w.~I- ~ ~ (i0'l . I~ ~~ ~ ~ i WORLD HEALTH ORGANIZATION INTERNATIONALAGENCY FOR RESEARCH ON CANCER IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC RISKS TO HUMANS Alcohol Drinking VOLUME 44 This publication represents the views and expert opinions of an IARC W orking Group on the Evaluation of Carcinogenic Risks to Rumans, which met in Lyon, . 13-20 October 1987 1988 lARe MONOGRAPHS ln 1969, the International Agency for Research on Cancer (lARC) initiated a pro- gramme on the evaluation of the carcinogenic risk of chemicals to humans involving the production of criticalIy evaluated monographs on individual chemicals. ln 1980, the pro- gramme was expanded to inc1ude the evaluation of the carcinogenic risk associated with exposures to complex mixtures. The objective of the programme is to elaborate and publish in the form of monographs critical reviews of data on carcinogenicity for chemicals and complex mixtures to which humans are known to be exposed, and on specifie occupational exposures, to evaluate these data in terms of human risk with the he1p of international working groups of experts in chemical carcinogenesis and related fields, and to indicate where additional research efforts are needed. This project was supported by PHS Grant No. 6 U01 CA33193-06 awarded by the US National Cancer Institute, Department of Health and Human Services. (9lnternational Agency for Research on Cancer 1988 ISBN 92 832 12444 ISSN 0250-9555 AlI rights reserved. Application for rights of reproduction or translation, in part or in tata, should be made to the International Agency for Research on Cancer. Distributed for the International Agency for Research on Cancer by the Secretariat of the World Health Organization PRINTED lN THE UK eONTENTS NOTE TO THE READER ............................................... 7 .. ........... ........... .......... ............ LIST OF PARTICIPANTS 9 PREAMBLE ........................................................... 15 Background ......................................................... 15 Objective and Scope .................................................. 15 Selection of Topics for Monographs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Data for Monographs ................................................. 16 The W orking Group ...... '. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 W orking Procedures .................................................. 17 Exposure Data ....................................................... 18 Biologica1 Data Relevant to the Evaluation of Carcinogenicity to Humans .... 19 Evidence for Carcinogenicity in Experimental AnimaIs ....... . . . . . . . . . . . . . . 20 Other Relevant Data in Experimental Systems and Humans ................ 22 Evidence for Carcinogenicity in Humans ................................. 23 Summary of Data Reported . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Evaluation .......................................................... 27 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 KING ALCOHOL DRIN 1. General Introduction: Alcohol Drinking and the Public Health 35 2. Worldwide Production and Use of Alcoholic Beverages ............ 41 2.1 W orldwide production ....................................... 41 (a) Kinds of alcoholic beverages ............................. 41 (b) Production methods .................................... 42 (c) Production volumes .................................... 45 CONTENTS 2.2 International trade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 (a) Beer .................................................. 51 (b) Wine ................................................. 52 (c) Spirits ................................................ 52 2.3 Trends in consumption ....................................... 54 (a) Total consumption per head ............................. 55 (b) Beer consumption ...................................... 55 (c) Wine consumption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 (d) Consumption of spirits .................................. 64 2.4 Drinking patterns ........................................... 66 3. Chemical Composition of A1coholic Beverages, Additives and Contaminants ................................................... 71 3.1 General aspects ............................................. 71 3.2 Compounds in beer .......................................... 73 3.3 Compounds in wine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 3.4 Compounds in spirits ........................................ 86 3.5 Additives and contaminants ................................... 93 4. Biological Data Relevant to the Evaluation of Carcinogenic Risk to H umans ......................................................... 101 4.1 Carcinogenicity studies in animaIs ............................. 101 (a) Ethanol and alcoholic beverages .......................... 101 (b) Modifying effects of ethanol on the activity of known carcinogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 (c) Carcinogenicity of metabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1I5 4.2 Other relevant data from experimental systems .................. 115 (a) Absorption, distribution and excretion .................... 115 (b) Metabolism ........................................... 116 (c) Modifying effects of ethanol on the metabolism of xenobiotics ............................................ 120 (d) Modifying effects of ethanol on intermediary metabolism .... 121 (e) Major toxic effects . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . 122 (f) Effects on reproduction and prenatal toxicity ............... 126 (g) Genetic and related effects ............................... 135 4.3 Other relevant data in humans ....... . . . . . . . . . . . . . . . . . . . . . . . . . . 142 (a) Absorption, distribution and excretion .................... 142 CONTENTS (b) Metabolism ........................................... 142 (c) Modifying effects of ethanol on the metabolism of xenobiotics ............................................ 144 (d) Modifying effects of ethanol on intermediary metabolism .... 145 (e) Major toxic effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145 (f) Effects on reproduction and prenatal toxicity ............... 148 omal effects .................... 151 (g) M utagenicity and chromos 5. Epidemiological Studies of Cancer in Humans ..................... 153 5.1 Measurement of alcohol intake in epidemiological studies ......... 153 5.2 Descriptive studies ........................................... 155 (a) Geographical and temporal studies .......... . . . . . . . . . . . . . . 155 cancer rates in cultural subgroups ............... 156 (b) Studies of 5.3 Analytical studies .................... . . . . . . . . . . . . . . . . . . . . . . . . 158 (a) General introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 (b) Cancer of the oral cavity and pharynx ..................... 165 (c) Cancer of the larynx .................................... 178 (d) Cancer of the oesophagus ............................... 186 the stomach, colon and rectum .................. 194 (e) Cancer of (f) Cancer of the lIver ...................................... 207 (g) Cancer of the pancreas .................................. 215 (h) Cancer of the breast .................................... 222 (i) Cancer of the lung ...................................... 232 U) Cancer of the urinary bladder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 (k) Cancers at other sites ................................... 246 6. Summary of Data Reported and Evaluation ....................... 251 6.1 Chemical composition, consumption and trends . . . . . . . . . . . . . . . . .. 251 6.2 Experimental carcinogenicity data ............................. 251 6.3 Human carcinogenicity data .................................. 252 6.4 Other relevant data .......................................... 257 6.5 Evaluation ................................................. 258 7. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 261 Appendix 1. Occurrence of flavour compounds and sorne other compounds in alcoholic beverages ................................... 325 Appendix 2. Genetic activity profiles ................................ 363 CUMULATIVE INDEX TO THE MONOGRAPHS SERIES. . . .. .... .. . . .. .. 379 NOTE TO THE READER The term 'carcinogenic risk' in the IARC Monographs series is taken to mean the probability that exposure to an agent wil ad to cancer in humans. le Inclusion of an agent in the M onographs does not imply that it is a carcinogen, only that the published data have been examined. EqualIy, the fact that an agent has not yet been evaluated in a monograph does not mean that it is not carcinogenic. The evaluations of carcinogenic risk are made by international working groups of independent scientists and are qualitative in nature. No recommendation is given for regulation or legislation. Anyone who is aware ofpublished data that may alter the evaluation of the carcinogenic risk of an agent to humans is encouraged to make this information available to the Unit of Carcinogen Identification and Evaluation, International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France, in order that the agent may be considered for re-evaluation by a future W orking Group. Although every effort is made to prepare the monographs as accurate1y as possible, mistakes may occur. Readers are requested to communicate any errors to the Unit of Carcinogen Identification and Evaluation, so that corrections can be reported in future volumes. -7- lARe WORKING GROUP ON THE EVALUATION OF eARelNOGENie RISKS TO HUMANS: ALeOHOL DRINKING Lyon, 13-20 October 1987 Membersl F. Berrino, National Institute for the Study and Treatment of Tumours, via Venezian 1, Milan, Italy M. Grant, Division of Mental Health, World Health Organization, 1211 Geneva 27, Switzerland L. Griciute, Oncological Institute of the LIthuanian SSR, 341 Dzerhinsky Shosse, 232021 Vilnius, Lithuanian SSR, USSR B. Holmberg, Department ofToxicology, National Institute ofOccupational Health, 17184 Solna, Sweden A.J. McMichael, CommunityMedicine Department, University of Adelaide, Adelaide SA 5000, Australia (Vice-chairman) O. MØller-Jensen, Danish Cancer Registry, 66 Landskronagade, 2100 Copenhagen ø, Denmark (Chairman) L. Nykänen, Alko Ltd, The Finnish State A1cohol Company Research Laboratories, PO Box 350, 00101 Helsinki 10, Finland G. Obe, Free University of Berlin, Division of Biology (FB23), Institute of General Genetics (WEI), ArnimalIee 5-7, 1000 Berlin (West) 33, Federal Republic of Germany J.K. Reddy, Northwestern University, The Medical School, Ward Memorial Building, 303 East Chicago Avenue, Chicago, IL 60611, USA R. Room, Alcohol Research Group, 1816 Scenic Avenue, Berkeley, CA 94709, USA Helsinki, M. Salaspuro, Research Unit of A1cohol Diseases, University Central Hospital of Tukholmankatu 8C, 00290 Helsinki, Finland lUnable to attend: C.S. Lieber, Alcohol Research and Treatment Center, Section of Liver Disease and Nutrition, 130 West Kingsbridge Road, Bronx, NY 10468, USA; S. Takayama, National Cancer Centre Research Institute, 5-1-1 Sukkiji-5-chome, Tokyo 104, Japan -9-