Alcohol-containing mouthwashes and oral cancer.
Critical analysis of literature

CARRETERO-PELÁEZ Mª A, ESPARZA-GÓMEZ GC, FIGUERO-RUIZ E, CERERO-LAPIEDRA R. ALCOHOL-CONTAINING MOUTHWASHES AND ORAL CANCER. CRITICAL ANALYSIS OF LITERATURE. MED ORAL 2004;9:116-23.

SUMMARY

For centuries, mouthwashes have been used in order to provide us with oral health or cosmetic benefits. Nowadays, in most countries, there is a variety of formulas available for the general public in the form of products which may require prescription or not.
Alcohol is used in mouthwashes as a solvent of other ingredients and as a preservative of the preparation. For years, different formulas of mouthwashes have been used, however, the question about its alcohol content being a threat for health or not has recently appeared. The high quantity of alcohol in some mouthwashes combined with the fact that they keep in contact with the oral mucosa for much more time than alcoholic drinks, can make us think about a harmful effect from a local mechanism. Mouthrinses increase the time of the mucosa being in contact with alcohol and it has been proved that those with a high content of alcohol do cause hyperkerastosic lesions both in human beings and laboratory animals.
At the moment and with the data we have, it has not been possible to establish a causal relationship between the use of alcohol-containing mouthwashes and the development of oral cancer. There is neither an evidence of the fact that alcohol increases the effects of antiplaque agents in mouthwashes.

Key words: Mouthwashes, mouthrinses, alcohol.

INTRODUCTION

Mouthwashes: Definition and purpose of alcohol in them.

Mouthwashes are liquid preparations intended for being applied on teeth and mucosa of the oral cavity and pharynx in order to exert an antiseptic, astringent and sedative local action (1, 2). The most commonly used vehicle in mouthwashes is water and the active principles are various, mainly, antiseptics, antibiotics, antifungals, astringents and anti-inflammatories.

Depending on its composition and the desired effects, mouthwashes can be considered as cosmetics for oral health which require an industrial registry or as products which require the pharmaceutical registry of dental product (Spanish Royal Decree 1599/1997, second supplementary provision: dental products and other) (3).

Alcohol can be used in mouthwashes as a solvent of the active principles. In solutions for external use, as in the case of mouthwashes, alcohol has qualities both as a solvent and an antiseptic, and moreover, it has been recognised as an active preservative to 10-12 % (4).

The presence of alcohol in a proportion until 5% in chlorexidine formulas seemed to increase the efficiency of the product, possibly due to the stabilization of the mixture and the decrease of the risk of contamination of the product (5). However, the formulas of the alcohol-free chlorexidine is equally effective in the control of the bacterial plaque and the reduction of the gingival inflammation (6). Therefore, this should be recommended in patients for whom alcohol is contraindicated, those with mucositis, immunocompromised, irradiated in the head and neck, those sensitive to alcohol, and in children (7). Likewise in cases of oral lesions because of the pain alcohol may cause (6).

The uses of mouthwashes.

Normally, the active ingredients of mouthwashes are antimicrobial agents which have a temporal effect of reducing the totality of the micro organisms of the oral cavity (8-10). One of the most common uses of mouthwashes is to fight against halitosis (11-13). Mouthwashes used in the treatment of gingivitis and periodontitis usually contain chlorexidine and must inhibit or diminish bacteria associated with plaque (14).

Mouthwashes have also been used as a symptomatic treatment for ulcerations, with ambiguous results or various interpretations, as a treatment of infection by Candida and as a relief for the pain and discomfort caused by oral inflammation (15-17).

Sodium fluoride-containing mouthwashes are recommendable for children, whose enamel is more porous, and in adults with high risk of suffering decay. The principles which are most commonly used for the treatment of dental hypersensitivity are potassium nitrate and sodium fluoride in different concentrations (18). The most frequently used antigallstones agents are the pyrophosphates (19).

Adverse effects of mouthwashes.

A high concentration of ethanol, a low value of pH and other ingredients of mouthwashes such as artificial sweeteners or flavouring agents, can be potential irritants, considered as individuals or in a synergic mode (20).

Alcohol has a caustic effect and, therefore, it destroys the tissues of the oral cavity. Local alterations such as epithelium detachment, mucosal ulcerations, gingivitis and petechias, have been observed in people who have used mouthwashes with 25% of alcohol or more. White lesions associated to long use of alcohol-containing mouthwashes have been observed in human oral mucosa and in laboratory animals (21, 22).

Ethanol, both in commercialized mouthwashes and mixed with water, can cause oral pain. The strength of the pain is directly proportional to the quantity of ethanol in the mouthwash and to the duration of the rinse. Ethanol levels under 10% do not usually cause important pain sensations (23).

As an example, we have in table 1 the alcohol-containing mouthwashes commercialized in Spain and the concentration of alcohol in each of them (24).

Mouthwashes may potentially cause immediate or late oral or systemic allergic reactions (17). The can also modify hard tissues causing enamel demineralization and dyeing. Moreover, mouthwashes may vary the hardness of the restoration materials, though their content of alcohol is not the only involved factor (25-27).

MATERIAL AND METHOD

Between 1979 and 1991 seven studies of cases and controls were published about the possible association between mouthwash use and the development of oral cancer (28-34). Elmore and Horwitz evaluated the epidemiologic evidence existing until 1995 (35). In 2001 Winn looked for the association of mouthwash use and the risk of suffering oral and pharyngeal cancer (36) (see table 2).

Out of a group of 200 individuals, Weaver, in 1979 (28) found 11 who were not tobacco or alcohol consumers but had developed oral cancer. Ten (nine women) of these eleven had used mouthwashes at least twice a day for more than twenty years. Only two of them diluted the mouthrinse sometimes and in the majority of the mouthwashes used by them the quantity of alcohol was of 25% (8 of them used the same trademark). The purpose of the s was to fight against halitosis.

From a study of 206 women with oral and pharyngeal cancer and 352 controls, Blot (29) concluded that there was not an increased risk in those who used mouthwashes. In the control group the mouthwash use was more frequent among smokers and patients with prosthesis.

In 1983, Wynder (30) studied 571 patients, men and women, with oral and pharyngeal cancer and 568controls. He pointed out that many commercial mouthwashes contained colouring and flavouring agents, as well as high quantities of ethanol. The frequent mouthwash use was separated in different categories depending on the duration of the use in years. The number of cases was low but no high risk was observed as the years of use increased. The highest risk was observed in those women who had been using mouthwashes for 1 to 4 years. This short-term effect may be due to the use of the mouthwash as a response to the symptoms of the disease.

Mashberg (31) studied the mouthwash use and its relation with oral and pharyngeal cancer in tobacco and alcohol consumers. There was a similar proportion of cases (43%) and controls (48%) that used mouthwashes often. The differences among these percentages were not significant for statistics.

Kabat, in 1989, (33) considered admissible that the long exposure to certain ingredients of mouthwashes could increase the risk of oral cancer. Cases did not react to an increased frequency of mouthwash use in comparison to controls. The reasons for using mouthrinses were associated to the exposure to tobacco and alcohol.

The data of Winn's work (34) related individually the mouthwash use with cancer in pharynx, tongue and other oral parts. In a more recent study (36) it was shown that a fourth of the cases of oral cancer in men and half of the cases diagnosed to women are not related to tobacco or alcohol. The search for an explanation led to the consideration of other potential risk factors, including the mouthwash use, diseases and infections of the oral cavity, lesions caused by prosthesis, deficient oral hygiene and bad state of dental health, dietary deficiencies and low levels of nutrients present in serum, such as carotenoids, and also the possible intervention of the human pappiloma virus.

In order to make a joint evaluation of the results obtained from the studies published, an analysis has been carried out in which two measurements have been taken into account, which are: odds ratio (OR) and the association index Phi (j). OR is a numeric value interpreted as the risk of getting a disease due to a certain exposure. The j index is based on the statistic number χ2 and it relates qualitative dichotomic variables (with two categories) (37, 38).

RESULTS

If we evaluated mouthwash exposure between cases and controls by OR, we would obtain the results shown in table 2. The reference value of OR is 1, which means that the studies whose data provide an OR more than 1 (28, 29, 30, 34) show a risk of 1.14; 1.04; 1.26 y 1.17 times more probability of developing cancer due to the mouthwash use. OR less than 1 show that there is not an increased risk of suffering cancer because of the mouthwash use.

In table 3 appear the results of the application of the j index to the review of the literature. The values obtained are so close to zero that it cannot be affirmed that there is a relation between mouthwash use and the suffering from cancer or between not using mouthwashes and not suffering from cancer. The values that would indicate a significant relation between the variables "using mouthwashes" and "having the disease" should be close to +1.

The results of Weaver's study (28) must be valued bearing in mind two of its own limits; on the one hand, the low number of cases that did not smoke or drink alcohol, and on the other hand, the impossibility of making a comparison between cases and controls. From his studies, Wey (39) was able to observe that oral cancer occurred in a significant sample of the people who did not smoke or drink alcohol, and that the trend was in old women that showed an early stage of the disease.

The results of Blot's study (29) showed that the risk of developing cancer increased, but not significantly, in non-smoking women who used mouthwashes. There was not a defined trend in the observed subgroup as for the frequency of use of the mouthwash, the time it was hold in mouth or whether it was diluted or not.

Wynder (30) concluded that in men, the duration of the mouthwash use was significant but it was reversely related to oral cancer (the longer it was the mouthwash use, the less the cancer developed). In women, the frequent mouthwash use (daily and occasionally) was significant, but the duration was again related to cancer in reverse manner.

In Mashberg's study (31) cancer was not statistically associated to the mouthwash use in alcohol or tobacco consumers. Neither was the trademark of the mouthwash related to the disease. In the same way that in Blot's study, a positive relation between mouthwash use and pharyngeal cancer is suggested in non-smokers.

Despite being a relatively low number of cases, the results of Kabat's study (33) did not support a causal relation between mouthwash use and the risk of cancer. Although this study was not able to rule the possibility that the chronic mouthwash use contributed to the risk of developing oral cancer in women out, the results conclude that there is not such an effect.

Winn's results (34) support an increase of the risk (OR=1.17) of developing the disease related to the frequent mouthwash use. This increase was bigger in women than in men, but it was not bigger in the group of people who did not smoke or drink alcohol (36). The risk increase as it did the frequency and the duration of the mouthwash use. With these results, it is not clear if the mouthwash use per se or some factor related to their use are involved in its relation with oral cancer.

Frequently, mouthwashes contain colouring, flavouring or sweetening agents, but the association of the increased risk with the use of trademarks with a content of alcohol equal or greater than 25 %, suggested that, at least in part, alcohol was responsible. Winn considered acceptable a causal relation between alcohol contained in mouthwashes and the development of oral cancer, since alcohol is a risk factor according to the epidemiologic studies carried out in different populations. Although the systemic effects of alcohol could contribute to this fact, it seems more probable that it is due to a local mechanism because of the direct contact of alcohol with the oral mucus. The local effects of alcohol may be the results of its metabolism in acetaldehyde in the oral epithelium or because of the oral bacteria, or of an increase of the oral mucus' permeability towards tobacco or other carcinogens.

The odds ratio's figures for the mouthwash use where found not to be high in individuals of any of the three genotypes (genotypes 1-1 and 1-2, and slow metabolism genotype 2-2) for the alcohol dehydrogenase type 3.

This last study showed that, as a whole, there was not a relation (OR = 0.87) between the frequent or normal mouthwash use and pharyngeal or oral cancer. Moreover, the risk did not increase as the exposure to the mouthwash increased, fact that was measured for the frequency and duration of the use or for other characteristics, such as the use of the mouthwash diluted. The risk was high, but not significantly, in the small group of people who where not alcohol or tobacco consumers. In this study, a higher risk of tumours in the tongue and the floor of the mouth was detected but this risk was not statistically significant in any case.

Nowadays there is a trend to commercialize products with a relatively low amount of alcohol and to formulate alcohol-free mouthwashes.

DISCUSSION AND FUTURE POSSIBILITIES

Eight studies of cases and controls that examine the relation between mouthwash use and oral cancer have been presented. Six of them were based on hospitalized patients, one of them (29) included people identified from death certificates. The other two were samples of the general population.

The compilation and analysis of data varied considerably among studies. The methodology of a study of cases and controls must consider a numerous sample with a selection of cases and controls out of the general population.

The lack of consistency between the findings of the published studies that evaluate the relationship between mouthwash use and the risk of oral and pharyngeal cancer can be related to the methodological variations, the limitation in sizes of samples, the difficulties for measuring exposures and the low levels of risks. As an example, it can be mentioned that in the Blot's and Wynder's studies, the relation existed only among women, while Winn found relations in both genders. In the same way, in some of the studies the relation was only among people who were not alcohol or tobacco consumers and in some other, among alcohol and tobacco consumers (40, 41).

It is likely to bear in mind that patients are not a true reflection of the real figures of exposure to tobacco or alcohol. This is a possible suggestion since it is known that alcohol consumers tend to admit that they consume less than the real quantity they consume. The same occurs with smokers. Nevertheless, there are no social pressures that make people give untrue information about the mouthwash use (40).

It is also possible that the mouthwash use is related to a risk factor which is unknown in people who are not alcohol or tobacco consumers.

It should be considered that the mouthwash use may be a response to oral cancer and not its cause (42).

Other factors which have been identified as able to increase the risk of developing oral cancer are the diet or some considerable lost teeth which are not replaced (42).

Despite the fact that it has not been proved that there is an increased risk related to mouthwash use in people with show or fast metabolism genotype for the alcohol dehydrogenase type 3, future studies of oral cancer should take into consideration the evaluation of the metabolic susceptibility genes, as long as it is possible.

The use of genetic and molecular markers of the metabolism of alcohol and tobacco can help to clarify the carcinogenetic mechanism of those factors, as well as the potential risk associated to the alcohol contained in mouthwashes.

CONCLUSION

The size and the analysis of the samples of the published studies of cases and controls lack homogeneity. Therefore, the results of the studies that evaluate the possibility of the mouthwash use being a risk factor for oral cancer are unconscious and sometimes contradictory. In the future it would be recommended to try to homogenize the samples of the subjects of the study in order to obtain conclusive results.

With the data we have, it has been impossible to establish a causative relation between mouthwash use and the development of oral cancer. In the other hand, it does not seem to be and evidence justifying the use of alcohol in mouthwashes, and even less in high quantities.

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