8. Health benefits conferred by the constituents of Areca nut. Part-V (Catechins)

 

Catechin, name was apparently derived from the word "catechu," a boiled extract/tannic juice of a Katch tree (Scientific name: Acacia catechu). This tree is called as “Kadira” in Sanskrit, “Khair” in Hindi. Kattha, a main product produced out of bark extract of Acacia catechu contains Catechins & its isomer epicatechin. As per an ancient Indian book, Jyotirnibandha written by Shivraj in AD 1524, Kattha (catechu extract) is a most important ingredient of Tambula (Betel quid) along with areca nut, betel leaf and lime. Apparently, the scientific name of Areca nut (Areca catechu) is derived due to the presence of large amount of catechin in Areca nuts. 

Catechin is one of the most abundant and important phenolic compounds found in areca nuts as well. Its concentration in areca nut depends upon the maturity of the areca nut harvested, processing method and the cultivars. The concentration can vary anywhere between 7 mg to 25 mg per gram of dried nuts.

Numerous studies involving cell-lines, animal models and in silico models have shown that Catechin/ epicatechin is a very important phytochemical. Its biological action encompasses antibacterial activity, anti-carcinogenic activity, anti-cataract activity, antifungal activity, anti-hypercholesterolemic activity, anti-inflammatory effect, anti-oxidative effect, antiproliferative activity, and antiviral activity. Though most studies relate their potential to anti-oxidative action and radical scavenging action, still the mechanism of action is not clearly understood. Recent studies shows that most of the beneficial functions of catechin/epicatechin is due to their ability to scavenge reactive oxygen species produced in the body, inhibiting transcription factors (controlling the expression of various genes in the body), and inhibition of pro-oxidant enzymes (tend to produce free-radicals in the body).

More than 18 clinical trials on the human population with different conditions have been carried out so far on the effectiveness of catechin /epicatechin. There is conclusive evidence that catechin / epicatechin are an effective and promising form of treatment of several disease conditions.

Most of the health benefits of Tea (Black & Green tea) is attributed to catechin/epicatechin & catechin gallates (gallic acid esters of catechins/epicatechins). Interestingly, areca nut contains considerable amount of catechins (7-25 mg/g) yet found little attention in scientific studies & food industries, which is rather surprising. 

References

Baranwal et al. (2022). Pharmacological Actions and Underlying Mechanisms of Catechin: A Review, Mini Reviews in Medicinal Chemistry, Vol. 22 (5), pp. 821-833(13).

7. Health benefits conferred by the constituents of Areca nut. Part-IV (Catechins)

 

Catechin is another very important phenolic substance present in areca nut in substantial quantity. Its concentration can range anywhere between 7-25 mg per gram of dry areca nut. The areca nuts of 6-7 months’ maturity were found to contain 24 mg of catechin, compared to the ripened areca nuts of  9-10 months’ maturity (8.51 mg/g) as per one Indonesian report. Interestingly, areca nuts harvested at 5 months maturity in China (Hainan province) for the production of Bing lang had only 7.2 mg per gram of dried areca nut, which is lesser than the matured areca nut.

Catechins are flavanols, which are also called proanthocyanidins or flavan-3-ols. Tea, wine and chocolates are some of the most prominent dietary suppliers of catechins to humans. Red wine, green, black and oolong teas, fruits like plum, apples, peach, strawberry and cherry, and beans and grains like broad bean, lentil and cocoa are rich in catechins. As per one study, Chocolate contributes 20% of the daily catechin intake in the Dutch population, and tea contributes 55%. Mediterranean diets, which are rich in wines and fresh fruits and vegetables, were found high in catechins. Mediterranean diet which is considered as one of the healthiest is found to provide about 100 mg of catechins and procyanidins per person per day.  Total catechin contents of green and black tea are about 420 and 250 mg/L, respectively.  About 12.5 grams of areca nut (Chali or white supari) or about 4 grams of red supari (Kempadike) can provide the equivalent amount of catechin to humans. 

Catechin are found to exhibit physiological effects, including antibacterial, antifungal, antiviral, antioxidative, and antitumor activities. Recent studies have suggested that catechins also promote oral health and contribute to a reduced risk for some systemic disease.

The oral cavity of humans contains more than hundred species of microbes. An increase in the number of these microorganisms like high pathogenic potential species, such as cariogenic and periodontopathic bacteria, and the change of microbial biota may result in, not only oral infection, but also systemic diseases, such as infective endocarditis and aspiration pneumonia. It is very important to control the growth of these microorganisms and its biota just after oral cleaning in order to suppress disease onset. Numerous studies have proved that catechin formulations inhibited the growth of the Actinomyces, periodontopathic bacteria and Candida strains tested, but did not inhibit that of the oral Streptococci that are important in the normal oral flora. Thus, it was clear that catechins can improve the oral hygiene and deter the onset of oral infection, and systemic diseases, such as infective endocarditis and aspiration pneumonia.

Perhaps, the ancient Indian medical practitioners were aware of the importance of catechin present in areca nut and hence had prescribed chewing of Tambula (Betel quid) after every meal.  

References

Tamura & Ochiai (2012) Exploring the possible applications of catechin (gel) for oral care of the elderly and disabled individuals, Japanese Dental Science Review, Vol. 48, pp. 126—134

Yusuf Yilmaz (2006). Novel uses of catechins in foods. Trends in Food Science & Technology, Vol. 17, pp. 64–71

Sari et al., (2020). Distinct phenolic, alkaloid and antioxidant profile in betel quid from four regions of Indonesia, Scientific Reports, Vol. 10 : 16254

Song et al., (2022). UHPLC-MS/MS identification, quantification of flavonoid compounds from Areca catechu L. extracts and in vitro evaluation of antioxidant and key enzyme inhibition properties involved in hyperglycemia and hypertension. Industrial Crops & Products. Vol. 189, pp. 115787.

 

6. Health benefits conferred by the constituents of Areca nut. Part-III (Arecatannins)

 

Tannins are an interesting class of polyphenols, believed to confer numerous health benefits. Tannins are categorized into two classes, namely, hydrolysable tannins and condensed tannins. Areca nut contains mainly condensed tannins which are having at least one monomer as catechin / epicatechin.   

Areca tannin is the main constituent of phenolic compounds found in areca nut. Its concentration can be as high as 40% by weight of the total phenolic content. It is made out of two epicatechin and one catechin molecules and hence categorized under condensed tannin group. 

Due to their complex structure, these tannins exhibit good antioxidant properties. Tannins can exert their function primarily at cellular but also physiological levels, presenting themselves as promising agents for preventing or treating several pathophysiological conditions. They exhibit important effects on cardiac well-being and inflammatory states. In addition, the antioxidant effect could also determine cascading effects that may prevent the growth of cancer cells. Tannins have the unique ability to complex with proteins. The interaction of tannin with proteins is one of the main mechanisms of biological activity of tannins.

Most consumed tannins can reach the colon almost intact, where the high molecular weight structures cannot be readily absorbed and must be further metabolized by the gut microbiota. The gut microbiota depolymerizes the condensed tannins and derivatize them into phenolic acids and valerolactones. Catechin and epicatechin can be readily absorbed in the proximal intestinal tract, while oligomer and polymer absorption rates decrease with increasing number of hydroxyl groups and molecular size.

Numerous research reports are showing that these tannins can help decrease the risk of cardiovascular and Alzheimer’s disease, delay cellular ageing, and maintain intestinal microbiota homeostasis. There are studies on their functions as molecules with pharmacological activity potentials, such as ROS (reactive oxygen species) reducing agent, anti-inflammatory, antifungal, antimicrobial, antiviral, anthelmintic, antimutagenic, and anticancer activities. Considering these health benefits, there is a serious contemplation to include tannins as “Nutraceuticals”.

References.

1.  Moura de Melo et al., (2023). Biological and pharmacological aspects of tannins and potential biotechnological applications, Food Chemistry, Vol. 414, 135645.

2.   Molino et al., (2023). Why is it important to understand the nature and chemistry of tannins to exploit their potential as nutraceuticals? Food Research International Vol. 173, 113329.

3.  Mugeri et al., (2022). Pharmacology and toxicology of tannins. Archives of Toxicology, Vol. 96, 1257–1277.

5. Health benefits conferred by the constituents of Areca nut. Part-II (Procyanidins)

 

B-type procyanidins are found to be one of the most abundant phenolic compounds found in Areca nuts. (–)-epicatechin is the most common monomeric unit of procyanidins. These procyanidins are also present in abundance in Cocoa, apples, grape seeds, and red wine.

These procyanidins have 20 times the antioxidant capacity of vitamin C and 50 times the antioxidant capacity of vitamin E. Procyanidins can neutralize the reactive oxygen species (ROS).

Several processes in our body, such as differentiation, metabolism, proliferation, and apoptosis, are maintained in a normal physiological state by our body’s endogenous antioxidative system. They keep the system in a state of dynamic redox equilibrium. Excessive production of reactive nitrogen species and reactive oxygen species (ROS) causes oxidative stress. Accumulation of ROS can trigger a cascade of reactions that causes direct damage to DNA, lipids, and proteins, ultimately leading to tissue dysfunction. Aside from that, ROS accumulation can contribute to the development of diseases, including cancers, neurodegenerative disorders, cardiovascular diseases, and metabolic disorders.

When the ROS level is low, it is usually advantageous and beneficial for cells and tissues, and normal rate of cell division, tissue repair, and angiogenesis happens without any interruption. Excessive ROS production disrupts multiple biomolecules, which can cause membrane damage. Furthermore, it will inactivate membrane receptors and enzymes, reduce membrane fluidity, increase membrane permeability to ions, and, in extreme cases, rupture the cell membrane and cell lysis leading to the cell death. In addition, lipid peroxides, nitric oxides, and superoxide radicals accumulate in cells and directly damage them by generating unstable radicals and interfering with natural antioxidant molecules and enzymes. Thus, high level of ROS causes apoptosis (programmed cell death), cell damage, DNA mutations, and cell death.

Procyanidin has been shown to prevent oxidative stress-induced DNA damage and promote DNA repair via various pathways. Furthermore, it is discovered that procyanidin could increase the expression and activity of antioxidant enzymes. One of the primary functions of antioxidants is to prevent apoptosis and reduce the level of ROS in cells. Procyanidins effectively does it.  Numerous researches have proved the beneficial effects of consumption of Cocoa, apples, grape seeds, and red wine and their ability to confer antioxidant property to the body. Procyanidins present in them is primarily responsible for the same. Interestingly, areca nut is one of the most abundant sources of procyanidins.

References

1.  Osakabe et al., (2023) Hormetic response to B-type procyanidin ingestion involves stress-related neuromodulation via the gut-brain axis: Preclinical and clinical observations, Frontier in Nutrition, DOI 10.3389/fnut.2022.969823.

2.   Dasiman et al., (2022) A Review of Procyanidin: Updates on Current Bioactivities and Potential Health Benefits, Biointerface Research in Applied Chemistry, Vol. 2 (5), pp. 5918 - 5940

4. Health benefits conferred by the constituents of Areca nut. Part-I (Procyanidins)

 

Areca nut contains a large number of phenolic compounds in substantial quantity. Depending on the stage of maturity they are harvested, and the method of processing, the concentration of phenolic content and type of phenolic compounds can vary. In general, total phenolic content are found to be highest in the areca nuts of 4-5 months maturity and keeps decreasing as it reaches maturity. Flavonoids (flavones, flavanones, flavanols, flavonols), phenolic acids and polyphenols (procyanidins, areca tannins etc.) are some of the important classes of phenolic compounds found in areca nuts. These compounds are responsible for the dark brownish colour in the boiled nuts (Red supari). They impart astringent taste to the nut. They turn red in the presence of lime. Most of the perceived therapeutic properties of areca nut are attributed to these flavonoids, phenolic acids and polyphenols. Almost all of them are highly potent antioxidants.

B-type procyanidins are found to be one of the most abundant phenolic compounds found in Areca nuts. B-type procyanidins can be categorized by their degree of polymerization: monomers form linkages leading to oligomers. The most common monomeric unit is (–)-epicatechin. B-type procyanidins containing 2–7 monomeric units are defined as oligoprocyanidins. They are abundantly available in Red supari (kempadike), produced out of areca nuts of  6-7 months maturity and Bing lang. These procyanidins are also present in abundance in Cocoa, apples, grape seeds, and red wine.

Various conclusive evidence suggests that the intake of foods rich in B-type procyanidins is linked to reduced risk for cardiovascular disease including coronary heart disease, myocardial infarction, and stroke. Randomized controlled trials and subsequent meta-analyses have confirmed that the dark chocolate containing large amounts of B-type procyanidins can mitigate states related to the metabolic syndrome, including hypertension, dyslipidemia (abnormally high levels of fats in the blood) and glucose intolerance. In addition, the latest largescale study found a 27% reduction in cardiovascular death by ingestion of cocoa flavanol fraction, which is rich in B-type procyanidin monomer and oligomers, for 3.6 years. Recent studies have focused on the benefit of B-type procyanidin ingestion for the central nervous system (CNS).

Almost all B-type procyanidins ingested in food move into the colon, and some are degraded by the beneficial bacteria residing in the small intestine. Further it is broken down into low molecular weight phenolic acids in the large intestine (colon). Because of their smaller size, monomeric procyanidins are more absorbable than dimeric procyanidins.

References

1.  Osakabe et al., (2023) Hormetic response to B-type procyanidin ingestion involves stress-related neuromodulation via the gut-brain axis: Preclinical and clinical observations, Frontier in Nutrition, DOI 10.3389/fnut.2022.969823.

2.   Dasiman et al., (2022) A Review of Procyanidin: Updates on Current Bioactivities and Potential Health Benefits, Biointerface Research in Applied Chemistry, Vol. 2 (5), pp. 5918 - 5940

3. Health benefits of Arecoline and Areca extracts as per contemporary research

 

Arecoline is a naturally occurring psychoactive alkaloid found in the pericarp (seeds) of Areca nuts of the areca palm (Areca catechu). Arecoline, arecaidine, guvacine, and guvacoline are the most important and prominent alkaloids found in the areca nut. Nicotine, dichroine, acatechu A, acatechu B, homoarecoline, N-ethyl-1,2,5,6-tetrahydro-1-methyl-3-pyridine carboxamide and arecatemines are some of the minor alkaloids found in areca nuts. Arecoline is found to be the most important alkaloid among all, due to its role in modulating many physiological functions upon human consumption. It is found to enhance alertness and learnability, enhance the mood, gives a feeling of great pleasure, causes awakening, stimulates the sexual desire, reduces anxiety and promote calmness.

Arecoline has a wide spectrum of pharmacological effects beyond Central Nervous System modulating cardiovascular, digestive and endocrine systems as well.  Like nicotine, arecoline also evokes addiction and withdrawal symptoms (upon discontinuation). Withdrawal symptoms could be mood swings, anxiety, irritability and insomnia. Due to its addictive nature and activity on central nervous system, it has become the fourth most commonly used human psychoactive substance after alcohol, nicotine, and caffeine. How arecoline is converted to other forms, and disposed in the human body is complex and poorly understood.

Liu & Chang have listed the therapeutic values of arecoline in their review article “The Controversial Roles of Areca Nut: Medicine or Toxin?” published in International Journal of Molecular Sciences. They concluded that arecoline and areca nut extracts can be used for developing alternate therapy for gastroesophageal reflux disease & can be used to stop the progression of hepatocellular carcinoma cells (liver cancer) and the progression of Alzheimer’s disease, eliminate the negative symptoms of psychosis, can be used as various types of worms (take worm, liver fluke, pin worms etc.). They observed that arecoline possesses anxiolytic-like activity.

Volgin and coworkers have concluded that arecoline and related compounds have a considerable potential in medicine with multiple positive neural effects, in their scientific review published in “ACS Chemical Neuroscience” (An American Chemical Society Journal). They went on to propose that Arecoline can be used effectively in neurology and psychiatry. They opined that further translational research is needed to focus on molecular mechanisms of arecoline pharmacology in both clinical and animal models, and to develop low-risk analogues of this drug for future clinical uses.

References:

Liu & Chang (2023). The Controversial Roles of Areca Nut: Medicine or Toxin?, International Journal of Molecular Science, Vol. 24, 8996.

Volgin et al. (2019). DARK Classics in Chemical Neuroscience: Arecoline, ACS Chemical  Neuroscience, Vol. 10 (5) 2176–2185.

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2. Health benefits of areca nut and its products as per Traditional Chinese Medicine system

 

Traditional Chinese medicine (TCM) has evolved over thousands of years. TCM practitioners use various psychological and/or physical approaches (such as acupuncture and tai chi) as well as herbal products to address health problems. Areca nut is an important ingredient in Traditional Chinese medicine. Traditional Chinese medicine system believes that areca nut has the effects of "killing parasites, breaking accumulation, reducing qi and stagnation, and promoting hydration". Areca nut has been used to treat tapeworms, hookworms, roundworms, worms, ginger worms and other parasitic infections.

"Compendium of Materia Medica" records that areca nut has many effects such as "down edema, joint joints, spleen tone, and heartache accumulation". Areca nut also has the functions of treating glaucoma, increasing blood pressure, stopping diarrhea and treating diarrhea, reducing inflammation and swelling, removing phlegm and asthma, purging qi and water, and killing parasites.

Binglong (areca nut ) Pill is frequently used for reinforcing vital energy. The combination of pumpkin seed and areca is most widely used, which comes from the prescription of ‘Qu Tao Tang’ (Cestode-expelling Decoction). The constituents of ‘Qu Tao Tang’ (Cestode-expelling Decoction) are very simple, 60–120 g fresh pumpkin seeds and 30–60 g areca. Areca is ground with a pestle, soaked for a few hours in 400 ml of water, decocted to 100 ml, and filtered, and the debris of the decoction are discarded. The treatment procedure consists of two steps: first, chewing up fresh pumpkin seeds or taking the powder form of it ground in advance and then drinking the decoction of areca 2 h later. Anhydrous sodium sulphate is used as laxative along with this. The worm was quickly paralyzed from head to tail with a mixture of betel nut and pumpkin seed water extract. Worm bodies would be discharged along with diarrhoea 4–5 h later.

More than 31 different formulations are being used for treating dysentery, abdominal distension, dyspepsia, parasitic diseases and constipation etc. The raw areca and charred areca nuts are the most common clinically used forms. The Charred areca nut is commonly prepared by stir-baking to a yellowish colour, stir-baking to dark brown, or carbonizing by stir-frying.

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1. Health benefits of areca nut / Tambula as per ancient Indian treatises

 

One of the earliest references describing the good qualities of Tambula is found in charter 77 of the Brhatsamhita of Varāhamihira believed to be written in 500 CE in Sanskrit. It says, “Tambula stimulates love, sets off the physical charm, creates popularity, gives good smell to the mouth, strengthens the body and dispels diseases arising from the phlegm”.

Areca nut has been mentioned in several ancient treatises such as Charaka Samhita, Susruta Samhita, Astanga Hridayam, Bhavaprakasa, Harivamsa, and Varahapurana. These classical texts consider areca nut as astringent and slightly sweet (kasaya), cold in potency (hima), helps taste (rucya), Removes moisture and dirt of the mouth (asyakleda malapaha) and bad taste (vaktravairsaya), creates dryness (ruksa), heavy for digestion (guru), stimulates digestion (dipana), it is purgative (bhedi) and intoxicant (mohana). Choorna of areca nut has been prescribed with several other medicinal ingredients for treating liver ailments as per Charakasamhita, which was believed to be written during 100 BCE to 200 CE.

As per Vatsayana’s Kamasutra, a noble person (nāgaraka) cleans his/her teeth and perfumes himself/herself in the morning, uses mouthwash, and chew some Tambula (Mixture of areca nut with slacked lime smeared betel leaf) to make himself / herself presentable. The Tambula chewing is considered as an integral part of an elaborate sexual act as per the Kamasutra. In the Kāmasūtra, it is suggested that a lover should use Tambula both as a precursor to sexual relations, at various points during the sexual act, and as a post-coital activity marking a ritualistic finish and freshening of the breath.

Jyotirnibandha written by Shivraj in AD 1524, prescribes that three parts nut, two parts betel leaf, one-part catechu and lime make an ideal Tambula. Apparently, the composition prescribed is based on weight. As per this treatise, the Tambula prepared as per this formula, shall produce pungency, bitterness, heat, sweetness, saltiness, power to remove Vata, possess antiseptic character, remove phlegm, excite passion, beautify the mouth, purify the mouth, and remove all bad odour from the mouth. The work also indicates that different numbers of areca nuts confer differing outcomes: one produces happiness; two bears fruit; three brings loss; four causes pain of misery; five brings long life; six causes death.

References

1.     P. K. Gode (1950). Studies in the history of tāmbūla — history of the verse about the thirteen qualities of tāmbūla — between A.D 1200 and 1900, Annals of the Bhandarkar Oriental Research Institute, Vol. 31, No. ¼, pp. 138-142.

2.     Andrea Gutierrez (2015). Modes of betel consumption in early India, Religion and Food, Scripta Instituti Donneriani Aboensis, Vol 26, pp. 114–34

3.      Ahuja & Ahuja (2011). Betel Leaf and Betel Nut in lndia: History and Uses, Asian Agri-History Vol. 15, No. l, pp. 13-35.

4.      Kosambi D.D (1964). The Culture and Civilisation of Ancient India in Historical Outline. First edition. Taylor & Francis. Landon.

11. Some of the most criticized IARC reports: Alcoholic beverages, Part-III

 

IARC released a monograph on alcohol consumption in 2010 (Vol 96). This monograph was prepared by a working group comprising 27 members drawn from reputed labs of 16 different countries. The monograph focused on beer, wine and spirits (whiskey, brandy, rum, vodka, Scotch and Gin etc..). Working Group concluded that acetaldehyde, the primary metabolite of ethanol, is the carcinogen that leads to the formation of various type of cancer. Working Group concluded that a large body of evidence from epidemiological studies of different design and conducted in different populations consistently shows that consumption of alcoholic beverages is associated with a higher risk for both oral and pharyngeal cancer, and that the risk increases with increasing amounts of alcohol consumed. Compared with non-drinkers, regular consumption of about 50 g alcohol (ethanol) per day (equivalent to about 150 ml of distilled spirits) is associated with an approximately threefold increase in risk oral and pharyngeal cancer cancers, two-fold increase in laryngeal & esophagus cancer. These studies provide firm evidence that the consumption of alcoholic beverages are an independent risk factor for primary liver cancer. The working group found sufficient evidence in experimental animals for the carcinogenicity of ethanol and acetaldehyde (the ethanol metabolite).  

The working group gave an overall evaluation as follows, 

 ·       Alcoholic beverages are carcinogenic to humans (Group 1).

·        Ethanol in alcoholic beverages is carcinogenic to humans (Group 1).

As per the data presented in the same IARC monograph, in Eastern European block countries (Belarus, Estonia, Hungary, Kazakhstan, Latvia, Lithuania, Republic of Moldova, Russian Federation, Ukraine), 63.7 % men consume more than 40 g of pure alcohol (in the form of alcoholic beverages) per day. Incidence of cancer in that bloc is supposed to be substantially higher compared to other regions. However, the data presented in the same monograph doesn’t provide the evidence for the same. This appears to be a serious anomaly. 

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).