7. Summary of IARC reports

 

The International Agency for Research on Cancer (IARC) has published four monographs so for on areca nut, its products (betel quid / Pan, Gutka, Mawa, Pan masala) and also chewable tobacco used along with areca nut. The monographs are an outcome of thorough analysis of research papers published in reputed journals by chosen experts, drawn from multiple nations across the world. The overall conclusions were as follows,

·        Betel quid with tobacco is carcinogenic to humans (Group 1).

·        Smokeless tobacco is carcinogenic to humans (Group 1).

·        Betel quid without tobacco is carcinogenic to humans (Group 1).

·        Areca nut is carcinogenic to humans (Group 1).

·        There is evidence suggesting lack of carcinogenicity in experimental animals for betel leaf.

·        There is evidence suggesting lack of carcinogenicity in experimental animals for slaked lime.

·        Arecoline is possibly carcinogenic to humans (Group 2B).

In a very clear terms, it was stated that all forms of chewable tobacco are carcinogenic. Areca nut mixed with tobacco (Gutka, Mawa, Pan) will certainly cause cancer. Interestingly, it states that betel quid (Pan / Tambula) without tobacco also causes cancer. Furthermore, it was concluded that areca nut is also carcinogenic similar to tobacco. Interestingly, slaked lime & betel leaf, essential ingredients of betel quid / Pan are stated to be safe. Most interestingly, the monographs fail to show conclusive evidence of carcinogenicity of arecoline, or other prominent alkaloids present in areca nut.

These monographs created huge uproar against areca nut and its products, globally. The cancer biologists, research community dealing with human health, doctors, policy makers and Government of several developed countries started initiating measures to curb the consumption of areca nut and its products. This also created a renewed interest in the research groups throughout the world to take up studies dealing with areca nut consumption and subsequent effect on human health.  

Note: as per IARC, the agents/substances are classified as Group 1, if the agent is carcinogenic to humans; Group 2B if the agent is possibly carcinogenic (not yet proven conclusively) to humans.

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6. Report published by IARC in 2021 on the carcinogenic hazards of arecoline

 

The International Agency for Research on Cancer (IARC), an intergovernmental agency affiliated to WHO of the UN, published its report on the carcinogenic hazards of arecoline in 2021 (Vol. 128). Various studies have shown that Arecoline is the most important alkaloid among four major alkaloids present in areca nut, due to its role in modulating many physiological functions upon human consumption. About 20 experts drawn from 11 countries including India were part of the “working group”. The working group assessed the following,

1.      The strength of the available evidence on that arecoline can cause cancer in humans, based on three streams of evidence: on cancer in humans, on cancer in experimental animals, and on mechanistic evidence (absorption, distribution, metabolism & excretion in humans & other model systems).

2.      The data on the incidence of cancer due to the direct exposure.

The working group concluded the following in their monograph,

1.      There is inadequate evidence in humans regarding the carcinogenicity of arecoline.

2.      There is limited evidence in experimental animals for the carcinogenicity of arecoline.

3.      There is strong evidence in human primary cells and in various experimental systems that arecoline exhibits multiple key characteristics of carcinogens.

The overall conclusion was,

Arecoline is possibly carcinogenic to humans (Group 2B).

The working group came to a conclusion that arecoline exhibit multiple key characteristics of carcinogens in general. It alters DNA repair mechanism and causes genomic instability in experimental systems. However, the group found limited evidence for cancer in experimental animals. The group didn’t find any studies on the incidence of cancer in humans, due to arecoline. Hence, with a greater degree of uncertainty, the working group concluded that arecoline might be a carcinogen.  

 

5. Report published by IARC in 2007 on the carcinogenic risk of chewable Tobacco.

 

The International Agency for Research on Cancer (IARC), an intergovernmental agency affiliated to World Health Organization (WHO) of the United Nations (UN) published its report on smokeless tobacco in 2007 in the form of a monograph (Vol. 89). Flavored / unflavored tobacco such as Zarda, Khiwam, loose tobacco leaves, khaini and flavored/ unflavored tobacco with additives such as betel quid/Pan, Gutka, Mawa etc. were considered as "smokeless tobacco" for the assessment. Altogether 19 experts drawn from 6 countries including India, called as “Working Group” deliberated on the issue in a week-long workshop held in Lyon, France in 2004 and brought out the manograph in 2007. The data on the exposure of the chewable tobacco to humans, data available on the cancer in humans due to the exposure, underlaying mechanism of cancer induction, experimental animal studies data, cell-line studies etc. published in reputed journals were reviewed by the working group.

The working group concluded the following in their monograph.

·        Tobacco-specific nitrosamines, the most abundant strong carcinogens in smokeless tobacco products have been detected in the saliva of tobacco chewers in many studies around the world.

·        Smokeless tobacco products are associated with the generation of reactive oxygen species, modulation of inflammatory mediators, inhibition of collagen synthesis and impairment of DNA repair capacity.

·        Smokeless tobacco products deliver nicotine in quantities and at rates that cause psychoactive effects, which eventually lead to tolerance and addiction.

·        There is sufficient evidence in humans for the carcinogenicity of smokeless tobacco. Smokeless tobacco causes cancers of the oral cavity and pancreas.

The overall conclusion was,

·        Smokeless tobacco is carcinogenic to humans (Group 1).

4. Report published by IARC in 2004, on the carcinogenic risk of areca nut & Betel quid (Tambula / Pan) chewing. Part-II

 

The International Agency for Research on Cancer (IARC) constituted a "working group" comprising 17 experts drawn from India, China/Taiwan, UK, USA, Germany, Netherlands and South Africa, to study the possible carcinogenic risk posed by areca nut and betel quid to humans. After a detailed study, the working group prepared a monograph having 300 pages, detailing the mode of the assessment and evaluation, the research papers considered for assessing each criterion, the type of research papers considered for the assessment etc. and was published in 2004 in Lyon, France.

The working group concluded the following in their monograph.

·    There is sufficient evidence in humans for the carcinogenicity of betel quid with tobacco. Betel quid with tobacco causes oral cancer and cancer of the pharynx and esophagus.

·    There is sufficient evidence in humans for the carcinogenicity of betel quid without tobacco. Betel quid without tobacco causes oral cancer.

·    There is sufficient evidence in experimental animals for the carcinogenicity of betel quid with and without tobacco.

·        There is sufficient evidence in experimental animals for the carcinogenicity of areca nut.

·      There is evidence suggesting lack of carcinogenicity in experimental animals for betel leaf and slaked lime.

·        There is limited evidence in experimental animals for the carcinogenicity of arecoline.

·        There is inadequate evidence in experimental animals for the carcinogenicity of arecaidine.

The working group concluded that areca nut causes oral submucous fibrosis, a precancerous condition in humans. Further it claims to have found sufficient evidence of carcinogenicity in experimental animals.

The overall conclusion was,

·        Betel quid with tobacco is carcinogenic to humans (Group 1).

·        Betel quid without tobacco is carcinogenic to humans (Group 1).

·        Areca nut is carcinogenic to humans (Group 1).

This monograph created a huge uproar against areca nut and its products among the cancer biologists, research community dealing with human health, doctors, policy makers and Government of several developed countries. This created a renewed interest in the research groups throughout the world to take up studies dealing with areca nut consumption and subsequent effect on human health.  

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3. Report published by IARC in 2004, on the carcinogenic risk of areca nut & Betel quid (Tambula / Pan) chewing. Part-I

 

The International Agency for Research on Cancer (IARC), an intergovernmental agency affiliated to World Health Organization (WHO) of the United Nations (UN) published its second report on areca nut / Tambula (betel quid/ Pan) in 2004 in the form of a monograph (Vol. 85). This monograph was an outcome of a one-year effort involving 17 member "working group" drawn from India, China/Taiwan, UK, USA, Germany, Netherlands and South Africa. Senior scientists from AIIMS New Delhi, TIFR Mumbai, Cancer Research Institute, Tata Memorial Centre Mumbai etc. were the working group members from India.

IARC claims that it will select the topic based on two criteria: (a) there is evidence of human exposure, and (b) there is some evidence or suspicion of carcinogenicity. As per IARC, a “carcinogen” is defined as any substance which is capable of increasing the incidence of malignant (cancerous) tumors upon human exposure. Based on these terms, IARC claims that there was sufficient evidence available to probe the carcinogenicity of areca nut & betel quid chewing in Human population.

As per IARC, Oral cancer is the leading type of malignancy in India and South-east Asia, whereas lung, breast, prostate and colorectum are the leading cancers in the Americas, Europe and Oceania. In South Central Asia, cancer of the oral cavity is the cancer with the highest incidence among the men and the third highest among women (after the cervix and breast). Large body of evidence arisen from studies in experimental animals and in-vitro studies (lab studies in petri plates) that investigated the effects of areca nut alone, as well as those of betel quid with or without tobacco during 1985 to 2003, provided an impetus for selecting areca nut / Tambula by the working group of IARC.

The working group considered the following in their study.

·        Exposure of general population to Tambula (with and without tobacco) and areca nut.

·        Research studies on oral cancer

·        Research studies on lesions and precancerous lesions and conditions

·        Studies on stomach, Liver and cervical cancer

·        Studies of cancer in experimental animals

·        Other data relevant to an evaluation of carcinogenicity and its mechanisms.

Note: To be continued in the next Part.