). The concentration of peroxide in the pulp chamber odontoblast morphology and dentinogenesis at both the 13-
was not determined in the above studies, and the clinical sig- and 62-day time points, and the severity of the changes was
nificance of the findings is therefore unclear. Structural pulp related to the length of each treatment. Repair of the lesions
damage was not observed in human premolars exposed to 35% was observed 92 days after the last treatment (Seale and
hydrogen peroxide in vivo and observed up to 30 days before Wilson, 1985). Tooth sensitivity was also a common symptom
the teeth were extracted and submitted for histological evalua- in patients who had not bleached their teeth, and their symp-
tion (Cohen and Chase, 1979; Robertson and Melfi, 1980; tom was correlated with gingival recession (Jorgensen and
Baumgartner et al., 1983). The longest exposure was three times Carroll, 2002). Patients with a previous history of tooth sensi-
for 30 min each (Cohen and Chase, 1979), and in two of the tivity may thus have a higher risk for such an adverse effect
studies, heat was used to accelerate the bleaching process from external tooth bleaching, and this should be taken into
(Cohen and Chase, 1979; Robertson and Melfi, 1980). Only one account before treatment begins.
study included patient reaction to the treatment, and it report-
ed that 78% of patients suffered from sensitivity to cold and Mucosal irritation
intermittent spontaneous pain lasting up to one day after treat- A high concentration of hydrogen peroxide (from 30 to 35%) is
ment (Cohen and Chase, 1979). Histological evaluation of the caustic to mucous membranes and may cause burns and
human pulp after vital bleaching overnight with 10% car- bleaching of the gingiva. In animal experiments, exposure of
bamide peroxide revealed mild inflammatory changes in 4 out the gingiva to 1% H2O2 for 6 to 48 hrs resulted in epithelial
of 12 teeth after both 4 and 14 days' treatment, and no inflam- damage and acute inflammation in the subepithelial connective
mation in teeth that were bleached with carbamide peroxide tissue (Martin et al., 1968). Long-term application of 3% or 30%
for 14 days followed by a "recovery" phase of 14 days hydrogen peroxide in the hamster cheek pouch twice weekly
(González-Ochoa, 2002). resulted in inflammatory changes (Weitzman et al., 1986). In
An in vivo study in dogs indicated that hydrogen peroxide clinical trials that used 10% carbamide peroxide in custom-
alone or in combination with heat caused alterations in odon- made trays, from 25 to 40% of the patients reported gingival
toblasts and deposition of dentin (Seale et al., 1981). irritation during treatment (Leonard et al., 1997; Tam, 1999a). It
Hemorrhage and inflammation were observed in teeth 3 and 15 is therefore advisable that the tray be designed to prevent gin-
days after bleaching, and the pulpal changes were reversed 60 gival exposure by the use of a firm tray that has contact with

14(4):292-304 (2003) Crit Rev Oral Biol Med 297

 implication of these findings may be that the
teeth are more susceptible to extrinsic dis-
coloration after bleaching due to increased
surface roughness.

Effects on restorations
Data from laboratory studies documented
increased mercury release from dental amal-
gams exposed to carbamide peroxide solu-
tions for periods ranging from 8 hrs to 14-28
days (Hummert et al., 1993; Rotstein et al.,
1997). The amount of mercury released var-
ied with type of amalgam and type of
bleaching agent and ranged from 4 times to
30 times higher than in saline controls. It has
been suggested that bleaching may increase
Figure 6. SEM photomicrographs of an enamel surface without (A) and with (B) exposure the solubility of glass-ionomer and other
to a bleaching procedure. The enamel of an extracted human tooth was cleaned with cements (Swift and Perdigão, 1998).
water-spray, and half of the surface was covered with nail varnish (the control). The tooth Furthermore, the bond strength between
was then exposed to 10% carbamide peroxide gel for 1 hr two times daily during 3 wks. enamel and resin-based fillings was reduced
After each bleaching procedure, the gel was removed by water-spray, and the tooth was
in the first 24 hrs after bleaching (Dishmann
stored in water between treatments. At the end of the bleaching period, the nail varnish
was removed, and comparative sections of bleached and unbleached enamel were pre- et al., 1994). After 24 hrs, there was no differ-
pared for direct scanning electron microscopy (Holmen et al., 1985). The enamel ence in the strengths of dental composite
microstructure of the bleached-enamel surface (B) illustrates an obvious enamel etch resin cement bonds to bleached and non-
caused by the bleaching agent, compared with the unbleached surface (A). bleached enamel (Homewood et al., 2001).
Following bleaching, hydrogen peroxide
residuals in the enamel inhibit the polymer-
ization of resin-based materials and thus
solely the teeth. In this respect, the newly introduced bleaching reduce bond strength (Lai et al., 2002). Therefore, tooth-bleach-
strips may be unfavorable, since the bleaching gel will come ing agents should not be used prior to restorative treatment
into contact with the gingiva. with resin-based materials.
Alteration of enamel surface (V-4) GENERAL SIDE-EFFECTS
Morphological alteration of the enamel following tooth bleach- The risk of adverse effects has not been the main focus in the
ing (Fig. 6) has been addressed in several studies. Enamel slabs design of clinical studies of external tooth bleaching. For exam-
were subjected to different bleaching agents containing 10% ple, for a case-reference study that detects a doubling of the risk
carbamide peroxide for 15 hrs a day, for two- and four-week for an adverse effect that occurs at a level of 1:1000 in the refer-
periods, and evaluated by scanning electron microscopy ence group, the study group must have at least 1000 people,
(Shannon et al., 1993). During the remaining 9 hrs every day, the and for detection of a 10% increase in the risk, more than 10,000
slabs were exposed to human saliva in vivo. Significant surface people must be enrolled in the study (Bjerre and LeLorier,
alterations in enamel topography were observed in slabs treat- 2000). In the clinical studies published on tooth bleaching that
ed with the bleaching solutions for 4 wks (Shannon et al., 1993). address adverse effects (Cohen and Chase, 1979; Nathanson
This finding was confirmed in a study with 30% hydrogen per- and Parra, 1987; Haywood et al., 1994; Schulte et al., 1994;
oxide and 30% hydrogen peroxide mixed with sodium perbo- Leonard et al., 1997; Tam, 1999a,b), the number of participants
rate (Ernst et al., 1996). Compared with the untreated control has been small compared with the above numbers, and many
surfaces, the enamel surface exposed to the bleaching agents studies did not have control groups. Therefore, the potential
underwent slight morphologic alterations. Teeth that were general adverse effects of external tooth bleaching cannot be
bleached in vivo with 35% carbamide peroxide (30 min/day for assessed at this time.
14 days) lost the aprismatic enamel layer, and the damage was
not repaired after 90 days (Bitter, 1998). By infrared spectro- (V-5) GENOTOXICITY AND CARCINOGENICITY
scopic analysis, it was found that in vitro treatment of extract-
OF BLEACHING AGENTS
ed teeth with 35% carbamide peroxide for 30 min/day for 4
days changed the inorganic composition of the enamel, where- The genotoxicity of hydrogen peroxide and of tooth whiteners
as 10% and 16% concentrations did not (Oltu and Gürgan, containing carbamide peroxide has been evaluated (IARC,
2000). Evaluation of casts made from impressions of teeth 1985; ECETOX, 1996; Li, 1996). The consensus arising from
bleached with 10% carbamide peroxide for 8-10 hrs/day for 14 these evaluations was that direct contact with hydrogen perox-
days revealed no or minimal changes in the enamel surface ide induced genotoxic effects in bacteria and cultured cells.
(Leonard et al., 2001), which may be due to inadequate repro- When hydrogen peroxide was administered to bacteria or cul-
duction of the minor enamel alterations in the impression. A tured cells in the presence of catalase or other metabolizing
high concentration of carbamide peroxide was detrimental to enzymes, the effect was reduced or abolished. Testing of hydro-
enamel surface integrity, but the damage was less than that gen peroxide for systemic genotoxic effects in animals revealed
seen after phosphoric acid etch (Ernst et al., 1996). A clinical no evidence of in vivo mutagenicity. Since hydroxy radicals,

298 Crit Rev Oral Biol Med 14(4):292-304 (2003)

TABLE 3
Tumorigenic Effects on the Gastro-intestinal Tract after Long-term Exposure to Hydrogen Peroxide

Type of Study Duration of Observation

and Animals Exposure Exposure Time Dose and Effects Reference

CAa, 100 mice H2O2 in drinking water 100 wks 100 wks Control 0.1% 0.4% Ito et al., 1981
duodenal hyperplasia 9% 40% 61%
duodenal adenoma 1% 6% 2%
duodenal carcinoma 0% 1% 5%
CAa, 138 mice H2O2 in drinking water 700 days 700 days duodenal carcinoma 0% 5% Ito et al., 1982
CTb, 85 mice H2O2 in drinking water 7 months 7 months duodenal tumors 5.3d 1.7d 0.7d Ito et al., 1984
11% 31% 100%
PRc, 61 rats (A) MNNGf in food 7 months 7 months A B C Takahashi et al.,
(B) MNNG in food + 1% forestomach 1986
H2O2 in drinking water papillomas 0% 100% 50%
(C) 1% H2O2 in fundus hyperplasia 0% 38% 0%
drinking water pylorus carcinomas 3% 10% 0%
duodenal carcinomas 10% 0% 0%

a CA = carcinogenicity study.
b CT = chronic toxicity study.
c PR = promoter studies.
d Catalase activity (10-4 k/mg protein).
e Duodenal tumors consisting of hyperplasia, adenomas, and carcinomas.
f MNNG = 1-methyl-3-nitro-1-nitrosoguanidine (CAS no. 70-25-7).

perhydroxyl ions, and superoxide anions formed from hydro- lowed for 50 wks (Klein-Szanto and Slaga, 1982).
gen peroxide are capable of attacking DNA, the genotoxic Hydrogen peroxide did not promote MNNG (1-methyl-3-
potential of hydrogen peroxide is dependent on the accessibil- nitro-1-nitrosoguanidine) (CAS no. 70-25-7)-initiated gastric
ity of free radicals to target DNA. This may explain why tumous in rats, but an increased number of forestomach papillo-
hydrogen peroxide induces genotoxicity in the presence of mas and fundus hyperplasia were observed in animals receiving
metabolizing enzymes neither in vitro nor in vivo. Tooth whiten- MNNG, food supplemented with 10% sodium chloride, and
ers containing carbamide peroxide were mutagenic in certain drinking water with 1% hydrogen peroxide ad libitum for 7 wks
bacterial strains and non-mutagenic in the presence of addi- (Takahashi et al., 1986). Painting of the hamster cheek pouch with
tional activating enzymes. Several in vivo studies addressing DMBA (7,12-dimethylbenz[a]anthracene) (CAS no. 57-97-6) in
the formation of micronuclei in bone marrow cells and sister combination with 3% or 30% hydrogen peroxide showed that
chromatide exchange after exposure to carbamide-peroxide- 30% hydrogen peroxide had a promoting effect on DMBA car-
containing products revealed no genotoxic effects. cinogenesis (Weitzman et al., 1986). A study on the tumor-pro-
Data on animal experiments evaluating long-term effects moting effects of hydrogen peroxide in mice via dermal applica-
of the oral administration of hydrogen peroxide are given in tion of 5 to 15% hydrogen peroxide in acetone following initia-
Table 3. A dose-dependent increased incidence of duodenal tion with DMBA showed increased incidence of skin papillomas
hyperplasia was observed in a study where 0.1% and 0.4% in the treated groups (Klein-Szanto and Slaga, 1982). In other
hydrogen peroxide was administered to mice via drinking similar experiments in mice, with DMBA as the initiator and 3%
water for 100 days (Ito et al., 1981). In addition, the number of and 6% hydrogen peroxide as the promoter, there was no signif-
adenomas and carcinomas increased in the duodenum of the icant increase in the incidence of skin tumors (Shamberger, 1972;
exposed groups, but not in a dose-related manner (Ito et al., Bock et al., 1975; Kurokawa et al., 1984), although epidermal
1981). In another study, mice were given 0.4% hydrogen perox- hyperplasia was evident in most treated mice in one of the
ide in the drinking water for up to 700 days. Benign and malig- experiments (Kurokawa et al., 1984). Skin painting with DMBA
nant lesions were found in the stomach and duodenum after 90 and 5% carbamide peroxide in water did not result in tumors
days' exposure (Ito et al., 1982). The incidence did not increase after 56 wks of the promoting stimulus (Bock et al., 1975).
with exposure time, but more severe lesions were observed Increased proliferation of gingival epithelial cells was observed
later in the experiment. The stomach lesions regressed com- in biopsies taken from patients after a five-week period of
pletely after an exposure-free period of 10-30 days, but some of bleaching with 10% carbamide peroxide (da Costa Filho et al.,
the duodenal lesions persisted. Strains with different catalase 2002).
activity and provided to mice with 0.4% hydrogen peroxide in Based on the aforementioned studies, hydrogen peroxide
the drinking water resulted in tumor incidence inversely relat- was shown to have a weak local carcinogenic-inducing poten-
ed to the catalase activity (Ito et al., 1984). In mice, topical appli- tial. The mechanism is unclear, but a genotoxic action cannot be
cation of 15% hydrogen peroxide in acetone on the skin for 25 excluded, since free radicals formed from hydrogen peroxide
wks resulted in an increased number of papillomas in the treat- are capable of attacking DNA. Several studies of DMBA car-
ed group, but no malignant changes were observed in mice fol- cinogenesis in mice skin and hamster cheek pouch indicate that

14(4):292-304 (2003) Crit Rev Oral Biol Med 299

hydrogen peroxide may act as a tumor-promoter (Klein-Szanto compound (van den Heuvel et al., 1990), but such data are often
and Slaga, 1982; Weitzman et al., 1986). provided and used for toxicological assessment. The single-
The International Agency for Research on Cancer (IARC) dose LD50 values for non-carbopol-containing 10% carbamide
concluded that there is limited evidence in experimental ani- peroxide solutions and a carbopol-containing 10% carbamide
mals and inadequate evidence in humans for the carcinogeni- peroxide solution in mice were found to be 143 mg/kg and 87
city of hydrogen peroxide and classified the chemical into mg/kg, respectively (Woolverton et al., 1993). This corresponds
Group 3: Unclassifiable as to carcinogenicity to humans (IARC, to 15 and 9 mg carbamide peroxide per kg BW. For hydrogen
1999). Recently, the genotoxic potential of hydrogen peroxide peroxide, the oral LD50 value was found to be approximately
in oral health products has been evaluated (SCCNFP, 1999). It 1600 mg/kg (Ito et al., 1976), but no other studies have con-
appears unlikely that oral health products containing or releas- firmed the above findings. In rats, a single oral dose of 5 g/kg
ing hydrogen peroxide up to 3.6% H2O2 will enhance cancer BW of proprietary solutions of 10%, 15%, and 35% carbamide
risk in individuals except in those who have an increased risk peroxide induced a concentration-dependent acute toxicity,
of oral cancer due to tobacco use, alcohol abuse, or genetic pre- and the rats showed respiratory depression, reduced weight
disposition (SCCNFP, 1999). To evaluate higher concentrations gain and water consumption, changes in estrous cycle, and, at
of hydrogen peroxide was not the task of the committee. necropsy, histological abnormalities of the stomach, including
necrotic mucosa and disrupted gastric glands (Cherry et al.,
(V-6) TOXICITY OF HYDROGEN PEROXIDE 1993). In the highest-concentration group, 3 animals died of
AND CARBAMIDE PEROXIDE gastric hemorrhage and bloating. Six of 36 rats died within 2
hrs after receiving, orally, 5 g/kg BW of a tooth whitener con-
Case reports of human exposure
taining 6% hydrogen peroxide (Redmond et al., 1997). After 15
The acute effects of hydrogen peroxide ingestion are dependent min, the stomach was grossly bloated with gas, and after 2 hrs
on the amount ingested and the concentration of the hydrogen the blood hematocrit was elevated, and histology revealed
peroxide solution. The outcomes of accidental ingestion, or inten- injury to the gastric mucosa. The gastric mucosa appeared nor-
tional ingestion for suicide, of solutions of 10% hydrogen perox- mal one week later, and the blood chemistry normalized 2 wks
ide and higher were more severe than those seen at lower con- after the exposure. In rats, stomach gavage of 15 and 50 mg car-
centrations (Dickson and Caravati, 1994). Accidental ingestion of bamide peroxide per kg BW or 150 and 500 mg of tooth whiten-
35% hydrogen peroxide has resulted in several fatal or near-fatal er containing 10% carbamide peroxide per kg BW resulted in
poisonings (Giusti, 1973; Giberson et al., 1989; Humberston et al., ulceration of the gastric mucosa after 1 hr; the lesions started to
1990; Christensen et al., 1992; Sherman et al., 1994; Litovitz et al., heal after 24 hrs (Dahl and Becher, 1995). The ulcerations from
1995; Ijichi et al., 1997). These individuals vomited, were cyanotic, the exposure to the tooth-bleaching agent were more pro-
and experienced convulsions and respiratory failure (Giberson et nounced than those observed after a comparable dose of car-
al., 1989). Cerebral infarction and ischemic changes of the heart bamide peroxide. This may be attributed to the hydrophobic
due to gas embolism have also been observed (Rackoff and nature of the gel and the content of carbopol in the bleaching
Merton, 1990; Christensen et al., 1992; Luu et al., 1992; Cina et al., agent, which likely increases tissue adherence and retards the
1994; Sherman et al., 1994; Ijichi et al., 1997). Young children are at decomposition of hydrogen peroxide (Dahl and Becher, 1995).
high risk for accidental ingestion. A two-year-old child died after In catalase-deficient mice that were given 100 ppm, 300
drinking 100 mL of a 35% hydrogen peroxide solution, which cor- ppm, 1000 ppm, or 3000 ppm hydrogen peroxide in distilled
responds to a dose of 290 mg hydrogen peroxide/kg BW water for 13 wks, the "no observed adverse effect level"
(Christensen et al., 1992). Also, ingestion of a lower concentration (NOAEL) was 100 ppm, corresponding to 26 and 37 mg/kg
of hydrogen peroxide has resulted in serious injury. Lung edema BW/day for males and females, respectively (Weiner et al.,
and diffuse intestinal emphysema were found on autopsy of a 16- 2000). In the 1000- and 3000-ppm groups, small duodenal
month-old child who had swallowed approximately 600 mg mucosal hyperplasias were observed; the lesions appeared
hydrogen peroxide/kg BW of a 3% hydrogen peroxide solution. reversible during a six-week recovery period. In a study of rats
When the child was first seen, white foam emerged from the given 50 mg/mL hydrogen peroxide by oral gavage 6 times a
child's mouth and nose, and the child died 10 hrs later (Cina et al., wk for three months, the NOAEL was found to be 56 mg/kg
1994). Portal venous gas embolism was observed in a two-year- BW/day (Ito et al., 1976). Deleterious localized effects on the
old child after unintentional ingestion of 3% hydrogen peroxide gastric mucosa, decreased food consumption, reduced weight-
solution (Rackoff and Merton, 1990). gain, and blood chemistry changes were observed in the affect-
One syringe (3.5 g) of 18% carbamide peroxide yields 210 ed animals. Rats exposed daily, by oral gastric tube, to 0.06%-
mg of hydrogen peroxide. Fatal poisoning is therefore not like- 0.6% hydrogen peroxide solutions for 40-100 days, and to doses
ly even if a two-year-old child (body weight approximately 12 above the NOAEL (30 mg/kg BW/day), exhibited significant
kg) ingests one syringe of bleaching agent. Ulceration of the reduction in plasma catalase levels, and, in the highest-dose
oral mucosa, esophagus, and stomach is more likely to occur in group, reduced weight-gain and blood chemistry changes were
such a case, accompanied by symptoms such as nausea, vomit- found (Kawasaki et al., 1969).
ing, abdominal distention, and sore throat, as have been
reported for other hydrogen peroxide-containing preparations (V-7) RISK ASSESSMENT
(Dickson and Caravati, 1994). It is therefore important to keep OF EXTERNAL TOOTH BLEACHING
syringes with bleaching agents out of the reach of children, to Risk assessment is traditionally considered to consist of four
prevent any possible accident. steps: the hazard identification, the dose-response relationship,
the exposure assessment, and the risk characterization (IPCS,
Animal studies 1999). The risk characterization is founded on a critical compar-
Oral LD50 determination is a crude estimate of the toxicity of a ison of the data on exposure and the dose-response relationship.

300 Crit Rev Oral Biol Med 14(4):292-304 (2003)

 The important ingredient in tooth whitening
today is hydrogen peroxide. The NOAEL values
based on repeated-dose studies with hydrogen
peroxide per os have been estimated to be from 26
to 56 mg/kg BW/day (Kawasaki et al., 1969; Ito et
al., 1976; Weiner et al., 2000). These three studies
are consistent in their findings of the "no adverse
effect" level, and we have selected 26 mg/kg
BW/day for the following risk assessment. Figure 7. The formula for calculating the safety factor based on general principles
The amount of bleaching agent used for for risk assessment (Woodward, 1996).
bleaching one arch of teeth has been calculated to
be 900 mg per application when administered
according to the manufacturer's instruction (Dahl
mandibular teeth at the same time are not advisable.
and Becher, 1995), and an average of 500 mg per application
based on clinical experiments (Li, 1996). At least 25% of the (V-8) LEGAL AND ETHICAL ASPECTS
bleaching agent administered in bleaching trays is ingested dur- OF EXTERNAL TOOTH BLEACHING
ing 2 hrs of bleaching (Matis et al., 2002). We have calculated the
exposure to hydrogen peroxide from tooth bleaching and the In the US, tooth-bleaching agents are included in the accep-
safety factor using different concentrations of the bleaching tance program of the American Dental Association (Burrell,
agent (Fig. 7). The results are given in Table 4. The safety factor 1997). The evaluation is based on laboratory studies, toxicolog-
(= NOAEL/exposure) varies between 350 and 55. In risk assess- ical studies, and clinical data, and the type of study required for
ment based on toxicity data derived from animal studies, the each product is dependent on the composition of the product
minimum accepted safety factor is 100 (Woodward, 1996). This (American Dental Association, 1998). For products with an
safety factor is not reached in preparations that deliver or contain ingredient for which safety and efficacy have already been
more than 12.6% H2O2 when 500 mg of bleaching agent is used evaluated, laboratory studies are sufficient for the evaluation.
for bleaching one arch. Longer bleaching periods per day, multi- Tooth whiteners are generally regarded in Europe as cos-
ple applications, bleaching maxillary and mandibular teeth at metic products (EU Commission, 1996). According to the cos-
the same time, and overfilling the tray increase the exposure and metic regulation, the maximum authorized content or release
reduce the safety factor. For example, if both maxillary and of hydrogen peroxide in such oral hygiene products is 0.1%
mandibular teeth are bleached at the same time, the minimum (EU Commission, 1992). Tooth-whitening products can also be
required safety factor will not be reached for preparations that claimed to be medical devices, and evaluated according to the
contain or deliver more than 7.9% H2O2, which corresponds to medical device regulation (EU Commission, 1993). Products
22% carbamide peroxide (Budavari et al., 1989). According to the granted the EU certification, i.e., the CE marking (CE =
exposure data from a previous evaluation (900 mg/application) Communauté Europeén), could be used for tooth bleaching pro-
(Dahl and Becher, 1995), the concentration of H2O2 should not vided that the claims of the manufacturer and the definition of
exceed 3.5%, which corresponds to 10% carbamide peroxide a medical device according to the European regulation are fol-
(Table 4). Based on the risk assessment, it must be concluded that lowed. The definition of a medical device includes "material or
selection of preparations with a low concentration of carbamide other article intended by the manufacturer to be used for the
peroxide is recommended for the optimum safety of the patient. purpose of treatment or alleviation of disease, or for the pur-
In addition, overfilling the tray without removing excess mater- pose of treatment, alleviation of or compensation for a handi-
ial, biting on the tray, and bleaching both maxillary and cap". At least in Europe, the use of bleaching agents containing

TABLE 4
Calculated Exposures to Hydrogen Peroxide during Two-hour Bleaching of One Arch with Custom-
made Tray and the Safety Factors Derived

Exposure to H2O2 Exposure to H2O2

Preparation H2O2 Concentrationa (mg/kg BW/application)b Safety Factorc (mg/kg BW/application)d Safety Factorc

Carbamide peroxide 10% 3.6% 0.075 350 0.14 185

Carbamide peroxide 15% 5.4% 0.11 240 0.20 130
Carbamide peroxide 22% 7.9% 0.16 160 0.29 89
Carbamide peroxide 35%e 12.6% 0.26 100 0.47 55

a H2O2 concentration determined based on the composition of carbamide peroxide that consists of 36% H2O2 (mol w) and 64% urea (Budavari et al., 1989).
b Exposure based on bleaching 10 teeth with 500 mg bleaching agent (Li, 1996), 25% of the bleaching agent ingested during 2 hrs (Matis et al., 2002),
and the WHO body weight estimate (60 kg) (Woodward, 1996).
c Safety factor = NOAEL/exposure (rounded to nearest 10) (Fig. 7). The NOAEL value is 26 mg/kg BW/day. The minimum acceptable safety factor, based
on data derived from animal studies, is 100 (Woodward, 1996).
d Exposure based on bleaching 10 teeth with 900 mg bleaching agent (Dahl and Becher, 1995), 25% of the bleaching agent ingested during 2 hrs (Matis
et al., 2002), and the WHO body weight estimate (60 kg) (Woodward, 1996).
e This concentration is intended for professional use only. The calculation is included in case the patient uses the preparation at home.

14(4):292-304 (2003) Crit Rev Oral Biol Med 301

more than 0.1% hydrogen peroxide requires a proper profes- Budavari S, O'Neil MJ, Smith A, Heckelman PE (1989). The Merck
sional diagnosis of a disease or a handicap. Bleaching must index. An encyclopedia of chemicals, drugs, and biologicals.
therefore be regarded as an alternative to other dental proce- Rahway, NJ: Merck and Co., Inc.
dures such as laminates and full crown therapy. Burrell KH (1997). ADA supports vital tooth bleaching. J Am Dent
Assoc 128(Suppl):3S-5S.
(VI) Concluding Remarks Caughman WF, Frazier KB, Haywood VB (1999). Carbamide per-
oxide whitening of nonvital single discolored teeth: case
We advocate a more selective use of tooth bleaching and a lim-
reports. Quintessence Int 30:155-161.
itation on its use to patients for whom such treatment could be Cherry DV, Bowers DE, Thomas L, Redmond AF (1993). Acute tox-
professionally justified. The need for bleaching solely to icological effects of ingested tooth whiteners in female rats. J
achieve a "perfect" smile and a youthful look (Burrell, 1997) is Dent Res 72:1298-1303.
thus questioned. We urge the dental profession to maintain Chng HK, Palamara JEA, Messer HH (2002). Effect of hydrogen
high ethical standards and not to recommend performing cos- peroxide and sodium perborate on mechanical properties of
metic adjustment of tooth color just to comply with the human dentin. J Endod 28:62-67.
demand of the patient. Our concerns are based on the lack of Christensen DV, Faught WE, Black RE, Woodward GA, Timmons
large-scale clinical investigations on adverse effects and the OD (1992). Fatal oxygen embolization after hydrogen peroxide
limited toxicological data on carbamide peroxide available in ingestion. Crit Care Med 20:543-544.
peer-reviewed journals. Furthermore, the risk assessment has Cina SJ, Downs JCU, Conradi SE (1994). Hydrogen peroxide: a
shown that the minimum accepted safety factors might not be source of lethal oxygen embolism. Am J Forensic Med Pathol
attained in certain clinical situations. 15:44-50.
Cohen SC, Chase C (1979). Human pulpal response to bleaching
Acknowledgments procedures on vital teeth. J Endod 5:134-138.
Dr. I. Eystein Ruyter, NIOM—Scandinavian Institute of Dental Materials, Cotton FA, Wilkinson G (1972). Oxygen. In: Advances in inorganic
Norway, is greatly acknowledged for providing data on the chemical reactions chemistry. A comprehensive text. Cotton FA, Wilkinson G, edi-
of the bleaching agents. This work was presented in part at the 84th Annual tors. New York: Interscience Publisher, pp. 403-420.
Meeting of the NOF-Scandinavian Division of the International Association Cvek M, Lindvall A-M (1985). External root resorption following
for Dental Research, Copenhagen, 2001. bleaching of pulpless teeth with oxygen peroxide. Endod Dent
Traumatol 1:56-60.
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