In the USA, intraoral cancers generally evolve from a precancerous lesion, 1 most often an oral leukoplakia. 2 Leukoplakia is defined as a white patch that cannot be characterized as any other disease. 3 The prevalence of oral leukoplakia is from 1 to 5% in the US adult population. 4,5 Tobacco and excessive alcohol use are important risk factors for leukoplakia. 3,6–8
An oral hygiene product that has recently begun to cause concern among oral pathologists is Viadent®, which contains sanguinarine, the principal alkaloid extract of the bloodroot plant (Sanguinaria canadensis L.). Sanguinarine has activity against bacterial dental plaque 9 and has been incorporated into both mouthwash and toothpaste.
A preliminary descriptive study of maxillary vestibule leukoplakia found that 89% of the individuals with leukoplakia had a history of Viadent® product use. 10 We designed a case-control study to evaluate the association between Viadent® use and oral leukoplakia.
Subjects and Methods
Cases of leukoplakia diagnosed between January 1997 through December 1998 were identified using records from the biopsy service, Section of Oral and Maxillofacial Pathology, College of Dentistry, The Ohio State University. Individuals were defined as cases if the biopsy showed hyperorthokeratosis, epithelial atrophy, and epithelial atypia or dysplasia. The control group comprised 148 individuals attending the student clinics at the College that were also referred to the Section for evaluation of a condition other than leukoplakia.
Once cases and controls were identified, data were collected by two methods: 1) a self-administered questionnaire, and 2) clinical examination or record review. The questionnaire developed for this study included demographic information; use of Viadent® rinse and paste, including frequency and duration of Viadent® use; and use of tobacco and alcohol consumption, including frequency and duration. Clinical data collected included site and size of lesion. All controls were examined to ensure that they did not have leukoplakia. To evaluate data reliability the questionnaire was re-administered to 5% of the sample.
For data analyses, we used Mantel-Haenszel methods with stratification, and logistic regression, simultaneously controlling for gender, age, tobacco use, alcohol consumption, and dental prosthesis use.
The kappa statistic for questionnaire data test-retest reliability was 0.90. Table 1 reports the demographic distribution and use of Viadent® products, tobacco products, alcohol consumption, and dental prosthesis in cases and controls. The mean age of the cases was 61.2 ± 1.1 years, which was substantially older than the controls (47.2 ± 1.5).
In the bivariate analyses (Table 2), we examined the use of Viadent® products, tobacco, alcohol, and a dental prosthesis. The risk of leukoplakia was greater for users of Viadent® products in any form, ranging from six to ten times. There was a slightly increased OR with the use of tobacco, alcohol, and dental prostheses.
Results of logistic regression (Table 3), controlling simultaneously for confounding factors, showed that those patients who had used Viadent® products were 9.7 (95% CI = 4.7–21.6) times more likely to be a case. Age was also a risk indicator; the risk of being a case increased by a factor of 1.06 for every year of age (CI = 1.04–1.09). Dose response relation was tested. The risk of leukoplakia was highest in users of both paste and rinse (OR = 11.0, CI = 4.4–32.0), followed by users of rinse only (OR = 10.4, CI = 2.5–63.4) (Table 4). Users of paste only had the lowest risk (OR = 7.2, CI = 2.0–30.7). Risk of leukoplakia increased 2.5 times with each increase in the daily frequency of use (CI = 1.8–3.7), by a factor of 1.1 for each year that the duration of use increased (CI = 1.05–1.2), and by a factor of 1.04 for each unit increase in frequency times duration (CI = 1.02–1.07).
A recent literature review 11 regarding Viadent® use and oral leukoplakia concluded that the association is spurious. Our results show that Viadent® users were eight to eleven times more likely to have leukoplakia, a finding not easily dismissed. We demonstrated a dose-response relation using three independent variables: type of product used (paste, rinse or both); daily frequency of use; and number of years the products were used.
Tobacco and excessive alcohol use have previously been identified as risk factors in leukoplakia. 3,7,8,11 Several tobacco variables were studied in this analysis, including any tobacco use versus no use; current use versus past use; smoke and smokeless tobacco versus no use. Except for current tobacco use versus past tobacco use (OR = 2.5, CI = 1.2–5.5), none of these other variables was associated with an important increase in risk of developing leukoplakia.
Measures were taken to reduce the potential effects of selection bias, information bias, and confounding in this study. To ensure that cases and controls were similar except for the condition being studied, a control group was selected that had also been referred to Oral Pathology. Also, all patients referred within a given time period were approached. As with any questionnaire, recall of the respondent is an issue. Since the cases and controls were not aware of the exact purpose of the study, except that it was to study the causes of white oral lesions, the recall error or bias is expected to be effectively random. Further, all the questions were close-ended, and examiners were blinded to the exposure status of the individual.
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