CancerCausesand Control,3, 137-143
Consumption of alcohol, coffee, and tobacco, and gasmc cancer i n Sp"aln Antonio Agudo, Carlos A. Gonz~ilez,Guillermo Marcos, Miguel Sanz, Eugeni Saigi, Juan Verge, Montserrat Boleda, and Javier Ortego (Received 23 September 1991;accepted in revisedform 6January 1992) A case-control study on gastric cancer was carried out between 1987 and 1989 in four regions of Spain. Three hundred and fifty-four cases of histologically confirmed adenocarcinoma were included (235 men and 119 women). For each case, a control was selected, matched by sex, age, and area of residence, from the same hospital as the case. No association was observed with smoking, nor with the consumption of coffee or tea. The usual consumption of alcohol was associated with gastric cancer in men (odds ratio -- 1.54, 95 percent confidence interval = 1.03-2.31), but there was no dose-response relationship. No association was observed in women. All estimations were carried out taking into account the effect of the dietary factors associated with gastric cancer. In accordance with previous evidence, the association observed between gastric cancer and alcohol appears not to be causal.
Key words: Alcohol, case-control studies, coffee, gastric cancer, Spain, tobacco smoking.
Introduction Tobacco smoke has a recognized carcinogenic effect on various tumorous locations) An increase in risk associated with consumption of alcohol also has been demonstrated for some digestive tract cancers, such as esophageal and oropharyngeal cancers, showing a multiplicative effect with tobacco? Although an association has been suggested between coffee consumption and certain cancers (of the pancreas and urinary bladder), no causality has been clearly established? The results of epidemiologic studies examining the
relationship of these factors with gastric cancer are contradictory, except for coffee consumption for which, in the majority of investigations, no association was observed. 41°Regarding tobacco, an increase in risk was observed in various studies, "-~9although there was no dose-response relationship, while in others, 7,9,~°a°-26 no association was found. In certain areas, a high risk was observed to be associated with alcohol consumption. 14t7'24'26 In several of these, the risk was attached to the high consumption of one alcoholic beverage in particular. In others, no association was observed. 6-10as-23,2s
Drs Agudo and Gonz,ilez are with the Unit of Epidemiology, Hospital de Matar6, Matar6, Spain. Dr Marcos is with the Department of Preventive Medicine, Hospital Clinico, Zaragoza, Spain. Dr Sanz is with the Department of Pathology, Hospital del INSALUD, Soria, Spain. Dr Saigi is with the Department of Oncology, Hospital General de Granollers, Granollers, Spain. Dr Verge is with the Department of Surgery, Hospital de Terrassa, Terrassa,Spain. Dr Boleda is with the Department of Oncology, HospitalS. Camil, Sant Pere de Riha, Spain. Dr Ortego is with the Department of Pathology, Hospital Cllnico, Zaragoza, Spain. Address correspondenceto Dr Agudo, Unit of Epidemiology, Hospital de Matar6, c. Hospital 31, 08301 Matar6, Spain. Thisstudy receivedfinancial supportfrom the Health ResearchFund (FIS) of the Spanish Ministry of Health (FinancialAid for Research exp. 87/1703, exp. 89/0018 and exp. 89/0743) and from the International Agency for Research on Cancer (Collaborative Research Agreement AEP/88/02). © 1992 Rapid Communications of Oxford Ltd
Cancer Causes and Control. Vol 3. 1992
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A. Agudo et al Between 1987 and 1989, a case-control study on gastric cancer was carried out in Spain, in which diet, occupation, tobacco consumption, and medical history were investigated. We present here the results with regard to smoking, alcohol, and coffee consumption.
Materials and methods Four regions of Spain were included in the study, comprising areas with low (Catalonia) and high (Zaragoza, Soria, Galicia) gastric cancer mortality rates within Spain. 27A total of 354 incident cases with histologically confirmed gastric adenocarcinoma were included, identified from 15 public hospitals, which cover more than 90 percent of the population in the participating areas. A control was included for each case, matched by sex, age (+- 3 years) and area of residence, selected from the same hospital as the case. Further details on methods of collecting information and risk factors studied have been reported elsewhere. 28 Data on the subjects' smoking habits were collected by means of a questionnaire structured by time periods. The number of cigarettes per day or cigars per week was ascertained for each period, as well as the age at the beginning and end of the period. A regular smoker was defined as any person who had sometime in their life smoked at least one cigarette per day and/or one cigar per week for at least six months. An exsmoker was defined as a regular smoker who had given up the habit at least five years before diagnosis (cases), or the date of the interview (controls). Information about alcohol and coffee consumption was collected within the dietary history. The dietary questionnaire was structured by meals, and the usual diet for a typical week one year before the onset of the illness was recorded, considering the quantity and frequency of consumption. All foods or drinks consumed at least once every two weeks were considered as being consumed habitually. The overall coffee consumption was recorded, without taking into account the different types of coffee and ways of preparing it. The consumption of alcoholic beverages was recorded separately for four types: wine, beer, spirits, and aperitifs. The quantity of alcohol was calculated by assigning the following mean alcohol contents (g/100 cc) for each type of drink: wine, 9 g; beer, 3.2; spirits, 35; and aperitifs, 15.29 The data analysis was carried out maintaining the pair-matching of the design. The point estimates of the relative risk (RR) were calculated using the conditional logistic regression method 3° and the confidence intervals (CI) were set at 95 percent. All analyses were carried out using a standard program. 3. Since the distribution of the main study factors (alcohol and 138
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tobacco) presented great differences between sexes, usually with a low proportion of consumers among women, the analysis was carried out separately for each sex, and the results focus especially on men. The odds ratios (OR) shown are adjusted for the total caloric intake (including calories provided by alcohol) as well as for the consumption of fruits, vegetables, cold cuts, and preserved fish, which appeared to be associated to the risk of gastric cancer in a previous analysis) 8
Results A total of 354 pair-matched sets were studied, including 235 (66.4 percent) males and 119 (33.6 percent) females. The mean age was 65.2 years for cases and 65.5 for controls, with a range from 31 to 88 years. Among cases, 55.6 percent presented with an intestinal gastric cancer, 25.7 percent diffuse, and the rest with another histologic type or a type difficult to classify. Only six women (three cases and three controls) were ever smokers, showing a very low prevalence of smoking habit (2.5 percent), which is in general accordance with the habit of Spanish women in this age group. Only six cases and seven controls (all males) smoked cigars or pipe exclusively, while the rest smoked cigarettes, in the main, exclusively; therefore, the results for tobacco smoking are presented only for cigarettes in men (Table 1). The results show that there is no association of gastric cancer with habitual cigarette smoking. When cigarette consumption was considered quantitatively, no association was observed with the mean number of cigarettes smoked per day, the total number of cigarettes, the duration of the habit, or the age at beginning (results not shown). The proportion of controls who regularly consumed tea was low: seven percent of the men and eight percent of the women. The ORs adjusted for diet were 0.8 for men and 1.76 for women; neither estimation was statistically significant. The proportion of coffee consumers was 75 percent in men and 65 percent in women, and very similar for cases and controls. The adjusted ORs were respectively 0.93 (CI = 0.60-1.44) and 1.06 (CI -- 0.53-2.11). No tendency was observed with relation to intensity of consumption. There were notable between-sex differences for alcohol consumption (Table 2). Only 20 percent of the women were usual consumers. In the males, 61 percent of the controls and 70 percent of the cases were regular consumers, giving a diet-adjusted OR of 1.54 compared with the nonconsumers, with the lower confidence limit slightly above one. However, no dose-response relationship was observed. The highest and only significant OR was observed in consumers of low quantities of alcohol.
Gastric cancer in Spain Table 1. Risk of gastric cancer and cigarette smoking in males' Controls
Cases
No.
%
No.
%
Ex-smokers Current smokers Ever smokers
58 52 117 169
25.6 22.9 51.5 74.4
63 50 115 165
27.6 21.9 50.5 72.4
Total
227
100.0
228
100.0
Never smokers
OR b
CI ¢
1.00 0.94 0.93 0.93
0.54-1.65 0.58 - 1.48 0.61 - 1.70
Information on smoking habit was missing or incomplete for one case and one control, and six cases and seven controls smoked exclusively cigars or pipe; seven cases and eight controls were excluded from the analysis. b O R = odds ratio, by conditional logistic regression. c CI=95% confidence interval.
Table 2. Risk of gastric cancer and alcohol consumption (g/day), by sex Controls No. Men c Nonconsumers Consumers (g/day)
1-9 10-18 19-36 >36
91 27 36 39 42
Cases %
No.
38.7 11.5 15.3 16.6 17.9
70 39 35 46 44
OR'
CP
1 2.12 1.37 1.53 1.22
1.14-3.95 0.77-2.43 0.85-2.77 0.68-2.19
%
29.9 16.7 15.0 19.7 18.8
P for trend = 0.32
Total consumers Women d Nonconsumers Consumers (g/day)
1- 9 10-18 19 - 36 >36
144
61.3
164
70.1
1.54
1.03-2.31
95 12 6 4 2
79.8 10.1 5.0 3.4 1.7
96 14 4 5 0
80.7 11.8 3.4 4.2 0.0
1 1.23 0.38 1.24
0.48 - 3.16 0.09-1.61 0.25 - 6.28
24
20.2
23
19.3
0.81
P for trend =0,25
Total consumers
0.38-1.73
a O R = o d d s ratio, by conditional logistic regression, adjusted for consumption of fruits, cooked vegetables, cold cuts, preserved fish and total
caloric intake. b CI =95% confidence intervals. 234 cases and 235 controls (for one case the information about diet is missing). d Cases = 119 and controls = 119.
Given the low proportion of female consumers of alcohol, a separate consideration of different alcoholic beverages was carried out for men only (Table 3); the reference category used was the nonconsumers of any type of alcoholic beverage. Wine accounted for 85 percent of the total consumption of alcohol and presented a risk pattern similar to that of total alcohol consumption. There was an increase in risk in the consumers of beer and spirits, which rose with intensity of consumption, although none of the ORs nor the trend test were statistically significant. In order to determine the risk
involved with each alcoholic beverage, the risk in exclusive consumers of each particular type was examined. The greatest risk was observed for exclusively beer consumers (OR = 2.34), although this estimation was based on a low number of individuals (CI = 0.49-11.15). Discussion The results of epidemiologic studies examining the relationship of gastric cancer with both coffee and tea Cancer Causes and Control. Vo13. 1992
139
A. Agudo et al Table 3. Risk of gastric cancer and consumption of alcoholic beverages in males' Controls
Cases
91
70
1
1 ~ 1 O0
27
101-200 201-300 > 300
34 21 49
38 36 30 43
2.08 1.32 1.88 0.98
N o n c o n s u m e r s of alcohol (ref. cat.)
OR b
CI °
Wine (cc/day) 1.11 - 3.91 0.71-2.46 0.91-3.88 0.54 - 1.80 P for trend = 0.63 Total consumers Wine exclusively Beer (cc/day) 1 - 100 > 100
131 85
147 93
1.51 1.48
0.99-2.31 0.93 - 2.33
16 11
18 19
1.22 1.78
0.31-4.84 0.55-5.75 P for trend = 0.34
Total consumers Beer exclusively Liquors (cc/day) 1-22 > 22
27 4
37 6
1.55 2.34
0.55 - 4.31 0.49 - 11.15
17 22
16 24
1.54 2.07
0.39-5.91 0.69-6.24 P for trend = 0.19
Total consumers Liquors exclusively Aperitifs Consumers Aperitifs exclusively
39 4
40 5
1.86 1.30
0.70-4.96 0.32-5.26
10 2
8 3
0.58 3.13
0.05- 6.24 0.44- 22.29
Cases = 234 and controls = 235 (for one case, the information about diet is missing). b O R = odds ratio, by conditional logistic regression adjusted for consumption of fruits, cooked vegetables, cold cuts, preserved fish and total caloric intake. c C I = 9 5 % confidence interval.
have shown no association. 4-1°In our study, neither of them appeared to be associated with stomach cancer. This observation is consistent with previous results. For tobacco smoking, a carcinogenic effect on the gastric mucosa has been demonstrated in vitro; ~2part of the smoke inhaled may reach the digestive tract either directly or through particles contained in ingested bronchial mucus. Some of the first studies on cancer of the stomach in the United States and Japan reported a slight increase of risk in smokers compared with nonsmokers, without dose-response relationship. "-~4 In other studies in Canada, the US, and China, 8,16-~9a slight association was found only in smokers of large quantities of cigarettes. A high risk for cigarette consumption was found in one study in France, ~5but this was based on only 40 cases. In many s t u d i e s , 7,9,~°,2°-26among them most of those carried out in Europe, no association has 140
Cancer Causes and Control, Vol 3. 1992
been observed. Because of this, it is believed that there is no causal association between gastric cancer and smoking? In our study, the proportion of female smokers is very low, so this study is not adequate to assess this risk factor in women. In men, smoking cigarettes does not appear to be a risk factor of cancer of the stomach in our study, supporting the hypothesis of no association. The reason for hospital admission was taken into account in the selection process for controls, and patients admitted for tobacco-related diseases were excluded. Among men, the proportion of current smokers and ex-smokers in our (hospital) control series who were residents in Catalonia were 53.5 and 26.7 percent, respectively. In a previous study on bladder cancer," among the (population) controls also residing in Catalonia, and with a similar age distri-
Gastric cancer in Spain bution, the proportion of current smokers was 52.3 percent and that of ex-smokers was 27.9 percent. The between-study comparison of the quantity of cigarettes smoked per day and the duration of the habit also gives similar proportions. This supports the idea that the results, at least with regard to smoking, are not distorted by selection bias related to the hospital origin of our controls. The association between gastric cancer and alcohol consumption has given contradictory results. No association was observed in most case-control studies. 6-~°,1~,2°,23An increase in risk was observed in one study in the US 16 and another in China? 7 In other studies, the risk was associated with the consumption of one beverage in particular: i.e., beer in Germany 26 and in Japanese immigrants in Hawaii, j4 wine in France, 15and vodka on an empty stomach in Poland. 24 Negative results were obtained in two prospective studies carried out in Hawaii in men of Japanese origin. 19,2~ A statistically significant risk was found in our study in male habitual consumers, but no increase in risk was observed in relation to intensity of alcohol consumption, and no statistical significance was observed for the trend test. The ORs adjusted for dietary factors and total caloric intake and the crude estimates yield very similar values. Several hypotheses have been put forward to explain the possible effects of alcohol on gastric cancer. Alcohol could act as a contributory factor, either by causing chronic irritation in the gastric mucosa, or enhancing the intragastric nitrosation process by reducing the gastric pH? 4 Another possibility to consider is that the risk is not associated with alcohol itself, but rather with some other substances contained in alcoholic beverages. Some alcoholic beverages, especially beer, contain nitrosamines. The nitrosamine content of beer is fundamentally a result of the type of malt employed and the drying process used, so there may be great variation between countries. While beer is one of the main sources of nitrosamines (2.5 ~g/l) in the US and Canada, ~ in a study in Poland, 36 a low nitrosodimethylamine (NDMA) content (0.2 ~g/1) was observed. In our study, it was difficult to assess the effects of exclusive consumption of one alcoholic beverage in particular, apart from wine, since there was a very low number of exclusive consumers (Table 3). The exclusive consumers of beer showed the greatest effect, although this estimation was based on a small number of cases and controls. It would be difficult to explain that, while beer consumption among the Spanish has increased recently, gastric cancer mortality, as in other Western countries, is decreasing. Another possible explanation is that the risk associated with alcohol consumption observed in our study
was the result of a selection bias due to the hospital origin of the controls. In a previous study, 37no differences were observed in diet between hospital controls and those recruited from the general population (neighbors), but some differences were observed in alcohol consumption. Although exclusion criteria were applied for the controls admitted to the hospital for diseases which could have been associated with diet in general, these criteria do not always exclude all of the disease states associated with factors considered secondary in the objectives of the study. The proportion of regular (at least once every two weeks) alcohol consumers in the male Spanish population above the age of 16 is 72 percent in Catalonia and Arag6n (including Zaragoza), and 79.5 percent in Castile (including Soria) and in Galicia? 8In our study, the proportion of consumers among the male controls, adjusted for age, varied between 64 and 66 percent in the same four regions; the possibility arises that this proportion is lower than that of the population in the study base; this could cause an overestimation of risk. Something similar could be true for other studies, since in nearly all case-control studies in which a positive association has been observed, cases and controls were recruited from hospitals. An under-representation of low consumers in our hospital controls also could explain the highest risk found in the category of low consumers.
Finally, the difficulty of studying, in complete detail, the effect of alcohol consumption should be emphasized. The information on alcohol consumption that was included in the diet questionnaire referred to the recent past (a year before the onset of the present illness), and therefore there was no information available about alcohol consumption during the individual's life-time. Thus, it was not possible to assess the influence of the duration of the habit, the age at beginning and, more generally, any of the exposure-modifying time aspects. To conclude, the results of our study, in which the effect of diet has been taken into account, support previous evidence that the consumption of coffee, tea, and cigarette smoking are not associated with gastric cancer. There was no dose-response relationship in the association observed for alcohol consumption in males. The possibility cannot be ruled out that some unknown factor present in some alcoholic beverages or associated with their consumption could increase the risk of gastric cancer. However, bearing in mind previous evidence and the possible underestimation of alcohol consumption in our hospital controls, it is reasonable to believe that the observed association is not causal. Cancer Causes and Control. Vol3. 1992
141
A. Agudo et al authors are grateful to Cristina Mas for her important work in the study office and to Matlas Torrent for his valuable assistance in developing and analyzing the data. We would like to express our gratitude to the oncologists, gastroenterologists and pathologists who collaborated in this study: A. Serrano, X. Balanz6, R. Diloy, A. Bad;a (H. Matar6); T. Cardona, A. Verdaguer, A. Garcia (Cl~nica Alianza, Matar6); L1. Cirera, T. Ribas, X. Garau, J. M. Viver (Mutua de Terrassa); A. Arcusa, R. Audell, J. Armengol (H. de Terrassa); M. Barnet, C. Padr6s, R. Pujol (H. General de Granollers); E. Batiste-Alentorn, F. Antonell, J. Brug~s (H. General de Vic); A. Tres, V. Tejedo, C. Aznar, R. Sainz (Hosp. Clinico, Zaragoza); G. Garcia, P. Solanilla (H. Miguel Acknowledgements--The
Servet, Zaragoza); M. Rey (H. de Sabadell); J. M. Badal, M. Aliart, Dr Badosa (H. S. Andreu, Manresa); X. Puig (Centre Hospitalari de Manresa); J. Sorribes, F. Porta (H. S. Joan de Deu, Manresa); F. Segura (H. de Sabadell); Dr Moreo (H. S. Camil, Sant Pere de Riba); E. Casariego (H. General de Lugo); Dr V~izquez (H. J. Canalejo, La Coruha); J. C. Alvarez (H. de E1 Ferrol); J. M. Ruiz, S. Rodriguez, V. del Villar, M. L. Mufioz (H. del Insalud, Soria).
References 1. International Agency for Research on Cancer. Tobacco Smoking. Lyon, France: IARC, 1986; IARC Monogr Eval Carcinog Risk Chem Human, Vol 38. 2. International Agency for Research on Cancer. Alcohol Drinking. Lyon, France: IARC, 1988; IARC Monogr Eval Carcinog Risk Chem to Humans, Vol. 44. 3. International Agency for Research on Cancer. Lyon, France: IARC, 1990; Cancer: Causes, Occurrence and ControL IARC Sci. Pub. No. 100. 4. Higgison J. Etiological factors in gastrointestinal cancer in man.JNCI 1966; 37: 527-45. 5. Graham S, Lilienfeld AM, Tidings JE. Dietary and purgation factors in the epidemiology of gastric cancer. Cancer 1967; 20: 2224-34. 6. Graham S, Scholz W, Martino P. Alimentary factors in the epidemiology of gastric cancer. Cancer 1972; 30: 927-38. 7. Trichopoulos D, Ouranos G, Day NE, et al. Diet and cancer of the stomach: a case-control study in Greece. Int J Cancer 1985; 36: 291. 8. Risch HA, Jain M, Choi NW, et aL Dietary factors and the incidence of cancer of the stomach. Am J Epidemiol 1985; 122: 947-59. 9. La Vecchia C, Negri E, Decarli A, D'Avanzo B, Franceschi S. A case-control study of diet and cancer in northern Italy. IntJ Cancer, 1987; 40: 484-9. 10. Demirer T, Icli F, Uzunalimoglu O, Kucuk O. Diet and stomach cancer incidence: a case-control study in Turkey. Cancer 1990; 65: 2344-8. 142
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11. Kahn HA. The Dorn study of smoking and mortality among US veterans. Report on eight and one-half years of observation. NCI Monogr 1966; 19:1-25 12. Hammond EC. Smoking in relation to the death rates of one million men and women. NCI Monogr 1966; 19: 127-204. 13. Hirayama T. Epidemiology of stomach cancer. Gann Monogr 1971; 11: 3-19. 14. Haenszel W, Kurihara M, Segi M, Lee RKC. Stomach cancer among Japanese in Hawaii. JNCI 1972; 49: 969-88. 15. Hoey J, Montvernay C, Lambert T. Wine and tobacco: risk factors for gastric cancer in France. Am J Epidemiol 1981; 113: 68-74. 16. Correa P, Fontham E, Pickle LW, Chen V, Lin Y, Haenszel W. Dietary determinants of gastric cancer in South Louisiana inhabitants.JNCl 1985; 75: 645-54. 17. Hu J, Zhang S,Jia E, et aL Diet and cancer of the stomach: A case-control study in China. Int J Cancer 1988; 41: 331-5. 18. You W, Blot WJ, Chang Y, et aL Diet and high risk of stomach cancer in Shandong, China. Cancer Res 1988; 48: 3518-23. 19. Nomura A, Grove JS, Stemmermann GN, Sverson RK. A prospective study of stomach cancer and its relation to diet, cigarettes and alcohol consumption. Cancer Res 1990; 50: 627-31. 20. Buiatti E, Palli D, Decarli A, et aL A case-control study of gastric cancer and diet in Italy. IntJ Cancer 1989; 44: 611-6. 21. Ferraroni M, Negri E, La Vecchia C, D'Avanzo B, Franceschi S. Socioeconomic indicators, tobacco and alcohol in the aetiology of digestive tract neoplasms. IntJ Epidemio11989; 18: 556-62. 22. Wynder EL, Kmet J, Dungal N, et aL An epidemiological investigation of gastric cancer. Cancer 1963; 16: 1461-96. 23. Haenszel W, Kurihara M, Locke FB, Shimuzu K, Segi M. Stomach cancer in Japan. JNCI 1976; 56: 265-78. 24. Jedrychowski W, Wahrendorf J, Popiela T, Rachtan J. A case-control study of dietary factors and stomach cancer risk in Poland. IntJ Cancer 1986; 38: 837-42. 25. Pollack ES, Nomura AM, Heilbrun LK, Stemmerman GN, Green SB. Prospective study of alcohol consumption and cancer. N EnglJ Med 1984; 310: 617-21. 26. Boeing H, Frentzel-Beyme R, BergerM, et aL Case-control study on stomach cancer in Germany. IntJ Cancer 1991; 47: 858-64. 27. L6pez-Abente G, Escolar A, Errezola M. Atlas del Cancer en Espa~a. Victoria-Gasteiz, Spain, 1984. 28. Gonz~ilezCA, Sanz JM, Marcos G, et aL Dietary factors and stomach cancer in Spain: a multicenter case-control study. IntJ Cancer 1991; 49: 513-9. 29. Jim~nez A, Cervera P, Bacardi M. Tabla de Composiddn de Alimentos. Barcelona, Spain: Wander, 1988. 30. Breslow NE, Day NE. Statistical Methods in Cancer Research. Vol 1. The Analysis of Case-Control Studies. Lyon, France: International Agency for Research on Cancer, 1980; IARC Sci. Pub. No. 32. 31. Epilog Plus. Statistical Package for Epidemiology and Clinical Trials. Pasadena, CA (US): 1988. 32. Tayler R, Piper DW. The carcinogenic effect of cigarette smoke. The effect of cigarette smoke on human gastric mucosal cells in organ culture. Cancer 1977; 39: 2520-3.
Gastric cancer m Spain 33. L6ez-Abente G, Gonz~ilez CA, Errezola M, et al. Tobacco smoke inhalation pattern, tobacco type, and bladder cancer in Spain. Am J Epidemiol 1991; 134: 830-9. 34. Mirvish SS. The etiology of gastric cancer: intragastric nitrosamide formation and other theories. JNCI 1983; 71: 630-47. 35. Howe GR, Harrison L, Jain M. A short diet history for assessing dietary exposure to N-nitrosamines in epidem-
ioIogic studies. ArnJ Epidernio11986; 124: 595-602. 36. Kubacki SJ, Havery DC, Fazio T. Volatile N-nitrosamines in Polish malt and beer. Food Addit Contain 1989; 6: 29-33. 37. Gonz~ilez CA, Torrent M, Agudo A, Riboli E. Hospital versus neighbourhood controls in the assessment of dietary risk factors. IntJ Epidemio11990; 19: 354-61. 38 Ministerio de Sanidad y Consumo. Encuesta Nacional de Salud. Madrid: Ministerio de Sanidad y Consumo, 1990.
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Consumption of alcohol, coffee, and tobacco, and gasmc cancer i n Sp"aln Antonio Agudo, Carlos A. Gonz~ilez,Guillermo Marcos, Miguel Sanz, Eugeni Saigi, Juan Verge, Montserrat Boleda, and Javier Ortego (Received 23 September 1991;accepted in revisedform 6January 1992) A case-control study on gastric cancer was carried out between 1987 and 1989 in four regions of Spain. Three hundred and fifty-four cases of histologically confirmed adenocarcinoma were included (235 men and 119 women). For each case, a control was selected, matched by sex, age, and area of residence, from the same hospital as the case. No association was observed with smoking, nor with the consumption of coffee or tea. The usual consumption of alcohol was associated with gastric cancer in men (odds ratio -- 1.54, 95 percent confidence interval = 1.03-2.31), but there was no dose-response relationship. No association was observed in women. All estimations were carried out taking into account the effect of the dietary factors associated with gastric cancer. In accordance with previous evidence, the association observed between gastric cancer and alcohol appears not to be causal.
Key words: Alcohol, case-control studies, coffee, gastric cancer, Spain, tobacco smoking.
Introduction Tobacco smoke has a recognized carcinogenic effect on various tumorous locations) An increase in risk associated with consumption of alcohol also has been demonstrated for some digestive tract cancers, such as esophageal and oropharyngeal cancers, showing a multiplicative effect with tobacco? Although an association has been suggested between coffee consumption and certain cancers (of the pancreas and urinary bladder), no causality has been clearly established? The results of epidemiologic studies examining the
relationship of these factors with gastric cancer are contradictory, except for coffee consumption for which, in the majority of investigations, no association was observed. 41°Regarding tobacco, an increase in risk was observed in various studies, "-~9although there was no dose-response relationship, while in others, 7,9,~°a°-26 no association was found. In certain areas, a high risk was observed to be associated with alcohol consumption. 14t7'24'26 In several of these, the risk was attached to the high consumption of one alcoholic beverage in particular. In others, no association was observed. 6-10as-23,2s
Drs Agudo and Gonz,ilez are with the Unit of Epidemiology, Hospital de Matar6, Matar6, Spain. Dr Marcos is with the Department of Preventive Medicine, Hospital Clinico, Zaragoza, Spain. Dr Sanz is with the Department of Pathology, Hospital del INSALUD, Soria, Spain. Dr Saigi is with the Department of Oncology, Hospital General de Granollers, Granollers, Spain. Dr Verge is with the Department of Surgery, Hospital de Terrassa, Terrassa,Spain. Dr Boleda is with the Department of Oncology, HospitalS. Camil, Sant Pere de Riha, Spain. Dr Ortego is with the Department of Pathology, Hospital Cllnico, Zaragoza, Spain. Address correspondenceto Dr Agudo, Unit of Epidemiology, Hospital de Matar6, c. Hospital 31, 08301 Matar6, Spain. Thisstudy receivedfinancial supportfrom the Health ResearchFund (FIS) of the Spanish Ministry of Health (FinancialAid for Research exp. 87/1703, exp. 89/0018 and exp. 89/0743) and from the International Agency for Research on Cancer (Collaborative Research Agreement AEP/88/02). © 1992 Rapid Communications of Oxford Ltd
Cancer Causes and Control. Vol 3. 1992
137
A. Agudo et al Between 1987 and 1989, a case-control study on gastric cancer was carried out in Spain, in which diet, occupation, tobacco consumption, and medical history were investigated. We present here the results with regard to smoking, alcohol, and coffee consumption.
Materials and methods Four regions of Spain were included in the study, comprising areas with low (Catalonia) and high (Zaragoza, Soria, Galicia) gastric cancer mortality rates within Spain. 27A total of 354 incident cases with histologically confirmed gastric adenocarcinoma were included, identified from 15 public hospitals, which cover more than 90 percent of the population in the participating areas. A control was included for each case, matched by sex, age (+- 3 years) and area of residence, selected from the same hospital as the case. Further details on methods of collecting information and risk factors studied have been reported elsewhere. 28 Data on the subjects' smoking habits were collected by means of a questionnaire structured by time periods. The number of cigarettes per day or cigars per week was ascertained for each period, as well as the age at the beginning and end of the period. A regular smoker was defined as any person who had sometime in their life smoked at least one cigarette per day and/or one cigar per week for at least six months. An exsmoker was defined as a regular smoker who had given up the habit at least five years before diagnosis (cases), or the date of the interview (controls). Information about alcohol and coffee consumption was collected within the dietary history. The dietary questionnaire was structured by meals, and the usual diet for a typical week one year before the onset of the illness was recorded, considering the quantity and frequency of consumption. All foods or drinks consumed at least once every two weeks were considered as being consumed habitually. The overall coffee consumption was recorded, without taking into account the different types of coffee and ways of preparing it. The consumption of alcoholic beverages was recorded separately for four types: wine, beer, spirits, and aperitifs. The quantity of alcohol was calculated by assigning the following mean alcohol contents (g/100 cc) for each type of drink: wine, 9 g; beer, 3.2; spirits, 35; and aperitifs, 15.29 The data analysis was carried out maintaining the pair-matching of the design. The point estimates of the relative risk (RR) were calculated using the conditional logistic regression method 3° and the confidence intervals (CI) were set at 95 percent. All analyses were carried out using a standard program. 3. Since the distribution of the main study factors (alcohol and 138
Cancer Causes and Control. Vol 3. 1992
tobacco) presented great differences between sexes, usually with a low proportion of consumers among women, the analysis was carried out separately for each sex, and the results focus especially on men. The odds ratios (OR) shown are adjusted for the total caloric intake (including calories provided by alcohol) as well as for the consumption of fruits, vegetables, cold cuts, and preserved fish, which appeared to be associated to the risk of gastric cancer in a previous analysis) 8
Results A total of 354 pair-matched sets were studied, including 235 (66.4 percent) males and 119 (33.6 percent) females. The mean age was 65.2 years for cases and 65.5 for controls, with a range from 31 to 88 years. Among cases, 55.6 percent presented with an intestinal gastric cancer, 25.7 percent diffuse, and the rest with another histologic type or a type difficult to classify. Only six women (three cases and three controls) were ever smokers, showing a very low prevalence of smoking habit (2.5 percent), which is in general accordance with the habit of Spanish women in this age group. Only six cases and seven controls (all males) smoked cigars or pipe exclusively, while the rest smoked cigarettes, in the main, exclusively; therefore, the results for tobacco smoking are presented only for cigarettes in men (Table 1). The results show that there is no association of gastric cancer with habitual cigarette smoking. When cigarette consumption was considered quantitatively, no association was observed with the mean number of cigarettes smoked per day, the total number of cigarettes, the duration of the habit, or the age at beginning (results not shown). The proportion of controls who regularly consumed tea was low: seven percent of the men and eight percent of the women. The ORs adjusted for diet were 0.8 for men and 1.76 for women; neither estimation was statistically significant. The proportion of coffee consumers was 75 percent in men and 65 percent in women, and very similar for cases and controls. The adjusted ORs were respectively 0.93 (CI = 0.60-1.44) and 1.06 (CI -- 0.53-2.11). No tendency was observed with relation to intensity of consumption. There were notable between-sex differences for alcohol consumption (Table 2). Only 20 percent of the women were usual consumers. In the males, 61 percent of the controls and 70 percent of the cases were regular consumers, giving a diet-adjusted OR of 1.54 compared with the nonconsumers, with the lower confidence limit slightly above one. However, no dose-response relationship was observed. The highest and only significant OR was observed in consumers of low quantities of alcohol.
Gastric cancer in Spain Table 1. Risk of gastric cancer and cigarette smoking in males' Controls
Cases
No.
%
No.
%
Ex-smokers Current smokers Ever smokers
58 52 117 169
25.6 22.9 51.5 74.4
63 50 115 165
27.6 21.9 50.5 72.4
Total
227
100.0
228
100.0
Never smokers
OR b
CI ¢
1.00 0.94 0.93 0.93
0.54-1.65 0.58 - 1.48 0.61 - 1.70
Information on smoking habit was missing or incomplete for one case and one control, and six cases and seven controls smoked exclusively cigars or pipe; seven cases and eight controls were excluded from the analysis. b O R = odds ratio, by conditional logistic regression. c CI=95% confidence interval.
Table 2. Risk of gastric cancer and alcohol consumption (g/day), by sex Controls No. Men c Nonconsumers Consumers (g/day)
1-9 10-18 19-36 >36
91 27 36 39 42
Cases %
No.
38.7 11.5 15.3 16.6 17.9
70 39 35 46 44
OR'
CP
1 2.12 1.37 1.53 1.22
1.14-3.95 0.77-2.43 0.85-2.77 0.68-2.19
%
29.9 16.7 15.0 19.7 18.8
P for trend = 0.32
Total consumers Women d Nonconsumers Consumers (g/day)
1- 9 10-18 19 - 36 >36
144
61.3
164
70.1
1.54
1.03-2.31
95 12 6 4 2
79.8 10.1 5.0 3.4 1.7
96 14 4 5 0
80.7 11.8 3.4 4.2 0.0
1 1.23 0.38 1.24
0.48 - 3.16 0.09-1.61 0.25 - 6.28
24
20.2
23
19.3
0.81
P for trend =0,25
Total consumers
0.38-1.73
a O R = o d d s ratio, by conditional logistic regression, adjusted for consumption of fruits, cooked vegetables, cold cuts, preserved fish and total
caloric intake. b CI =95% confidence intervals. 234 cases and 235 controls (for one case the information about diet is missing). d Cases = 119 and controls = 119.
Given the low proportion of female consumers of alcohol, a separate consideration of different alcoholic beverages was carried out for men only (Table 3); the reference category used was the nonconsumers of any type of alcoholic beverage. Wine accounted for 85 percent of the total consumption of alcohol and presented a risk pattern similar to that of total alcohol consumption. There was an increase in risk in the consumers of beer and spirits, which rose with intensity of consumption, although none of the ORs nor the trend test were statistically significant. In order to determine the risk
involved with each alcoholic beverage, the risk in exclusive consumers of each particular type was examined. The greatest risk was observed for exclusively beer consumers (OR = 2.34), although this estimation was based on a low number of individuals (CI = 0.49-11.15). Discussion The results of epidemiologic studies examining the relationship of gastric cancer with both coffee and tea Cancer Causes and Control. Vo13. 1992
139
A. Agudo et al Table 3. Risk of gastric cancer and consumption of alcoholic beverages in males' Controls
Cases
91
70
1
1 ~ 1 O0
27
101-200 201-300 > 300
34 21 49
38 36 30 43
2.08 1.32 1.88 0.98
N o n c o n s u m e r s of alcohol (ref. cat.)
OR b
CI °
Wine (cc/day) 1.11 - 3.91 0.71-2.46 0.91-3.88 0.54 - 1.80 P for trend = 0.63 Total consumers Wine exclusively Beer (cc/day) 1 - 100 > 100
131 85
147 93
1.51 1.48
0.99-2.31 0.93 - 2.33
16 11
18 19
1.22 1.78
0.31-4.84 0.55-5.75 P for trend = 0.34
Total consumers Beer exclusively Liquors (cc/day) 1-22 > 22
27 4
37 6
1.55 2.34
0.55 - 4.31 0.49 - 11.15
17 22
16 24
1.54 2.07
0.39-5.91 0.69-6.24 P for trend = 0.19
Total consumers Liquors exclusively Aperitifs Consumers Aperitifs exclusively
39 4
40 5
1.86 1.30
0.70-4.96 0.32-5.26
10 2
8 3
0.58 3.13
0.05- 6.24 0.44- 22.29
Cases = 234 and controls = 235 (for one case, the information about diet is missing). b O R = odds ratio, by conditional logistic regression adjusted for consumption of fruits, cooked vegetables, cold cuts, preserved fish and total caloric intake. c C I = 9 5 % confidence interval.
have shown no association. 4-1°In our study, neither of them appeared to be associated with stomach cancer. This observation is consistent with previous results. For tobacco smoking, a carcinogenic effect on the gastric mucosa has been demonstrated in vitro; ~2part of the smoke inhaled may reach the digestive tract either directly or through particles contained in ingested bronchial mucus. Some of the first studies on cancer of the stomach in the United States and Japan reported a slight increase of risk in smokers compared with nonsmokers, without dose-response relationship. "-~4 In other studies in Canada, the US, and China, 8,16-~9a slight association was found only in smokers of large quantities of cigarettes. A high risk for cigarette consumption was found in one study in France, ~5but this was based on only 40 cases. In many s t u d i e s , 7,9,~°,2°-26among them most of those carried out in Europe, no association has 140
Cancer Causes and Control, Vol 3. 1992
been observed. Because of this, it is believed that there is no causal association between gastric cancer and smoking? In our study, the proportion of female smokers is very low, so this study is not adequate to assess this risk factor in women. In men, smoking cigarettes does not appear to be a risk factor of cancer of the stomach in our study, supporting the hypothesis of no association. The reason for hospital admission was taken into account in the selection process for controls, and patients admitted for tobacco-related diseases were excluded. Among men, the proportion of current smokers and ex-smokers in our (hospital) control series who were residents in Catalonia were 53.5 and 26.7 percent, respectively. In a previous study on bladder cancer," among the (population) controls also residing in Catalonia, and with a similar age distri-
Gastric cancer in Spain bution, the proportion of current smokers was 52.3 percent and that of ex-smokers was 27.9 percent. The between-study comparison of the quantity of cigarettes smoked per day and the duration of the habit also gives similar proportions. This supports the idea that the results, at least with regard to smoking, are not distorted by selection bias related to the hospital origin of our controls. The association between gastric cancer and alcohol consumption has given contradictory results. No association was observed in most case-control studies. 6-~°,1~,2°,23An increase in risk was observed in one study in the US 16 and another in China? 7 In other studies, the risk was associated with the consumption of one beverage in particular: i.e., beer in Germany 26 and in Japanese immigrants in Hawaii, j4 wine in France, 15and vodka on an empty stomach in Poland. 24 Negative results were obtained in two prospective studies carried out in Hawaii in men of Japanese origin. 19,2~ A statistically significant risk was found in our study in male habitual consumers, but no increase in risk was observed in relation to intensity of alcohol consumption, and no statistical significance was observed for the trend test. The ORs adjusted for dietary factors and total caloric intake and the crude estimates yield very similar values. Several hypotheses have been put forward to explain the possible effects of alcohol on gastric cancer. Alcohol could act as a contributory factor, either by causing chronic irritation in the gastric mucosa, or enhancing the intragastric nitrosation process by reducing the gastric pH? 4 Another possibility to consider is that the risk is not associated with alcohol itself, but rather with some other substances contained in alcoholic beverages. Some alcoholic beverages, especially beer, contain nitrosamines. The nitrosamine content of beer is fundamentally a result of the type of malt employed and the drying process used, so there may be great variation between countries. While beer is one of the main sources of nitrosamines (2.5 ~g/l) in the US and Canada, ~ in a study in Poland, 36 a low nitrosodimethylamine (NDMA) content (0.2 ~g/1) was observed. In our study, it was difficult to assess the effects of exclusive consumption of one alcoholic beverage in particular, apart from wine, since there was a very low number of exclusive consumers (Table 3). The exclusive consumers of beer showed the greatest effect, although this estimation was based on a small number of cases and controls. It would be difficult to explain that, while beer consumption among the Spanish has increased recently, gastric cancer mortality, as in other Western countries, is decreasing. Another possible explanation is that the risk associated with alcohol consumption observed in our study
was the result of a selection bias due to the hospital origin of the controls. In a previous study, 37no differences were observed in diet between hospital controls and those recruited from the general population (neighbors), but some differences were observed in alcohol consumption. Although exclusion criteria were applied for the controls admitted to the hospital for diseases which could have been associated with diet in general, these criteria do not always exclude all of the disease states associated with factors considered secondary in the objectives of the study. The proportion of regular (at least once every two weeks) alcohol consumers in the male Spanish population above the age of 16 is 72 percent in Catalonia and Arag6n (including Zaragoza), and 79.5 percent in Castile (including Soria) and in Galicia? 8In our study, the proportion of consumers among the male controls, adjusted for age, varied between 64 and 66 percent in the same four regions; the possibility arises that this proportion is lower than that of the population in the study base; this could cause an overestimation of risk. Something similar could be true for other studies, since in nearly all case-control studies in which a positive association has been observed, cases and controls were recruited from hospitals. An under-representation of low consumers in our hospital controls also could explain the highest risk found in the category of low consumers.
Finally, the difficulty of studying, in complete detail, the effect of alcohol consumption should be emphasized. The information on alcohol consumption that was included in the diet questionnaire referred to the recent past (a year before the onset of the present illness), and therefore there was no information available about alcohol consumption during the individual's life-time. Thus, it was not possible to assess the influence of the duration of the habit, the age at beginning and, more generally, any of the exposure-modifying time aspects. To conclude, the results of our study, in which the effect of diet has been taken into account, support previous evidence that the consumption of coffee, tea, and cigarette smoking are not associated with gastric cancer. There was no dose-response relationship in the association observed for alcohol consumption in males. The possibility cannot be ruled out that some unknown factor present in some alcoholic beverages or associated with their consumption could increase the risk of gastric cancer. However, bearing in mind previous evidence and the possible underestimation of alcohol consumption in our hospital controls, it is reasonable to believe that the observed association is not causal. Cancer Causes and Control. Vol3. 1992
141
A. Agudo et al authors are grateful to Cristina Mas for her important work in the study office and to Matlas Torrent for his valuable assistance in developing and analyzing the data. We would like to express our gratitude to the oncologists, gastroenterologists and pathologists who collaborated in this study: A. Serrano, X. Balanz6, R. Diloy, A. Bad;a (H. Matar6); T. Cardona, A. Verdaguer, A. Garcia (Cl~nica Alianza, Matar6); L1. Cirera, T. Ribas, X. Garau, J. M. Viver (Mutua de Terrassa); A. Arcusa, R. Audell, J. Armengol (H. de Terrassa); M. Barnet, C. Padr6s, R. Pujol (H. General de Granollers); E. Batiste-Alentorn, F. Antonell, J. Brug~s (H. General de Vic); A. Tres, V. Tejedo, C. Aznar, R. Sainz (Hosp. Clinico, Zaragoza); G. Garcia, P. Solanilla (H. Miguel Acknowledgements--The
Servet, Zaragoza); M. Rey (H. de Sabadell); J. M. Badal, M. Aliart, Dr Badosa (H. S. Andreu, Manresa); X. Puig (Centre Hospitalari de Manresa); J. Sorribes, F. Porta (H. S. Joan de Deu, Manresa); F. Segura (H. de Sabadell); Dr Moreo (H. S. Camil, Sant Pere de Riba); E. Casariego (H. General de Lugo); Dr V~izquez (H. J. Canalejo, La Coruha); J. C. Alvarez (H. de E1 Ferrol); J. M. Ruiz, S. Rodriguez, V. del Villar, M. L. Mufioz (H. del Insalud, Soria).
References 1. International Agency for Research on Cancer. Tobacco Smoking. Lyon, France: IARC, 1986; IARC Monogr Eval Carcinog Risk Chem Human, Vol 38. 2. International Agency for Research on Cancer. Alcohol Drinking. Lyon, France: IARC, 1988; IARC Monogr Eval Carcinog Risk Chem to Humans, Vol. 44. 3. International Agency for Research on Cancer. Lyon, France: IARC, 1990; Cancer: Causes, Occurrence and ControL IARC Sci. Pub. No. 100. 4. Higgison J. Etiological factors in gastrointestinal cancer in man.JNCI 1966; 37: 527-45. 5. Graham S, Lilienfeld AM, Tidings JE. Dietary and purgation factors in the epidemiology of gastric cancer. Cancer 1967; 20: 2224-34. 6. Graham S, Scholz W, Martino P. Alimentary factors in the epidemiology of gastric cancer. Cancer 1972; 30: 927-38. 7. Trichopoulos D, Ouranos G, Day NE, et al. Diet and cancer of the stomach: a case-control study in Greece. Int J Cancer 1985; 36: 291. 8. Risch HA, Jain M, Choi NW, et aL Dietary factors and the incidence of cancer of the stomach. Am J Epidemiol 1985; 122: 947-59. 9. La Vecchia C, Negri E, Decarli A, D'Avanzo B, Franceschi S. A case-control study of diet and cancer in northern Italy. IntJ Cancer, 1987; 40: 484-9. 10. Demirer T, Icli F, Uzunalimoglu O, Kucuk O. Diet and stomach cancer incidence: a case-control study in Turkey. Cancer 1990; 65: 2344-8. 142
Cancer Causes and Control. Vol 3. 1992
11. Kahn HA. The Dorn study of smoking and mortality among US veterans. Report on eight and one-half years of observation. NCI Monogr 1966; 19:1-25 12. Hammond EC. Smoking in relation to the death rates of one million men and women. NCI Monogr 1966; 19: 127-204. 13. Hirayama T. Epidemiology of stomach cancer. Gann Monogr 1971; 11: 3-19. 14. Haenszel W, Kurihara M, Segi M, Lee RKC. Stomach cancer among Japanese in Hawaii. JNCI 1972; 49: 969-88. 15. Hoey J, Montvernay C, Lambert T. Wine and tobacco: risk factors for gastric cancer in France. Am J Epidemiol 1981; 113: 68-74. 16. Correa P, Fontham E, Pickle LW, Chen V, Lin Y, Haenszel W. Dietary determinants of gastric cancer in South Louisiana inhabitants.JNCl 1985; 75: 645-54. 17. Hu J, Zhang S,Jia E, et aL Diet and cancer of the stomach: A case-control study in China. Int J Cancer 1988; 41: 331-5. 18. You W, Blot WJ, Chang Y, et aL Diet and high risk of stomach cancer in Shandong, China. Cancer Res 1988; 48: 3518-23. 19. Nomura A, Grove JS, Stemmermann GN, Sverson RK. A prospective study of stomach cancer and its relation to diet, cigarettes and alcohol consumption. Cancer Res 1990; 50: 627-31. 20. Buiatti E, Palli D, Decarli A, et aL A case-control study of gastric cancer and diet in Italy. IntJ Cancer 1989; 44: 611-6. 21. Ferraroni M, Negri E, La Vecchia C, D'Avanzo B, Franceschi S. Socioeconomic indicators, tobacco and alcohol in the aetiology of digestive tract neoplasms. IntJ Epidemio11989; 18: 556-62. 22. Wynder EL, Kmet J, Dungal N, et aL An epidemiological investigation of gastric cancer. Cancer 1963; 16: 1461-96. 23. Haenszel W, Kurihara M, Locke FB, Shimuzu K, Segi M. Stomach cancer in Japan. JNCI 1976; 56: 265-78. 24. Jedrychowski W, Wahrendorf J, Popiela T, Rachtan J. A case-control study of dietary factors and stomach cancer risk in Poland. IntJ Cancer 1986; 38: 837-42. 25. Pollack ES, Nomura AM, Heilbrun LK, Stemmerman GN, Green SB. Prospective study of alcohol consumption and cancer. N EnglJ Med 1984; 310: 617-21. 26. Boeing H, Frentzel-Beyme R, BergerM, et aL Case-control study on stomach cancer in Germany. IntJ Cancer 1991; 47: 858-64. 27. L6pez-Abente G, Escolar A, Errezola M. Atlas del Cancer en Espa~a. Victoria-Gasteiz, Spain, 1984. 28. Gonz~ilezCA, Sanz JM, Marcos G, et aL Dietary factors and stomach cancer in Spain: a multicenter case-control study. IntJ Cancer 1991; 49: 513-9. 29. Jim~nez A, Cervera P, Bacardi M. Tabla de Composiddn de Alimentos. Barcelona, Spain: Wander, 1988. 30. Breslow NE, Day NE. Statistical Methods in Cancer Research. Vol 1. The Analysis of Case-Control Studies. Lyon, France: International Agency for Research on Cancer, 1980; IARC Sci. Pub. No. 32. 31. Epilog Plus. Statistical Package for Epidemiology and Clinical Trials. Pasadena, CA (US): 1988. 32. Tayler R, Piper DW. The carcinogenic effect of cigarette smoke. The effect of cigarette smoke on human gastric mucosal cells in organ culture. Cancer 1977; 39: 2520-3.
Gastric cancer m Spain 33. L6ez-Abente G, Gonz~ilez CA, Errezola M, et al. Tobacco smoke inhalation pattern, tobacco type, and bladder cancer in Spain. Am J Epidemiol 1991; 134: 830-9. 34. Mirvish SS. The etiology of gastric cancer: intragastric nitrosamide formation and other theories. JNCI 1983; 71: 630-47. 35. Howe GR, Harrison L, Jain M. A short diet history for assessing dietary exposure to N-nitrosamines in epidem-
ioIogic studies. ArnJ Epidernio11986; 124: 595-602. 36. Kubacki SJ, Havery DC, Fazio T. Volatile N-nitrosamines in Polish malt and beer. Food Addit Contain 1989; 6: 29-33. 37. Gonz~ilez CA, Torrent M, Agudo A, Riboli E. Hospital versus neighbourhood controls in the assessment of dietary risk factors. IntJ Epidemio11990; 19: 354-61. 38 Ministerio de Sanidad y Consumo. Encuesta Nacional de Salud. Madrid: Ministerio de Sanidad y Consumo, 1990.
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