Alcohol concentration and risk of oral cancer in Puerto Rico

Alcohol consumption is a major risk factor for cancers of the mouth and pharynx (oral cancer), but the differential risks by beverage type are unclear. In this 1992-1995 study, the authors examined oral cancer risk in Puerto Rico, comparing alcohol intake among 286 male cases aged 21-79 years and 417 population-based male controls, frequency matched by age. Heavy consumers of liquor (>/=43 drinks per week) had strongly increased risks of oral cancer (odds ratio = 6.4, 95% confidence interval: 2.4, 16.8); beer/wine showed only modest effects. Among liquor drinkers, risks were consistently greater for those who drank straight (undiluted) liquor than for those who usually drank mixed (diluted) liquor (odds ratio = 4.0, 95% confidence interval: 2.4, 6.7). Risks associated with combined exposure to tobacco were also more pronounced when subjects drank liquor straight. The elevated risks associated with drinking homemade rum were similar to those for other types of liquor. These results suggest that alcohol concentration is a risk factor for oral cancer independent of the total quantity of alcohol consumed.     

Alcohol and liver cancer.

Hepatocellular carcinoma is the eighth most frequent cancer in the world, accounting for approximately 500,000 deaths per year. Unlike many malignancies, hepatocellular carcinoma occurs predominantly within the context of known risk factors, with hepatic cirrhosis being the most common precursor to the development of hepatocellular carcinoma. After ethanol ingestion, the liver represents the major site of metabolism. Ethanol metabolism by alcohol dehydrogenase leads to the generation of acetaldehyde and free radicals that bind rapidly to numerous cellular targets, including components of cell signaling pathways and DNA. In addition to direct DNA damage, acetaldehyde depletes glutathione, an antioxidant involved in detoxification. Chronic ethanol abuse leads to induction of hepatocyte microsomal cytochrome P450 2E1, an enzyme that metabolizes ethanol to acetaldehyde and, in doing so, causes further free radical production and aberrant cell function. Cytochrome P450 2E1-dependent ethanol metabolism is also associated with activation of procarcinogens, changes in cell cycle, nutritional deficiencies, and altered immune system responses. The identification of oxidative stress in mediating many deleterious effects of ethanol in the liver has led to renewed interest in the use of dietary antioxidants as therapeutic agents. Included in this group are S-adenosyl-L-methionine and plant-derived flavanoids.     

Alcohol and epithelial ovarian cancer.

The relationship between alcohol consumption and the risk of epithelial ovarian cancer was analysed using data from a case-control study of 801 histologically confirmed epithelial ovarian cancers and 2114 controls in hospital for acute, non-neoplastic, gynecological, or hormone-related conditions, admitted to a network of teaching and general hospitals in the greater Milan area, northern Italy, i.e. a region with comparatively frequent alcohol consumption by women. Compared to alcohol abstainers, the multivariate relative risks (RRs) were 1.0 [95% confidence interval (CI), 0.7 to 1.4] for less than one, 1.1. (95% CI 0.9 to 1.6) for one to two, 1.2 (95% CI 1.0 to 1.5) for two to three and 1.3 (95% CI 0.9 to 1.8) for three or more drinks per day. A significant direct trend in risk with dose emerged. This finding chiefly derived from an association between ovarian cancer risk and consumption of wine (which accounts for over 90% of alcohol intake in this female population). Although no significant interaction between the effect of alcohol consumption and various women's characteristics emerged, there was a hint that the adverse influence of alcohol consumption is more marked in middle-age and less educated women. Thus, the results of this study suggest that relatively elevated alcohol intake (of the order of 40 g per day or more) may cause a modest increase of epithelial ovarian cancer risk.     

Alcohol and cancer

Epidemiological data have identified chronic alcohol consumption as a significant risk factor for upper alimentary tract cancer, including cancer of the oropharynx, larynx and the oesophagus and of the liver. The increased risk attributable to alcohol consumption of cancer in the large intestine and in the breast is much smaller. However, although the risk is lower, carcinogenesis can be enhanced with relatively low daily doses of ethanol. Considering the high prevalence of these tumours, even a small increase in cancer risk is of great importance, especially in those individuals who exhibit a higher risk for other reasons. The epidemiological data on alcohol and other organ cancers is controversial and there is at present not enough evidence for a significant association. Although the exact mechanisms by which chronic alcohol ingestion stimulates carcinogenesis are not known, experimental studies in animals support the concept that ethanol is not a carcinogen but under certain experimental conditions is a cocarcinogen and/or tumour promoter. The metabolism of ethanol leads to the generation of acetaldehyde (AA) and free radicals. Evidence has accumulated that acetaldehyde is predominantly responsible for alcohol associated carcinogenesis. Acetaldehyde is carcinogenic and mutagenic, binds to DNA and proteins, destructs folate and results in secondary hyperproliferation. Acetaldehyde is produced by tissue alcohol hydrogenases, cytochrome P 4502E1 and through bacterial oxidative metabolism in the upper and lower gastrointestinal tract. Its generation or its degradation is modulated due to functional polymorphisms of the genes coding for the enzymes. Acetaldehyde can also be produced by oral and faecal bacteria. Smoking, which changes the oral bacterial flora, and poor oral hygiene also increase acetaldehyde. In addition, cigarette smoking and some alcoholic beverages such as calvados contain acetaldehyde. Other mechanisms by which alcohol stimulates carcinogenesis include the induction of cytochrome P-4502E1, which is associated with an enhanced production of free radicals and enhanced activation of various procarcinogens present in alcoholic beverages; in association with tobacco smoke and in diets, a change in the metabolism and distribution of carcinogens; alterations in cell cycle behaviour such as cell cycle duration leading to hyperproliferation; nutritional deficiencies, such as methyl-, vitamin E-, folate-, pyridoxal phosphate-, zinc- and selenium deficiencies and alterations of the immune system eventually resulting in an increased susceptibility to certain virus infections such as hepatitis B virus and hepatitis C virus. In addition, local mechanisms may be of particular importance. Such mechanisms lead to tissue injury such as cirrhosis of the liver, a major prerequisite for hepatocellular carcinoma. Also, an alcohol-mediated increase in oestradiols may be at least in part responsible for breast cancer risk. Thus, all these mechanisms functioning in concert actively modulate carcinogenesis leading to its stimulation.     

Alcohol, vitamin A, and cancer.

Chronic and excessive alcohol intake is associated with an increased risk of a variety of cancers (e.g., oral cavity, larynx, esophagus, liver, lung, colorectal, and breast). Retinoids (vitamin A and its derivatives) are known to exert profound effects on cellular growth, cellular differentiation, and apoptosis, thereby controlling carcinogenesis. Lower hepatic vitamin A levels have been well documented in alcoholics. Substantial research has been done, investigating the mechanisms by which excessive alcohol interferes with retinoid metabolism. More specifically, (1) alcohol acts as a competitive inhibitor of vitamin A oxidation to retinoic acid involving alcohol dehydrogenases and acetaldehyde dehydrogenases; (2) alcohol-induced cytochrome P450 enzymes (CYP), particularly CYP2E1, enhance catabolism of vitamin A and retinoic acid; and (3) alcohol alters retinoid homeostasis by increasing vitamin A mobilization from liver to extrahepatic tissues. As a consequence, long-term and excessive alcohol intake results in impaired status of retinoic acid, the most active derivative of vitamin A and a ligand for both retinoic acid receptors and retinoid X receptors. Moreover, this alcohol-impaired retinoic acid homeostasis interferes with (1) retinoic acid signaling (e.g., down-regulates retinoid target gene expression) and (2) retinoic acid "cross-talk" with the mitogen-activated protein kinase [(MAPK), including Jun N-terminal kinase, extracellular signal-regulated kinase, and p38 kinase] signaling pathway. In addition, restoration of retinoic acid homeostasis by retinoic acid supplementation restored the normal status of both retinoid and MAPK signaling, thereby maintaining normal cell proliferation and apoptosis in alcohol-fed animals. These observations would have implications for the prevention of alcohol-promoted liver (and peripheral tissue) carcinogenesis. However, a better understanding of the alcohol-retinoid interaction and the molecular mechanisms involved is needed before retinoids can be pursued in the prevention of alcohol-related carcinogenesis in human beings, particularly regarding the detrimental effects of polar metabolites of vitamin A.     

Alcohol and breast cancer

We examined breast cancer incidence in a cohort of about 69,000 women who answered detailed questions about alcohol consumption from 1979 to 1984. Among women with no prior cancer, breast cancer had developed in 303 by the end of 1984 for an age-adjusted incidence of 1.3/1,000 person years of follow-up. In analysis controlling only for age there was a progressive increase in breast cancer incidence corresponding to each higher level of reported alcohol consumption. In multivariate analyses controlling for age, race, body mass, and smoking, the relative risk at 1-2 drinks/day was 1.5 (95% confidence interval (CI) 1.0-2.3), at 3-5 drinks/day was 1.5 (95% CI 0.8-2.8), and at 6 or more drinks/day was 3.3 (95% CI 1.2-9.3). Past drinkers tended to have been heavier drinkers than current drinkers and had a relative risk of 2.2 (95% CI 1.2-3.9). Study of wine, beer, and liquor use did not suggest that any particular alcoholic beverage was responsible. Significant associations with heavy alcohol consumption were strongest among white and postmenopausal women. This study adds support to the growing evidence that alcohol may be a risk factor for development of breast cancer.     

Alcohol, iron-associated oxidative stress, and cancer.

Oxidative stress is recognized to play an important role in the initiation and promotion events of carcinogenesis. Alcoholic liver disease is associated with significant oxidative stress as well as the hepatic accumulation of iron, a transition element also documented to initiate oxidative stress. The combined prooxidant potential of ethanol and iron is at least additive and possibly synergistic with respect to inducing hepatocellular oxidative stress and antioxidant depletion. One cellular consequence of sustained oxidative stress and redox imbalance resulting from the combined actions of alcohol and iron is lipid peroxidation, resulting in the production of aldehydic products such as 4-hydroxy-2-nonenal, which has been linked to site-specific mutations of the p53 gene. In addition, the accumulation of iron in hepatic macrophage isolated from laboratory animals chronically ingesting alcohol is associated with activation of nuclear factor-kappa B and production of tumor necrosis factor-alpha, providing a proinflammatory cellular environment also favorable for initiation and promotion of carcinogenesis. Consequently, there is persuasive evidence that the potential of ethanol and iron to induce oxidative stress may be an important pathogenic mechanism for the increased occurrence of hepatocellular carcinoma in individuals with hepatic iron overload who ingest alcohol.     

Alcohol consumption and cancer risk

This review focuses on selected aspects of the relation between alcohol consumption and cancer risk. Heavy alcohol consumption (i.e., ≥4 drinks/day) is significantly associated with an increased risk of about 5-fold for oral and pharyngeal cancer and esophageal squamous cell carcinoma, 2.5-fold for laryngeal cancer, 50% for colorectal and breast cancers, and 30% for pancreatic cancer. These estimates are based on a large number of epidemiological studies and are generally consistent across strata of several covariates. The evidence suggests that at low doses of alcohol consumption (i.e., ≤1 drink/day) the risk is also increased by about 20% for oral and pharyngeal cancer and 30% for esophageal squamous cell carcinoma. Thus, for these sites there is little evidence of a threshold effect. While consumption of fewer than 3 alcoholic drinks/wk is not associated with an increased risk of breast cancer, an intake of 3 to 6 drinks/wk might already yield a (small) increase in risk. On the other hand, intakes up to 1 drink/day are not associated to the risk of laryngeal, colorectal, and pancreatic cancer. The positive association between alcohol consumption and the risk of head and neck cancers is independent from tobacco exposure.     

Alcohol drinking and bladder cancer

The relation between alcoholic beverage consumption and bladder cancer risk was investigated using data from a case-control study conducted between 1985 and 1992 in two areas of northern Italy. Cases were 727 patients with incident, histologically confirmed bladder cancer, and controls 1,067 patients admitted to the same network of hospitals for acute, non-neoplastic, nonurologic, or genital tract diseases. Compared to nondrinkers, the odds ratio (OR) was 0.79 (95% confidence interval, CI, 0.58-1.08) for drinkers, and 0.84 (95%CI, 0.58-1.22) for > or =6 drinks/day. The OR was 0.86 (95%CI, 0.60-1.23) for > or =5 wine drinks/day, 0.69 for beer, and 0.85 for spirits. No trend was observed with duration (OR =1.00 for > or =40 years). ORs were consistent across various strata of covariates including age, sex, and smoking habits. Our study, based on a population with high alcohol (mainly wine) intake, found no association between bladder cancer risk and alcohol intake, even at high levels of consumption.     

Alcohol consumption and ovarian cancer risk

To study the influence of alcohol consumption on the risk of ovarian cancer in women under age 55, the authors examined data collected in a multicenter, population-based case-control study--the Centers for Disease Control's Cancer and Steroid Hormone Study. Between August 1981 and December 1982, 433 women 20-54 years of age with newly diagnosed ovarian cancer and 2,915 women 20-54 years of age selected at random from the same geographic areas were asked about their consumption of alcoholic beverages during the previous five years. Women who drank any alcohol during the five-year period had a risk of ovarian cancer of 0.9 (95% confidence interval (CI) = 0.7-1.2) compared with nondrinkers. Risk was not associated with the type of alcoholic beverage consumed, nor were the results affected by controlling for demographic characteristics and oral contraceptive use. Although there was no association between moderate alcohol consumption and ovarian cancer, women who drank more than about 20 drinks per week had a relative risk of ovarian cancer of 0.5 (95% CI = 0.2-0.9) compared with women who did not drink.     

Alcohol drinking and tobacco smoking in gastric cancer. A case-control study

This study compares 210 cases of cancer of the stomach (138 males and 72 females) with 630 controls (414 males and 216 females) afflicted with a wide variety of diseases. All patients (cases and controls) were admitted for treatment at the University Hospital of Montevideo, Uruguay in the time period July 1985-December 1988. They were submitted to the same detailed questionnaire by 3 social workers unaware of the objectives of the study. The analysis was performed at the Louisiana State University of New Orleans, using multiple logistic regression. The variables analyzed were cigarette smoking, alcohol ingestion, salted meat intake, total vegetable consumption, total fruit consumption and "mate" ingestion. Strong positive associations were found in both sexes for low fruit and vegetable consumption, high intake of salted meat and "mate" ingestion. Only males showed significantly elevated OR's for tobacco smoking and alcohol drinking. Of the main tobacco variables, time-dependent one's (age at start, duration) displayed significant gradients of increasing risks. Thus, a prolonged exposure seems more important than the amount smoked per day for the risk of developing gastric carcinoma. Both wine and hard liquor carried increased OR's, but heavy drinkers of wine displayed a six-fold increase in risk, replicating previous reports from France.