- Email: [email protected]
Mouthwash and oral cancer risk: An update
Oral Oncology (2009) 45, 198– 200
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/oraloncology
REVIEW
Mouthwash and oral cancer risk: An update Carlo La Vecchia
*
Istituto di Ricerche Farmacologiche ‘‘Mario Negri’’ Milano e Istituto di Statistica Medica e Biometria ‘‘G.A. Maccacaro’’, ` degli Studi di Milano, Via Giuseppe La Masa 19, 20156 Milano, Italy Universita Received 10 July 2008; received in revised form 26 August 2008; accepted 27 August 2008 Available online 25 October 2008
KEYWORDS Alcohol; Case–control studies; Mouthwash; Oral cancer; Risk
Summary The possible relationship between mouthwash use and oral cancer risk has been the subject of at least 10 case–control studies published over the last three decades. Three of these reported relative risks above unity and seven no consistent association. Only a few studies, moreover, included information on different types of mouthwash, and addressed the issue of alcohol-containing mouthwash. Thus, critical review of published data revealed that a link between mouthwash use, specifically alcohol-containing mouthwash, and oral cancers is not supported by epidemiological evidence.
ª 2008 Elsevier Ltd. All rights reserved.
The possible relationship between mouthwash use and oral cancer risk has been considered in at least 10 case– control studies published over the last three decades. Only a few of these, however, included information on different types of mouthwash, and addressed the issue of alcoholcontaining mouthwash. Their main summary results for users versus non-users of mouthwash are given in Table 1. Two of these were conducted by the US National Cancer Institute (NCI) and included distinction between alcohol-containing and other mouthwashes. The first one was a population-based case– control study conducted in 1984–85 in four US cancer registration areas (Los Angeles County and the San Francisco Bay area, California, Greater Atlanta, and the State of the New Jersey) including 1114 oral cancer cases and 1268 controls.1 Direct information on mouthwash use was available on 866 cases and 1243 controls. Overall, 52% of the cases versus * Tel.: +39 02 390141; fax: +39 02 33200231. E-mail address: [email protected]
44% of the controls reported ever mouthwash use, corresponding to a multivariate relative risk (RR) (adjusted for tobacco, alcohol, education, and fruit consumption) of 1.4 (95% confidence interval, CI 1.0–1.8) in men and of 1.6 (95% CI 1.1–2.3) in women. The RRs tended to increase with frequency and duration of use, but the trends were not uniform. The study also provided data on use of various types of mouthwashes. Compared to subjects who used mouthwashes non containing alcohol, the RRs were below unity for those reporting mouthwash use with low alcohol content, and above unity (around 1.6) for those reporting use of mouthwash with high alcohol content, or mixed use, in the absence, however, of consistent trends across these categories. Indeed, the RR was apparently higher for subjects reporting mouthwash use with high alcohol content in men (RR = 1.6), and mixed use (RR = 2.0) in women. A re-analysis of the same dataset was subsequently made, with distinction of 75 non-mucosal cases (38 in men, 37 in women; 11 adenocarcinomas, 12 adenoid cystic carcinomas, 17 mucoepidermal carcinomas, 13 sarcomas,
1368-8375/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2008.08.012
Mouthwash and oral cancer risk: An update Table 1
199
Mouthwash use and oral cancer Number of cases: number of controls using mouthwash
Relative riska for users versus nevers (95% CI)
62:119 140:161 247:271
0.73 (0.49–1.10) 1.68 (1.24–2.29) 1.66 (1.28–2.15)
109:189
1.0 (0.7–1.4)
Mashberg et al. (1985), USA12 Young et al. (1986), USA11
10:40 91:149 75:94 259:205 41:440 –
Kabat et al. (1989), USA13
59:54
Guha et al. (2007), South America5 D’Souza et al. (2007), USA7
148:118 45:14
2.5 – 1.15 (0.8–1.7) 0.93 (0.61–1.29) occasional use 1.44 (1.10–1.84) daily use 0.82 (0.53–1.25) 0.86 (0.60–1.25) oral 0.84 (0.53–1.33) oropharyngeal and hypopharyngeal 0.95 (0.38–2.08) occasional 0.65 (0.34–1.22) regular 1.58 (1.26–1.88) 1.45 (0.91–2.29)
Studies including information on alcohol containing mouthwash Winn et al. (1991), USA1 Non alcohol mouthwash Alcohol mouthwash Mixed Winn et al. (2001), Puerto Rico4 Alcohol mouthwash Studies not including separate information on alcohol containing mouthwash Weaver et al. (1979), USA8 Blot et al. (1983), USA9 Wynder et al. (1983), USA10
Summary results from epidemiologic studies. a Relative risk computed from available data were not given in the original reports.
and 22 Hodgkin’s and other lymphomas).2 The RRs for alcohol were 3.8 for mucosal versus 0.8 for non-mucosal and those for tobacco 5.3 versus 0.7, i.e. were appreciably higher for mucosal than for non-mucosal oral cancers.2 This is in agreement with our knowledge of oral cancer epidemiology.3 However, the associations with ethanol containing mouthwash (1.6 versus 3.1) or mixed use of mouthwash (1.7 versus 3.4) were apparently higher for non-mucosal than for mucosal cases, thus shedding doubts on the existence of a real association between alcohol-containing mouthwashes and epithelial oral cancer.2 The second study providing detailed information on alcohol-containing mouthwash was also conducted by the NCI, and included 342 cases of oral and pharyngeal cancer and 521 controls from Puerto Rico.4 The overall RR for users versus non-users of mouthwash was 1.0 (95% CI 0.7–1.4), and there was no relation with frequency of use (RR for P2 times per day = 0.9, 95% CI 0.5–1.4 day), duration of use (RR = 1.2, 95% CI 0.7–2.0 for P30 years), dilution (RR = 0.6, 95% CI 0.3–1.1 for full strength or combined use), time in mouth (RR = 1.0, 95% CI 0.6–1.7 for longer time), gargle (RR = 1.0, 95% CI 0.7–1.6) or rinse (RR = 1.1, 95% 0.7–1.7). Further, there was no excess risk for mouthwash use among alcohol drinkers, nor among light and heavy cigarette smokers, for whom any alcohol-induced lesion of the oral mucosa would be more relevant. The results were also similar for oral (n = 205) and pharyngeal (n = 123) cancers.
There are at least eight additional studies reporting some information on mouthwash use and oral and pharyngeal cancer, in the absence of adequate distinction between alcohol-containing and other types of mouthwash. Their main results are also given in Table 1. One of these5 is a combined analysis of a multicenter case–control study of squamous cell carcinomas of the head and neck conducted in central Europe and South America. For the subset of studies conducted in South America, including 1457 cases and 1361 controls, information was available on mouthwash use, in the absence, however, of specification of alcohol-containing versus other types of mouthwash. Compared to never mouthwash users, the RRs of oral, pharyngeal and laryngeal cancers combined were 1.3–1.5 (non-significant) for users up to 1 time per day, and rose to 3.5 (95% CI 2.0–6.2) for users P2 times per day. These, however, included only about 3.5% of cases and 1.5% of controls. It is therefore possible that selection and/or information bias (underreporting of alcohol and tobacco use)6 in this small subgroup partly or largely account for the apparent association between mouthwash use and head and neck cancers. Mouthwash use may also be more frequent in subjects with oral inflammatory or pre-neoplastic conditions (reverse causation).6 The association was apparently stronger for oral than for pharyngeal and laryngeal cancers, in the absence, however, of significant differences. There was also no significant difference in the relation between mouthwash use and head and neck cancer
200 across strata of never, former and current smokers. Given the interaction between tobacco and alcohol on head and neck cancer risk, this weighs against a real association between mouthwash use and head and neck cancers. Likewise, in a recent study on papilloma virus and oropharyngeal cancers7 only 5% of the cases and 1.5% and the controls reported mouthwash use P3 times per day. An apparent association, of borderline significance, was restricted to this subgroup, and the RR was 1.3 (95% CI 0.8– 2.1) for use 1–2 times per day versus <1 time per day. The trend in risk was non-significant, and no information was given on type of mouthwash (alcohol-containing versus others), nor on modalities or duration of use. Among the other six studies, published between 1979 and 1989, and including some information on mouthwash use, three8–10 reported RRs above unity, one11 no association in men (RR = 1.0) and a reduced risk in women (RR = 0.5), and two12,13 RRs below unity. There was, however, no significant association in all studies except one (which however provided no information on use of alcohol-containing mouthwashes versus other types).10 Further, there was no consistent relation with duration, frequency or concentration, and no association among tobacco users nor alcohol drinkers.9,12 Another case–control study from New York State14 gave no RR estimate, and reported an association with recent mouthwash use, but not with duration of use. In conclusion, therefore, epidemiological findings on mouthwash and oral cancer were not consistent across various studies, populations and strata of major risk factors considered, including smokers and nonsmokers.15 More specifically, the pattern of risk is not different with reference to alcohol-containing mouthwashes, and other types or mixed use of mouthwashes. This, again, weighs against any relevant association between alcohol-containing mouthwashes and oral cancer risk. This absence of association is also consistent with our knowledge of the dose-risk relationship between alcohol consumption and risk of upper digestive tract cancers, which show no excess risk for low doses of ethanol.16
Conflict of interest statement None declared.
Acknowledgements This work was conducted with the support of the Italian Asssociation for Cancer Research and the Italian League against Cancer. Johnson and Johnson Consumer provided partial
C.L. Vecchia unconditioned support. The work in this paper was undertaken while CLV was a senior fellow at the International Agency for Research on Cancer.
References 1. Winn DM, Blot WJ, McLaughlin JK, Austin DF, Greenberg RS, Preston-Martin S, et al. Mouthwash use and oral conditions in the risk of oral and pharyngeal cancer. Cancer Res 1991;51:3044–7. 2. Cole P, Rodu B, Mathisen A. Alcohol-containing mouthwash and oropharyngeal cancer: a review of the epidemiology. J Am Dent Assoc 2003;134:1079–87. 3. La Vecchia C, Tavani A, Franceschi S, Levi F, Corrao G, Negri E. Epidemiology and prevention of oral cancer. Oral Oncol 1997;33:302–12. 4. Winn DM, Diehl SR, Brown LM, Harty LC, Bravo-Otero E, Fraumeni Jr JF, et al. Mouthwash in the etiology of oral cancer in Puerto Rico. Cancer Causes Contr 2001;12:419–29. 5. Guha N, Boffetta P, Wunsch Filho V, Eluf Neto J, Shangina O, Zaridze D, et al. Oral health and risk of squamous cell carcinoma of the head and neck and esophagus: results of two multicentric case–control studies. Am J Epidemiol 2007;166:1159–73. 6. Shapiro S, Castellana JV, Sprafka JM. Alcohol-containing mouthwashes and oropharyngeal cancer: a spurious association due to underascertainment of confounders? Am J Epidemiol 1996;144:1091–5. 7. D’Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM, et al. Case–control study of human papillomavirus and oropharyngeal cancer. New Engl J Med 2007;356:1944–56. 8. Weaver A, Fleming SM, Smith DB. Mouthwash and oral cancer: carcinogen or coincidence? J Oral Surg 1979;37:250–3. 9. Blot WJ, Winn DM, Fraumeni Jr JF. Oral cancer and mouthwash. J Natl Cancer Inst 1983;70:251–3. 10. Wynder EL, Kabat G, Rosenberg S, Levenstein M. Oral cancer and mouthwash use. J Natl Cancer Inst 1983;70:255–60. 11. Young TB, Ford CN, Brandenburg JH. An epidemiologic study of oral cancer in a statewide network. Am J Otolaryngol 1986;7:200–8. 12. Mashberg A, Barsa P, Grossman ML. A study of the relationship between mouthwash use and oral and pharyngeal cancer. J Am Dent Assoc 1985;110:731–4. 13. Kabat GC, Hebert JR, Wynder EL. Risk factors for oral cancer in women. Cancer Res 1989;49:2803–6. 14. Marshall JR, Graham S, Haughey BP, Shedd D, O’Shea R, Brasure J, et al. Smoking, alcohol, dentition and diet in the epidemiology of oral cancer. Eur J Cancer B Oral Oncol 1992;28B:9–15. 15. Elmore JG, Horwitz RI. Oral cancer and mouthwash use: evaluation of the epidemiologic evidence. Otolaryngol Head Neck Surg 1995;113:253–61. 16. Polesel J, Dal Maso L, Bagnardi V, Zucchetto A, Zambon A, Levi F, et al. Estimating dose–response relationship between ethanol and risk of cancer using regression spline models. Int J Cancer 2005;114:836–41.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/oraloncology
REVIEW
Mouthwash and oral cancer risk: An update Carlo La Vecchia
*
Istituto di Ricerche Farmacologiche ‘‘Mario Negri’’ Milano e Istituto di Statistica Medica e Biometria ‘‘G.A. Maccacaro’’, ` degli Studi di Milano, Via Giuseppe La Masa 19, 20156 Milano, Italy Universita Received 10 July 2008; received in revised form 26 August 2008; accepted 27 August 2008 Available online 25 October 2008
KEYWORDS Alcohol; Case–control studies; Mouthwash; Oral cancer; Risk
Summary The possible relationship between mouthwash use and oral cancer risk has been the subject of at least 10 case–control studies published over the last three decades. Three of these reported relative risks above unity and seven no consistent association. Only a few studies, moreover, included information on different types of mouthwash, and addressed the issue of alcohol-containing mouthwash. Thus, critical review of published data revealed that a link between mouthwash use, specifically alcohol-containing mouthwash, and oral cancers is not supported by epidemiological evidence.
ª 2008 Elsevier Ltd. All rights reserved.
The possible relationship between mouthwash use and oral cancer risk has been considered in at least 10 case– control studies published over the last three decades. Only a few of these, however, included information on different types of mouthwash, and addressed the issue of alcoholcontaining mouthwash. Their main summary results for users versus non-users of mouthwash are given in Table 1. Two of these were conducted by the US National Cancer Institute (NCI) and included distinction between alcohol-containing and other mouthwashes. The first one was a population-based case– control study conducted in 1984–85 in four US cancer registration areas (Los Angeles County and the San Francisco Bay area, California, Greater Atlanta, and the State of the New Jersey) including 1114 oral cancer cases and 1268 controls.1 Direct information on mouthwash use was available on 866 cases and 1243 controls. Overall, 52% of the cases versus * Tel.: +39 02 390141; fax: +39 02 33200231. E-mail address: [email protected]
44% of the controls reported ever mouthwash use, corresponding to a multivariate relative risk (RR) (adjusted for tobacco, alcohol, education, and fruit consumption) of 1.4 (95% confidence interval, CI 1.0–1.8) in men and of 1.6 (95% CI 1.1–2.3) in women. The RRs tended to increase with frequency and duration of use, but the trends were not uniform. The study also provided data on use of various types of mouthwashes. Compared to subjects who used mouthwashes non containing alcohol, the RRs were below unity for those reporting mouthwash use with low alcohol content, and above unity (around 1.6) for those reporting use of mouthwash with high alcohol content, or mixed use, in the absence, however, of consistent trends across these categories. Indeed, the RR was apparently higher for subjects reporting mouthwash use with high alcohol content in men (RR = 1.6), and mixed use (RR = 2.0) in women. A re-analysis of the same dataset was subsequently made, with distinction of 75 non-mucosal cases (38 in men, 37 in women; 11 adenocarcinomas, 12 adenoid cystic carcinomas, 17 mucoepidermal carcinomas, 13 sarcomas,
1368-8375/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2008.08.012
Mouthwash and oral cancer risk: An update Table 1
199
Mouthwash use and oral cancer Number of cases: number of controls using mouthwash
Relative riska for users versus nevers (95% CI)
62:119 140:161 247:271
0.73 (0.49–1.10) 1.68 (1.24–2.29) 1.66 (1.28–2.15)
109:189
1.0 (0.7–1.4)
Mashberg et al. (1985), USA12 Young et al. (1986), USA11
10:40 91:149 75:94 259:205 41:440 –
Kabat et al. (1989), USA13
59:54
Guha et al. (2007), South America5 D’Souza et al. (2007), USA7
148:118 45:14
2.5 – 1.15 (0.8–1.7) 0.93 (0.61–1.29) occasional use 1.44 (1.10–1.84) daily use 0.82 (0.53–1.25) 0.86 (0.60–1.25) oral 0.84 (0.53–1.33) oropharyngeal and hypopharyngeal 0.95 (0.38–2.08) occasional 0.65 (0.34–1.22) regular 1.58 (1.26–1.88) 1.45 (0.91–2.29)
Studies including information on alcohol containing mouthwash Winn et al. (1991), USA1 Non alcohol mouthwash Alcohol mouthwash Mixed Winn et al. (2001), Puerto Rico4 Alcohol mouthwash Studies not including separate information on alcohol containing mouthwash Weaver et al. (1979), USA8 Blot et al. (1983), USA9 Wynder et al. (1983), USA10
Summary results from epidemiologic studies. a Relative risk computed from available data were not given in the original reports.
and 22 Hodgkin’s and other lymphomas).2 The RRs for alcohol were 3.8 for mucosal versus 0.8 for non-mucosal and those for tobacco 5.3 versus 0.7, i.e. were appreciably higher for mucosal than for non-mucosal oral cancers.2 This is in agreement with our knowledge of oral cancer epidemiology.3 However, the associations with ethanol containing mouthwash (1.6 versus 3.1) or mixed use of mouthwash (1.7 versus 3.4) were apparently higher for non-mucosal than for mucosal cases, thus shedding doubts on the existence of a real association between alcohol-containing mouthwashes and epithelial oral cancer.2 The second study providing detailed information on alcohol-containing mouthwash was also conducted by the NCI, and included 342 cases of oral and pharyngeal cancer and 521 controls from Puerto Rico.4 The overall RR for users versus non-users of mouthwash was 1.0 (95% CI 0.7–1.4), and there was no relation with frequency of use (RR for P2 times per day = 0.9, 95% CI 0.5–1.4 day), duration of use (RR = 1.2, 95% CI 0.7–2.0 for P30 years), dilution (RR = 0.6, 95% CI 0.3–1.1 for full strength or combined use), time in mouth (RR = 1.0, 95% CI 0.6–1.7 for longer time), gargle (RR = 1.0, 95% CI 0.7–1.6) or rinse (RR = 1.1, 95% 0.7–1.7). Further, there was no excess risk for mouthwash use among alcohol drinkers, nor among light and heavy cigarette smokers, for whom any alcohol-induced lesion of the oral mucosa would be more relevant. The results were also similar for oral (n = 205) and pharyngeal (n = 123) cancers.
There are at least eight additional studies reporting some information on mouthwash use and oral and pharyngeal cancer, in the absence of adequate distinction between alcohol-containing and other types of mouthwash. Their main results are also given in Table 1. One of these5 is a combined analysis of a multicenter case–control study of squamous cell carcinomas of the head and neck conducted in central Europe and South America. For the subset of studies conducted in South America, including 1457 cases and 1361 controls, information was available on mouthwash use, in the absence, however, of specification of alcohol-containing versus other types of mouthwash. Compared to never mouthwash users, the RRs of oral, pharyngeal and laryngeal cancers combined were 1.3–1.5 (non-significant) for users up to 1 time per day, and rose to 3.5 (95% CI 2.0–6.2) for users P2 times per day. These, however, included only about 3.5% of cases and 1.5% of controls. It is therefore possible that selection and/or information bias (underreporting of alcohol and tobacco use)6 in this small subgroup partly or largely account for the apparent association between mouthwash use and head and neck cancers. Mouthwash use may also be more frequent in subjects with oral inflammatory or pre-neoplastic conditions (reverse causation).6 The association was apparently stronger for oral than for pharyngeal and laryngeal cancers, in the absence, however, of significant differences. There was also no significant difference in the relation between mouthwash use and head and neck cancer
200 across strata of never, former and current smokers. Given the interaction between tobacco and alcohol on head and neck cancer risk, this weighs against a real association between mouthwash use and head and neck cancers. Likewise, in a recent study on papilloma virus and oropharyngeal cancers7 only 5% of the cases and 1.5% and the controls reported mouthwash use P3 times per day. An apparent association, of borderline significance, was restricted to this subgroup, and the RR was 1.3 (95% CI 0.8– 2.1) for use 1–2 times per day versus <1 time per day. The trend in risk was non-significant, and no information was given on type of mouthwash (alcohol-containing versus others), nor on modalities or duration of use. Among the other six studies, published between 1979 and 1989, and including some information on mouthwash use, three8–10 reported RRs above unity, one11 no association in men (RR = 1.0) and a reduced risk in women (RR = 0.5), and two12,13 RRs below unity. There was, however, no significant association in all studies except one (which however provided no information on use of alcohol-containing mouthwashes versus other types).10 Further, there was no consistent relation with duration, frequency or concentration, and no association among tobacco users nor alcohol drinkers.9,12 Another case–control study from New York State14 gave no RR estimate, and reported an association with recent mouthwash use, but not with duration of use. In conclusion, therefore, epidemiological findings on mouthwash and oral cancer were not consistent across various studies, populations and strata of major risk factors considered, including smokers and nonsmokers.15 More specifically, the pattern of risk is not different with reference to alcohol-containing mouthwashes, and other types or mixed use of mouthwashes. This, again, weighs against any relevant association between alcohol-containing mouthwashes and oral cancer risk. This absence of association is also consistent with our knowledge of the dose-risk relationship between alcohol consumption and risk of upper digestive tract cancers, which show no excess risk for low doses of ethanol.16
Conflict of interest statement None declared.
Acknowledgements This work was conducted with the support of the Italian Asssociation for Cancer Research and the Italian League against Cancer. Johnson and Johnson Consumer provided partial
C.L. Vecchia unconditioned support. The work in this paper was undertaken while CLV was a senior fellow at the International Agency for Research on Cancer.
References 1. Winn DM, Blot WJ, McLaughlin JK, Austin DF, Greenberg RS, Preston-Martin S, et al. Mouthwash use and oral conditions in the risk of oral and pharyngeal cancer. Cancer Res 1991;51:3044–7. 2. Cole P, Rodu B, Mathisen A. Alcohol-containing mouthwash and oropharyngeal cancer: a review of the epidemiology. J Am Dent Assoc 2003;134:1079–87. 3. La Vecchia C, Tavani A, Franceschi S, Levi F, Corrao G, Negri E. Epidemiology and prevention of oral cancer. Oral Oncol 1997;33:302–12. 4. Winn DM, Diehl SR, Brown LM, Harty LC, Bravo-Otero E, Fraumeni Jr JF, et al. Mouthwash in the etiology of oral cancer in Puerto Rico. Cancer Causes Contr 2001;12:419–29. 5. Guha N, Boffetta P, Wunsch Filho V, Eluf Neto J, Shangina O, Zaridze D, et al. Oral health and risk of squamous cell carcinoma of the head and neck and esophagus: results of two multicentric case–control studies. Am J Epidemiol 2007;166:1159–73. 6. Shapiro S, Castellana JV, Sprafka JM. Alcohol-containing mouthwashes and oropharyngeal cancer: a spurious association due to underascertainment of confounders? Am J Epidemiol 1996;144:1091–5. 7. D’Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM, et al. Case–control study of human papillomavirus and oropharyngeal cancer. New Engl J Med 2007;356:1944–56. 8. Weaver A, Fleming SM, Smith DB. Mouthwash and oral cancer: carcinogen or coincidence? J Oral Surg 1979;37:250–3. 9. Blot WJ, Winn DM, Fraumeni Jr JF. Oral cancer and mouthwash. J Natl Cancer Inst 1983;70:251–3. 10. Wynder EL, Kabat G, Rosenberg S, Levenstein M. Oral cancer and mouthwash use. J Natl Cancer Inst 1983;70:255–60. 11. Young TB, Ford CN, Brandenburg JH. An epidemiologic study of oral cancer in a statewide network. Am J Otolaryngol 1986;7:200–8. 12. Mashberg A, Barsa P, Grossman ML. A study of the relationship between mouthwash use and oral and pharyngeal cancer. J Am Dent Assoc 1985;110:731–4. 13. Kabat GC, Hebert JR, Wynder EL. Risk factors for oral cancer in women. Cancer Res 1989;49:2803–6. 14. Marshall JR, Graham S, Haughey BP, Shedd D, O’Shea R, Brasure J, et al. Smoking, alcohol, dentition and diet in the epidemiology of oral cancer. Eur J Cancer B Oral Oncol 1992;28B:9–15. 15. Elmore JG, Horwitz RI. Oral cancer and mouthwash use: evaluation of the epidemiologic evidence. Otolaryngol Head Neck Surg 1995;113:253–61. 16. Polesel J, Dal Maso L, Bagnardi V, Zucchetto A, Zambon A, Levi F, et al. Estimating dose–response relationship between ethanol and risk of cancer using regression spline models. Int J Cancer 2005;114:836–41.