IARC Monographs on the Evaluation of Carcinogenic Risks to Humans VOLUME 85 Betel-quid ...

349 Pages·2007·7.44 MB·English

WORLD HEALTH ORGANIZATION
INTERNATIONALAGENCY FOR RESEARCH ON CANCER
IARC Monographs on the Evaluation of
Carcinogenic Risks to Humans
VOLUME 85
Betel-quid and Areca-nut Chewing and
Some Areca-nut-derived Nitrosamines
LYON, FRANCE
2004
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WORLD HEALTH ORGANIZATION
INTERNATIONALAGENCYFOR RESEARCH ON CANCER
IARC Monographs on the Evaluation of
Carcinogenic Risks to Humans
VOLUME 85
Betel-quid and Areca-nut Chewing and
Some Areca-nut-derived 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,
11–18 June 2003
2004
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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 associated 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 Internet:
http://monographs.iarc.fr/
This project was supported by Cooperative Agreement 5UO1CA33193 awarded by the
United States National Cancer Institute, Department of Health and Human Services. Addi-
tional support has been provided since 1993 by the United States National Institute of
Environmental Health Sciences.

International Agency for Research on Cancer, 2004
Distributed by IARCPress(Fax: [phone]; E-mail: [email protected])
and by the World Health Organization Marketing and Dissemination, 1211 Geneva 27
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All rights reserved. Application for rights of reproduction or translation, in part or in toto,
should be made to the International Agency for Research on Cancer.
IARC Library Cataloguing in Publication Data
Betel-quid and areca-nut chewing and some areca-nut-derived nitrosamines /
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans
(2003 : Lyon, France)
(IARC monographs on the evaluation of carcinogenic risks to humans ; v. 85)
1. Areca – adverse effects 2. Carcinogens 3. Esophageal neoplasms 4. Mouth
neoplasms 5. Neoplasms 6. Nitrosamines – toxicity 7. Pharyngeal neoplasms
8. Tobacco, smokeless I. IARC Working Group on the Evaluation of Carcinogenic
Risks to Humans II. Series
ISBN 92 832 1285 1 (NLM Classification: W1)
ISSN 1017-1606
PRINTED IN FRANCE
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2 3 4 5
1 6
7
1 Betel quid stand at a Phnom Penh local market (provided by Peter Reichart)
2 Betel quid, unfolded
3 Betel quid, folded
4 Gutka, as commercially manufactured and sold in Southeast Asia
5 Pan masala, as commercially manufactured and sold in Southeast Asia
6 Lao-hwa areca nuts, as sold in Taiwan, China (provided by Peter Reichart)

7 Pan masala, as served in restaurants after the meal
Cover design by Georges Mollon, IARC
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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
Betel-quid and Areca-nut Chewing ........................................................................39
1. Exposure Data..................................................................................................41
1.1 Composition of betel quid........................................................................41
1.1.1 Betel quid ....................................................................................41
1.1.2 Areca nut......................................................................................42
1.1.3 Betel leaf......................................................................................50
1.1.4 Betel inflorescence ......................................................................50
1.1.5 Slaked lime..................................................................................50
1.1.6 Catechu........................................................................................51
1.1.7 Tobacco........................................................................................51
1.1.8 Miscellaneous additives and contaminants..................................51
1.2 Areca nut-based industrial packaged products........................................52
1.3 Consumption by geographical region......................................................52
–v–
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vi IARC MONOGRAPHS VOLUME 85
1.3.1 India ............................................................................................52
(a) Adults....................................................................................53
(b) Children and adolescents......................................................59
1.3.2 Pakistan ......................................................................................61
1.3.3 Bangladesh ..................................................................................62
1.3.4 Sri Lanka......................................................................................62
1.3.5 Maldives ......................................................................................63
1.3.6 People’s Republic of China ........................................................63
1.3.7 Taiwan, China..............................................................................64
1.3.8 Myanmar......................................................................................68
1.3.9 Thailand ......................................................................................68
1.3.10 Lao People’s Democratic Republic ............................................69
1.3.11 Cambodia ....................................................................................69
1.3.12 Malaysia ......................................................................................69
1.3.13 Singapore ....................................................................................70
1.3.14 Indonesia......................................................................................70
1.3.15 The Philippines............................................................................71
1.3.16 Papua New Guinea......................................................................71
1.3.17 Palau ............................................................................................72
1.3.18 Guam............................................................................................73
1.3.19 Others ..........................................................................................73
1.3.20 Migrant populations ....................................................................74
(a) South Africa..........................................................................74
(b) United Kingdom....................................................................75
(c) Others....................................................................................78
1.3.21 Placement of the quid in the mouth ............................................78
1.4 Regulations and legislation......................................................................78
Regulation of import and sale of areca-containing products ..................79
(a) India......................................................................................79
(b) North America ......................................................................79
(c) European Union....................................................................79
(d) Limited bans in other countries............................................80
2. Studies of Cancer in Humans..........................................................................80
2.1 Oral cancer ..............................................................................................80
2.1.1 India, Pakistan and Sri Lanka......................................................80
(a) Descriptive studies and case series ......................................80
(b) Cohort studies ......................................................................86
(c) Case−control studies ............................................................87
(d) Cross-sectional surveys ......................................................101
(e) Synergism............................................................................101
2.1.2 Taiwan, China............................................................................104
(a) Descriptive study................................................................104
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CONTENTS vii
(b) Case−control studies ..........................................................105
2.1.3 South-East Asia..........................................................................108
(a) Malaysia..............................................................................108
(b) Myanmar ............................................................................110
(c) Thailand ..............................................................................110
2.1.4 Papua New Guinea ....................................................................111
2.1.5 Migrant populations ..................................................................112
(a) South Africa........................................................................112
(b) United Kingdom..................................................................112
2.2 Some betel quid-associated lesions, and precancerous lesions and
conditions ..............................................................................................113
2.2.1 Introduction................................................................................113
2.2.2 Betel quid-associated oral lesions..............................................113
2.2.3 Leukoplakia and erythroplakia..................................................113
(a) India....................................................................................114
(b) Taiwan, China ....................................................................116
(c) South-East Asia ..................................................................123
(d) Migrants..............................................................................123
2.2.4 Oral submucous fibrosis............................................................123
(a) India and Pakistan ..............................................................123
(b) People’s Republic of China................................................127
(c) Taiwan, China ....................................................................128
(d) South-East Asia ..................................................................128
(e) Migrants..............................................................................128
2.2.5 Oral lichen planus......................................................................129
(a) India....................................................................................129
(b) South-East Asia ..................................................................130
2.2.6 Multiple and mixed lesions........................................................130
2.2.7 Malignant transformation..........................................................131
(a) India and Pakistan ..............................................................131
(b) Taiwan, China ....................................................................132
(c) Migrants..............................................................................132
2.3 Other upper aerodigestive cancer ..........................................................132
2.3.1 India ..........................................................................................132
2.3.2 Taiwan, China............................................................................137
2.4 Other cancers..........................................................................................137
2.4.1 Stomach cancer..........................................................................137
2.4.2 Lung cancer................................................................................137
2.4.3 Cervical cancer..........................................................................139
2.4.4 Liver cancer ..............................................................................139
(a) Taiwan, China ....................................................................139
(b) Thailand..............................................................................140
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viii IARC MONOGRAPHS VOLUME 85
3. Studies of Cancer in Experimental Animals..................................................142
3.1 Oral administration................................................................................142
3.1.1 Mouse ........................................................................................142
3.1.2 Rat..............................................................................................145
3.1.3 Hamster......................................................................................146
3.2 Skin application......................................................................................147
Mouse ....................................................................................................147
3.3 Subcutaneous administration ................................................................147
3.3.1 Mouse ........................................................................................147
3.3.2 Rat..............................................................................................148
3.4 Intraperitoneal administration................................................................148
Mouse ....................................................................................................148
3.5 Administration to the oral mucosa or cheek pouch ..............................149
3.5.1 Rat..............................................................................................149
3.5.2 Hamster......................................................................................149
3.5.3 Baboon ......................................................................................154
3.6 Intravaginal instillation..........................................................................154
Mouse ....................................................................................................154
3.7 Administration with known carcinogens or modifiers of cancer risk ..154
3.7.1 Mouse ........................................................................................154
3.7.2 Rat ............................................................................................156
3.7.3 Hamster......................................................................................156
4. Other Data Relevant to an Evaluation of Carcinogenicity
and its Mechanisms ......................................................................................160
4.1 Absorption, distribution, metabolism and excretion..............................160
4.1.1 Humans ....................................................................................160
(a) Constituents of betel quid ..................................................160
(b) Biomarkers of constituents of betel quid............................162
4.1.2 Experimental systems................................................................166
(a) Areca nut/arecoline ............................................................166
(b) Betel leaf/hydroxychavicol/eugenol ..................................168
(c) Formation of nitrosamines..................................................169
(d) Formation of reactive oxygen species from betel-quid
ingredients ..........................................................................170
(e) Antioxidant effects..............................................................172
4.2 Physiological and toxic effects..............................................................173
4.2.1 Humans......................................................................................173
(a) Psychopharmacological effects ..........................................173
(b) Effects on oral hard and soft tissues ..................................173
(c) Effects on various physiological systems ..........................175
(d) Other effects........................................................................180
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CONTENTS ix
4.2.2 Experimental systems................................................................180
(a) In-vivo studies ....................................................................180
(b) In-vitro studies....................................................................186
4.3 Reproductive and developmental effects ..............................................190
4.3.1 Humans......................................................................................190
4.3.2 Experimental systems................................................................191
(a) Pan masala..........................................................................191
(b) Areca nut ............................................................................192
(c) Arecoline ............................................................................192
(d) Stems of Piper betle............................................................193
(e) Nicotine ..............................................................................193
4.4 Genetic and related effects ....................................................................194
4.4.1 Humans......................................................................................194
(a) Genotoxicity and mutagenicity ..........................................194
(b) Genomic instability ............................................................196
(c) Oncogenes and tumour-suppressor genes ..........................196
(d) Polymorphism in carcinogen-metabolizing enzymes ........203
4.4.2 Experimental systems................................................................213
(a) Genotoxicity and mutagenicity ..........................................213
(b) Oncogenes and tumour-suppressor genes ..........................226
(c) Polymorphisms in carcinogen metabolizing genes............227
(d) Markers of tumour promotion............................................227
(e) Preventive effects................................................................227
4.5 Mechanistic considerations....................................................................228
5. Summary of Data Reported and Evaluation..................................................230
5.1 Exposure data ........................................................................................230
5.2 Human carcinogenicity data ..................................................................231
5.3 Animal carcinogenicity data..................................................................232
5.4 Other relevant data ................................................................................235
5.5 Evaluation..............................................................................................238
6. References......................................................................................................239
Some Areca-nut-derived N-Nitrosamines ............................................................279
1. Exposure Data................................................................................................281
1.1 Chemical and physical data ..................................................................281
1.1.1 Synonyms and structural and molecular formulae....................281
1.1.2 Chemical and physical properties..............................................282
1.2 Production..............................................................................................282
1.3 Occurrence ............................................................................................283
1.4 Analysis..................................................................................................284
2. Studies of Cancer in Humans........................................................................284