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  In this article
 »  Abstract
 » Introduction
 »  Materials and Me...
 »  Mutagenic and Ge...
 »  Carcinogenic Eff...
 »  Effect of Pan Ma...
 »  Effect of Pan Ma...
 »  Effect of Pan Ma...
 »  Other Effects of...
 »  Dependence and A...
 »  Protection from ...
 »  Policy Issues Co...
 » Conclusion
 » Acknowledgment
 »  References
 »  Article Figures

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  Table of Contents  
REVIEW ARTICLE
Year : 2015  |  Volume : 52  |  Issue : 4  |  Page : 663-666
 

A review on harmful effects of pan masala


Department of Head and Neck Surgery, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication10-Mar-2016

Correspondence Address:
A Garg
Department of Head and Neck Surgery, Tata Memorial Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.178449

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 » Abstract 

Pan masala (PM) is a mixture of areca nut with slaked lime, catechu and other flavoring agents. It is widely available and used by all the sections of the Indian society. It is genotoxic as it increases sister chromatin exchange and chromatin aberrations. Among humans, it is a leading cause of oral submucous fibrosis that often progresses to oral cancer. Among experimental animals, it leads to neoplastic lesions in lung, liver and stomach. It is hepatotoxic leading to increased level of enzymes, deranged carbohydrate and lipid metabolism. It is harmful to kidneys and testes leading to increased creatinine and sperm deformities respectively. PM is a very harmful substance affecting almost all organ systems, and there is immediate need for a national policy on complete ban on the production, storage, sale and marketing of PM.


Keywords: Carcinogen, pan masala, public policy, toxicology


How to cite this article:
Garg A, Chaturvedi P, Mishra A, Datta S. A review on harmful effects of pan masala. Indian J Cancer 2015;52:663-6

How to cite this URL:
Garg A, Chaturvedi P, Mishra A, Datta S. A review on harmful effects of pan masala. Indian J Cancer [serial online] 2015 [cited 2018 Jul 19];52:663-6. Available from: http://www.indianjcancer.com/text.asp?2015/52/4/663/178449





 » Introduction Top


Areca nut, the seed of Arecacatechu is the fourth most common addictive substance in this world. It is primarily consumed in South-East Asia, Taiwan and Papua New Guinea and is a leading cause of oral cancers in these regions. In India, areca nut is consumed in many forms such as pan masala (PM), betel quid, gutka, etc., and has become a part of the lifestyle in many rural and urban areas. As opposed to betel quid, PM is a dehydrated, nonperishable preparation of areca nut, catechu (Acaciacatechu), slaked lime (Calcium oxide and calcium hydroxide), cardamom and many artificial perfuming and flavoring substances.[1] It is being extensively used by the young people due to the marketing and promotion tactics of the industry targeting them and false claims about their safety. Its popularity is also due to its packaging in small sachets that are cheap, widely available and easy to carry.[2] Even women have become habituated to PM and it is considered a status symbol to carry its sachets and offer it to one's social contacts. Areca nut and betel quid even without tobacco are carcinogenic and addictive substances having systemic and far reaching effects on the human body.[3] The aim of this article is to review the effects of PM on all the major organs the human body and assess its mutagenic and carcinogenic potential. The adverse effects of areca nut on the human body have already been highlighted in a previous publication.[4] In this review article, we have restricted to articles that have evaluated harmful effects of PM that possesses many additives in addition to areca nut.


 » Materials and Methods Top


A search of the relevant literature was done in PubMed, Medline and Cochrane databases of articles using various combinations of the following key words.

”Pan masala,” “public policy,” “carcinogen” and “toxicology.” Articles published till December 2014 were included in the literature search. Search with key word “Pan Masala” yielded 79 articles, “pan masala” and “public policy” yielded 3 articles, “pan masala” and “carcinogen” yielded 4 articles, “pan masala” and “toxicology” yielded 6 articles. Only studies that considered PM as a mixture of areca nut, catechu, lime and other flavoring substances were included in the study and the studies using tobacco in this mixture were excluded. Totally, 36 articles that met these criteria were used eventually.


 » Mutagenic and Genotoxic Effect of Pan Masala Top


The mutagenic and genotoxic potential of PM and its main constituents are assessed through many studies [summarized in [Figure 1].[1]In vitro studies using aqueous extract of PM on Chinese hamster ovaries (CHO) have shown that there is elevation in sister chromatin exchange (SCE), chromosomal aberration (CA) and micronucleated cells (MN).[5],[6],[7] Studies in male mice using aqueous suspension of PM have shown increased X-Y univalent frequency, sperm head abnormalities and significant delay in cell cycle progression.[8],[9] The increased production of superoxide ions led to increased lipid peroxidation, DNA fragmentation and triggered apoptotic cell death which was similar to tobacco containing products.[10] Mice fed on diet containing PM showed that the percentage of micronuclei in polychromatic and normochromatic erythrocytes was 0.42–1.66 and 0.30–0.74 respectively with respect to the controls 0.42 and 0.30 respectively.[11]
Figure 1: Factors leading to oral cancers in pan masala chewers

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 » Carcinogenic Effect of Pan Masala Top


Of the several ingredients of PM, areca nut is a proven carcinogen and catechu, lime may have carcinogenic potential.[1] PM mixture contains nitrosamines, polycyclic aromatic hydrocarbons, residual pesticides and toxic metals like lead, cadmium, nickel.[12],[13] Areca nut contains various alkaloids (arecoline, arecaidine, guvacine, guvacoline) which lead to formation of nitrosamines in the saliva. Two of these nitrosamines are accepted as carcinogenic in animal studies. Out of which 3-(methyl-N-nitrosamino) propionitrile (MNPN) is the most carcinogenic [Figure 2]. There is enhanced nitrosation of amines present in areca nut in people with poor oral hygiene due to greater formation of nitrite and bacterial enzyme mediated reactions. MNPN leads to the formation of O 6− MeG adducts, thus leading to G→A transition following DNA replication. Slaked lime or calcium hydroxide leads to the formation of reactive oxygen species (ROS) in presence of areca nut and causes oxidative damage to DNA. Catechu induces SCE and dominant lethal mutation. In combination with lime and areca nut, it also leads to formation of ROS. Heavy metals such as iron and copper that are found in areca nut lead to increased production of ROS as they act as catalyst in the reaction.[1],[14] ROS oxidizes DNA bases, e.g., deoxyguanosine to yield 8-oxo-dG that promotes tumor formation in oral cavity. Tender areca nut causes more 8-oxo-dG formation in DNA than the ripe variant.[1] An in vitro study had shown that areca nut extract increased expression of COX-2 and prostaglandin production in human oral mucosa cells which aids in carcinogenesis.[1] The frequency of CA (0.86–3.36), SCE (3.61–6.64) and MN (0.104–0.656) increases with the number of pouches consumed every day and age of the subject. People with increase CA have 2 times more chances of developing cancer.[13] PM users do not spit the juice which leads to carcinogenic effects not only at oral cavity but at other sites too. Studies in Swiss mice had shown that neoplastic lesions were most common in lung, liver, stomach and rarely in prostate, testis, skin. The most common malignant tumor seen was lung adenocarcinoma with statistically significant dose response relationship.[12]
Figure 2: Factors leading to mutations in pan masala chewers

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A study using aqueous extract of areca nut and alcohol on CHO cells had shown elevation in CA frequency as compared to when they were used alone. Thus, alcohol consumption may increase the risk of oral cancer in PM chewers.[15]


 » Effect of Pan Masala on Oral Premalignant Lesion and Sub-Mucous Fibrosis Top


Areca nut, the main constituent in PM, is the major causative agent for oral sub-mucous fibrosis (OSMF). As compared to betel quid chewers developing OSMF in 9.5 years, 75% PM users develop it within 4.5 years. It may be partly due to higher proportionate dry weight of areca nut in PM compared to betel quid. The relative risk of developing OSMF in PM users as compared to nonusers is 498.[1] As compared to users of tobacco without any visible oral lesion, the relative risk of oral cancer in a subject with OMSF is 397.3.[16] The rate of transformation of OSMF to oral cancer varies from 4.5% to 7.6%, and this is mainly responsible for an increase in oral cancer in young subjects.[3] The duration was also shorter in the subjects who have higher frequency of use per day and daily consumption was more important than the total duration for development of OSMF.[17] The abrasive nature of areca nut is responsible for local trauma and injury to the oral mucosa which is more severe with the use of PM due to the granular nature.[1]In vivo study in albino rats had shown that PM use lead to increased keratoses, parakeratoses, inflammatory cell infiltrate with loss of nuclear polarity leading to increased sub mucosal collagen deposition.[18] Copper which is found in PM in large quantity up-regulates collagen synthesis and increased cross-linkage of elastins and collagens.[1] OSMF is caused by decreased fibroblastic phagocytosis of collagen, interference with lysyl oxidase, matrix metalloproteinases and increased secretion of growth factors, inflammatory cytokines.[19]


 » Effect of Pan Masala on Gastrointestinal System Top


PM users often ingest the juice obtained from chewing it leading to multiple effects on the gastrointestinal system. In a study on 110 subjects, half of whom consumed PM, 66% showed histological and morphological changes similar to OSMF in the esophagus. The changes were more pronounced when history of use exceeded 5 years.[20]In vivo study in Swiss mice had shown survival and body weight was lower in mice fed on PM with presence of weakness and lethargy. The changes may be due to chronic liver damage and nutritional deficiency. Cystic changes were seen in the stomach of exposed mice. There was presence of acanthosis and hyperkeratosis due to fibrosis and thickening of horney and prickle cell layer and lead to formation of ulcer and papiloma which converted to peptic tumors eventually. The commonest lesion found in liver was hemangioma.[12]In vivo studies in Swiss, mice fed on PM mixed with diet have shown that there is rise in lactate dehydrogenase (LDH), alkaline phosphatase, acid phosphatase, glutamate pyruvate transaminase, glutamic oxaloacetic transaminase showing hepatic damage and impairment. The free radicals produced due to PM contents lead to increased LDH. The chronic inflammatory changes affect the cellular immune function and increase cytokine release. This affects the lipid metabolism leading to lipid oxidation, hypertriglyceridemia. There was disturbance in hypothalamic-pituitary-adrenal axis leading to increased concentration of adrenaline, noradrenaline, adrenocorticotropic hormone, cortisol and glucagon. The lipid metabolism was altered due to the eventual increase in activity of 3-hydroxyl-3-methyl glutryl Co-enzyme A reductase by the increased cytokines. This caused an increase in production and decreased clearance of triglycerides and hepatic lipogenesis leading to increased serum triglycerides and glucose.[21],[22],[23] PM users had altered albumin/globulin ratio due to increase in both globulin and total proteins. The serum Iron and Vitamin C levels decreased possibly due to increased collagen synthesis.[24],[25]


 » Effect of Pan Masala on Genito-Urinary Tract Top


A study done on Swiss mice exposed to diet containing PM showed presence of testicular cysts, increased structural abnormalities in sperms and decreased weight of testis. The ovaries and kidneys were also affected showing inflammatory reaction and cysts.[1],[12]


 » Other Effects of Pan Masala Top


A study in mice showed that dams fed upon PM during pregnancy had reduced gestation period. The pups born had increased neonatal death, reduced body weight and altered weaning index, thus showed in-utero and lactational fetotoxic effects of PM.[26] Slaked lime in PM lead to up to 3 times increase in serum calcium.[22] A study in healthy volunteers showed that there was acute increase in pulse rate, systolic and diastolic blood pressure on consumption of PM.[27] Every gram of PM consumed leads to exposure of about 1.2–2 mg aluminum and 23.5–185 µg fluorine leading to adverse effects due to toxic accumulation.[28],[29]


 » Dependence and Addiction of Pan Masala Top


A study conducted at a de-addiction center in Chennai showed that most of the PM users had characteristics features of substance abuse comprising tolerance that developed in 2–3 months, craving and substance seeking behavior. Within 2–3 hours of abstinence, the subjects developed withdrawal symptoms comprised anxiety, restlessness, tremors, loss of appetite, body pains, insomnia, lacrimation, giddiness, breathlessness, vomiting and intense craving. Few withdrawal symptoms mimicked opiate withdrawal. Three out of four patients with addiction were successfully treated using benzodiazepines.[30]


 » Protection from Damage by Pan Masala Top


An in vitro study in CHO had shown that short-term treatment with alpha-tocopherol (AT) decreased the frequency of CA in cells treated with PM extracts. Continuous treatment with AT resulted in statistically significant reduction in CA frequency.[31] In another study, CHO cells, when treated with beta-carotene and retinoic acid showed decreased frequency of SCE and CA in cells treated with PM extracts which was more pronounced on continuous treatment.[32]


 » Policy Issues Concerning Pan Masala Top


Pan masala use is rampant in India by all the sections and age groups of the society. It has emerged as a major cause of oral cancer in India. National Family Health Survey-2 showed that 21% of people over 15 years of age consumed PM or tobacco.[3] Study in the state of Tamil Nadu showed that the age at which people start consuming areca nut products ranges from 12 to 70 years. 58% of the subjects chewed the products more than twice a day.[33] Advertising tobacco products including PM containing tobacco is banned in India since May 1, 2004. To bypass this ban tobacco companies are advertising PM ostensibly without tobacco, heavily in all forms of media. PM is surrogate for tobacco products as the money spent on marketing, and advertising is many times of the revenue generated from the sale of PM.[34] In Mumbai after the ban on PM and gutka the sale has come down and the percentage of users quitting and reducing the habit was 23.53% and 55.88% respectively. The main reason of quitting and reduction in consumption was nonavailability of these products. In spite of the ban gutka was still available but in different forms or at increased cost.[35],[36] Strict law in the form of cigarettes and other tobacco products act 2003 has been made in India, but the enforcement and compliance is lax. There is a need for strong enforcement and compliance of laws throughout the country. The genotoxic, carcinogenic properties and numerous other harmful effects of PM need immediate and strict action by the government on PM without tobacco as it has banned PM with tobacco. The consumers should also be made aware of the harmful effects of PM as they are under a false impression that it is not harmful.


 » Conclusion Top


Pan masala is widely used across all the strata of society and is freely available in many parts of the country. It is carcinogenic, genotoxic, and has harmful effects on the oral cavity, liver, kidneys and reproductive organs. Government action is immediately required to restrict the consumption and to make the people aware about its harmful effects.


 » Acknowledgment Top


Dr. Prakash C. Gupta Dsc. Director of Healis-Sekhsaria institute of public health, Navi Mumbai for his extremely valuable suggestions and help in editing the manuscript. Dr. Arunee Garg MDS for her valuable help in editing the manuscript.

 
 » References Top

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Khrime RD, Mehra YN, Mann SB, Mehta SK, Chakraborti RN. Effect of instant preparation of betel nut (pan masala) on the oral mucosa of albino rats. Indian J Med Res 1991;94:119-24.  Back to cited text no. 18
    
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22.
Kumari S, Dutta A. Histochemical studies on the induced toxicity of pan masala on various organs of swiss mice and the protective effect of Elettariacardamom (L.) Maton. Ann Biol Res 2012;3:1919-22.  Back to cited text no. 22
    
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24.
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26.
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27.
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28.
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29.
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30.
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31.
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32.
Patel RK, Trivedi AH, Jaju RJ, Kukreti MS, Bhatavdekar JM, Shah PM, et al. Protection from pan masala induced genomic damage by beta-carotene and retinoic acid – An in vitro experience. Neoplasma 1998;45:169-75.  Back to cited text no. 32
    
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