Tooth bleaching using peroxide compounds has been practiced in dentistry for more than a century. The procedure, which typically involves the use of high concentrations of hydrogen peroxide (H2O2, usually 30–35%), was exclusively performed by dentists in their offices (Li 1996). Home bleaching, however, was not available until 1989, when the at-home bleaching procedure was introduced by Haywood and Heymann (Haywood and Heymann 1989). The initial home-use tooth bleaching gel contained 10% carbamide peroxide, which is equivalent to approximately 3.5% H2O2, as the active ingredient, and it was available only from dentists. With its demonstrated efficacy, its low cost compared with in-office bleaching, and the convenience of self-application by the user, at-home bleaching quickly gained popularity and has now become an integrated procedure in esthetic dentistry (Kihn 2007). In addition, over-the-counter (OTC) and infomercial home-use bleaching products have now become available directly to consumers without involving dental professionals. In recent years, tooth bleaching using materials and procedures similar to those used for in-office bleaching but performed in nondental settings, such as mall kiosks, spas, and cruise ships, has become available (American Dental Association [ADA] 2009a).
Although attempts have been made to introduce at-home tooth whiteners that claimed to contain no peroxide, such products did not gain acceptance because of the lack of evidence regarding their efficacy and controversy over their nonperoxide claim (Li 2003). Current tooth bleaching materials, regardless of their use for in-office or at-home bleaching, are typically made in the form of a gel and contain a peroxide compound as the active ingredient, with carbamide peroxide and H2O2 being the most common (Li 1996, 2003). In general, H2O2 in concentrations ranging from 25–40% is the choice for in-office bleaching gels, and at-home bleaching formulations use carbamide peroxide and/or H2O2 in concentrations of 10–22% carbamide peroxide or 3–7.5% H2O2. In recent years, there has been a trend toward elevating the H2O2 concentration in home-use bleaching gels, and products of up to 15% H2O2 have now become available directly to consumers.
Throughout the history of tooth bleaching using peroxide-based gels, there has been little dispute regarding the efficacy. However, safety concerns associated with potential toxicologic effects of peroxides used in bleaching gels have been raised. With the accumulation of scientific data over the last two decades, most of the toxicologic concerns with bleaching using peroxide-based gels have diminished. Nevertheless, controversy concerning their safety has continued, and there have been reports of adverse effects of bleaching on oral tissues (see Figures 21.1C and 21.5) and restorative materials (Cubbon and Ore 1991, Hammel 1998, Dahl and Pallesen 2003, Attin et al. 2004, Goldberg et al. 2010).
This chapter provides an overview on safety issues in tooth bleaching in relation to biologic properties of H2O2 and discusses proper use of bleaching to maximize the benefits while minimizing the potential risks.
SAFETY CONCERNS WITH TOOTH BLEACHING RELEVANT TO BIOLOGIC PROPERTIES OF H2O2
Peroxide compounds typically form H2O2 in aqueous solutions. Chemically, carbamide peroxide is composed of approximately 3.5 parts of H2O2 and 6.5 parts of urea, so a bleaching gel of 10% carbamide peroxide contains approximately 3.5% H2O2. Consequently, H2O2 is the active ingredient regardless of whether a bleaching gel contains carbamide peroxide or H2O2.
The chemistry of H2O2 is well understood. As a chemical, H2O2 was first identified in 1818; it was detected in human respiration in 1880. The well-known Fenton reaction was proposed in 1894. Two important enzymes for H2O2 metabolism in humans, peroxidase and catalase, were found in 1898 and 1901, respectively. Since 1969 when H2O2 was recognized as an important byproduct in oxygen metabolism after the discovery of another important enzyme, superoxide dismutase (SOD), in human physiology and biochemistry, the research efforts on the biologic properties of H2O2 have significantly increased (Li 1996). H2O2 is now known as a normal intermediate metabolite in the human liver, with a daily production of approximately 6.48 g.
A key characteristic of H2O2 is its capability of producing free radicals, which are known to be capable of inducing various toxicities, including hydroxyl radicals that have been implicated in various stages of carcinogenesis. More relevant to safety is that oxidative reactions of free radicals with proteins, lipids, and nucleic acids are believed to be involved in a number of potential pathologic consequences; the damage from oxidative free radicals may be associated with aging, stroke, and other degenerative diseases (Harman 1981, Lutz 1990). H2O2 is highly cytotoxic to cultured mammalian cells at concentrations ranging from 1.7–19.7 µg/mL (0.05–0.58 mmol/L) (Li 2003). The oxidative reactions and subsequent damage in cells by free radicals are believed to be the major mechanisms responsible for the observed toxicity of H2O2.
On the other hand, there are various defensive mechanisms available at cellular and tissue levels to prevent potential damage to cells during oxidative reactions and to repair any damage sustained. Enzymes such as catalase, SOD, peroxidase, and selenium-dependent glutathione peroxidase, which exist widely in body fluids, tissues, and organs, effectively metabolize H2O2 (Floyd 1990). Studies have shown that the cytotoxicity of H2O2 can be effectively reduced or eliminated by simply increasing serum concentration in the culture media (Sacks et al. 1978, Rubin and Farber 1984). In a cell culture study, 20 mM H2O2 was undetectable after 30 minutes in the culture media alone and after 15 minutes in the media with bone tissues, indicating decomposition and inactivation of H2O2 in cell culture systems (Ramp 1987). Human saliva has also been found to contain these enzymes; in fact, salivary peroxidase has been suggested to be the body’s most important and effective defense against the potential adverse effects of H2O2 (Carlsson 1987).
Because of the known toxicology of H2O2, especially the effects of free radicals, there have been concerns regarding potential systemic adverse effects if the bleaching gel is ingested as well as local adverse effects on enamel, pulp, and gingiva when the gel directly contacts the tissues (see Figures 21.1 and 21.6) (Li 1996, 2001, ADA 2009). The safety controversies surrounding peroxide-based tooth bleaching have prompted not only scientific deliberations but also legal challenges to the use of these products in dentistry (Weiner et al. 2000, Scientific Committee on Consumer Products 2005).
POTENTIAL EXPOSURE TO BLEACHING GEL
Exposure is one of the important factors that determine toxicologic consequences of an agent. For in-office bleaching, the exposure to bleaching gel during the treatment appears to be minimal (see Figures 21.1, 21.3, and 21.6) because the soft tissues are adequately protected with use of barrier materials (see Figure 21.5B). In addition, at the end of treatment the gel is first removed with a high-volume evacuator, and the teeth are rinsed thoroughly with water. Little, if any, gel is left behind for possible ingestion. Furthermore, because of its high concentration of H2O2, any gel contact with oral soft tissues would immediately cause irritation and signal its presence to the patient and dentist. Accordingly, the actual exposure dose of H2O2 during in-office tooth bleaching is minute if the product is used properly.
For at-home bleaching, the initial study estimated that the approximate dose of carbamide peroxide for each at-home application was 90 mg (Haywood and Heymann 1989). This was confirmed in a later report in which the average amount of bleaching gel used clinically for 10 maxillary teeth (full arch) was 502 mg per application (Li 1996). When both arches are being bleached, the average amount of bleach is approximately 1.0 g. For a bleaching gel containing 10% carbamide peroxide, the exposure dose would be 100 mg per application. Dahl and Becher (1995) estimated that approximately 10% of the applied bleaching gel may be consumed during the application. Therefore, for an individual of 60-kg body weight who performs at-home bleaching for both arches once daily, the exposure to the bleaching gel can be calculated at 1.67 mg/kg/day, and the exposure to carbamide peroxide through a gel containing 10% carbamide peroxide will be 0.167 mg/kg/day. Carbamide peroxide contains approximately 3.5% H2O2; consequently, the estimated H2O2 exposure is 0.058 mg/kg/day, or 3.48 mg H2O2 per day for an adult of 60-kg body weight.
This estimation appears conservative, because it assumes a constant concentration of 10% carbamide peroxide in the gel during the whole bleaching period, which usually lasts an hour to overnight. Studies have shown that the H2O2 content decreases with the time—particularly significant during the earlier part of the application (Matis 2000, Sagel et al. 2001, Al-Qunaian et al. 2003). The rate of peroxide decomposition appears to be associated with the viscosity of the material. A clinical study found that the human oral cavity, including that of adults, juveniles, infants, and adults with impaired salivary flow, was capable of eliminating 30 mg H2O2 in less than 1.5 minutes (Marshall et al.). Consequently, the estimated exposure dose of 3.48 mg H2O2 during at-home bleaching does not appear to constitute a significant risk.
SAFETY CONCERNS WITH POTENTIAL SYSTEMIC ADVERSE EFFECTS OF PEROXIDE-BASED TOOTH BLEACHING
Potential systemic toxicity of H2O2 and peroxide-based tooth bleaching gels has been the subject of a comprehensive body of literature, which includes topics of acute and subacute systemic toxicity, sensitization or allergic reaction, reproductive toxicity and teratology, genotoxicity, and carcinogenicity (Li 1996). Accidental ingestion of large amounts of concentrated H2O2 solution can cause acute toxic consequences including death (Humberston et al. 1990, Rackoff and Merton 1990, Christensen et al. 1992, Cina et al. 1994, Dickson and Caravati 1994). Such incidences appear to be more common in the pediatric population (71% for patients younger than 18 years of age) than adults (Dickson and Caravati 1994). One major factor associated with the toxicity of H2O2 is its concentration. Ingestion of H2O2 solutions of less than 10% usually produces no significant adverse effects, although it may cause mild irritation to mucous membranes that results in spontaneous emesis or mild abdominal bloating (Humberston et al. 1990, Rackoff and Merton 1990). Exposure to higher concentrations of H2O2 (>10%), however, can result in severe tissue burns (see Figure 21.6) and significant systemic toxicity. In addition to the oxidative tissue damage, gas embolism is responsible for various pathologic consequences of H2O2 ingestion (Humberston et al. 1990, Rackoff and Merton 1990, Dickson and Caravati 1994).
Subacute systemic toxicities of H2O2 and peroxide-based tooth bleaching gels have been investigated in animals only. The no-observed-effect level (NOEL) of H2O2 in rats was 30 and 56.2 mg/kg/day for 100 and 90 days, respectively (Kawasaki et al. 1969, Ito et al. 1976). Mice receiving a higher H2O2 dose at 150 mg/kg/day for 35 weeks grew normally and showed no visible abnormalities; necropsy results, however, showed changes in the liver, kidney, stomach, and small intestine (U.S. Food and Drug Administration [FDA] 1983). In rats, the dose of H2O2 at 506 mg/kg for 90 days caused suppressed body weight gain, decreased food consumption, and changes in hematology, blood chemistry, and organ weights (Ito et al. 1976).
Published research on sensitization potential, reproductive toxicity, and teratology of H2O2 and peroxide-based tooth bleaching gels remains sparse. Available data appear to indicate a low risk of sensitization potential because peroxide compounds exist ubiquitously in our environment and diet, and H2O2 is a normal intermediate metabolite of humans (Li 1996). A plausible explanation for the negative productive toxicity or teratologic effects of H2O2 is that the ingested H2O2 is quickly and effectively metabolized before it reaches the target organs (Hankan 1958, Burnett et al. 1976, Korhonen et al. 1984, de Lamirande and Gagnon 1994).
The results of studies on the genotoxicity of H2O2 and peroxide-based tooth bleaching gels have been somewhat controversial. The overall data available so far show that H2O2 and peroxide-based tooth bleaching gels are genotoxic only in in vitro systems without enzymatic activation; when enzymatic activation is incorporated in in vitro assays or when tested in animals, H2O2 and peroxide-based tooth bleaching gels are nongenotoxic (Li 1997, 2000, 2011b). Again, such observations are most likely related to the effective metabolic process of peroxide by microsomes or in vivo defensive systems.
Consequently, with the available toxicologic data on H2O2 as well as the research on bleaching gels and their exposure assessment, safety concerns regarding most potential systemic toxicities associated with the use of gels containing 10% carbamide peroxide have largely diminished. When these products are used appropriately, the H2O2 exposure from bleaching is essentially limited to the oral cavity, and it is incapable of reaching a systemic level to be toxic because of the effective metabolic defensive mechanisms.
However, the issue of carcinogenicity of H2O2 has remained controversial in the literature, and results of some studies are contradictory (Li 2000, 2011b). Most found no evidence of carcinogenicity of H2O2; a few showed that H2O2 was anticarcinogenic, whereas several investigators reported carcinogenicity or cocarcinogenicity of H2O2. The studies that have been cited most frequently as evidence of carcinogenicity and cocarcinogenicity of H2O2 were reported by Ito et al. (1981, 1982, 1984) and Weitzman et al. (1986). However, evaluation of these studies found significant deficiencies in design and conduct of the experiments as well as in the assessment of the results; consequently, the findings of these four studies were determined to be inadequate to substantiate their conclusions (Li 1996, 2011b).
It is obvious that any carcinogenicity or cocarcinogenicity of tooth bleaching constitutes a significant health risk. Because of the potential significance of the Weitzman study, which used local application of H2O2 on oral mucosa of Syrian golden hamsters, the same study was repeated using proper design and methods; the results found no evidence of carcinogenicity or cocarcinogenicity of 3% H2O2 (Marshall et al. 1996). Consequently, bleaching using 10% carbamide peroxide, which is equivalent to 3.5% H2O2, is regarded as having no significant carcinogenic or cocarcinogenic risks. The overall data on bleaching obtained from more than 20 years also appear to support this conclusion. However, because of the significance of the carcinogenicity and relatively limited data available on the topic for bleaching, especially for products with more than 10% carbamide peroxide, questions and debates over the carcinogenic risks of bleaching arise periodically. Future research is encouraged to help clarify the controversy and concerns with the topic.
POTENTIAL LOCAL ADVERSE EFFECTS ASSOCIATED WITH PEROXIDE-BASED TOOTH BLEACHING