10. Necessity to evaluate IARC reports on Areca nut and its products

 

Prof. Geoffrey Kabat, a cancer epidemiologist at the Albert Einstein College of Medicine New York, USA, observes that in its assessments of carcinogenicity, IARC places the greatest value on studies in humans, that is, evidence from epidemiologic studies. Interestingly, as per IARC’s own account, the evidence from epidemiological studies shows no indication of a positive association with any cancer with coffee. So, the obvious question is, why wasn’t coffee reassigned to Group 4: “unlikely to cause cancer in humans”?   Yet IARC chose to place coffee in Group 3, which essentially meant “The agent is not classifiable as to its carcinogenicity to humans”. Prof. Geoffrey Kabat observes that IARC’s process appears to be afflicted with a deeply-ingrained double standard. He opines that IARC’s assessments are placing too much weight on isolated findings that appear to suggest a risk, while ignoring more solid studies that do not support the existence of risk.

Interestingly, IARC stated in its monograph that “coffee may protect against cancer." But then it went on to justify its designation of “unclassifiable as to its carcinogenicity in humans.” This flagrant contradiction highlights the problems with IARC’s process, its classification scheme, and the messages it puts out to the public.

Looking into various controversies created over the years through its reports on coffee, meat and cell phones tec., Prof. Geoffrey Kabat observes that IARC is motivated more by the drive for publicity than by a concern for communicating useful information to the public (Courtesy: IARC Lets Coffee Off The Hook But Only Deepens The Confusion, Jun 18, 2016, Forbes magazine).

Unfortunately, Areca nut and its products are appeared to be the victims of such reports by IARC. Due to the stature and clout of IARC, Indian Govt. is forced to initiate action to curb the consumption of Areca nut. At the same time, any possible ban or the restriction on the consumption of areca nut or its products is going to threaten the lively hood of millions of areca farmers across India.

From this, it is amply clear that there is a necessity to evaluate and scrutinize all the reports of IARC on areca nut and Pan/Tambula from several perspectives. This becomes all the more important in case of areca nut, due to the diverse method of consumption (areca nut of different maturity, different ways of processing and different adjuncts including tobacco), frequency of consumption by an individual, complex mechanism of metabolism of areca nut constituents in human body (yet to be elucidated completely) etc. Being a member of IARC, Indian Government must initiate such action in liaison with IARC.   

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9. Some of the most criticized IARC reports: Coffee, Part-II

 

The International Agency for Research on Cancer (IARC) released a monograph in 1991 on the carcinogenic risks caused by coffee (Vol. 51). The monograph was an outcome of year long study and a weak long workshop held in 1990 in Lyon, by a working group comprising 23 experts drawn from 16 countries.  Based on the published literature available from reputed sources, the working group evaluated the reports on epidemiological and experimental studies on the carcinogenicity ln experimental animals, Structure-activity considerations, Absorption, distribution, excretion and metabolism, toxicity, Genetic and related effects, and evidence for carcinogenicity in humans. The working group in its monograph observed that,

·        There is limited evidence in humans that coffee drinking is carcinogenic in the urinary bladder.

·        There is evidence suggesting lack of carcinogenicity of coffee drinking in the human female breast and in the large bowel.

·      There is inadequate evidence in humans that coffee drinking is carcinogenic in the pancreas, ovary and other body sites.

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

The working group concluded that,

·        Coffee is possibly carcinogenic to the human urinary bladder (Group 2B).

This attracted widespread criticism on this report among the public, law makers and scientist's world over. This triggered an in-person enquiry of officials of the U.S. government’s health research agency, “National Institute of Health” by the Congressional committee of United States of America (USA), on its grants to the International Agency for Research on Cancer (IARC) (As per Reuters report dated October 6, 2016). As per the news agency Reuters, the briefing comes after the committee’s chairman added his voice to growing concerns among some senior U.S. lawmakers about the way IARC reviews and classification of substances such as coffee, mobile phones, processed meat and the weed killer glyphosate as carcinogenic. As per Reuters, the Chairman of the Committee on Oversight and Government Reform, Mr. Jason Chaffetz wrote a letter to the NIH Director, and alleged that “IARC’s standards and determinations for classifying substances as carcinogenic, and therefore cancer-causing, appear inconsistent with other scientific research, and have generated much controversy and alarm” and questioned NIH policy to fund IARC.

In 2016, IARC constituted a working group of 23 members drawn from 11 countries to reevaluate the carcinogenic risk posed by Coffee. They released report in 2016 and brought out a monograph on coffee in 2018 (Vol. 116).

The working group observed in its monograph that,

·       There is inadequate evidence in humans for the carcinogenicity of drinking coffee.

·      There is evidence suggesting lack of carcinogenicity of drinking coffee in humans for cancers of the pancreas, liver, female breast, uterine endometrium, and prostate. Inverse associations with drinking coffee have been observed with cancers of the liver and uterine endometrium.

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

The working group concluded that,

·        Drinking coffee is not classifiable as to its carcinogenicity to humans (Group 3).

The working group also observed that coffee drinking is associated with a beneficial effect on liver fibrosis and cirrhosis.

This triggered an allegation that IARC takes decisions in haste and retract their findings due to public pressure after the publication of monograph on coffee and glyphosate. IARC’s director, Chris Wild defended IARC’s evaluation of coffee and said that “The (coffee) report in 2016 was not a ‘retraction’ but a re-evaluation based on an additional 25 years of scientific evidence” (As per Reuters report). 

Nevertheless, this is a classic example where IARC has reversed its assessment on a most popular consumer item. 

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8. Some of the most criticized IARC reports: Red and processed meat, Part-I

 

In general, IARC reports and monographs are taken very seriously by Governments, policy makers and scientists throughout the world. These reports often become a basis for creating new policies, implementing various measures to combat cancer and new research initiatives. However, there are instances where IARC reports / monographs have attracted widespread criticism. IARC attracted huge criticism from scientists and general public due to their reports on subjects like red meat, hot beverage consumption and mobile phones etc.

In 2015, working Group comprising 22 experts drawn from 10 countries evaluated the carcinogenicity of the consumption of red meat & processed meat. After a year long study and deliberations, and a week-long workshop, IARC published a monograph in 2018 (Vol. 114). In the monograph, it was concluded that the “consumption of red meat is probably carcinogenic to humans” & “consumption of processed meat is carcinogenic to humans”. The processed meat has been denoted as Group I carcinogen and red meat as Group 2A carcinogen. It was concluded that the processed meat causes cancer of colorectum, whereas red meat may cause colorectal cancer, and pancreatic and prostate cancer. This was heavily criticized by several senior scientists.

Immediately after the publication of monograph on red meat, researchers from five top universities of South Korea, published a research article in a top-rated international journal called “Critical Reviews in Food Science and Nutrition” (Taylor & Francis Journal) questioning the veracity of the claims that red and processed meat causes cancer of colorectum. The title of the research article was “Controversy on the correlation of red and processed meat consumption with colorectal cancer risk: an Asian perspective”. In the study explained in the article, they had investigated the relationship between meat intake and colorectal cancer risk from an Asian, particularly Korean, perspective. The had conducted an in-depth analysis of prospective, retrospective, case-control and cohort studies, systematic review articles, and IARC monograph reports. They had claimed in their article that the IARC monograph (Vol. 114) is biased and gave higher weightage to the results of studies (published in research article elsewhere) based in Western countries more than the studies conducted on colorectal cancer incidence in Asians. They showed that among 73 epidemiological studies, approximately 76% were conducted in Western countries, whereas only 15% of studies were conducted in Asia. Furthermore, most studies conducted in Asia showed that processed meat consumption is not related to the onset of cancer. Moreover, there have been no reports showing significant correlation between various factors that directly or indirectly affect colorectal cancer incidence, including processed meat product types, raw meat types, or cooking methods.

Note: As per IARC, the agents/substances are classified as Group 1, if the agent is carcinogenic to humans; Group 2A if the agent is probably carcinogenic to humans.

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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.