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The Carcinogenicity of Smokeless Tobacco and Areca Nut
Kurt Straif, MD PhD MPH Head IARC Evidence Synthesis and Classification
Global burden and control of cancer • Rising burden of cancer: estimates
by 2035 24.0 million new cases/a compared to 14.1 million in 2012
• Majority of the increase in cancer burden expected in low- and middle-income countries (LMIC)
• Prevention probably the single most effective response to these challenges,
• The first step in cancer prevention is to identify the causes of human cancer (Monographs) and what prevents cancer (IARC Handbooks)
The IARC Monographs “The encyclopaedia of carcinogens” The IARC Monographs evaluate
Ø Chemicals Ø Complex mixtures Ø Occupational exposures Ø Physical and biological agents Ø Personal habits
More than 1000 agents have been evaluated Ø 120 are carcinogenic to humans (Group 1) Ø 81 are probably carcinogenic to humans (Group 2A) Ø 299 are possibly carcinogenic to humans (Group 2B)
National and international health agencies use the Monographs Ø As a source of scientific information on known or suspected carcinogens Ø As scientific support for their actions to prevent exposure to known or suspected
carcinogens
Lorenzo Tomatis 1929-2007
The IARC Monographs, a worldwide endeavour that since 1971 has involved over 1000 scientists from over 50 countries
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Overall carcinogenicity evaluation
IARC Monographs, Volume 100 A Review of Human Carcinogens
• Scope of volume 100 – Update the critical review for each carcinogen in Group 1 – Identify tumour sites and plausible mechanisms – Compile information for subsequent scientific publications
• The volume was developed over the course of 6 meetings A. Pharmaceuticals (23 agents, Oct 2008) B. Biological agents (11 agents, Feb 2009) C. Metals, particles and fibres (14 agents, Mar 2009) D. Radiation (14 agents, June 2009) E. Lifestyle factors (11 agents, Sept 2009) F. Chemicals and related occupations (34 agents, Oct 2009)
IARC Handbooks of Cancer Prevention
• Launch in 1995 to complement the IARC Monographs’ evaluations of carcinogenic hazards with evaluations of cancer-preventive agents.
• Working procedures and evaluation scheme closely mirror those of the Monographs.
• Cancer Prevention HBs re-launched in 2014 with initial broader scope on primary and secondary prevention
History of IARC Handbooks of Cancer Prevention IARC Sc Pub #139 Principles of Chemoprevention (Nov 1995) Preventive Agents Vol 1 NSAIDs Vol 2 Carotenoids Vol 3 Vitamin A Vol 4 Retinoids Vol 5 Sunscreens Vol 6 Weight Control & Physical Activity Vol 8 Fruit and Vegetables Vol 9 Cruciferous Vegetables,Isothiocyanates and Indoles Vol 16 Avoidance of Body Fatness (amended Working Procedures)
Screening Vol 7 Breast Cancer Screening (Working procedures) Vol 10 Cervix Cancer Screening Vol 15 Breast Cancer Screening
Tobacco Control Vol 11 Reversal of Risk after Quitting Smoking Vol 12 Methods for Evaluating Tobacco Control Policies Vol 13 Evaluating the Effectiveness of Smoke-free Policies Vol 14 Effectiveness of Price and Tax Policies for Control of Tobacco
History of the cancer sites recognized to be causally associated with tobacco smoking
Year (Report) Tumour sites
1957 (Expert committees in The Netherlands, the USA and the UK)
Lung
1986 (IARC, Volume 38) Upper digestive tract, respiratory tract, pancreas, urinary bladder, renal pelvis
2004 (IARC, Volume 83) Oral cavity, oro-, naso-, and hypopharynx, oesophagus (adeno- and squamous cell carcinoma), stomach, liver, pancreas, nasal cavity and paranasal sinuses, larynx, lung, uterine cervix, urinary bladder, kidney (body and pelvis), ureter, bone marrow (myeloid leukaemia)
Secondhand smoke: Lung 2009 (IARC, Volume 100) Oral cavity, oro-, naso-, and hypopharynx, oesophagus
(adeno- and squamous cell carcinoma), stomach, colorectum, liver, pancreas, nasal cavity and paranasal sinuses, larynx, lung, uterine cervix, ovary (mucinous), urinary bladder, kidney (body and pelvis), ureter, bone marrow (myeloid leukaemia) Breast (limited)
IARC Monographs & IARC Cancer Prevention Handbooks Tobacco-related Monographs Vol 83 Tobacco Smoke & Involuntary Smoking Vol 85 Betel-quid & Areca- nut Chewing and Some Areca-nut- derived Nitrosamines Vol 89 Smokeless Tobacco & Some Tobacco- specific N-Nitrosamines Vol 100E Personal habits & indoor combustions
Tobacco Control Handbooks Vol 11 Reversal of Risk after Quitting Smoking Vol 12 Methods for Evaluating Tobacco Control Policies Vol 13 Evaluating the Effectiveness of Smoke-free Policies Vol 14 Effectiveness of Price & Tax Policies for Control of Tobacco
WHO/TFI-IARC Working Group on Tobacco Product Regulation The scientific basis of tobacco product regulation.
Betel-quid and areca-nut chewing and some areca-nut related nitrosamines.
Betel-quid and areca-nut chewing widely practiced in many parts
of Asia and Asian-migrant communities elsewhere in the world Hundreds of millions of users worldwide
Areca nut is a common ingredient of the betel quid
Aggressive advertising, targeted at middle class and children Since the 1980s, use of industrially manufactured products, often containing tobacco, increased, especially among adolescents.
Betel quid w/o tobacco
Areca nut
Vol. 37 - 1985Betel quid w/ tobaccoOral cavity
Betel quid w/ tobacco
Vol. 85 - 2003
Cancer sites causally associated with betel quid with or without tobacco or areca nut
Oral cavityPharynxOesophagus
Oral cavity
Oral cavity
Areca-nut is carcinogenic to humans (Group 1) Several studies observed very high relative risks of oral submucous fibrosis among chewers of areca nut. Follow-up studies showed high risks for malignant transformation.
Areca nut (or extracts) given by gavage, diet, s.c. injection or cheek pouch application to mice or hamsters produced carcinomas locally, of the oesophagus, stomach, liver or lung, and malignant lymphomas
There is sufficient evidence in experimental animals for the carcinogenicity of areca nut
Strong mechanistic evidence in chewers: areca-nut derived nitrosamines detected in saliva; formation of ROS in oral cavity; elevated micronucleus formation, sister chromatid exchange and chromosome breaks
Smokeless Tobacco
Wide variety of commercially and non-commercially prepared products used either orally or nasally: Chewing tobacco, oral and nasal snuff; khaini, naswar, mishri, gudakhu, shammah etc.
Constituents • Nicotine • Tobacco-specific N-nitrosamines (NNN, NNK)
Use differs by age, gender, and social class
Cancer sites for the different forms of tobacco evaluated, Vol 100E, 2009
Tobacco smoking
Second-hand smoke
Smokeless tobacco
Betel quid with tobacco/ without tobacco
Lung S S
Oral cavity S S S/S
Larynx S L
Pharynx S L S/--
Esophagus S S S/S
Pancreas S S
Evidence for carcinogenicity in humans : S, sufficient; L, limited.
• Random-effects meta-analysis of 50 publications assessing the relationship between oral/oropharyngeal cancer and chewing betel quid, with (BQ+T) or without added tobacco (BQ-T)
• Exposure-response, by daily amount and years of BQ
chewed assessed by spline models • Attributable fractions (PAF%) were calculated to estimate
the public health impact
Results for Indian subcontinent
Strata BQ with tobacco BQ without tobacco mRR 95% CI mRR 95% CI overall 7.74 5.38 - 11.1 2.56 2.00 - 3.28 smoking adj. 6.19 4,16 - 9.21 2.94 2.01 - 4.28 Tob/alc adj. 7.03 4.68 - 10.6 3.22 2.11 - 4.92 men 5.37 3.91 7.36 2.14 1.48 . 3.10 women 14.56 7.63 - 27.8 3.02 1.79 - 5.08 Subsites Oral cavity 8.47 6.49 11.05 2.41 1.82 3.49 Oropharynx 4.36 2.23 8.53 2.61 1.74 3.92
Results for Indian subcontinent and Taiwan, China
Risk of oral/oropharyngeal cancer increased with increasing daily amount and duration (yrs) of chewing
Natural spline model with 95% CI for exposure-response by duration of chewing betel quid with added tobacco in India and the risk of oral/oropharyngeal cancer
The IARC Monographs and Handbooks are supported by grants from Ø U.S. National Cancer Institute (since 1982) Ø European Commission, DG Employment, Social Affairs and Inclusion
(since 1986) Ø U.S. National Institute of Environmental Health Sciences (since 1992) Ø Institut National du Cancer (INCa), France Ø U.S. Center for Disease Control (CDC) Ø American Cancer Society (ACS)
Acknowledgements
Open research and PH questions Analytical epidemiology • Update meta-analysis (MA) with new studies • Refine MA: varieties of BQ habits, gender, age, ethnicities, • MA for other cancer sites pharynx, esophageal, liver,… Burden estimates • Age and cohort-specific analysis of trends of oral and lung cancer incidence based on cancer registry data • PAF by country, extrapolate from available mRR using national exposure data Interventions • Evaluation of effectiveness of interventions (taxation, price policies, advertising bans, interventions for cessation