Smokeless Tobacco and Some Tobacco-Specific N-Nitrosamines

641 Pages·2007·3.2 MB·English

by  International Agency for Research on Cancer

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
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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