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© Masson, Paris, 1988. Rev. Epid~m. et Sant~ PubL, 1988, 36, 389-394 Black tobacco, wine and mate in oropharyngeal cancer. A case-control study from Uruguay Tabac noir, alcool, 'Mate; et cancer de la cavitJ orale et du pharynx. Etude cas-t~moins en Uruguay Eduardo DE STEFANIc~, Pelayo CORREAc-'~, Femando OREGGIA~, Hugo DENEO-PELLE- GRINI"~, Gustavo FERNANDEZ~31, Diego --~2~ ZAVAL,~ , Julio CARZOGLIO~u, Juan LEIVAC~l, Eliza- beth FONTHAMCz~, Santiago RIVEROC3~ (1) Department of Pathology, University Hospital, (Reprint requests : M.D.E. de Stefani), Avenida Italia y las Heras, Montevideo, Uruguay. (2) Department of Pathology. Louisiana State University. New Orleans. (3) Department of Otolaryngology. University Hospital, Mofitevideo, Uruguay. Une dtude portant sur 108 cas de cancers de la cavitd orale et du pharynx et sur 286 tdmoins a dtd rdalisde ?z l'H6pital Universitaire de Montdviddo, Uruguay. Les estimations du RR associd au tabac, h I'aIcool, fi la nutrition et h l'ingestion d'une infusion chaude appeIde 'mate' (Ilex paraguarie~sis) ont dtd obtenues par une analyse de rdgression logistique. Les fumeurs de tabac noir ont un RR 3,4 fois plus dlevd que les fumeurs de tabac blond et les grands buveurs de vin ont un OR de 17,2. L"exposition au 'mate' prdsente une relation dose-r~ponse significative aprks contr61e de l~zge, du tabac et de la consommation d'alcool, avec un risque 5 fois plus fort pour les grands buveurs de cette infusion. L'exposition combinde au taba¢ noir et au vin a dtd caractdrisde par des RR trOs dlevds. Les rdsultats sugg~rerit que les taux importants de cancers de l'oropharynx pourraient 6tre expliqudes par l'effet muItipIicatif du tabac noir, de l'alcool et du 'mate '. Tabac noir. Vin. "Mate'. Cancer de la cavit6 orale. Cancer du pharynx. A case-control study of oral and pharyngeal cancer involving interviews with" 108 cases and 286 controls was carried out in the University Hospital of Montevideo, Uruguay. The study was restricted to males and cases afflicted with lip, salivary gland and nasopharyngeal cancer were excluded. Point estimates of RR associated with smoking variables, alcohol variables, nutritional items and ingestion of hot infusions of the herb Ilex paraguariensis ('Mate') were obtained by logistic regression analysis. Dark tobacco smokers showed a RR 3.4 times higher than light tobacco users and heavy drinkers of wine displayed an OR of 17.2. Mate exposure showed a significant dose-response, after adjustement for age, tobacco and alcohol intake, with a fivefold increase in risk for heavy consumers. Joint exposure to black tobacco and wine displayed very high risks and no significant interactions were observed. The results suggest that the high rates of oropharyngeal cancer could be explained by the multiplicative effect of black tobacco smoking, wine drinking and mate ingestion. Black tobacco. Wine. Mate. Orophau'ngeal cancer. Case-control study. Texte refu le 1'~ septembre 1987. Acceptation ddfinitive le 15 mars 1988.

390 E. DE STEFANI AND COLLABORATORS INTRODUCTION According' to international comparisons [I], Uruguay occupies the 9th place in the world for cancer of the oral cavity and pharynx among males, with an age-adjusted death rate of 7.6 x l0s. Since several of the leading countries for pharyngeal cancer (Hong Kong, Singapore) are characterized by a high frequency of nasopharyngeal carci- noma, it is of interest to note that cancer of this site is uncommon in Uruguay. This resembles the pattern observed in France, Italy and Spain [2], with high rates of oral and pharyngeal cancers, excluding nasopharynx. Regarding incidence, relative frequency data showed an ASCAR of 6.0 % [3]. Although the ideal situation would be to study separately each one of the subsites coded ICD-O 140-149, a severe constraint to this approach is the relatively small accrual of incident cases for subsite. This has resulted, as a logical consequence, in a lumping of loca- tions in most analytic studies. Nevertheless, cancers of the lip, salivary gland and naso- pharynx, which are associated with different sets of etiologic factors should be excluded from such studies. Furthermore, restriction to cases with diagnosis of squamous cell carci- noma is desirable. Although no analytic studies on the subject have been performed in Uruguay, clinical data suggest that ciga- rette smoking and alcohol consumption are important risk factors. Also, the prevalent habit of drinking hot infusions of the herb Ilex paraguariensis (known with the folk name of mate) has been associated with the occur- rence of oesophageal cancer [4]. This study aims to elucidate the importance of different types of tobacco, different kinds of alcoholic beverages and mate consumption as risk factors for the development of oropharyngeal cancer in Uruguay. MATERIAL AND METHODS for reasons outlined previously. The final number of cases was 108. In the same period, 286 patients afflicted with diseases considered not related with tobacco and/or alcohol exposure and treated in the University.Hospital were admitted into the study as controls. Their selection was based on the clinical diagnosis, without previous knowledge of exposure histories and they could be considered as beIonging to the same base population from which the eases were drawn. In order to minimize selection bias, controls were selected from multiple categories of diseases. Study was restricted to males with an age range of 40-79 years and no matching was performed. Both eases and controls were submitted shortly after admittance to a detailed questionnaire which included : a) demographic section ; b) tobacco section, including information on type of tobacco (dark, blond, mixed), smoker status, age at start, duration of smoking in years, amount in cigarettes/day, }'ears since stopping and filter use, e) alcohol section, including type of beverage (beer, wine, hard liquor), intensity in co/day after conversion in pure alcohol equivalents; d) "mate' section, including age at start, duration and amount, in liters/day; and e) nutrition section, including current and past (10 years ago) consumption of selected items (green and yellow vegetables and citric fruits). Interviews ~tere performed by 3 trained social wor- kers, unaware of the objectives of the study. The relative risk (RR), approximated by the odds ratio (OR), was the estimator chosen in order to measure the point estimate of effect. Ninety-five percent confidence limits were estimated as the regression coefficient (plus or minus 1.96 x standard error). Tests for linear trend were measured by the likelihood ratio test with one degree of freedom. Joint exposures were estimated by logistic regression, as well as control of confounding and asessment of inte- raction. All statistical calculations were carried out with the GLIM package [5]. RESULTS In table L age distribution of cases and controls is shown. Mean ages were very similar (62 years for cases and 61 years for controls). Cases were classified according to site of origin (table II) and hypopharyng_eal tumors represented 32.4 % of the total, follo- wed by squamous cancer of the tongue TABLE I. -- Age distribution of cases and controls. Distribu'tion de l'dge des cas et des tdmoins. Age group Cases Controls Total (24.1 e: table syster ses ot tract value,, contr~ expo~ cantl., Also gnific inges: than table light for main (ll-2 blacl~ ratio age ~ and playe toba~ Tests kin& tobm 67~32 sho~ redu use f drint wed for- patt( tive: and item que.~ and and of t sligt higk and rett~ of 1: for bac~ was All incident cases of cancer of the oral cavity and pharynx admitted to the Department of Otolaryngology 4049 (University Hospital) in the time period from June 1985 50-59 to May 1986 were included in the study. In all patients 60-69 the pathologic diagnosis was squamous cell carcinoma. 70-79 Subsequently, patients with cancer of the lip (5 cases) and All ages with nasopharyngeal carcinoma (I0 cases) were excluded Mean 8 30 38 39 84 123 40 114 154 21 58 79 108 286 394 61.7 61.4 61.5

BLACK TOBACCO (24.1%) and tumors of the tonsil (17.6 %). In table HI distribution of controls by organ system is depicted; only patients with disea- ses of the ear, urogenital tract and digestive tract showed percentages over 10 %. Mean values for some of the variables studied are contrasted in table IV. Amount of tobacco exposure, discriminated by brand was signifi- cantly different between cases and controls. Also wine and spirits consumption was si- gnificantly higher in cases. Regarding mate ingestion, cases used to drank 500 cm3 more than controls (1.55 vs 1.02 liters per day). In table V, dose-response patterns of dark and light cigarettes are contrasted. Higher risks for dark tobacco exposure were evident, mainly in the category of moderate smokers (11-20 cigarettes/day) with OR's of 26.7 for black cigarettes and 4.6 for light tobacco (risk ratio of 5.8). After adjusting intensity for age, age at start, duration, years since stopping and filter use, dark tobacco smokers dis- played a RR 3.4 higher than that of light tobacco users (95 % confidence limits 1.8-6.5). Tests for linear trend were significant for both kinds of tobacco (likelihood ratio for black tobacco = 72.06 and for blonde cigarettes = 67.32). Age at start and duration of smoking showed non-significant increases in risk. Risk reductions of 60 % were observed for filter use for both types of tobacco. When alcoholic drinks were" compared, wine exposure sho- wed a greater effect for heaw drinkers (17.3 for wine vs 8.6 for spirits). Dose-response patterns were also different, with a steeper slope for wine consumption (table VI). Rela- tive risks associated with deficit in vegetable and fruit intake are shown in table VII. Both items displayed moderate effects, but infre- quent users shdwed OR's of 1.8 for vegetables and 2.2 for fruits. Joint exposure to tobacco and wix~e is shown in table VIII. Adjustement of both variables for each other, revealed slight confounding. RR's were markedly higher for the combination of black tobacco and wine, mainly in the row of 11-20 ciga- rettes per day. Intersection with the column of 151 + cc of wine showed a risk of 454.0 for dark cigarettes and 60.4 for blonde to- bacco (risk ratio of 7.5). The greater effect was observed for the combination of smokers AND ORAL CANCER 391 TAttLE II. -- .Distribution of cases by anatomic site. -- Distribution des cancers par localisat~on anatomique. ICD-0 Site Number % 141.9 Tongue 26 24.1 143.1 Maxilla 2 1.9 144.9 Floor of mouth 6 5.6 145.5 Palate 5 4.6 146.0 Tonsil 19 17.6 146.9 Oropharynx 15 i3.9 148.1 Pyriform sinus 29 26.9 148.9 Hypopharynx 6 5.6 Total 108 100 T~Lv. III. ---Distribution of controls by system. -- Distribution des tdmoins par appareil. Site Number .Auditive tract 57 19.9 Urogenital tract 38 13.3 Digestive system 33 11.5 Musculoskeletal system 29 I0.1 Malignant tumors 29 10.1 Ocular system 28 9.8 Skin diseases 27 9.4 Respiratory tract 24 8.4 Benign tumors 9 3.1 Nervous system 6 2. I Venous system 4 1.4 Hemopoyetic system 2 0.7 Total 286 100 T~r.z IV. -- Mean values of study variables. -- Valeurs moyennes des variables dtudi~es. Variable Cases Controls Tobacco amount (dark)' 32 2I Tobacco amount (light)' 35 20 Wineb 102 36 Spirits~ 111 28 Matec 1.55 1.03 cigarettes/day, b co/day, ° liters/day TABLZ V. -- Dose-response for different types of tabacco. -- Relation dose-r~ponse pour les diff~rents types de tabac. Intensity Dark Light (cig/day) OR 95 % CL OR 95 % CL 0-10 11-20 21 +

392 E. DE STEFANI AND TABLE VI. -- Dose-response for alcoholic beverages. -- Relation dose-rdponse pour les boissons alcoolisdes. Amount Wine Hard Liquor (co/day) OR 95 % CL OR 95 % CL 0-50 1.0 -- ~ - 1.0 -- 51-150 3.3 1.9-5.9 5.9 3.1-11.5 151 + 17.3 6.3-47.3 8.6 3.9-18.5 TABLE VII. -- Dose-response relation for nutritional variables. -- Relation dose-rdponse pour les variables concernant la nutrition. Consumption Vegetables Fruits OR 95 % CL OR 95 % CL Daily 1.0 -- 1.0 -- Weekly 1.6 0.9-2.9 0.9 0.5-I .9 Infrequent 1.8 " 0.9-3.4 2.2 1.3-3.9 TABLE VIIi'. -- RR's for joint exposure to tabacco and wine. -- Risques relatifs pour l'exposition combinde au tabac et au vin. Type of Amount Wine (ee/day) tobacco (cig/day) ~ 50 51-150 151 + Light 0-10 1.0 3.0 14.3 11-20 4.2 12.5 60.4 21 .+ 16.7 49.4 238.4 Black 0-10 1.0 3.4 18.3 I 1-20 24.7 84.1 454.0 21 + 26.4 89.8 484.9 TABLE IX. -- RR's for joint exposure to tabacco and hard liquor. -- Risques relatifs pour l'exposition combinde au tabac et aux alcools forts. Type of Amount Spirits (cc/day) tobacco (cig/day) ~ 50 51-150 151 + Light 0-10 1.0 4.4 5.4 11-20 4.2 18.6 22.6 21 + 15.4 69.0 ,83.7 Black 0-10 1.0 4.1 5.7 11-20 19.7 82.3 112.2 21 + 23.3 97.5 132.8 of 21 or more black cigarettes and 151 or more cc of wine (RR = 484.9). When interac- tion terms were tested no significant depar- ture from the multiplicative model was obser- ved. Joint exposure of tobacco and hard liquor is shown in table IX. Again, black tobacco smokers displayed higher risks than COLLABORATORS users of light tobacco, and hard liquor users showed similar OR's for both kinds of to- bacco. Confounding of tobacco exposure by spirits ingestion was more evident and the same applies to hard liquor, confounded by tobacco exposure. On the other hand, the combination of dark tobacco and wine seems to be associated with a RR 3.6 higher than that showed by the joint effect of dark tobacco and spirits. Ta- ble X displays the RR's associated with exposure to tobacco smoking and mate drin- king. After adjustement for tobacco effect, RR's associated with mate exposure are of lesser magnitude (8.8 unadjusted vs 5.0 to- bacco-adjusted). Similarly, after adjustement for mate effect, both kinds of tobacco show smaller OR's, mainly for heavy smokers. Dose-response of mate exposure were similar for both types of tobacco and the combina- tion of black tobacco and mate drinking carried a risk 5.9 times higher.compared with the joint effect of light tobacco smoking and mate drinking. It should be noted that the joint exposure to black tobacco and mate attains much of its effect for moderate smo- kers category, and only a moderate increase in risk is observed for heavy smokers. Interac- tion terms were non-significant and no depar- ture for the multiplicative fit were observed.. -'--- Table XI shows the dose-response pattern for mate exposure after adjustement for age,. ~~- tobacco and alcohol. Likelihood ratio test for trend remained highly significant and heavy. drinkers of the herb displayed a RR of 5.2.~ Finally, in Table XII, the final model is fit~d after stepwise entrance of risk factors, begin2 :~ ~ ning with total tobacco consumption and TABLE X. -- RR's for joint exposure to tabacco and rnat~?~ -- Risques relatifs pour l'exposition combinde au tabac eti~ Type of ~ -- Mate (co/day) ' tobacco (ci / ay 11-20 3.5 8.1 17.6 ~.Z: - Black 21 + 14.6 33.4 72.2"'~ 0-10 1.0 2.2 5.0 11-20 20.5 46.4 103.7 IN) 21 + 22.2 50.1 112.1 C) " TABLE XI. -- Cr. Comparaison de Consumption 0.04).99 1.0-1.99 2.0 + Total TABLE XII. -- /~ logistique. Variable Dark tabacc~ Wine Mate Hard liquor Variables left o Total tobacco Total alcohol Fruits Vegetables total alcohol successive spirits expos hal variables The results suggested in importance and mate ir bacco and 1 cant after t~ the model. consumptior was 1.456 ar for wine and On the othe ned signific:' The final ~ equation in Dark tobacc + 0.9071 H~ DISCUSSIO?, Previous predominenl alcohol expc: ryngeal cane, lesser magni tobacco sm~ cancer couk

BLACK TOBACCO AND ORAL CANCER 393 TABLE XI. -- Crude and age, tobacco and alcohol adjusted dose-response for mate exposure. -- Dose-r~ponse du 'mate: Comparaison des risques bruts e~ ajustds pour l'&ge, le tabac et l'alcooI. Consumption Cases Controls Crude RR Adj. RR 95 % CL 0.0-0.99. 15 117 1.0 1.0 -- 1 .IN1.99 42 t 18 2.8 2.5 1. I-5.7 2.0 + 51 51 7.8 5.2 2..1-13.1 Total 108 286 TABLE XII. -- Multivariate regression analysis. Final model. -- ModHe final aprOs l'emploi des mdthodes de rdgression Iogistique. Variable Coefficient Standard error Chi-square Dark tabacco 1.0240 0.1729 35.08 Wine 1.3861 0.2701 26.33 Mate 0.8770 0.2222 15.57 Hard liquor 0.9071 0.3527 6.62 Variables left out of the model : Total tobacco 0.5362 0.2737 3.83 Total alcohol 0.3284 0.4397 0.55 Fruits 0.1783 0.0989 3.26 Vegetables 0.3968 0.3659 1.18 total alcohol ingestion. This was followed by successive fits for dark tobacco, wine and spirits exposures. Finally, mate and nutritio- nal variables were incorporated in the model. The results are in accordance with those suggested in previous tables, displaying the importance of dark tobacco, wine drinking and mate intake. Coefficients for total to- bacco and light tobacco turned non-signifi- cant after the inclusison of dark tobacco in the model. The same applies to total alcohol consumption; the coefficient for this variable was 1.456 and after the introduction of terms for wine and spirits exposure failed to 0.4248. On the other hand, 'mate' beta-value remai- ned significant after multiple adjustements. The final model could be expressed in an equation in which : log RR = 0.07 + 1.024 Dark tobacco + 1.386 Wine + 0.8770 'Mate' + 0.9071 Hard liquor. DISCUSSION Previous reports [6, 7, 8, 9] emphasized the predominent role played by tobacco and alcohol exposures in the causation of oropha- ryngeal cancer. It should be pointed out the lesser magnitude of the RR's associated with tobacco smoking, but the inclusion of lip cancer could contribute to this fact. On the other hand, these papers were concerned with a population characterized by smoking blonde cigarettes. This is not the situation in Uruguay, country in which almost 50 % of the smoking population used black tobacco, fre- quently hand rolled. Similar conditions pre- vails in Latin European countries (France, Italy) which display both frequent use of dark tobacco and high rates of oral cancer [I0]. The use of black cigarettes has been asso- ciated with high risks of bladder cancer [111, oesophageal cancer [12] and lung cancer [13, 14, 15]. Chemically, this kind of air-cured tobacco shows higher concentrations of N-nitroso compounds and higher alkalinity than blond tobacco [16]. In experimental carcinogenesis studies [17] black tobacco has shown a greater turnout yield than light tobacco. It is possible that due to its strong taste and higher alkalinity, black tobacco is less easily inhaled and remains longer in contact with buccaI and pharyngeal structu- res. This could explain the high RR's obser- ved in this study. On the other hand, light tobacco smokers display somehow similar RR's to that observed in American studies [6]. Regarding the effect of alcoholic beverages, it should be pointed out that Williams and Horm [7] communicated similar RR's for wine in pharyngeal cancer.

394 E. DE STEFANI AND COLLABORATORS © Masson, Paris, 1 According'to the models fitted, joint expo- sur~ to black tobacco and wine resulted in very high risks, and no significant interaction was observed. Mate effect remained signifi- 8. cant, even after multiple adjustements were performed. The fivefold increase in risk for heavy mate users is similar to the effect 9. observed in oesophageal cancer [4]. Although thermal injury has been suggested as the I0. likely mechanism of action, chemical carci- nogenesis cannot be ruled out. It should be noted "that mate contains tannins and poly- phenols, and the presence of N-nitroso com- pounds has been suspected [18]. Marshall et aI. showed that deficient vitamin intake in- l l. creased the risk of oral cancer [17]. Similarly, Winn et al. [20] reported a decrease in risk of oral cancer (RR = 0.52) for frequent users of 12. vegetables and fruits. Our results show rather similar point estimates for vegetables and fruits, suggesting a role for nutritional deficits in a base population of low SES. It could be 13. concluded that the present study suggests that the high rates of oropharyngeal cancer obser- ved in Uruguay could be explained by the 14. multiplicative effect of black tobacco smo- king, alcohol drinking and mate use. This work has been supported by a Fulbright grant # 08103 awarded to Eduardo De Stefani, M.D. 15. ACKNOWLEDGEMENTS. The authors wish to thank Dr. William Haenszel £or his most valuable suggestions. REFERENCES 16. 1. Silverberg E. : Cancer Statistics 1985. CA, 1985, 35, 5-22. 2. Waterhouse J., Muir C., Shanmugaratnam K., Poweil J. : Cancer Incidence in Five Continents. IARC sci. pub. No. 42. Lyon, 1982. 17. 3. De Stefani E. : Uruguay. In D.M. Parkin (editor) : Cancer occurrence in Developing Countries. IARC sci. pub. No. 75. Lyon, 1986. t8. 4. Vassallo A., Correa P., De Stefani E., Cendan M., Zavala D., V., Carzoglio J., Deneo-Pellegrini H. : Esophageal cancer in Uruguay : A case-control study. J. Natl. Cancer Inst, 1985, 75, 1005-1009. I9. 5. Payne C.D. : The GLIMsystem. Release 3.77 Manual. Numerical Algorithms Group. Oxford, 1985. 6. Wynder E.L., Bross LJ., Feldman R.M. : A study of 20. the etiologic factors in cancer of the mouth. Cancer 1957, 10, 1300-1323. 7. Williams R.R. and Horm J.W. : Association of cancer sites with tobacco and alcohol consumption and socioeconomic status of patients: Interview study from the Third National Cancer.Survey. J. Natl. Cancer Inst., 1977, 58, 525-547. Graham S., Dayal H., Rohrer T. : Dentition, diet, tobacco and alcohol in the epidemiology of oral cancer. J. Natl. Cancer Inst., 1977, 59, 1611-1617, Rothman K.J., Keller A. : The effect of joint .expo- sure to alcohol and tobacco on risk of cancer of the mouth and pharynx. J. Chron. Dis., 1972, 25, 711-716. 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Cancer Inst., 1961, 26, 1085-1108. ... Joly O., Lubin J., Caraballoso M. : Dark tobacco and. lung cancer in Cuba. 3". Natl. Cancer Inst., 1983, 70, Hoffmann D., Brunnem'ann K.D., Adams ~'.D. Hecht S.S. : Formation and amalysis of nes in tobacco products and tion in consumers. In O'Neill I.K., Von Borstel Miller C.T., Long L, Barstch H. (editors) : compounds. : Occurrence, biological effects vance to human cancer. IARC sci. pub. No. 57,. 1984. Mufioz N., Correa P., Boek F.G. : carcinogenic effect of two types of tobacco. 1968, 21, 376-389. Adams J.D., Hoffmann D. : studies on the herb flex paragi~ariensis as it is in the preparation of ~ mate >~, American Foundation, Valhalla, New York. Unt minary report. 1986. Marshall J., Graham S., Mettlin C., Shedd Swanson M. : Diet in the epidemiology of cancer.: Nutr. Cancer, 1982, 3, 145-149. Winn D.M., Ziegler R.G., Pickle L.W., Gridle~ G.,: Blot W.J., Hoover R.N. : Diet in the etiology and pharyngeal cancer among women from Southern Umted States. Cancer Res., 1984, Evaluation e, l'hrmoglobin, scolaire des ~ Cost-effectivene. in southeast Fr~ J.P. MOATrI°), (1) INSERM Unit6 Cedex. ( Tir~s ,~ par (2) Laboratoire, d'~: Depuis 1977 prdvention des a scolaire dans le efficacitd, la strc l'hypoth~se d'un (14/16 ans), da. dans cette popul, 2,5 %~ de porter de grandeur rai. l'ensemble des ~ des seuls portez optimisation co~ intention de I'd1 prdsdlection dan seuls groupes g~ coat/efficacitd ~ Hgmoglobin. ~ses. ~-' Screening in out experimenta study compares, strategies in all dchool populati~ for HbS, prosp~ (1987) dependin comparison witk. haemoglobin el, screened. Furthc to ethnic group,~ Haemoglobinopath Texte regu le 24 no~