Aug. 10, 2004 Washington, DC -- Only one in ten diagnosed with squamous cell carcinoma of the oral cavity (oral cancer) is younger than 45 years. Many young adults lack the traditional risk factors for oral cancer, namely, long term tobacco and/or alcohol use. As a result, investigation of other factors which may contribute to the development of cancer in these patients is difficult because of the relative rarity of the cases and the wide array of potential carcinogens. Past research has revealed that heavy alcohol and tobacco use was prevalent in some young oral cancer patients, but not at a higher rate than in a control population without cancer.
This has led clinical epidemiologists to wonder what, if any, potentially avoidable environmental exposures may predispose some young patients to develop oral cancer. One answer may be from an otolaryngology—head and neck cancer department at a major academic medical center. Two young patients were diagnosed with oral cancer and both reported the use of tooth whiteners in the years before their diagnosis. Physician specialists and researchers joined to create a clinical history of these two patients and performed a retrospective survey of oral cancer patients to determine the prevalence of tooth whitener use in the entire population and in patients less than 45 years old.
The authors of “Tooth Whiteners as a Risk Factor for Oral Cavity Squamous Cell Carcinoma: A Report of Cases,” are Alan R. Burningham, MD, Bruce J. Davidson MD, Sonya Malekzadeh, MD., Rahul Dasgupta, B. Emmerich Yoder, MD, and Kenneth A. Newkirk, MD, all from the Department of Otolaryngology-Head and Neck Surgery, Georgetown University Hospital, Washington, DC. Their findings are being presented at the 6th International Conference on Head and Neck Cancer (http://www.sic2004.org) being held August 7-11, 2004, at the Wardman Park Marriott, in Washington, D.C.
Background: The active ingredient in most tooth whiteners used today is carbamide peroxide. In general, a carbamide peroxide gel is placed in a dental tray, which is then worn by the patients for anywhere from a few hours to overnight. Although initially available from a dentist, these preparations have become available directly to consumers. Some of these products have concentrations of carbamide peroxide of up to 22 percent. Carbamide peroxide is composed of approximately 35 percent hydrogen peroxide, and when used as a whitener in an aqueous solution, it decomposes to release hydrogen peroxide and urea. The hydrogen peroxide is responsible for the tooth whitening effect of these products.
The discussion of the safety of tooth whiteners with peroxide has focused on the harmful effects of the free radicals generated in the whitening process. Although free radicals are produced by normal cellular metabolism, free radicals outside the cell can cause cellular damage by reacting directly with proteins, lipids, and nucleic acids. Past research showed that chronic ingestion of hydrogen peroxide increased the incidence of duodenal adenocarcinoma in mice; the substance has also been implicated as a tumor promoter in hamster cheek pouch mucosa.
Under ideal conditions, the peroxide containing gel used in tooth whiteners would not come into contact with the oral mucosa, but studies have shown that often less than 50 percent of the whitener is present in the trays one hour after application. The amount of leakage may be even higher in over-the-counter whitening products in which the trays are not custom fitted by a dentist. Therefore, during the whitening process, the oral mucosa is exposed to high concentrations of peroxide. The argument can be made that hydrogen peroxide is rapidly metabolized in the oral cavity by superoxide dimutase, catalase, salivary peroxidase, ascorbic acid and other anti-oxidants, and therefore does not have a significant clinical affect on the mucosa. However, studies on peroxide metabolism in the oral cavity have focused on whole mouth metabolism, not focal areas of high peroxide concentration for an extended period of time.
Methodology: The research protocol was reviewed by the MedStar Research Institute Institutional Review Board and approved. Patients with primary oral cancer diagnosed at Georgetown University Medical Center between 1997 and 2003 were identified. The charts were reviewed, and patients were contacted by phone for interviews. Demographic and tumor information was obtained from the chart. Patients were asked specifically regarding the use of tooth whiteners, alcohol, and tobacco products. Results were analyzed using an unpaired t-test or the Mann-Whitney test for ordinal data.
The clinical histories of the two young patients examined included the following:
Patient #1: A 26-year-old male presented with a T1N1M0, Stage 3, squamous cell carcinoma of the right lateral tongue. He presented with a six month history of a plaque on his right lateral tongue, a biopsy confirmed squamous cell carcinoma. He was a nonsmoker and consumed only three alcoholic beverages (beer) per week. He used tooth whitening trays on multiple occasions two years prior to his presentation. In addition, he used toothpaste with whitener and twice daily fluoride rinse.
Patient #2: A 22-year-old female presented with a T2N1M0, Stage 3, squamous cell carcinoma of the right lateral tongue. She presented with a two month history of a nonhealing ulceration on her right tongue that was treated by her dentist with topical antifungals. A biopsy showed moderately differentiated SCCA. A CT scan revealed a 3.8 cm enhancing mass in her right tongue extending into the right submandibular space and 1 cm right level II necrotic lymph node. She rarely smoked cigarettes and admitted to only light social alcohol use. She used a commercially available tooth whitening product for one month, three years prior to presentation.
Results: Nineteen patients agreed to participate in the study. Three (16 percent) of patients reported a history of tooth whitener use in the past. There was no significant difference in age at diagnosis between the patients who used and did not use tooth whiteners, however the tooth whitener users tended to be younger (mean age 34.3 vs. 52.4, p = 0.11). There was no significant difference in gender distribution. Alcohol use and smoking history were similar in the two groups. There was no significant difference in initial T-stage, M-stage, or overall stage between the two groups. However, patients who used tooth whiteners were more likely to present with regional lymph node disease, than those who did not use tooth whiteners. All three patients presented with node positive disease as opposed to 3 of 16 (19 percent) patients without a history of tooth whitener use.
Conclusions: Tooth whiteners containing carbamide peroxide were used infrequently in this small sample of patients with oral cancer. However, patients who used these products tended to be less than 45 years old, to have nodal disease at presentation, and to not have other risk factors for cancer. This data does not establish a link between these products and the development of oral cancer, but it does raise some intriguing possibilities. Even though carbamide peroxide and the hydrogen peroxide generated in the whitening process are not proven carcinogens in the oral cavity, they cause local inflammation and mucosal trauma at high concentrations. The complex interactions of this inflammatory response combined with the ability of free radicals to act directly upon nucleic acids has an unpredictable effect on the tissues. The data suggests that the patients who used tooth whiteners were more likely to present with metastatic lymph nodes. This finding, if confirmed by larger studies with more statistical power, would certainly implicate whiteners as a significant factor in oral cancer tumor biology.
The authors concede that the main weakness of the study is that the sample included few patients who used tooth whiteners, and no non-cancer control population. Overall, the study had a poor patient participation rate and the data is subject to recall bias. Also, the fact that the two patients who used peroxide containing tooth whiteners were under the age of 45 years old may simply reflect the demographics of people who use these products. In the future, the researchers hope to collect data on tooth whitener use in all patients who present with oral cancer, and find a suitable control group for comparison.
In summary, peroxide containing tooth whiteners were used by two young patients who presented with oral cancer, and one older patient with the disease used a tooth polish. These data do not necessarily suggest a causative relationship between the use of these products and the development of oral cancer. However, free radicals generated in the whitening process have carcinogenic potential, and therefore the use of these products in this patient population should be studied further.
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