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American Journal of Epidemiology Advance Access originally published online on August 30, 2007
American Journal of Epidemiology 2007 166(10):1159-1173; doi:10.1093/aje/kwm193
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American Journal of Epidemiology © The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

Oral Health and Risk of Squamous Cell Carcinoma of the Head and Neck and Esophagus: Results of Two Multicentric Case-Control Studies

Neela Guha1, Paolo Boffetta1, Victor Wünsch Filho2, Jose Eluf Neto3, Oxana Shangina4, David Zaridze4, Maria Paula Curado5, Sergio Koifman6, Elena Matos7, Ana Menezes8, Neonila Szeszenia-Dabrowska9, Leticia Fernandez10, Dana Mates11, Alexander W. Daudt12, Jolanta Lissowska13, Rajesh Dikshit1 and Paul Brennan1

1 International Agency for Research on Cancer, Lyon, France
2 Department of Epidemiology, School of Public Health, University of São Paulo, São Paulo, Brazil
3 Departamento de Medicina Preventiva, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
4 Institute of Carcinogenesis, Cancer Research Center, Moscow, Russia
5 Associação de Combate ao Câncer em Goiás, Goiânia, Brazil
6 National School of Public Health, Oswaldo Cruz Foundation Ministry of Health, Rio de Janeiro, Brazil
7 Angel H. Roffo Oncology Institute, University of Buenos Aires, Buenos Aires, Argentina
8 Departamento de Clinica Medica, Faculdade de Medicina, Universidade Federal de Pelotas, Pelotas, Brazil
9 Institute of Occupational Medicine, Lodz, Poland
10 Instituto Nacional de Oncologia y Radiobiologia, La Havana, Cuba
11 Institute of Hygiene, Public Health, Health Services, and Management, Bucharest, Romania
12 Oncology Unit, Hospital de Clinica de Porto Alegre, Porto Alegre, Brazil
13 Department of Epidemiology and Cancer Prevention, Cancer Center and M. Sklodowska-Curie Institute of Oncology, Warsaw, Poland

Correspondence to Dr. Paul Brennan, Genetic Epidemiology Group, Genetics and Epidemiology Cluster, International Agency for Research on Cancer, 150 cours Albert Thomas, 69008 Lyon, France (e-mail: brennan{at}iarc.fr).

Received for publication September 28, 2006. Accepted for publication May 31, 2007.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Poor oral health has been reported as a risk factor in the etiology of head and neck cancer. Data on oral health were ascertained as part of two multicenter case-control studies comprising 924 cases and 928 controls in central Europe and 2,286 cases and 1,824 controls in Latin America. Incident cases of squamous cell carcinoma of the head and neck (oral cavity, pharynx, larynx) and esophagus, as well as age (in quinquennia)- and sex frequency-matched controls, were enrolled from 1998 to 2003. Poor condition of the mouth (central Europe: odds ratio (OR) = 2.89, 95% confidence interval (CI): 1.74, 4.81; Latin America: OR = 1.89, 95% CI: 1.47, 2.42), lack of toothbrush use (Latin America: OR = 2.36, 95% CI: 1.28, 4.36), and daily mouthwash use (Latin America: OR = 3.40, 95% CI: 1.96, 5.89) emerged as risk factors for head and neck cancer, independent of tobacco use and alcohol consumption. Missing between six and 15 teeth was an independent risk factor for esophageal cancer (central Europe: OR = 2.84, 95% CI: 1.26, 6.41; Latin America: OR = 2.18, 95% CI: 1.04, 4.59). These results indicate that periodontal disease (as indicated by poor condition of the mouth and missing teeth) and daily mouthwash use may be independent causes of cancers of the head, neck, and esophagus.

dentition; dentures; esophageal neoplasms; gingivitis; head and neck neoplasms; mouthwashes; oral hygiene; periodontal diseases

Abbreviations: CI, confidence interval; OR, odds ratio


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Cancers of the upper aerodigestive tract (head and neck (oral cavity, pharynx, and larynx) and esophagus) collectively account for approximately 10 percent of the world's total new cancer cases (1). There have been substantial increases occurring in the incidence and mortality from oral and pharyngeal cancers in many areas of the world, most notably in central and eastern European countries (1–3). In contrast, there are data to suggest that the incidence of oropharyngeal cancer is decreasing in some areas of Latin America (4, 5). Incidence rates vary for upper aerodigestive tract cancers worldwide: Latin America and central Europe experience some of the highest rates and thus represent important regions for study (1).

Tobacco use and alcohol consumption are the main risk factors for this group of cancers (6). However, these cancers also occur among lifelong tobacco and alcohol abstainers and, thus, other risk factors such as conditions related to oral health and hygiene (i.e., poor condition of the mouth, dentition, bleeding gums, and mouthwash use) have been suspected to contribute to its etiology (3, 7–28).

Previous studies of oral health in relation to head and neck cancer have been limited by such factors as small numbers of cases or a lack of detailed information on oral health indicators. Thus, we describe the results of two multicentric case-control studies in Latin America and central Europe, the largest and most comprehensive studies to date of oral health and hygiene in relation to head and neck cancer.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study design and study population
Two hospital-based case-control studies were conducted in central and eastern Europe and Latin America to assess lifestyle, occupational, and genetic risk factors for head and neck and esophageal cancers. Cases and controls were recruited in Russia (Moscow), Romania (Bucharest), and Poland (Lodz and Warsaw) from 1998 to 2002 and in Argentina (Buenos Aires), Cuba (La Habana), and Brazil (Rio de Janeiro, São Paulo, Pelotas, Porto Alegre, Goiânia) from 1998 to 2003. Both studies were coordinated by the International Agency for Research on Cancer according to an identical protocol for both case and control recruitment. Incident cancer cases of the oral cavity (International Classification of Diseases for Oncology, Second Edition, codes C00.3–C00.9; C03.0–C03.1, C03.9; C04.0–C04.1, C04.8, C04.9; C05.0; C06.0–C06.2, C06.8, C06.9), pharynx (C01.9; C02.8–C02.9; C05.1–C05.2, C05.8, C05.9; C09.0–C09.1, C09.8, C09.9; C10.0–C10.4; C12.9; C13.0–C13.2, C13.8, C13.9; C14.0, C14.2, C14.8), larynx (C32.0–C32.3, C32.8, C32.9), and esophagus (C15.0–C15.5, C15.8, C15.9; C16.0) were recruited at participating hospitals (total: central Europe = 1,007 and Latin America = 2,423).

Trained medical staff reviewed medical records to extract relevant diagnostic information, including date and method of diagnosis, histologic type, tumor location, stage, and grade. All cases had a histologically or cytologically confirmed diagnosis of squamous cell carcinoma and were enrolled consecutively.

Eligible controls included residents of the study areas for at least 1 year who were admitted to the same hospitals as the cases or in a comparable catchment area (controls in São Paulo were not recruited from oncology hospitals, and population-based controls were enrolled in Warsaw). Controls were hospitalized for prespecified conditions thought to be unrelated to tobacco use or alcohol consumption, such as infections or parasitic diseases; diseases of the blood and blood-forming organs; endocrine, nutritional, or metabolic disorders; mental and behavioral disorders; diseases of the eye and adnexa or of the ear and mastoid process; diseases of the circulatory, respiratory (i.e., pharyngitis, sinusitis, and vocal chord polyp), digestive, genitourinary, and central nervous systems; disease of the skin and subcutaneous tissue; disease of the musculoskeletal system and connective tissue; injury, poisoning, and certain other consequences of external causes; congenital malformation, deformation, and chromosomal abnormalities; and symptoms, signs, and abnormal clinical and laboratory findings. No single group comprised more than 20 percent of the overall control group. In each center, controls were frequency matched (approximately 1:1) on age (in quinquennia) and sex to cases enrolled during the same time period (total: central Europe = 928 and Latin America = 1,824).

Trained interviewers conducted in-person interviews to elicit information on demographic background, tobacco use and alcohol consumption, occupational history, and dietary and other lifestyle habits (i.e., oral health and hygiene practices) using identical protocols across all centers for each study. Each center received approval by an ethical committee before conducting the study.

Variables
Oral health indicators.
The questionnaires used in the central European and Latin American studies were similar although not identical. Tooth-brushing frequency (1 = never, 2 = less than once per day, 3 = once per day, 4 = twice or more per day) and the type and duration of denture use were assessed in both studies. Conversely, the instrument and material used to clean teeth, the occurrence of bleeding gums (1 = no, 2 = sometimes, 3 = always or almost always), frequency of mouthwash use (1 = never, 2 = less than once per day, 3 = once per day, 4 = twice or more per day), and regularity of dental visits (1 = every year, 2 = every 2–5 years, 3 = less than every 5 years, 4 = never) were assessed by self-report and only in the Latin American study. A trained interviewer (a professional dentist was used in some centers) recorded the number of missing teeth, presence of visible lesions, and general oral health (1 = good, 2 = average, 3 = poor) through visual inspection of the mouth in both studies. General oral health/hygiene was assessed in both studies by use of standard criteria designed to elicit the presence of tartar, gingival bleeding, mucosal irritation, and decaying teeth.

Covariates.
Covariates included age, gender, center, education, tobacco use, and alcohol consumption. The age at which full-time education was completed (central Europe) or the highest level of education completed (Latin America) was used as a measure of socioeconomic status.

Lifetime smoking habit was measured in tobacco pack-years, and subjects were also classified as ever/never smokers. A tobacco pack-year was defined as smoking the equivalent of one pack of cigarettes (cigarette, papirossi, cigar, or pipe) daily for 1 year. A former smoker was defined as having quit for at least 2 years, while a never smoker did not use more than 100 cigarettes, papirossis, cigars, or pipes in his/her lifetime. Data were not collected on smokeless tobacco use.

Lifetime alcohol consumption was calculated as the product of the ethanol content (in grams), frequency, and duration of consumption for all types of beverage(s). A never drinker had never consumed alcoholic drinks (central Europe) or had consumed them less than once a month (Latin America).

Given the uncertain role of diet and upper aerodigestive tract cancers, as well as its unknown association with socioeconomic status and oral hygiene variables, we did not attempt adjustment for diet because of the possibility of overadjustment.

Statistical analysis
We analyzed the data from the central European and Latin American studies separately. Multivariable logistic regression models including terms for oral health indicators, age, sex, education, country (central Europe) or center (Latin America), tobacco pack-years, and cumulative alcohol consumption were used to obtain odds ratios and 95 percent confidence intervals with SAS software, version 8.0 (SAS Institute, Inc., Cary, North Carolina). All oral hygiene indicators and covariates were analyzed as categorical variables, except for the following covariates which were analyzed as continuous variables: age, cumulative alcohol consumption, tobacco pack-years, and age when full-time education was completed. Case-control comparisons were made using t tests for continuous variables and chi-square tests for categorical variables, and two-sided p values were obtained.

Effect modification was assessed by stratifying on smoking (never/former/current) and drinking (never/ever) habit. p values for interaction were obtained by fitting the multivariable models with a cross-product term of the main effect by the smoking or alcohol variable. Heterogeneity between centers was tested in the multivariable models by adding the cross-product term of oral hygiene and center. Chi-square tests for trend were performed by treating the independent categorical main effect variable as an ordinal variable. Complete case analysis was used so that cases with missing data were omitted from the analysis. The advantages of this method are that it is the simplest approach and that it leads to unbiased parameter estimates under the assumption that data are missing at random (29).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Head and neck squamous cell carcinoma cases were composed of the following subsites: oral cavity (central Europe: 30 percent; Latin America: 18 percent), pharynx (central Europe: 19 percent; Latin America: 36 percent), and larynx (central Europe: 38 percent; Latin America: 38 percent). The remainder of the cases were esophageal squamous cell carcinoma cancers (central Europe: 14 percent; Latin America: 8 percent). A total of 83 cases (8.2 percent) in central Europe and 137 cases (5.7 percent) in Latin America were excluded because they were not squamous cell carcinoma. Most of the cases were male (85 percent), aged 50–69 years (central Europe: 66 percent; Latin America: 63 percent), ever drinkers (central Europe: 85 percent; Latin America: 89 percent), ever smokers (central Europe: 91 percent; Latin America: 94 percent), and of lower educational status (central Europe: 47 percent; Latin America: 87 percent). In general, cases used larger amounts of tobacco and alcohol than did the controls (p < 0.0001) (table 1).


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  		TABLE 1. Characteristics of study subjects in central Europe and Latin America, 1998–2003*,{dagger}

 
Tests for heterogeneity showed that the risk of head and neck cancer associated with missing teeth (the most objective variable) (p = 0.32) or the other oral health indicators (p > 0.05) did not differ by center in central Europe. In Latin America, the results differed by center for the risk of head and neck cancer associated with missing teeth (p = 0.03) but not with the other oral health indicators (p > 0.05). Therefore, we combined the data from all of the centers in central Europe and Latin America, respectively (data not shown).

Multivariable analysis for the oral health indicators in central Europe is shown stratified by subsite in table 2. Poor or average versus good condition of the mouth was a strong risk factor for all subsites, but especially for the oral cavity (odds ratio (OR) = 4.51, 95 percent confidence interval (CI): 1.95, 10.44; ptrend < 0.0001) and pharynx (OR = 7.66, 95 percent CI: 2.94, 19.97; ptrend < 0.0001). Missing teeth, denture use, and tooth-brushing frequency in general did not appear to be associated with head and neck cancer. However, brushing teeth less than once per day increased the risk of laryngeal cancer by 87 percent (95 percent CI: 6, 233; ptrend = 0.03) when compared with those who brushed at least twice daily, although never brushing teeth was not a statistically significant risk factor.


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  		TABLE 2. Results for oral health indicators stratified by subsite in central Europe, 1998–2003*

 
A similar analysis for Latin America is detailed in table 3. Poor oral hygiene upon visual inspection and twice daily mouthwash use were risk factors for head and neck cancer across all subsites; however, the strongest effects were seen in the oral cavity (for poor hygiene vs. good: OR = 2.91, 95 percent CI: 1.87, 4.52; ptrend < 0.0001; for frequent mouthwash use vs. never use: OR = 5.86, 95 percent CI: 2.91, 11.77; ptrend < 0.0001). Using fingers or sticks to clean teeth (OR = 5.28, 95 percent CI: 2.39, 11.71) and frequent gum bleeding (OR = 1.94, 95 percent CI: 1.07, 3.52; ptrend = 0.02) significantly increased risk only for oral cavity cancers, while never having a dental check-up was significantly associated with cancers of the pharynx (OR = 2.14, 95 percent CI: 1.34, 3.41; ptrend < 0.0001) and larynx (OR = 1.63, 95 percent CI: 1.08, 2.48; ptrend = 0.01). Missing six or more teeth was significantly associated with cancer of the pharynx (OR = 1.45, 95 percent CI: 1.03, 2.05) and larynx (OR = 1.67, 95 percent CI: 1.16, 2.42). Denture use was significantly associated with pharyngeal cancer (OR = 1.41, 95 percent CI: 1.08, 1.83). Tooth-brushing frequency and the material used with the toothbrush did not affect risk.


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  		TABLE 3. Results for oral health indicators stratified by subsite in Latin America, 1998–2003*

 
To assess effect modification by tobacco use, we stratified by never/former/current smoking habit (table 4). Poor oral hygiene was a significant risk factor only among current smokers in both study populations (central Europe: ORpoor vs. good = 3.60, 95 percent CI: 1.95, 6.62; ptrend < 0.0001; Latin America: ORpoor vs. good = 1.98, 95 percent CI: 1.37, 2.85; ptrend < 0.0001). Never having a dental check-up was also a risk factor only among current smokers (OR = 1.85, 95 percent CI: 1.20, 2.85; ptrend = 0.004), while twice daily mouthwash use increased the risk among former smokers (OR(≥2 times vs. 1) = 4.98, 95 percent CI: 1.72, 14.43; ptrend = 0.003) and current smokers (OR = 9.15, 95 percent CI: 2.13, 39.22; ptrend = 0.0002). Tooth-brushing frequency, gum bleeding, and the instrument or material used to clean teeth were not significantly associated with head and neck cancer, regardless of smoking status.


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  		TABLE 4. Oral hygiene variables stratified by smoking habit in central Europe and Latin America, 1998–2003*

 
The effect of oral health risk factors depending on ever/never alcohol use was assessed in table 5. Poor oral hygiene was a significant risk factor for head and neck cancer only among ever drinkers in both study populations (central Europe: ORpoor vs. good = 2.53, 95 percent CI: 1.53, 4.18; ptrend < 0.0001; Latin America: OR = 1.81, 95 percent CI: 1.36, 2.40; ptrend < 0.0001). Missing six or more teeth significantly increased cancer risk by 43–47 percent in comparison with missing five or fewer teeth among ever drinkers only in the Latin American population. Using fingers or sticks to clean teeth and daily mouthwash use imparted substantial risks, regardless of alcohol use. Tooth-brushing frequency and gum bleeding showed no association across alcohol use categories.


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  		TABLE 5. Select oral hygiene variables stratified by drinking habit in central Europe and Latin America, 1998–2003*

 
Table 6 shows the association between oral health indicators and esophageal cancer in central Europe and Latin America. Missing 6–15 teeth more than doubled the risk of esophageal cancer compared with missing five or fewer teeth in both studies (central Europe: OR = 2.84, 95 percent CI: 1.26, 6.41; ptrend = 0.36; Latin America: OR = 2.19, 95 percent CI: 1.04, 4.63; ptrend = 0.26), while the other oral health indicators were not significantly associated.


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  		TABLE 6. Oral hygiene indicators and risk of esophageal cancer in central Europe and Latin America, 1998–2003*

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Although previous studies have been inconsistent, they suggested that oral health and hygiene indicators are associated with risk of head and neck cancer (2, 3, 7–22, 24–28, 30–34). Our results show that poor condition of the mouth, poor dentition, regular mouthwash use, lack of toothbrush use, and never having a dental check-up are risk factors for head and neck cancers, independent of tobacco use and alcohol consumption.

The strengths of the present studies are 1) the collection of comprehensive information on oral health indicators and 2) the large number of study subjects enrolled and interviewed by trained interviewers in central Europe and Latin America, regions that have a high incidence of head and neck cancer. To our knowledge, these are the largest studies to date addressing the issue of oral hygiene and these cancers.

Both the interviewer-assessed (general oral hygiene and missing teeth) and self-assessed (i.e., dental visits, mouthwash use) variables related to oral health were significantly associated with increased risk of head and neck cancers. Oral hygiene, as assessed by interviewer inspection of the oral cavity for the presence of visible lesions, decaying teeth, tartar, and mucosal irritation, emerged as a strong risk factor for all subsites of the oral cavity, pharynx, and larynx.

Missing 6–15 teeth was observed to increase the odds ratio of esophageal squamous cell carcinoma by more than twofold in both Latin America and central Europe. However, when missing teeth were more than 15 in number, no increase in risk was observed. If we argue that loss of teeth is caused by periodontal disease, then no increase in risk after loss of more than 15 teeth may be due to the absence of a periodontal pathogen with no/minimal teeth remaining. However, it should be noted that, in Latin America, dental care is restricted virtually to the high social class (even to a small fraction), and dental extraction has been, and still is, a current and culturally accepted practice for the majority of the population facing tooth pain. In the absence of preventive programs, tooth extraction is cheaper and widely accepted, thus affecting the general population at an early age and often before periodontal disease has installed. In this sense, missing teeth could be a risk factor because it is an indicator of periodontal disease but can also represent an indicator of low socioeconomic status in Latin America. This could also partially explain why the results for tooth loss differ slightly between the Latin American and central European study populations.

Bleeding gums were also associated with an increase of oral cavity cancer. As poor oral hygiene could result in periodontal disease and also because tooth loss and bleeding gums are indications of periodontal inflammation, our results seem to suggest that periodontal disease is associated with an increased risk of head and neck cancer.

The association between periodontal disease, as possibly indicated by poor oral hygiene, tooth loss, and bleeding gums, and head and neck cancer is biologically plausible, as periodontal infection can lead to a release of inflammatory mediators (proinflammatory cytokines) (35). The host responses to bacterial inflammation are known to play a role in development of cancer (36). The observed association of missing teeth with esophageal cancer is not surprising, as poor dentition may cause individuals to swallow large pieces of poorly chewed food that may irritate the esophagus (37).

Poor dentition has also been associated with oral flora that can produce carcinogenic by-products to increase the risk of upper gastrointestinal cancer. Abnet et al. (38) have suggested that individuals with missing teeth may have a greater burden of an oral flora that is more effective in the reduction of nitrate to nitrite (39) or in the production of acetaldehyde, a metabolite of alcohol that has proved to be carcinogenic (40–42). Our results on oral hygiene, tooth loss, and gum bleeding are in agreement with those of many other studies conducted on this subject (3, 7–21, 38, 43–45).

Variables such as oral hygiene and gum bleeding are, however, subjective in nature. It is possible that these subjective exposures may have been misclassified, depending on whether an interviewer or dentist was performing the examination to assess oral hygiene. For example, necrosis and halitosis associated with the cancer itself may be interpreted as poor oral hygiene by the investigator. A limitation of this study was that we were not able to evaluate interviewer bias by stratifying the results of the oral hygiene assessment by whether the oral examinations were conducted by dentists versus nondentists. It was also not possible to blind the interviewers; however, participant identification codes did not indicate case/control status, and all other local staff were blinded (i.e., data coders) in order to minimize observer bias. Additionally, oral hygiene may be affected by the presence of symptomatic precancerous oral lesions or cancer. Because we do not have any history of oral hygiene and gum bleeding, one may argue that these are the effect of recent disease rather than its cause.

We also observed that an increasing frequency of dental check-ups was a protective factor for developing head and neck cancer. This may be partly explained by the assumption that individuals who have regular dental visits are concerned about their oral hygiene; this could be an indicator of good oral health care that could reduce or prevent exposures to some carcinogens. As regular dental visits would also allow trained practitioners to screen for any premalignant changes during a routine examination, our results seem to be plausible.

In summary, neither the frequency nor the material used for tooth brushing was associated with upper aerodigestive tract cancers. Use of fingers or sticks for cleaning was a risk factor for oral cancer, and this effect was modified by alcohol use. Interestingly, using fingers or sticks to clean teeth also elevated risks among lifelong alcohol abstainers. Fingers and sticks do not adequately clean the teeth, thereby allowing carcinogens to remain longer and to penetrate the oral mucosal surface (3, 9, 15, 17, 19, 20). Poor cleaning can also allow bacteria to grow, which in turn can produce acetaldehyde (41, 46). Using fingers and sticks could be a strong indicator of factors related to lower socioeconomic status. For example, in 2002, approximately 22 percent of the Brazilian population did not have access to water supply services, and 38 percent did not have access to sanitation facilities, with these rates being higher in the northern, northeastern, and midwestern regions (4). In addition, it can be very difficult to access diagnostic and treatment services in some areas for specific groups of the population in Brazil (4). Neither denture use nor duration of denture use was generally associated with head and neck cancer risk in either of our studies, consistent with previous publications (3, 9, 11, 12, 17, 18, 31). However, denture use was a protective factor for pharyngeal cancer in Latin America (table 3).

In our study, mouthwash use was a significant risk factor for all subsites except the esophagus, where mouthwash is less likely to come in contact, and had the strongest association with cancer of the oral cavity. Twice daily mouthwash use significantly increased risk among current and former smokers and drinkers, as well as among lifelong alcohol abstainers. This increase in risk among alcohol abstainers suggests that the alcohol content of certain mouthwashes (up to 30 percent) may be a causal agent for head and neck cancers. Winn et al. suggest that "oral swishing with a mouthwash containing 25 percent ethanol might provide a local mucosal tissue exposure similar to drinking a 100-proof (50 percent ethanol) alcoholic beverage diluted with equal parts of water or other mixers" (13, p. 3046). Our results are consistent with those of previous studies in which mouthwash increased the risk of oral cancer among smokers and drinkers (12, 13, 18, 19, 27, 30, 31), as well as among tobacco and alcohol abstainers (26, 30, 47).

Because daily mouthwash use imparted large risks especially among drinkers and smokers, we tested to see if mouthwash use was significantly correlated with tobacco use and alcohol consumption. Pearson's correlation showed that there was no association between tobacco pack-years (r = –0.02, p = 0.22) or cumulative alcohol consumption (r = –0.03, p = 0.10) and increasing frequency of mouthwash use.

Our mouthwash results should be interpreted with caution, as they are limited by our recording only the frequency of use. Questions on the brand of mouthwash, alcohol content, duration of use, and how long it was retained in the mouth were not asked. Mouthwash is an expensive product in Latin America and is therefore not widely used. Our data show that most of our Latin American study population never used mouthwash and that there were greater proportions of people with secondary and university education (our measure of socioeconomic status) using mouthwash more frequently (r = 0.07, p < 0.0001).

Further, mouthwash use was strongly correlated with the presence of visible oral lesions (r = 0.29, p < 0.0001). This suggests that increased mouthwash use could be in response to symptoms of disease and could explain why other studies have not observed increased risk for head and neck cancer with use of mouthwash (12, 18, 28, 30, 34, 47). The lack of correlation between mouthwash use and smoking and drinking suggests that, if the mouthwash does have a high alcohol content, this could be a possible mechanism because it is thought that alcohol could act as a solvent for carcinogens and facilitate their penetration into tissues (46). However, it would be difficult to separate the independent effects of alcohol or the other mouthwash components to determine their roles as carcinogens. It would be interesting to stratify by alcohol content in mouthwash in future studies.

In conclusion, oral hygiene indicators appear to be strong, independent risk factors in our study, and our results are consistent with those of previously published reports. Although our results may be generalized to our target populations in central Europe and Latin America, the replication of results among these populations and the consistency with previous research suggest that poor oral hygiene and its indicators may be independent risk factors for upper aerodigestive tract cancers. These are the largest and most comprehensive studies to date examining oral health and hygiene and risk of head and neck cancer; however, more detailed questions in future studies are warranted. Education was used as a measure for socioeconomic status in our studies, and the results may be influenced by residual confounding due to socioeconomic status. Access to dental and overall health care may be limited to those of higher socioeconomic status, especially in Brazil and Buenos Aires, thereby contributing to the incidence and mortality of these cancers. Lockhart et al. (32) questioned whether the oral hygiene indicators are cofactors in disease or if they reflect poor compliance with overall health care. Our results suggest that periodontal disease, as measured by gum bleeding, dentition, and condition of the mouth, is likely a cause of head and neck cancers, and they emphasize the importance of frequent screening programs for prevention.

An alternative approach to identifying whether this observed effect is causal is via the analysis of genes that metabolize ethanol to acetaldehyde. Assuming that ethanol in mouthwash is an important causal factor, one may predict that gene variants that metabolized ethanol rapidly would have an important protective effect. We have recently identified a strongly significant protective effect for one such variant in the ADH2 gene that resulted in a 50 percent decrease in risk among fast metabolizers (p < 0.0002) (48). We plan to test this hypothesis in the Latin American study.


   ACKNOWLEDGMENTS
 
Neela Guha was supported by a Special Training Award from the International Agency for Research on Cancer. These studies were supported by grants from the INCO Copernicus program (contract ERBIC15-CT96-0313 (central Europe) and contract IC18-CT97-0222 (Latin America)) and the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (contract 2001/01768-2).

The authors would like to thank Dr. Mia Hashibe for her advice and Gilles Ferro for data management.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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