The Carcinogenicity of Smokeless Tobacco and Areca Nut

Kurt Straif, MD PhD MPH Head IARC Evidence Synthesis and Classification

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Overall carcinogenicity evaluation

IARC Monographs, Volume 100 A Review of Human Carcinogens

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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