01-Vital Tooth Bleaching Review Efectos Adversos PDF

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Q U I N T E S S E N C E I N T E R N AT I O N A L
Vital tooth bleaching:

Biologic adverse effectsA review
Maryline Minoux, DMD1/Ren Serfaty, DMD, PhD2
Depending on etiology, the esthetic treatment of dyschromia may involve vital tooth
bleaching techniques. Hydrogen peroxide is the active molecule used for such procedures; however, its action mechanism is not clearly understood. Moreover, a variety of contradictory studies make difficult the evaluation of the safety of bleaching techniques. The
purpose of this article is therefore to review the available literature (1) to describe the
physicochemical properties of hydrogen peroxide and (2) to assess the safety of its use as
a vital toothbleaching agent. Indeed, based on hydrogen peroxides capacity to generate
free radicals that diffuse throughout the dental hard tissues, concerns have been
addressed regarding the adverse effects that bleaching products can induce on the
enamel and dentin structures, pulp, and bonding to a composite resin system. Moreover,
during self-application of home bleaching products, hydrogen peroxide is released into
the oral cavity and ingested. Some questions have therefore arisen concerning its toxicity
and its possible carcinogenicity. (Quintessence Int 2008;39:645659)
Key words: adverse effects, bleaching, cancer, carbamide peroxide, enamel, hydrogen
peroxide, tooth, toxicity
Tooth whitening is an esthetic solution for

patients displaying tooth discolorations. The
natural color of teeth is influenced essentially
by the light-transmitting and reflecting properties of the dental hard tissues, the overall
color of the tooth being determined mostly by
the optical properties of the dentin.1 This
Assistant Professor, Department of Restorative Dentistry,

Faculty of Dentistry, Universit Louis Pasteur, Strasbourg,
France.
Associate Professor, Department of Restorative Dentistry,

Faculty of Dentistry, Universit Louis Pasteur, Strasbourg,
France.
Correspondence:
Dr
Maryline
Minoux, Department
of
Restorative Dentistry, Faculty of Dentistry, Universit Louis

Pasteur, 4 Place de lHpital, 67000 Strasbourg, France. E-mail:
minoux@igbmc.u-strasbg.fr
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natural color can be modified by intrinsic or

extrinsic discolorations. Intrinsic discolorations result from a change in the molecular nature, structure, or thickness of both the
dentin and the enamel. Their origin can be
pre- or posteruptive. Intrinsic discolorations
are preeruptive when they occur during tooth
morphogenesisthey can be induced by
trauma, genetic disorder, administration of
tetracycline, or intake of high levels of fluoride. The posteruptive discolorations are
mainly caused by trauma (with tooth vitality
preservation) and the aging process. In contrast to intrinsic discolorations, extrinsic
stains are superficial and produced by the
deposit of dietary chromogens or other external elements on the enamel surface or within
the pellicle layer.2,3
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Fig 1 Action mechanisms of hydrogen peroxide. Equations 1, 2, and 3 represent reactions that hydrogen
peroxide (H2O2) undergoes in the presence of heat or UV light, whereas equations 4 and 5 represent reactions
occurring under alkaline conditions. (H) Hydrogen; (O) Oxygen; (HO) Hydroxyl radical; (HO2) Perhydroxyl
radical (O2-) superoxide anion. A red dot represents the free radicals unpaired electron.
Fig 2 Disruption of double bonds by free radicals.
To stabilize their molecular structure, free radicals
get an electron from conjugated double bonds.The
resulting disruption of these double bonds leads to
production of less chromatogenic molecules. (C)
Carbon; (O) Oxygen; (H) Hydrogen. A red dot represents the free radicals unpaired electron.
The diagnosis of these dental discolorations is essential because their appropriate
treatment is highly dependent on their etiology.
Indeed, while a classic professional cleaning
is often sufficient for removing most external
stains, the treatment of intrinsic discolorations is more complex and based on different
methods and approaches, such as the macroabrasion used with ceramic or composite
resin, the microabrasion technique, or tooth
bleaching.2
Tooth bleaching can be performed intracoronally in root-filled teeth (nonvital tooth
bleaching) or externally (vital tooth bleaching).4 Despite the large number of methods
that have been described in the literature
concerning the external bleaching of vital
teeth, all of these are based on the direct use
of hydrogen peroxide (H2O2) or its precursor,
carbamide peroxide.
Basically, 3 major approaches exist for
vital tooth bleaching: in-office bleaching, clinician-supervised nightguard bleaching, and
use of commercial bleaching products.57 In
the nightguard technique, the hydrogen peroxidecontaining gel is applied on the teeth
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with the help of a custom-fabricated tray. The

guard is generally worn at night for at least 2
weeks. In this technique, the carbamide peroxide concentration in the gel is relatively low
(10% to 15%), which corresponds to a concentration of 3% to 5% hydrogen peroxide.8,9
In contrast, with the in-office bleaching technique, a higher concentration of hydrogen
peroxide is used (25% to 35%) for a shorter
period of time, and a heat or light source is
often used to accelerate tooth whitening.1013
The efficiency of tooth bleaching has
been extensively described in the literature
during the last 15 years1416; however, concerns have been addressed only recently
about its potential adverse effects. The purpose of this article is therefore to review the
data described in the literature concerning
the biologic adverse effects of hydrogen peroxide used as a vital toothwhitening agent.
Topics will be focused on the effect that
hydrogen peroxide can induce on enamel
and dentin structure, pulp, and bonding to a
composite resin system. The potential local
and systemic toxicity and carcinogenicity of
hydrogen peroxide will also be evaluated.
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PHYSICOCHEMICAL
PROPERTIES AND ACTION
MECHANISM OF HYDROGEN
PEROXIDE: GENERATION
OF FREE RADICALS
Even though hydrogen peroxide has been
successfully used in dentistry for many years,
the mechanism by which bleaching occurs is
currently not clearly understood. Several
reactions may account for bleaching efficiency,
depending on the environmental conditions,
such as temperature, pH, ultraviolet (UV)
light, and the presence of some ions.17 Under
alkaline conditions, hydrogen peroxide can
undergo an ionic dissociation to give rise to
the formation of the perhydroxyl anion (Fig 1,
equation 4). The perhydroxyl anion (HO2-)
can be, by itself, the active species in the
bleaching process18 but can also be an electron donor to initiate the formation of free radicals (Fig 1, equation 5).
Price et al19 have shown that even if the
majority of the bleaching products have an
acidic pH, some of them (especially when
the hydrogen peroxide concentration is low)
could also have a basic pH. Moreover, it has
been shown that the pH in the tray and saliva
increases in the 15 minutes following tooth
bleaching with 10% carbamide peroxide.
This increase of pH seems to be attributed to
ammonia originating from the degradation of
urea within carbamide peroxide.20 According
to these studies, a moderate basic pH can be
found in the tray, suggesting that in particular
conditions, anionic dissociation of hydrogen
peroxide could contribute to tooth bleaching.
In addition to the anionic dissociation, hydrogen peroxide can undergo a homolytic cleavage. This reaction is mainly promoted by
high temperature and UV light and can result
in the appearance of a powerful oxidant
agent called hydroxyl radical (HO) (Fig 1,
equation 1).21,22 A chain reaction ensues to
form new oxygen free radicals such as perhydroxyl radical (HO2) and superoxide anion
(O2 -) (Fig 1, equations 2 and 3).22,23
Free radicals are highly unstable because
they contain 1 or more unpaired electrons in
their atomic orbital. To stabilize their molecular
structure, they will have the tendency to get
an electron from an adjacent compound.
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They are therefore strong oxidative agents.

The conjugated double bonds involving carbon, nitrogen, and oxygen atoms are powerful electron donors and represent the main
target of peroxide action. These double
bonds are essential for organic molecules
that generate color and that are referred to as
chromophores. By disrupting the electron
conjugation of the double bonds, free radicals will change the absorption energy of the
molecule (Fig 2). It results in a shift of the visible absorption spectrum of the compound
from a longer to a shorter wavelength, leading to the production of less chromatogenic
compounds.24 The precise molecular nature
of the chromophores localized within the
tooth is still unknown; therefore, only an
extrapolation from the general mechanism of
hydrogen peroxide action can be made on
such chromatogenic molecules. Moreover,
what also remains unknown is the degree of
teeth chromophores degradation regarding
the bleaching conditions (concentration of
H2O2, time of exposure, presence of a catalyzer), as well as how far this oxidation reaction can be reversed.
HYDROGEN PEROXIDES
EFFECTS ON ENAMEL
AND DENTIN STRUCTURE
In addition to disrupting pigmented molecules, it has been demonstrated that free radicals can also disrupt lipids and proteins that
are organic components of the dental hard
tissues.25 The alteration of the enamel and
dentin has therefore been hypothesized to
be among the possible adverse effects of
bleaching products.
Morphologic alterations of the enamel surface have been evaluated by different techniques, notably scanning electron microscopy and profilometric analysis. Several
studies have revealed no significant micromorphologic changes associated with the
whitening process using 10% carbamide peroxide,2629 20% carbamide peroxide,30 and
even 35% hydrogen peroxide.31,32 Other studies, however, have described slight morphologic surface alterations of the enamel follow-
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ing tooth bleaching using 10% carbamide

peroxide or 35% hydrogen peroxide. The
defects noted include an alteration in surface
roughness and deeper clefts,33 as well as a
small and nonuniform increase in surface
porosity.3437 According to Bistey et al,38 the
alteration in enamel following tooth bleaching
was proportional to the treatment time and
concentration of hydrogen peroxide used.
Indeed, the increase in the depth of grooves
observed by Fourier Transformed Infrared
(FT-IR) spectroscopy was more pronounced
when 30% hydrogen peroxide was used than
with 10% carbamide peroxide.25 Several studies have confirmed the deleterious effect of a
high concentration of hydrogen peroxide on
enamel surface integrity3941; however, some
authors also reported alterations in enamel
surface morphology even following exposure
to 10% carbamide peroxide.4245
Conflicting results have also arisen concerning enamel surface microhardness
modification. Indeed, while some studies
have demonstrated that no changes were
associated with tooth bleaching when a concentration of carbamide peroxide ranging
from 10%24,29,44,4649 to 15%50 was used, other
studies have shown that the same concentrations of carbamide peroxide can lead to a
decrease of enamel microhardness.5155 A
decrease in enamel microhardness is related
to a demineralization or a loss of mineral
content from the outer tooth structure.56
Accordingly, Efeoglu et al57 observed that the
application of 10% carbamide peroxide
decreased the hydroxyapatite mineral content in the outer 50 m of enamel. It has also
been described that a small amount of phosphorous and/or calcium were lost from
enamel exposed to a 10% carbamide peroxide solution48,58; however, the authors concluded that these chemical changes in
enamel were not clinically significant.
The small molecular weight of hydrogen
peroxide and its by-products allows them to
diffuse throughout the enamel and dentin. By
direct application of 10% carbamide peroxide
on the dentin, some studies showed a
decrease in microhardness,54,55,59,60 whereas
other studies did not.47,50 In their in vitro study,
Tam et al61 showed that direct application of
10% carbamide peroxide on the dentin
648
decreased the flexural strength and modulus

of this tissue. However, when applied on
enamel of intact teeth, 10% carbamide peroxide did not affect the mechanical properties of
the underlying dentin. Similarly to the enamel,
it remains unclear which inorganic or organic
phase of the dentin is affected. Indeed,
Rotstein et al62 found a significant reduction of
the calcium/phosphorous ratio in the dentin
following treatment with 10% carbamide
peroxide or 30% hydrogen peroxide, whereas
Kawamoto and Tsujimoto63 suggested that
hydrogen peroxide does not influence hydroxyapatite but only disrupts the organic components of the dentin.
The variability of the results obtained by
the different studies focusing on the effects
of bleaching products on the enamel structure can be explained by the methodology
employed, such as the type of teeth, storage
medium, time of exposure, composition of
commercial bleaching agents, and solution
pH.29 A wide variation of pH has been found
in the different available bleaching gels, and
it has been suggested that both decrease of
enamel microhardness and alteration of its
surface morphology can be attributed, to
some degree, to the acidic property of some
bleaching agents.44,47 However, the defects
observed after vital tooth bleaching are (1)
less severe than those produced by application of 37% phosphoric acid33 and (2) do not
seem to increase the susceptibility of enamel
to caries.64,65 Moreover, some studies have
postulated that the effects of bleaching products on enamel and dentin may be counteracted by the salivas remineralizing potential.29,44,59 The presence of fluoride in some
bleaching products could also lead to a remineralization effect and therefore an increase
of enamel microhardness during the treatment and posttreatment period.53
Collectively, the large amount of data
obtained by these studies has shown that no
or slight alterations of dental hard tissues are
associated with vital tooth bleaching.
However, in light of these disparate studies, it
would be of interest to standardize treatment
protocols aiming to (1) directly compare the
reagent employed and (2) identify a susceptible group in the population.
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BLEACHING PRODUCTS
EFFECTS ON ENAMEL AND
DENTIN BONDING TO A
COMPOSITE RESIN SYSTEM
The adhesive potential of a composite resin
system to bleached enamel has been
addressed by microtensile and shear bond
strength evaluation. A reduction in the enamelresin bond strength has been reported when
the bonding procedure is immediately realized after vital tooth bleaching and independently of the hydrogen or carbamide peroxide
concentration used.6671 This bond strength
reduction could account for a compromised
interface between enamel and resin. Indeed,
large zones of nonattachment,67,72 as well as
shorter and poorly defined resin tags,73 have
been described.
Usually, bleaching products are applied on
enamel; however, because enamel and
dentin are permeable to hydrogen peroxide,
application of bleaching products on enamel
can also affect the dentin beneath. Moreover,
in case of gingival recessions, adhesive
restorative procedures could be performed
on root surfaces with cervical dentin margins.
As for the enamel, the reduction in dentin
adhesion strength observed immediately after
bleaching has been described for both athome and in-office bleaching regimens.7476
The initial reduction in dental bond
strength has been attributed mostly to the
inhibition of resin polymerization by residual
peroxide and/or oxygen radicals present in
the enamel67,69,70 or in the dentin, since it has
been suggested that the dentin acts as an
oxygen reservoir.67,72,73 It has, however, been
accepted that the adverse effects on bond
strength can be reversed with time. Studies
have reported that dental bond strength values return to normal levels between 24
hours69 and 3 weeks after bleaching,77 which
allows the outward diffusion of the residual
peroxide from the bleached enamel surface.78 Based on these data, it has been recommended to delay adhesive restorative procedures for at least 24 hours after bleaching.
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EFFECT OF HYDROGEN
PEROXIDE ON PULP:
TOOTH SENSITIVITY
Tooth sensitivity is a major adverse effect of
vital tooth bleaching and has been reported by
several clinical studies with various incidences.7986 According to the study of
Haywood et al,81 tooth sensitivity was experienced by 52% of the patients who underwent
nightguard vital bleaching with 10% carbamide peroxide for 6 weeks. However, most
studies have reported that tooth sensitivity is
transient and disappears with or soon after the
cessation of treatment,8183 with most toothsensitive days occurring early in the whitening
procedure.83 If tooth sensitivity develops during
vital tooth bleaching, it has been suggested
to decrease of the amount of bleaching solution in the guard, to decrease the number of
hours of usage per treatment, or to interrupt
the procedure for a few days.87 The use of
desensitizing agents such as potassium nitrate
and fluoride has also been proposed to
reduce tooth sensitivity.88,89
Tooth sensitivity has mainly been attributed to the penetration of the bleaching agent
into the pulp chamber, thus resulting in a
reversible pulpitis. In vitro experiments have
shown that hydrogen peroxide, whether
applied directly or derived from carbamide
peroxide, diffuses throughout the enamel and
the dentin into the pulp chamber,90,91 even in
a short exposure time of 15 minutes.90
Various factors can influence the pulpal penetration of peroxide. Studies have reported
that the amount of hydrogen peroxide recovered in the pulp was positively correlated to
the length of time the agent was in contact
with the tooth surface91 and the concentration
of the bleaching agent used.92,93 Moreover,
Gkay et al94,95 found that the amount of penetration of hydrogen peroxide into the pulp
chamber of restored teeth was higher than
that into sound teeth and was influenced by
the type of restorative material.
Histologically, in vivo studies have
revealed that hydrogen peroxide diffusion
into the pulp chamber results in a reversible
inflammation of the pulp tissue, the degree of
this inflammation varying according to the
studies. Following a 2-week nightguard vital
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bleaching with 10% carbamide peroxide,

Fugaro et al96,97 described a slight and localized pulp reaction without increase of inflammatory markers. The slight histologic
changes observed were reversible within 2
weeks posttreatment. Seale et al,98 however,
noted in their in vivo study on dogs that application of 35% hydrogen peroxide for 30 minutes, for each of 4 weekly periods, caused,
within 3 days after treatment, a very marked
pulpal response in the area immediately
under the treated enamel surface. A resolution of this inflammatory response was
observed 60 days after the end of the treatment. In this study, the damages caused by
hydrogen peroxide were not intensified by
the addition of heat of 62C; moreover, no
deleterious effects on the pulp were
observed following application of heat alone.
However, concerns have been expressed
about the effect of the heat generated by
lamps used for the bleaching process on
pulp vitality. Indeed, Eldeniz et al99 and
Sulieman et al100 showed in their in vitro study
that the intrapulpal temperature increase
induced by using a diode laser-based lamp
was above the critical threshold of 5.6C
known to produce irreversible pulpal damage
in 15% of rhesus monkey teeth.101 Moreover,
aside from its potential effect on pulpal vitality, the elevation of temperature has also been
shown to promote hydrogen peroxide diffusion into the pulp chamber.102
At a cellular level, Bowles and Burns103
showed in their in vitro study that hydrogen
peroxide alone or with heat can inhibit several
pulpal enzymes. Hanks et al104 also reported
that diffusion of hydrogen peroxide from a
bleaching agent through dentin disks in vitro
reached a level capable of causing cytotoxic
effects on cultured fibroblasts. However, in
vitro studies are limited in their ability to simulate clinical conditions.104 Indeed, in vivo, it
has been proposed that the positive pressure
of the pulp and the osmotic pressure of the
gel are able to reduce the inward diffusion of
the bleaching agent molecules toward the
pulp.104,105 The amount of hydrogen peroxide
employed in in vitro studies may therefore be
higher than the amount effectively present in
the pulp chamber after a bleaching treatment in vivo.91,102
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Moreover, it has been suggested that the

pulp protects itself against damages induced
by hydrogen peroxide. Indeed, Lee et al106
have shown that treatment with hydrogen
peroxide at concentrations below 0.3
mmol/L increases the ability of odontoblasts
to produce dentin. Thus, it seems that odontoblasts can react in some degree to the action
of hydrogen peroxide and that mechanisms
in the pulp protect this tissue from radicals
generated by hydrogen peroxide. These
mechanisms can contribute to the reversibility
of both histologic damages and teeth sensitivity. Accordingly, no long-term irreversible
pulpal effects have been described following
vital tooth bleaching.81,84,107
TOXICITY
Adverse effects on the oral cavity
Several animal studies have described the
short-term adverse effects of hydrogen peroxide when applied on the oral tissues. In
rats, 4 applications at 15-minute intervals of
30% hydrogen peroxide on the tip of the
tongue have been shown to induce a vast
edema of the submucosal tissues. The healing
of this edema occurred within 7 days.108 In
mice, a topical application on the dorsal skin
of 15% to 30% hydrogen peroxide produced
a massive epidermal necrosis, as well as
inflammation and vascular damage.109 On
the sixth day, however, areas of epidermal
hyperplasia were seen and marked a mechanism of regeneration. Accordingly, gingival
irritation has often been reported in clinical
studies as a common adverse effect of nightguard vital bleaching.83,87 To prevent gingival
exposure to the bleaching product, it is therefore advisable that the guard cover only
enamel. Moreover, mechanical protection of
the gingival mucosa via the use of rubber
dam with ligatures and isolating cream is recommended when the vital bleaching is performed in office with a high concentration of
hydrogen peroxide.
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Acute systemic toxicity
Chronic systemic toxicity
Toxic effects of hydrogen or carbamide peroxide have been addressed in several animal
studies. In rats, 1 administration by stomach
gavage of 15 and 50 mg carbamide peroxide
per kilogram of body weight (BW) (or 150 and
500 mg of tooth whitener containing 10% carbamide peroxide) induced ulceration of the
gastric mucosa after 1 hour.110 The ulceration
started to heal 24 hours after the administration of these products. By administering a single oral dose of 5 g/kg BW of a tooth whitener
containing 10%, 15%, or 35% carbamide peroxide, Cherry et al111 showed that the acute toxicity of carbamide peroxide is concentrationdependent in rats. Three of 22 animals that
received the highest concentration of carbamide peroxide died within 48 hours; the others showed distress signs such as reduced
respiratory rate, decreased body temperature,
and labored breathing. Rats receiving smaller
concentrations of carbamide peroxide exhibited similar but milder signs of toxicity. These
data suggest that the acute effect of commercial tooth whiteners depends on the amount
and the concentration ingested. High concentration is acutely toxic to rats and sometimes
fatal. However, tooth-whitening products containing 35% carbamide peroxide are restricted
to the in-office technique, and their use is
therefore under clinical surveillance. In addition, it is unlikely that during nightguard vital
bleaching such an amount of tooth whiteners
would be ingested.112 Toxicity of tooth-bleaching products is therefore more related to an
accidental ingestion of these products, by a
young child, for example.
Because many symptoms observed in
humans after hydrogen peroxide ingestion
are similar to those reported in animal studies, it is likely that toxic effects of commercial
tooth whiteners are caused by hydrogen peroxide or its by-products. Typically, symptoms
induced by hydrogen peroxide ingestion in
humans have included bloating of the stomach with gas, gastric hemorrhaging, vomiting,
respiratory failure, convulsions, neurologic
damage, and death.113121 Even if no case
report has been described in the literature
concerning poisoning with tooth whiteners, it
is important to keep these products out of
the reach of children to avoid any accident.
In a Good Laboratory Practice Organization

for Economic Cooperation and Development
(OECD) guideline study, Weiner et al122 evaluated the subchronic toxicity of hydrogen peroxide (the active component in tooth whitening) when administered continuously for 13
weeks in the drinking water of catalase-deficient (C57 BL/6N) mice. The animal groups
that received 3,000 and 1,000 ppm hydrogen peroxide displayed small duodenal
mucosal hyperplasia. The duodenal lesions
were, however, reversible during a 6-week
recovery period. The no observed adverse
effect level (NOAEL) defined in this study was
100 ppm, corresponding to 26 and 37 mg
hydrogen peroxide/kg BW/day, respectively
for males and females. Extrapolation of these
data to human risk generally needs the use
of a safety factor, which aims to determine
the maximum level of exposure acceptable in
humans. Referring to the data obtained by
animal tests, this factor provides a margin of
safety to the person exposed to the chemical.
Assuming that humans are 10 times more
sensitive than animals and that differences
among personal sensitivities are in a 10-fold
range, Dahl and Pallesen123 have applied a
safety factor of 100.
For a NOAEL of 26 mg hydrogen peroxide/
kg BW/day and a safety factor of 100, the
daily exposure limit for a person should not
exceed 0.26 mg/kg BW/day. However,
because the NOAEL has been established
on a catalase-deficient strain of mice (which
is considered more sensitive to the potential
effects of hydrogen peroxide), the safe leve of
exposure to hydrogen peroxide in humans is
likely more important than 0.26 mg/kg
BW/day.
Several studies have shown that during
application of home bleaching products, peroxide is released into the oral cavity and
therefore possibly ingested.124130 The use of
10% carbamide peroxide (3.3% hydrogen
peroxide) when 500 mg of product is applied
in the tray has, however, been shown to be
safe, according to a study by Hannig et al,126
who found that 0.04 mg hydrogen peroxide/kg BW was recovered in the saliva of a
person of 60 kg after a 60-minute bleaching
period. In addition to the tray-based system,
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Hannig et al126 also determined the amount

of hydrogen peroxide released following the
application of strip (Crest Whitestrips, Procter
& Gamble; 5% hydrogen peroxide) and paint-on
(160 mg, between 5.0% and 5.5% hydrogen
peroxide) bleaching products. They noted
that the amount of hydrogen peroxide recovered in the saliva for the different products
varies between 0.004 and 0.046 mg/kg BW,
which is less than the safe recommended
daily dose.
These data suggest that when using low
doses and concentrations of hydrogen peroxide, the home bleaching systems are safe.
However, it appears that the amount of peroxide recovered in the saliva differs considerably depending on the products used.
Indeed, 1 of the paint-on gels tested by
Hannig et al126 was swept away in the first few
minutes of bleaching, leading, after 1 hour, to
a significant release of peroxide in the saliva.
The bleaching efficacy and the benefit/risk
ratio of products, which have a limited time of
contact with tooth surface, could therefore
be discussed. Moreover, studies generally
determine the amount of peroxide released
into the saliva during the first 2 hours of tooth
bleaching, whereas longer bleaching periods
are recommended for at-home bleaching
systems. Determination of peroxide recovered in the oral cavity at various intervals in
the recommended daily application time
should therefore be more appropriate for
evaluating the daily dose of exposure of
bleaching products.
GENOTOXICITY AND
CARCINOGENICITY OF
BLEACHING PRODUCTS
Hydrogen peroxide does not contain an
unpaired electron on its molecular orbital;
therefore, it is not a radical. However, in the
presence of partially reduced metal ions, in
particular iron, hydrogen peroxide is converted
into the highly reactive hydroxyl radical
through the Fenton reaction.23 Hydroxyl radical, along with superoxide anion radical and
singlet oxygen, is a reactive oxygen species
(ROS) normally generated by cellular metab-
652
olism.131 The 3 species are involved in the

mitochondrial respiratory chain,132 intracellular signaling cascades, and inflammatory
mechanisms.133 Under normal physiologic
conditions, the production of ROS is counterbalanced by the action of enzymatic and
nonenzymatic oxidants that contribute to
maintain ROS at a low steady-state concentration. Oxidative stress occurs when there is
an imbalance between cellular production of
ROS and antioxidant defense mechanisms
in favor of the oxidants. This process can
result from an increase of the cellular level of
either endogenous or exogenous ROS.134,135
In vitro studies
Experimental data support an important role
of excess ROS in the modification of cellular
DNA. DNA damage is the major cause of
cancer development, and elevated levels of
oxidative DNA lesions have been shown in
various tumors, making hydrogen peroxide a
potential carcinogenic agent.131
One of the most studied oxidative DNA
lesions is the formation of 8-hydroxyguanine
(8-OH-G) by the interaction of ROS, and particularly hydroxyl radical, with guanine.136 By
in vitro DNA synthesis, 8-OH-G directs the
incorporation of either desoxycytosin-5monophosphate (dCMP) or desoxyadenosin5-monophosphate (dAMP) in the DNA
strand opposite the lesion.137 It has also been
shown that this oxidative pair modification is
mutagenic in mammalian cells inducing targeted Guanine to Thymine transversions,138,139
a mutation that is found in oncogenes and
tumor suppressor genes of human cancer.140
8-OH-G is therefore mutagenic and potentially carcinogenic.133 Base pair substitution has
also been observed at the hypoxanthine guanine phosphoribosyltransferase (HPRT) locus
in primary human lymphocytes after cells
culture with hydrogen peroxide treatment.141
Other DNA damages produced by ROS in
vitro include deletions,141 frame shifts, DNA
strand breaks,142,143 sister chromatin exchange,
and chromosomal rearrangements.135,144146
In vitro studies have been essential to understanding the mechanism of action of hydrogen peroxide; they have therefore allowed
the characterization of the genotoxic and
mutagenic effects of ROS on DNA. Never-
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theless, they are not sufficient by themselves

to study the potential carcinogenic effect of
bleaching products in vivo because they do
not take into account the adsorption, distribution, kinetics, and excretion of hydrogen
peroxide.147 Moreover, the presence at much
lower levels of antioxidant molecules in isolated cells compared to endogenous tissues148,149 precludes the correlation between
in vitro and in vivo studies. Consistent with
this, chromosomic damages induced by
hydrogen peroxide in V-79 Chinese hamster
cells are prevented by the addition of antioxidant enzymes (catalases).144,150,151
In vivo studies
In vivo studies are essential to evaluating the
carcinogenic effect of hydrogen peroxide
used during tooth bleaching, as the points
discussed below, altogether, demonstrate.
The potential involvement of hydrogen
peroxide in carcinogenesis has been evaluated at both local and systemic levels. Studies
have focused on its ability to act as an initiator, a promoter, or a complete carcinogen.
To evaluate its influence on oral carcinogenesis, hydrogen peroxide has been
applied directly on either the skin or the oral
mucosa of experimental animals. Kurokawa
et al152 and Klein-Szanto and Slaga109 tested
the promoting and complete carcinogenic
activities of hydrogen peroxide on mice skin.
Kurokawa et al152 found that hydrogen peroxide has neither promoting nor complete carcinogenic activity. Epidermal hyperplasia,
however, was noticed in 45% of the mice in
the promotion test. By using higher concentrations of hydrogen peroxide, however,
Klein-Szanto and Slaga,109 concluded that
hydrogen peroxide was an extremely weak
promoter. In addition to skin-painting studies
on mice, side-of-contact effects for hydrogen
peroxide have been evaluated in the hamster
buccal cavity. Weitzman et al153 painted the
cheek pouches of hamsters twice weekly
with a 0.25% solution of dimethylbenzanthracene (DMBA) for 19 and 22 weeks and
twice weekly with 3% or 30% hydrogen peroxide (the day after DMBA application). No
significant increase in cheek carcinoma incidence was noted in hamsters treated with
DMBA and 3% hydrogen peroxide when
VOLUME 39
NUMBER 8
compared to the application of DMBA alone.

A trend toward augmentation of carcinomas
was observed, however, when 30% hydrogen
peroxide was used in combination with DMBA,
suggesting that 30% hydrogen peroxide had a
promoting effect on DMBA carcinogenesis.
The application of 30% hydrogen peroxide
alone, however, twice a week for 19 and 22
weeks did not induce tumors, but pathologic
changes frequently associated with preneoplastic lesions were observed.
As some amount of hydrogen peroxide is
possibly ingested during vital tooth bleaching (particularly with nightguard vital tooth
bleaching), it is important to consider the
potential carcinogenic effect of hydrogen
peroxide not only in the oral cavity but also at
a systemic level. In an experiment in which
mice were exposed to 0.1% and 0.4% hydrogen peroxide in drinking water for 100
weeks, an increase in dose-dependent incidence of duodenal hyperplasia appeared 10
weeks after the initial administration of hydrogen peroxide. After 65 weeks, a small but
statistically significant increase in carcinoma
was observed. From this study, the authors
concluded that hydrogen peroxide may have
enhanced the spontaneous occurrence of
duodenal hyperplasia or transformed hyperplastic lesions into neoplastic nodules.154 In
another study, mice were exposed to 0.4%
hydrogen peroxide in the drinking water for
up to 700 days. Erosion and hyperplasia in
the stomach and in the duodenum, as well
as duodenal cancer, were found after 90
days of exposure. The stomach lesions
regressed completely in mice exposed to
hydrogen peroxide for 180 days followed by
an exposure-free period of 30 days, but
some of the duodenal lesions persisted.155
In the light of all the animal studies that
have been performed, the International
Agency for Research on Cancer (IARC)156
has commented on the carcinogenic potential of hydrogen peroxide and concluded that
there is limited evidence in experimental animals and inadequate evidence in humans.
The IARC based its conclusions on the fact
that the weak enhancing, promoting, and/or
carcinogenic effect shown by some animal
studies occurred after repeated and highdose exposure of hydrogen peroxide, mak-
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ing these studies unrepresentative of low

quantities of hydrogen peroxide used for
tooth whitening. Regarding the mechanism
of hydrogen peroxide action and the inappropriate studies that have been performed on
animals, a large-scale clinical study is now
required to definitively exclude a carcinogenic risk for patients presenting susceptibilities, eg, a failure of the natural antioxidant
defenses, failure of DNA repair enzymes, or
tobacco and alcohol intake.
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Minoux.

Vital tooth bleaching:

Tooth whitening is an esthetic solution for

Assistant Professor, Department of Restorative Dentistry,

Associate Professor, Department of Restorative Dentistry,

Restorative Dentistry, Faculty of Dentistry, Universit Louis

natural color can be modified by intrinsic or

with the help of a custom-fabricated tray. The

They are therefore strong oxidative agents.

ing tooth bleaching using 10% carbamide

decreased the flexural strength and modulus

bleaching with 10% carbamide peroxide,

Moreover, it has been suggested that the

Acute systemic toxicity

Chronic systemic toxicity

In a Good Laboratory Practice Organization

Hannig et al126 also determined the amount

olism.131 The 3 species are involved in the

theless, they are not sufficient by themselves

compared to the application of DMBA alone.

ing these studies unrepresentative of low

6. Barghi N. Making a clinical decision for vital tooth

Concerns about the biologic adverse effects

Educ Dent 1998;19:831838.

1. Bleaching products induce no major alterations of enamel and dentin structures.

tooth whitening with peroxide. J Am Dent Assoc

in-office, at-home). Oper Dent 2005;30:156163.

The authors thank Dr Nicolas Matt and Suzanne Kleitz

evaluation of the efficacy of various bleaching

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34. Ben-Amar A, Liberman R, Gorfil C, Bernstein Y. Effect

whitening products. J Can Dent Assoc 2000;66:

of mouthguard bleaching on enamel surface. Am J

20. Leonard RH Jr, Bentley CD, Haywood VB. Salivary pH

changes during 10% carbamide peroxide bleach-

hydrogen peroxide on the light reflectance and

ing. Quintessence Int 1994;25:547550.

morphology of bovine enamel. J Oral Rehabil 2002;

21. Kashima-Tanaka M,Tsujimoto Y, Kawamoto K, Senda

N, Ito K, Yamazaki M. Generation of free radicals

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and/or active oxygen by light or laser irradiation of

tron microscopy study of dental enamel surface

hydrogen peroxide or sodium hypochlorite. J

exposed to 35% hydrogen peroxide: Alone, with

saliva, and with 10% carbamide peroxide. J Esthet

Restor Dent 2003;15:154164.

enamel in vitro. J Dent Res 1992;71:13401344.

trated hydrogen peroxide solutions on the surface

25. Hegedus C, Bistey T, Flora-Nagy E, Keszthelyi G, Jenei

morphology of human tooth enamel. J Endod 1988;

A. An atomic force microscopy study on the effect

26. Haywood VB, Leech T, Heymann HO, Crumpler D,

cus mutans to enamel after vital bleaching. J Dent

agents effects on enamel surface. J Oral Rehabil

dentin ultrastructureA confocal laser scanning

42. McGuckin RS, Babin JF, Meyer BJ. Alterations in

microscopy pilot study. Compend Contin Educ Dent

human enamel surface morphology following vital

bleaching. J Prosthet Dent 1992;68:754760.

28. Leonard RH Jr, Eagle JC, Garland GE, Matthews KP,

43. Bitter NC. A scanning electron microscopy study of

Rudd AL, Phillips C. Nightguard vital bleaching and