un SURGEON 9 (2011) 278-285 ELSEVIE! available at www.sciencedirect.com The Surgeon, Journal of the Royal Colleges of Surgeons of Edinburgh and Ireland wwwa.thesurgeon.net SURGEON A review of the relationship between alcohol and oral cancer J. Reidy’, E. McHugh, L.F.A. Stassen Department of Oral and Maxillofacial Surgery, Oral Medicine and Oral Pathology, Dublin Dental University Hospital, Lincoln Place, Trinity College, Dublin 2, ireland ARTICLE INFO ABSTRACT Artie history Received 15 December 2010 Accepted 23 January 2011, ‘Available online 22 February 2021 ‘consumption and oral cancer Tis paper aims to review the current literature regarding the association between alcohol The authors have discussed the constituents of alcohol- containing beverages, the metabolism of ethanol and its effect on the oral microflore. The Tcal and eystemic carcinogenic effects of alcohol have been éetalled. The Beneficial effects ‘of alcohol consumption on general health have also been considered. A possible rela: Keywords Alcohol consumption Alcohol-containing beverages oral eancer Alcohol-containing mouthrinses the literature tionship between alcchol-containing mouthrinses and oral cancer has been suggested in the authors conclude that this relationship has not yet been firmly estab- lished. However, the use of alcohol-containing mouthrinsee in high-risk populations ‘should be restricted, pending the outcome of further research 18 2011 Royal College of Surgeons of E ourgh (Scottish charity number 36005317) and Royal College of Surgeons in Ireland, Published by Elsevier Ltd. All rights reserved. Introduction Alcohol consumption has long been recognized as one of the ‘major modifiable risk factors for the development of oral cancer.” The excessive consumption of alcchol-containing beverages is also associated with an increased risk of devel- ‘oping other cancers of the head and neck such as pharyngeal and laryngeal cancer,"* as well as other chronic diseases including heart disease, Alzheimer's disease, stroke, liver disease, cancer, chronic respiratory disease, diabetes mellitus and bone disease.** Despite the definite association between chronic alcohol consumption and oral cancer, the exact role of alcohol in the pathogenesis of the disease is not fully understood, and the following point should be considered: Not all oral cancer patients consume alcohol, and not all people who drink alcoholic beverages develop oral cancer. In addition, smoking ‘and alcohol consumption are synergistic risk factors for oral ccatcinogenesis.°-" This makes it dificult to assess the effects of these factors individually,*” with approximately 75% ofall coral cancers arising in association with both alcohol and Corresponding author E-mail address: john reldye@dental tod. J. Reidy) tobacco use.** Difficulties also arise in establishing an accu- rate measurement of alcohol intake, with variation in quan- tity, type and alcohol concenteation existing between, patients, Patient subjectivity of alcohol consumption also impacts upon the accuracy of the measurement of alcoho! intake, thus making it difficult to fully evaluate the role of alcohol in the development of oral cancer? ‘This article will review the most recent literature on the effects of alcohol on the oral mucosa, and the possible mechanisms by which alcohol is thought to act as a catcin= ogen. The article will also consider the possible link between alcohol-containing mouthrinses and oral cancer Constituents of alcoholic drinks The alcohol family is comprised of three main members, including methyl alcohol (methanol), isopropyl alcohol (propan-2-0l) and ethyl alcohol (ethanol, ¢;Hs0H).’ Methanol and propan-2-ol are toxic to consume,” while ethanol, along 1478-655K/$ — see front matter © 2011 Royal College af Surgeons of Edinburgh (Scottish charity number $c005317) and Rayal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved 40:10 1016) surge-2011.01.010sunceon 9 (2012) 278-28 279 with water and glucose are the main constituents of aleohol- containing beverages.? Ethanol ig produced by the fermentation of simple carbo- hydrates in fruitand starch n grains by yeasts. pitits, such as, whiskey, brandy and vodka are produced by distillation of the fermented products. Carbohydrate fermentation is incom- plete in beer and complete in wine, with resulting alcohol concentrations between 3-8% and 7-18% respectively. Distilled products, such as liqueurs and spirits, are 30% or greater alcohol by volume." Other constituents of beer, wine and spirits include volatile (monocarboxylic acids and their esters, nitogen- and sulphu-containing compounds, hydo- carbons, terpenic compounds, and heterocyclic and aromatic, compounds) and non-volatile (unfermented sugars, di- and uibasie carboxylic acids, colouring substances, tannic, poly- phenolic substances, and inorganic salts) favour compounds, Alcoholic beverages may also contain certain carcinogenic imputities, such as N-nittosodiethylamine in some beers and whiskeys, and polycyctic aromatic hydrocarbons in some whiskeys However, ethanol itself is not thought to have a direct carcinogenic effect on the oral mucosa. Acetaldehyde, the first metabolite of ethanol is known to be a mutagenic and carci- rnogenic substance, and is thought to play the main role in, carcinogenesis, Ethanol metabolism Following consumption, ethanol is rapidly absorbed unal- fed in the stomach and small intestine. It is then distrib- luted to all the tissues and fluids of the body in direct, proportion to the blood level before being metabolized in the liver, The three main hepatic enzyme systems responsible for converting ethanol to its frst metabolite, acetaldehyde, are alcohol dehydrogenase (found in the cytoplasm of hepato cytes), the microsomal ethanol oxidising system/cytochrome 450 261/CYP 2E1 (found in the endoplasmic reticulum), and catalase (found in peroxisomes). Of these, the main enzyme system involved in ethancl ‘metabolism is alcohol dehydrogenase (ADH). The activity of ‘the microsomal ethanol oxidizing system/CYP2E1 is increased, im chronic alcohol consumption and when blood alcoho! levels are high, accounting for less than 10% of ethanol ‘metabolism under normal conditions. Gatalase will also smetabolise a small percentage of ethanol Allof these enzyme systems oxidize ethanol to acetaldehyde" Acetaldehyde is then converted to non-toxic acetate, catalysed by the enzyme aldehyde dehydrogenase (ALDH). Acetate is Gnally oxidised to produce carbon dioxide, fatty acids and water Metabolism of alcohol and acetaldehyde also occurs outside the iver in gastric mucosa, cezophageal mi oral mucosa. Both ADH and ALDH are present in these tissues.‘ In the ora tissues, mucosal ALDH is present at lower levels than mucosal ADE, resulting in an imbalance between the two enzymes. This allows for the increased accumulation, of acetaldehyde, a toxic and irritating metabolite.” Ethanol metabolism can vary in different ethnic groups.” The variant allele ALDH2-2 encodes an inactive subunit of the enzyme ALDH2. This is dominant and highly prevalent in certain populations of Asian ethnicity (28~45%), but rare in other ethnic groups. Most homozygous carriers of this allele (ALDHY'2/2) are abstainers or infeequent drinkers, because the enzyme deficiency would cause a strong facial flushing response, physical discomfort, and severe toxic reactions following alcohol consumption, In heterozygous cartiers (ALDH2-1/-2) with about 10% residual ALDH2 activity, chese acute adverse effects are ess severe, but these carriers are an increased risk of developing several alcohol-related aero- digestive cancers because of acetaldehyde accumulation in their oral mucosa.”* Alcohol and the oral microflora ‘While acetaldehyde is produced from ethanol in the oral epithelium by mucosal alcohol dehydrogenase, the oral microflora also contributes to the acetaldehyde levels by oxidizing ethanol directly" This acetaldehyde production has been found to vary widely between individuals, however acetaldehyde levels were found to be significantly ineeased bby smoking Therefore, further studies are required to distinguish between the effects of smoking and alcohol alone, and their combined effects ‘Anincrease in the numberof microbeshas been observed on the epithelial cells of malignant tissues in comparison to healthy mucosa*** The specific microbes found to be associ- ated with high acetaldehyde production include Gram-positive aciobic bacterial strains and yeast, in particular Streptococcus salivaris, Streptococus viridans haemolytic variant, Corynebac term sp. and Stomatococus sp. interestingly, the oral microflora in smokers was found to be more conducive tothe growth of Gram-postivebactera, suchas Streptococcus salivarus and Streptococcus virdians, rather than Gram negative bacteria This again suggests a syneigistic relationship between alcohol consumption and smoking” Paradoxical, it should be mentioned that some microbes may infact protect the indi- vidual rom acetaldehyde-mediated carcinogenesis. The role of bacteria in acetaldehyde production was farther highlighted when salivary concentrations of acetal- dehyde were found tobe reduced in subjects following the use of antiseptic chlorhexidine prior to alcohol consumption * ‘A link has also been demonstrated between bacterial overgrowth (and consequently higher levels of acetaldehyde produced) and poor oral hygiene amongst heavy consumers of alcohol,” explaining why there appears to be an increased incidence of oral cancer among alcoholic patients with poor oral hygiene ***9® an association between poor oral hygiene and increased number of missing teeth with oral cancer has also been demonstrated by other authors. Carcinogenic effects of ethanol Ethanol consumption can act asa risk factor, both locally and systemically, in the development of oral cancer”: Local effects: (0) Ethanol and mucosal penetrability: An extracellular layer of lipids present in the superficial regions of the oral280 un SURGEON 9 (2011) 278-285 @ a @ “ epithelium acts as a banter tothe diffusion of water and harmful compounds in the oral cavity through the mucosa’ Alcohol may increase the penetration of carcinogens across the oral mucosa by either increasing their solubility, or by increasing the permeability of the mucosa by dissolving the lipid component of the epithelium that normally acts as a protective bartier °° ‘The permeability of the thin non-keratinised tissues of the buccal mucosa, the lateral border of tongue and the floor of the mouth is much greater than thicker kerat: nised tissues such as the hard palate and gingivae.”® Mucosal morphology: In vitro animal studies have shown that chronic exposure to alcohol can cause epithelia atrophy and decreazed basal cell size of rat oesophageal mucosa,” Short-term exposure of rabbit oral mucosa to alcohol resulted in varying degrees of tissue damage depending on the concentrations of alcohol used.”> Long-term (12 month) exposure resulted in dysplastic changes with keratosis, increased density of the basal cell layer and a slightly increased number of mitotic figures." Histological analysis of human tongues found that alcohol and tobacco were associated with a reduc- tion in epithelial thickness due to a red ‘maturation layer due to cell shrinkage. Paradoxically, there was an increase in the thickness of the basal cel layer due to hypertrophy rather than hyperplasia. These changes were more severe with alcohol than tobacco* Cellular damage by acetaldehyde: Acctaldehyde is a mutagenic and carcinogenic substance that can cause significant harm.” The effects of acetaldehyde on human cells include: Interference with the synthesis and reparation of DNA; induction of exchanges between sister chromatids; production of gene rmuta- tions; inhibition of the enzyme O6-methylguani- tuansferase (responsible for repairing injuries to DNA caused by alkylating agents); binding of cellular proteins and DNA resulting in morphological and cellular injury. Genotoxicty: Several studies have shown that alcohol can potentiate the genotoxicity of other mutagenic, clastogenic (ability to disrupt chromosomal material) of carcinogenic agents.° Hamster cheek pouches painted with the carcinogen dimethylbenzanthracene (DMBA) and alcohol developed larger epithelial tumours earlier than those painted with DMBA alone.” In vitro studies have shown that the clastogenicity of ultraviolet light and the cytotoxic drugs bleomycin, methyl methane sulfonate and mitomycin C is algo potentiated by tweatment with alcohol.” In addition, the clastogenic effect of four mutagenic agents (bleomycin, 4-nitro- quinolone-1-oxide, cytosine arabinoside, tiethylene- ‘melamine and cigarette smoke condensate) in vitro was found to be increased when administered concurrently with aleolol?” Alcohol and salivary flow: Parotid gland enlargement due to sialosis may occur in some patients who consume large quantities of alcohol on a long-term basis. The condition results from an ethanol-produced peripheral autonomic neuropathy that disrupts salivary gland jon in the ‘metabolism and causes reduced parotid gland salivary flow Chronic alcohol consumption also leads to atrophy and lipomatous transformation of the paren- chyma of the parotid and submandibular glands, resulting in impaired saliva flow and an increase in ite viscosity. Ae a result of the hyposalivation, the oral ‘mucosal surface is inadequately rinsed and is exposed to higher concentrations of locally acting carcinogens. Reduced salivary flow will prolong the contact time of ‘the carcinogens with the mucosa, increasing the risk of| cancer development.” Systemic effects: () Abnormal hepatic metabolism of toxic substances: Chronic alcohol consumption may affect the liver's ability to deal With toxic or potentially carcinogenic compounds.* For example, ethanol consumption results in reduced fist pass metabolism of nitrosamine by the liver, resulting in an increased metabolism in extrahepatic Ussues. This ‘may play a contributing role in carcinogenesis."° (i) Immunosuppression: Chronic alcohol consumption is associated with impairment of both the innate and acquired immune systems, resulting in increased susceptibility to infection and certain neoplasms.” Suppression of natural killer (NK) cell activity by expo- sure to alcohol is thought to play an important role as these cells are involved in tumour cell surveillance.”” other effects of excessive alcohol consumption on the immune system inclide impaired tissue recruitment of PMNs during infection and inflammation,” impaired production of haemopoietic stem cells,*“* and impaired cytokine production by haemopoietic stem cells” Other causes of immunosuppression related to alcohol consumption include malnutrition, vitamin deficiencies (ii) Malnutrition: Several studies have illustrated an inverse relationship between diets with a high content of fresh fruit and vegetables and the prevalence of oral cancer. Generally, frequent consumption of vegetables, citrus fruit, fish and vegetable oils are associated with a low tisk for cancer of the oral cavity.” On the other hand, there is a greater reported risk fr oral cancer associated ‘with high intake of meat and processed meat products,? Im heavy drinkers, there may be nutritional deficiency ue to decreased consumption, or impaired absorption, utilization or storage of nutrients, thus increasing cancer tisk” Deficiencies of folate iron, zine and gelenium have all been associated with an increased isk of cancer development.” Beneficial effects of alcohol Alcohol has been shown to have beneficial effects when consumed in moderation. Since 1974, studies have examined the relationship between coronary heart disease (CHD) and alcohol consumption."* These studies have suggested an “inverse association between alcohol and cardiovascular disease morbidity and mortality’“?-** The exact mechanism bby which alcohol exerts a protective effect las been found tosunceon 9 (2012) 278-28 281 be due to “increased high-density lipoprotein cholesterol” levels, resulting in a reduced risk of myocardial infarc jon.*°°5° Other mechanisms include increased levels of haemostatic markers such as tissue-type plasminogen acti- vvator, resulting in increased antithrombotic activity."°99975 The are conflicting views in the literature regarding the effect that moderate drinking has on the incidence of stroke Mukamal etal. found that moderate alcohol consumption is associated with an increased sisk of stroke,” while others claim that it has a protective effect in relation to ischaemic stroke." One author showed that the inverse association ‘between alcohol consumption and stroke occurred ata lower dose of alcohol and to a lesser degree compared to the reduction in risk for coronaty heart disease.“ Alcobolintake has also been found toreduce the risk oftype 2 diabetes mellius® by increasing circulating levels of adipo- nectin, an adipokine that impraves insulin sensitivity” Furthermore alcohol decreases gluconeogenesis and post- prandial circulating ghucose levels." Alcohol-containing mouthrinses and oral cancer Mouthrinses are used for the treatment of a wide range of oral conditions, ranging from the management of halitosis to the ‘weatment of oral infections. °’ Ethanol is used as a solvent for the active agents in many commercially available mouth- rinses, with concentrations ranging from 6% to 26.9% The. advantages of ethanol include its antiseptic and preservative properties, its low cost and ease of production.” A possible harmful effect of alcohol-containing mouthrinses has been suggested due to the fact that many of these mouthrinses contain high concentrations of ethanol, and mouthrinses are kept in the mouth in direct contact with the oral mucosa for longer periods than alcohol-containing beverages.”” Their suggested adverse effects include an increased risk of devel- coping oral cancer, as well as causing a burning sensation in the mouth, drying ofthe oral mucosa and softening effects on, composite filling materials.”® However, opinions in the literature at present regarding the relat ship, if any, between the use of alcohol-containing mouth- rinses ané oral cancer. (One of the most recent met analysis on the relationship between alcohol-containing mouthrinses and oral cancer by 1a Vecchhia concluded that a link between mouthrinse use, specifically alcohol-containing mouthrinses, and oral cancer | not supported by epidemiological evidence.” Reviews by Cole et al, and Flmore and Horowitz also came to the conclusion that the available epidemiological evidence did rot support a link between alcohol-containing mouthrinse tuse and oral cancer”? A review of epidemiological studies by the Food and Drug Administration (PDA) and Ametican Dental Association (ADA) investigating the possible associa- tion between the use of alcohol-containing mouthrinsees and oral cancer revealed the following deficiencies about the studies” - Lack of a dose-response based on frequency and/or duration «= Inconsistent ndings among studies, - Lack of a scientific or biological basis to explain inconsistent findings between males and females = Absence of correction for alcoholic beverage ingestion and tobacco use. + Inclusion of pharyngeal cancer, an improper classification as mouthrinses only contact the oral cavity, and inclusion of other head and neck carcinomas, lymphomas, and sarcomas as oral cancer, an improper classification as mouthrinses only contact the oral cavity In addition, a population-based case-control study of oral cancer in Puerto Rico did not provide any evidence of Imereased risk associated with the use of alcohol-containing mouthrinses’™ However there are several studies that do not concur with these conclusions. A review article by McCullough and Farah {im 2008 concluded that there is sufficient evidence to accept the proposition that developing oral cancer is increased or contributed to by the use of alcohol-containing mouth- tinzees.” They recommended that the use of alcohol-con- taining mouthrinses should be limited to short-term therapeutic situations for a limited and controlled period of ‘ime, Two multicentric case-control studies conducted in 2007 in Central Europe and South America also found that twice daily mouthrinse use significantly increased otal cancer risk among current and former emokers and drinkers, as well as among lifelong alcohol abstainers.”” Lachenmeier etal. found that the acetaldehyde content of saliva following mouthrinee use was significantly above endogenous evelsin the range 50150 um, and corresponded to concentrations notmally found after alcoholic beverage consumption.” These acetaldehyde concentrations in saliva, are associated with DNA adduct formation and sister chromatid exchange in vitro, raising concerns about the local carcinogenic effects in the oral cavity.” Poggi etal 3 also advise against the use of alcohol-containing moutihrinses due to the metabolic enzymatic imbalance present in the human mouth during alcohol oxidation, which leads to the accumulation of acetal= Gehyde whichis toxic and irritating to the oral mucosa."* Conclusion’ The Ielationship between alcohol consumption and oral cancer is clearly complex, Oral cancer is a disease with, ple interacting aetiologies, resulting in difficulties in determining the precige role of each agent independently. Despite this, the evidence supporting the role of alcohol in the aetiology of oral cancer is convincing, with @ significant proportion of oral cancer deaths attributable to heavy alcohol, consumption * This illustrates the need for increase public awareness campaigns to reinforce the detrimental effects that chronic heavy alcohol consumption can have on both general, and oral health, Evidence regarding the carcinogenic effect of alcohol-containing mouthrinses is conflicting, and a link between alcohol-containing mouthrinses and oral cancer has not yet been firmly established, However, considering what is known about the local effects of ethanol on the oral mi may be judicious to limie their use, particulary in high-risk patients such as smokers.282 E suRCEOM 3 (201 ) 278283 ‘The authors appreciate the difficulty in isolating alcohol as 1 sole factor in the pathogenesis of oral cancer, Considering the rapidly increasing use of aleohol-containing mouthrinses in certain populations, there is potential for further research, tobe conducted on a more widespread scale, It is hoped that the outcomes of this research will allow clinicians to provide the public with informed advice on the harmful effects of alcohol exposure. 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