WORLD HEALTH ORGANIZATION INTERNATIONAL AGENCY FOR RESEARCH ON CANCER IARC Monographs on the Evaluation of Carcinogenic Risks to Humans VOLUME 89 Smokeless Tobacco and Some Tobacco-specific N-Nitrosamines LYON, FRANCE 2007 WORLD HEALTH ORGANIZATION INTERNATIONALAGENCY FOR RESEARCH ON CANCER IARC Monographs on the Evaluation of Carcinogenic Risks to Humans VOLUME 89 Smokeless Tobacco and Some Tobacco-specific N-Nitrosamines This publication represents the views and expert opinions of an IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, which met in Lyon, 5–12 October 2004 2007 IARC MONOGRAPHS In 1969, the International Agency for Research on Cancer (IARC) initiated a programme on the evaluation of the carcinogenic risk of chemicals to humans involving the production of critically evaluated monographs on individual chemicals. The programme was subsequently expanded to include evaluations of carcinogenic risks asso- ciated with exposures to complex mixtures, life-style factors and biological and physical agents, as well as those in specific occupations. The objective of the programme is to elaborate and publish in the form of monographs critical reviews of data on carcinogenicity for agents to which humans are known to be exposed and on specific exposure situations; to evaluate these data in terms of human risk with the help of international working groups of experts in chemical carcinogenesis and related fields; and to indicate where additional research efforts are needed. The lists of IARC evaluations are regularly updated and are available on the Internet at http://monographs. iarc.fr/. This programme has been supported by Cooperative Agreement 5UO1CA33193 awarded since 1982 by the United States National Cancer Institute, Department of Health and Human Services. Additional support has been provided since 1986 by the European Commission, Directorate-General EMPL(Employment, and Social Affairs), Health, Safety and Hygiene at Work Unit, and since 1992 by the United States National Institute of Environmental Health Sciences. Published by the International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France ©International Agency for Research on Cancer, 2007 Distributed by WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail:[email protected]). Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved. The International Agency for Research on Cancer welcomes requests for permission to reproduce or translate its publications, in part or in full. 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The IARC Monographs Working Group alone is responsible for the views expressed in this publication. IARC Library Cataloguing in Publication Data Smokeless Tobacco and Some Tobacco-specific N-Nitrosamines/ IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (2004 : Lyon, France) (IARC monographs on the evaluation of carcinogenic risks to humans ; v. 89) 1. Carcinogens 2. Nitrosamines −adverse effects 3. Tobacco, Smokeless −adverse effects I. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans II. Series ISBN 978 92 832 1289 8 (NLM Classification: W1) ISSN 1017-1606 PRINTED IN FRANCE Cover legend: Schematic diagramme of the metabolism of nicotine, an addictive chemical present in all tobacco products. The tobacco-specific N-nitrosamines NNK, NNN, NAB and NAT are reviewed in the second Monograph of this volume. Cover design: Georges Mollon, IARC CONTENTS NOTE TO THE READER..................................................................................................1 LISTOF PARTICIPANTS..................................................................................................3 PREAMBLE........................................................................................................................7 1. Background..............................................................................................................9 2. Objective and Scope................................................................................................9 3. Selection of Topics for Monographs ....................................................................10 4. Data for Monographs ............................................................................................11 5. The Working Group ..............................................................................................11 6. Working Procedures ..............................................................................................11 7. Exposure Data........................................................................................................12 8. Studies of Cancer in Humans................................................................................14 9. Studies of Cancer in Experimental Animals..........................................................17 10. Other Data Relevant to an Evaluation of Carcinogenicity and its Mechanisms ..............................................................................................20 11. Summary of Data Reported ..................................................................................22 12. Evaluation..............................................................................................................23 13. References..............................................................................................................28 GENERALREMARKS....................................................................................................33 THE MONOGRAPHS......................................................................................................37 Smokeless Tobacco..........................................................................................................39 1. Description of Smokeless Tobacco Practices ........................................................41 1.1 Historical overview........................................................................................41 1.1.1 Tobacco chewing................................................................................41 1.1.2 Snuff taking........................................................................................43 1.1.3 Attitudes and beliefs regarding smokeless tobacco use ....................46 1.2 Manufacture and use of smokeless tobacco products....................................47 1.2.1 Oral use ..............................................................................................49 1.2.2 Nasal use ............................................................................................54 1.3 Chemical composition of smokeless tobacco................................................55 1.3.1 General overview................................................................................55 1.3.2 Carcinogenic compounds in smokeless tobacco................................57 1.3.3 Smokeless tobacco products ..............................................................60 1.3.4 Kentucky (KY)reference smokeless tobacco products ....................85 1.3.5 Pesticide residues................................................................................86 –v– vi IARC MONOGRAPHS VOLUME 89 1.4 Production, consumption and prevalence of use of smokeless tobacco products............................................................................................86 1.4.1 Europe ................................................................................................88 1.4.2 North and South America ..................................................................98 1.4.3 South Asia ........................................................................................109 1.4.4 Africa................................................................................................137 1.4.5 Association between smokeless tobacco use and cigarette smoking............................................................................................144 1.4.6 Occupational exposure to unburnt tobacco......................................154 1.5 Regulations..................................................................................................156 1.5.1 Framework Convention on Tobacco Control ..................................156 1.5.2 Australia and New Zealand..............................................................156 1.5.3 Europe ..............................................................................................157 1.5.4 North America..................................................................................158 1.5.5 Asia ..................................................................................................161 1.5.6 Africa................................................................................................165 2. Studies of Cancer in Humans ..............................................................................166 2.1 Introduction..................................................................................................166 2.2 Oral use........................................................................................................167 2.2.1 Cancer of the oral cavity and pharynx ............................................167 2.2.2 Precancerous lesions ........................................................................191 2.2.3 Cancer of the oesophagus ................................................................201 2.2.4 Cancer of the pancreas......................................................................205 2.2.5 Cancers at other sites........................................................................209 2.3 Nasal use......................................................................................................229 2.3.1 Cancer of the oral cavity..................................................................229 2.3.2 Cancer of the oesophagus ................................................................231 2.3.3 Cancer of the paranasal sinus ..........................................................231 2.3.4 Cancer of the larynx ........................................................................231 2.3.5 Cancer of the lung............................................................................233 3. Studies of Cancer in Experimental Animals........................................................233 3.1 Tobacco........................................................................................................233 3.1.1 Oral administration ..........................................................................233 3.1.2 Application to the oral mucosa or cheek pouch ..............................234 3.1.3 Skin application................................................................................236 3.1.4 Other routes of administration..........................................................237 3.1.5 Skin application with known carcinogens or modifiers ..................238 3.2 Snuff tobacco ..............................................................................................239 3.2.1 Oral administration ..........................................................................239 3.2.2 Application to the oral mucosa or cheek pouch ..............................240 3.2.3 Subcutaneous administration............................................................243 3.2.4 Administration with known carcinogens or modifiers ....................244 CONTENTS vii 3.3 Biditobacco, mishriand naswar ................................................................247 3.3.1 Biditobacco......................................................................................247 3.3.2 Mishri................................................................................................247 3.3.3 Naswar..............................................................................................250 4. Other Data Relevant to an Evaluation of Carcinogenicity and its Mechanisms ....................................................................................................251 4.1 Absorption, distribution, metabolism and excretion....................................251 4.1.1 Humans ............................................................................................251 4.1.2 Experimental systems ......................................................................267 4.2 Toxic effects ................................................................................................272 4.2.1 Humans ............................................................................................272 4.2.2 Experimental systems ......................................................................333 4.3 Reproductive, developmental and hormonal effects ..................................336 4.3.1 Humans ............................................................................................336 4.3.2 Experimental systems ......................................................................338 4.4 Genetic and related effects ..........................................................................341 4.4.1 Humans ............................................................................................341 4.4.2 Experimental systems ......................................................................359 4.5 Mechanistic considerations..........................................................................362 5. Summary of Data Reported and Evaluation........................................................363 5.1 Exposure data ..............................................................................................363 5.2 Human carcinogenicity data........................................................................363 5.3 Animal carcinogenicity data........................................................................366 5.4 Other relevant data ......................................................................................367 5.5 Evaluation....................................................................................................370 6. References............................................................................................................370 Some Tobacco-specific N-Nitrosamines ......................................................................419 1. Exposure Data......................................................................................................421 1.1 Chemical and physical data (by compound)................................................421 1.2 Technical products and impurities, analysis, production and use ..............426 1.2.1 Technical products and impurities....................................................426 1.2.2 Analysis............................................................................................426 1.2.3 Production ........................................................................................427 1.2.4 Use....................................................................................................427 1.3 Occurrence ..................................................................................................427 1.3.1 Fresh tobacco....................................................................................429 1.3.2 Cured tobacco ..................................................................................429 1.3.3 Cigarette tobacco..............................................................................431 1.3.4 Mainstream cigarette smoke ............................................................436 1.3.5 Sidestream cigarette smoke..............................................................442 1.3.6 Other smoked tobacco products ......................................................442 viii IARC MONOGRAPHS VOLUME 89 1.3.7 Secondhand tobacco smoke..............................................................444 1.3.8 Smokeless tobacco products ............................................................444 1.4 Biomonitoring in saliva, urine and other tissues ........................................451 1.4.1 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its metabolites ..................................................................................451 1.4.2 N′-Nitrosonornicotine (NNN) ..........................................................455 1.4.3 N′-Nitrosoanabasine (NAB) ............................................................456 1.4.4 N′-Nitrosoanatabine (NAT)..............................................................456 2. Studies of Cancer in Humans ..............................................................................457 3. Studies of Cancer in Experimental Animals........................................................457 3.1 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) ..........................457 3.1.1 Intraperitoneal administration..........................................................457 3.1.2 Intravesicular administration............................................................460 3.1.3 Administration in the drinking-water ..............................................460 3.1.4 Oral cavity swabbing........................................................................461 3.1.5 Cheek pouch application..................................................................461 3.1.6 Subcutaneous administration............................................................461 3.1.7 Transplacental or neonatal exposure................................................464 3.1.8 Administration with known carcinogens or modifying factors........467 3.1.9 Carcinogenicity of NNK metabolites ..............................................468 3.2 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) ..........................468 3.2.1 Intraperitoneal administration..........................................................469 3.2.2 Administration in the drinking-water ..............................................470 3.2.3 Administration with known carcinogens or modifying factors........470 3.3 N′-Nitrosonornicotine (NNN)......................................................................471 3.3.1 Intraperitoneal administration..........................................................471 3.3.2 Skin application................................................................................473 3.3.3 Oral administration ..........................................................................473 3.3.4 Cheek pouch application..................................................................474 3.3.5 Subcutaneous administration............................................................475 3.3.6 Administration with known carcinogens or modifying factors........476 3.3.7 Carcinogenicity of NNN metabolites ..............................................477 3.4 N′-Nitrosoanabasine (NAB) ........................................................................478 3.4.1 Intraperitoneal administration..........................................................478 3.4.2 Administration in the drinking-water ..............................................479 3.4.3 Subcutaneous administration............................................................479 3.5 N′-Nitrosoanatabine (NAT)..........................................................................479 4. Other Data Relevant to an Evaluation of Carcinogenicity and its Mechanism ......................................................................................................480 4.1 Absorption, distribution, metabolism and excretion....................................480 4.1.1 Humans ............................................................................................480 4.1.2 Experimental systems ......................................................................502 CONTENTS ix 4.2 Toxic effects ................................................................................................530 4.2.1 Humans ............................................................................................530 4.2.2 Experimental systems ......................................................................531 4.3 Reproductive and developmental effects ....................................................531 4.4 Genetic and related effects ..........................................................................532 4.4.1 Humans ............................................................................................532 4.4.2 Experimental systems ......................................................................532 4.5 Mechanistic considerations..........................................................................543 4.5.1 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)................543 4.5.2 N′-Nitrosonornicotine (NNN) ..........................................................548 5. Summary of Data Reported and Evaluation........................................................548 5.1 Exposure data ..............................................................................................548 5.2 Human carcinogenicity data........................................................................549 5.3 Animal carcinogenicity data........................................................................549 5.4 Other relevant data ......................................................................................551 5.5 Evaluation....................................................................................................553 6. References............................................................................................................553 GLOSSARY....................................................................................................................585 LISTOF ABBREVIATIONS..........................................................................................589 CUMULATIVE INDEX TO THE MONOGRAPHSSERIES........................................593