EPI 242 Cancer Epidemiology Nov 16 2009 Alcohol

- EPI 242 Cancer Epidemiology, Nov 16, 2009 - Alcohol and Cancer Nai-chieh Yuko You, M. S. , Ph. D. 1

Outlines o Introduction o Health effect o Epidemiologic studies o Alcohol and Cancer o Current interests and issues of alcohol and cancer research 2

Introduction 3

Alcohol Beverages o Drinks made by fermenting fruit juices, sugars, and fermentable carbohydrates with yeast to form alcohol. o The predominant types of commercially produced alcoholic beverages are beer, wine and spirits. o The main components of all alcoholic beverages are ethanol and water; beers also contain substantial amounts of carbohydrates. Some components and occasional contaminants include known and suspected carcinogens. Beers and wines also contain vitamins and other nutrients which are usually absent from distilled spirits. 4

Alcohol by Volume (ABV) Type of beverage ABV (w/w in %) beer, cider, and Perry 4 -6 wine 9 -13 spirits (e. g. brandy, gin, rum, vodka, whisky) made by distilling fermented liquor 38 -45 liqueurs made from distilled spirits, sweetened and flavored 20 -40 fortified wines (aperitif wines, Madeira, port, sherry) made by adding spirit to wine 18 -25 5

Trends in Ethanol Consumption in the US, 1960 -97 Source: NIAAA, NIH 6

Percent Drinking Alcohol (1984 and 1995) Caetano and Clark, J Stud Alcohol, 1998 7

Prevalence of Alcohol Use o Almost half of Americans aged 12 and older reported being current drinkers of alcohol in the 2000 survey (46. 6%). This translates to an estimated 104 million people. o About 35% of the adult US population abstains from alcohol use, about 60% are occasional to moderate drinkers, and about 5 to 7 % are diagnosable with alcohol abuse or dependence (NIAAA, 1997). Of the some 16 million Americans who meet the diagnostic criteria for abuse or dependence, only about 1. 5 million seek and receive treatment (SAMHSA, 2003). o Alcohol consumption causes some 100, 000 deaths annually in the US, including more than 16, 000 alcohol related traffic fatalities (Meister et al. , 2000; NIAAA, 2000). 8

Health Effect 9

Health Effect o o o Cardiovascular Disease Cancers (upper aerodigestive tract cancer, HCC, colorectal cancer and breast cancer) Obesity Diabetes Birth defect Breastfeeding Aging Alcohol abuse and dependence Hepatic effect (Alcohol-related liver disease, included cirrhosis and alcoholic hepatitis ) Genetic and related effects Injury/Accident Total mortality 10

The proposed model for alcohol consumption, health and social behavior The relationship of average volume of alcohol consumption and patterns of drinking to burden of disease: an overview 11 Jürgen Rehm , Robin Room , Kathryn Graham , Maristela Monteiro , Gerhard Gmel & Christopher T. Sempos Addiction ; Volume 98 Issue 9 Page 1209 - September 2003

Global Mortality Burden (deaths in thousands) Attributable to Alcohol by Major Disease Categories – 2000 Eur Addict Res 2003; 9: 157– 164 Global Burden of Disease Attributable to Alcohol 12 Jürgen Rehma, Robin Room, Maristela Monteiro, Gerhard Gmel, Kathryn Graham, Nina Rehn, Christopher T. Sempos, David Jernigan

Alcohol-Attributable Deaths (in thousands) in 2000 by Disease and Subregion Eur Addict Res 2003; 9: 157– 164 Global Burden of Disease Attributable to Alcohol 13 Jürgen Rehma, Robin Room, Maristela Monteiro, Gerhard Gmel, Kathryn Graham, Nina Rehn, Christopher T. Sempos, David Jernigan

Global burden of disease (DALYs in thousands) attributable to alcohol by major disease categories – 2000 Eur Addict Res 2003; 9: 157– 164 Global Burden of Disease Attributable to Alcohol 14 Jürgen Rehma, Robin Room, Maristela Monteiro, Gerhard Gmel, Kathryn Graham, Nina Rehn, Christopher T. Sempos, David Jernigan

Alcohol-related disease burden in DALYs (in thousands) by disease category and region Eur Addict Res 2003; 9: 157– 164 Global Burden of Disease Attributable to Alcohol 15 Jürgen Rehma, Robin Room, Maristela Monteiro, Gerhard Gmel, Kathryn Graham, Nina Rehn, Christopher T. Sempos, David Jernigan

Alcohol and Cancer o o o Nearly 100 years ago, Lamy noticed an increased incidence of esophageal cancer in absinth drinkers (Lamy, 1910). Since then, extensive epidemiological data has accumulated which identified alcohol as a major risk factor for UADT cancer Furthermore, substantial epidemiological evidence accrued over the past 50 years has shown that alcohol contributes to the development of these cancers. In 1988, IARC concluded that there is sufficient evidence that alcohol beverage are carcinogenic in humans. Nevertheless, the mechanisms underlying alcohol-related cancer development remain largely unclear. 16

9 Possible Mechanisms How Alcohol Intake Increase Cancer Risk According to Blot et al (1992) 1. Contain congeners and other contaminants that may be carcinogenic 2. Generated metabolites that are carcinogenic to humans 3. Act as solvent, increasing penetration of other carcinogens into target tissue 4. Reduce intake and bioavailability of nutrition 5. Inhibit the detoxification of carcinogenic compounds 6. Catalyze the metabolic activation of some compounds into carcinogens 7. Affect hormonal status 8. Increase cellular exposure to oxidants 9. Suppress immune function 17

Selected Chemical Compounds in Alcoholic beverage which have been found to be carcinogenic compound Aflatoxin Identified in Beer Wine + Arsenic Asbestos + IARC evaluation Spirits human animal Overall + S S 1 + S L 1 + + S S 1 Benzene + + S S 1 Chromium + S S 1 Nickle + S S 1 Benz(a)anthracene + ND S 2 A Benzo(a)pyrene + ND S 2 A L S 2 A Cadmium + Formaldehyde + + + L S 2 A N-Nitrosodiethylamine + + + ND S 2 A N-Nitrosodimethylamine + + + ND S 2 A S=Sufficient; L=Limited; I=Inadequate; ND=No data 18

IARC o o Group 1: The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans Group 2 n n o o Group 2 A: The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans. Group 2 B: The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. Group 3: The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans Group 4: The agent (mixture) is probably not carcinogenic to humans. 19

9 Possible Mechanisms How Alcohol Intake Increase Cancer Risk According to Blot et al (1992) 1. Contain congeners and other contaminants that may be carcinogenic 2. Generated metabolites that are carcinogenic to humans 3. Act as solvent, increasing penetration of other carcinogens into target tissue 4. Reduce intake and bioavailability of nutrition 5. Inhibit the detoxification of carcinogenic compounds 6. Catalyze the metabolic activation of some compounds into carcinogens 7. Affect hormonal status 8. Increase cellular exposure to oxidants 9. Suppress immune function 20

Alcohol Metabolism Source: Klaassen, CD (1998) Casarett & Doull's Toxicology: The basic science of poisons, fifth edition 21

Acetaldehyde-derived DNA Adducts Chemical Structures of Deoxyguanosine, the DNA Base that is the target for acetaldehyde, as well as the acetaldehyde-derived DNA lesions. The atoms in red represent the acetaldehydederived chemical modifications. The 2007 International Agency for Research on Cancer Working Group on alcohol and cancer specifically noted the substantial mechanistic evidence supporting a causal role for acetaldehyde in alcohol-related esophageal cancer Baan et al. (2007) Carcinogenicity of alcoholic beverages. Lancet Oncol 8: 292– 293 22 Brooks PJ et al. PLo. S Med. 2009 Mar 24; 6(3): e 50

9 Possible Mechanisms How Alcohol Intake Increase Cancer Risk According to Blot et al (1992) 1. Contain congeners and other contaminants that may be carcinogenic 2. Generated metabolites that are carcinogenic to humans 3. Act as solvent, increasing penetration of other carcinogens into target tissue 4. Reduce intake and bioavailability of nutrition 5. Inhibit the detoxification of carcinogenic compounds 6. Catalyze the metabolic activation of some compounds into carcinogens 7. Affect hormonal status 8. Increase cellular exposure to oxidants 9. Suppress immune function 23

Other Possible Mechanisms o Direct toxic effect due to highly concentrated alcoholic beverage on the epithelium o Enhance reflux o Decrease several other phase II enzyme levels, included liver glutathione and SAM level o Inhibit the activity of DNA methylase found in animal studies, but can’t confirm in human. 24

Animal & Human researches o Animal studies o Correlation Studies o Cohort and Case-Control Studies 25

Animal Study o The results of animal experiment on alcohol and cancer depend on the experimental design, type of carcinogen used, its time, duration of exposure, dosage and administration route. o When alcohol applied locally to oral and esophageal mucosa, it increases the occurrence of tumor probably due to irritant effect of alcohol (Seitz et al, 1998) o When ethanol is given systematically, stimulating effect on chemical induced carcinogenesis is noted. (Seitz et al, 1998) When alcohol is given chronically to rodents have shown that life-time exposure to alcohol do not develop more cancer than do controls. o Most of animal studies were expected to find HCC, however, they found the rate of extra hepatic tumor increased, especially UADT. 26

Correlation Studies o Per capita alcohol consumption was associated with cancer mortality, including cancer of esophagus (Tuyns et al, 1976), gastrointestine (Konoet al, 1979), larynx (Tuyns et al, 1976), and pancreas (Qiao et al, 1988). o Time trends was found in per capita alcohol consumption and mortality from esophageal and laryngeal cancer (Tuyns et al, 1976), and colorectal cancer (Mc. Michael et al, 1979). 27

Cohort/Case Control Studies n. Oral and pharyngeal cancer n. Esophageal cancer n. Stomach cancer n. Liver cancer n. Colorectal cancer n. Lung cancer n. Breast cancer 28

Cancers of Upper Aerodigestive Tract (UADT) o Alcohol strong risk factor for cancers of the oral cavity and pharynx, esophagus, and larynx o Earliest report, 1836 by Boston surgeon, J. C. Warren who described a case of tongue cancer in a tobacco chewer with a “predisposition” due to chronic use of spirits o Earliest “association”, an excess of esophageal cancer among alcoholics in Paris in 1910 o 25 -80% are attributable to alcohol o Smoking also strong risk factor; risk greatest for heavy drinkers and smokers 29

Cancer of Oral Cavity and Pharynx o The mucosa of the oral cavity and pharynx (excluding the nasopharynx) comes into close contact with alcohol upon ingestion. o Biological plausible that alcohol directly affect carcinogenesis in these sites via physiochemical or metabolic effects. o Epidemiological studies clearly indicate that drinking of alcoholic beverages is causally related to cancers of the oral cavity and pharynx (excluding the nasopharynx). There is no indication that the effect is dependent on type of beverage. 30

Relative Risks of Alcohol Consumption for Oral Cancer Bagnardi et al , British Journal of Cancer 2001 31

Alcoholic Beverage Use and Risk of Oral Cancer in Puerto Rico by Gender o Subjects – Puerto Rican men and women, aged 2179 o Cases - 286 males, 249 females o Controls - 417 males, 614 females o ORs adjusted for tobacco, diet, education, age Hayes et al. , Cancer Causes Control, 1999 32

Liquor Use and Risk of Oral Cancer in Puerto Rico by Concentration Huang et al. , Am J Epidemiol, 2003 33

RR Of Oral Cancer According to Daily Consumption of Tobacco and Alcohol Consumption (ethanol/day) Tobacco Consumption (in g per day) 0 <20 20 -39 40+ 0 1. 00 1. 63 1. 62 3. 40 <0. 4 oz(9. 5 g) 1. 66 1. 89 3. 29 3. 35 0. 4 -1. 5(9. 5 -36 g) 1. 88 4. 85 4. 84 8. 20 1. 6+ oz(36+g) 2. 27 4. 79 9. 97 15. 6 Number of cases 26 44 248 143 Tuyns et al, 1977 34

Cancer of Esophagus o Alcohol drinking has been classified as a risk factor for esophageal cancer based on data from epidemiologic studies, although ethanol in its pure form does not act as a carcinogen in experimental models. o Potential reasons are (1)alcohol acts as a solvent for tobacco carcinogens or that impurities in alcoholic drinks are the carcinogenic agents. (2) exposure to high levels of acetaldehyde is responsible for the increased cancer risk. o However, alcohol does not appear to be an important risk factor for adenocarcinoma of esophagus. 35

Pooled RR for Esophageal Cancer Associated with Intake of Alcohol Bagnardi et al. , Br J Cancer, 2001 36

Trends in Esophageal Cancer Incidence Rates* in 9 SEER Areas in The US by Gender, Race, and Cell Type from 1973 -1975 through 1996 -2000 *Age standardized to 2000 US population 37

Alcoholic Beverage Use and Risk of SCCE in US Men by Race o Black rate=19. 4; white rate=3. 6 in 1986 o Subjects - black & white men, 30 -79 Cases - 124 white, 249 black Controls - 750 white, 614 black ORs adjusted for tobacco, diet, income, age, area o o Brown et al. , JNCI, 1994 38

RR of Esophageal Cancer According to Daily Consumption of Tobacco and Alcohol Consumption Tobacco Consumption (in g per day) (g ethanol/day) 0 -9 10 -19 20+ 0 -40 1. 0 3. 4 5. 1 41 -80 7. 3 8. 4 12. 3 81+ 18. 0 19. 9 44. 4 78 58 308 Number of cases Tuyns et al, 1977 39

The risk of head and neck cancer associated with cigarette smoking in never drinkers of alcohol ( left ) and with alcohol drinking in never users of tobacco ( right ), overall and by study, using International Head and Neck Cancer Epidemiology consortium pooled data Hashibe et al, J Natl Cancer Inst, 2007 40

Cancer of Stomach o Stomach is exposed directly to ingested ethanol o Although the concentration of alcohol is diluted by gastric juice, it is biological plausible that stomach cancer risk could be increased by some direct carcinogenic effect of ethanol upon the mucosa o In view of the overall lack of excess risk for stomach cancer in the cohort studies, the inconsistent results of the casecontrol studies, and the inadequate control for dietary and socioeconomic factors, there is little in the aggregate data to suggest a causal role for drinking of alcoholic beverages in stomach cancer. 41

Relative Risks of Alcohol Consumption for Each Cancer Site Cases Relative risks 25 g day 50 g day 100 g day Oral cavity and pharynx 7, 954 1. 8 2. 9 6. 0 Esophagus 7, 239 1. 5 2. 2 4. 2 Larynx 3, 759 1. 4 1. 9 4. 0 Breast 44, 033 1. 7 2. 7 Liver 2, 294 1. 2 1. 4 1. 9 Colon and rectum 11, 296 1. 1 1. 2 1. 4 Stomach 4, 518 1. 1 1. 2 1. 3 Ovary 1, 651 no association 1. 2 1. 5 Prostate 4, 094 no association 1. 1 1. 2 Bagnardi et al , British Journal of Cancer 2001 42

Cancer of Liver o There have been reports over many decades of associations between chronic alcohol abuse, alcoholic liver cirrhosis and primary liver cancer. o Potential confounding due to hepatitis B virus, tobacco smoking and aflatoxin was not explored in all the studies; whenever it was, it did not alter the findings qualitatively. The available results, taken together, indicate that drinking of alcoholic beverages is causally related to liver cancer. 43

Trends in Liver Cancer Incidence Rates* in 9 SEER Areas in The US by Gender and Race from 1973 -1975 through 1996 -2000 *Age standardized to 2000 US population 44

Pooled RR for Liver Cancer Associated with Intake of Alcohol Bagnardi et al. , Br J Cancer, 2001 45

Cancer of Colorectum o Although numerous studies reported a positive association between alcohol drinking and colorectal cancer risk, it remains unclear whether alcohol drinking is causally related to carcinogenesis of the colorectum o Since ethanol absorbed efficiently from within the stomach and upper intestine, it is unlikely that ethanol has direct effect upon the large bowel. o However, some researches suggested alcohol consumption behavior may modified the colorectal cancer risk o Colorectal cancer is common in developed countries; modest increases in risk can have important public health implications 46

Trends in colorectal cancer incidence rates* in 9 SEER areas in the US by gender and race from 1973 -1975 through 1996 -2000 *Age standardized to 2000 US population 47

Pooled RR for colorectal cancer associated with intake of alcohol Moskal et al, 2007 48

Study-specific and Pooled Multivariate Relative Risks for Colorectal Cancer for Alcohol Intake of 30 g/day or Greater versus 0 g/day. Cho et al, Annual Int Med, 2004 49

RRs (highest vs. lowest category) for Published Cohort Studies or Nested Case-Control Studies on the between Total Alcohol Consumption and Colon Cancer Incidence. Moskal et al, IJC, 2007 50

RRs (highest vs. lowest category) for Published Cohort Studies or Nested Case-Control Studies on the between Total Alcohol Consumption and Rectal Cancer Incidence. Moskal et al, 2007 51

Intake of baseline wine, beer and spirits/liquors intakes (g/day) and risk of colorectal, colon and rectal cancer (men and women combined). Ferrari et al, Int J Cancer, 2007 52

Cancer of Female Breast o Many epidemiologic studies have identified chronic alcohol consumption as a risk factor for breast cancer. o Previous meta-analyses have shown a positive association between alcohol intake and breast cancer o 4% of breast cancers in developed countries may be attributable to use of alcohol 53

Individual Study Estimates of Crude Odds Ratios (log scale) of the Risk of Breast Cancer Associated with Drinkers versus Non. Drinkers and 95% CI 54 Key et al, Cancer Causes and Control, 2006

Trends in Breast Cancer Incidence Rates* in 9 SEER Areas in the US by Race from 1973 -1975 through 1996 -2000 *Age standardized to 2000 US population 55

Pooled RR for Breast Cancer Associated with Median Alcohol Intake Collaborative group on hormonal factors in breast cancer, Br J Cancer, 2002 56

Cancer of Pancreas o Most epidemiologic studies have found little or no support for a causal relationship between light and moderate alcohol use and risk of pancreatic cancer 57

Trends in Pancreas Cancer Incidence Rates* in 9 SEER Areas in the US by Gender and Race from 1973 -1975 through 1996 -2000 *Age standardized to 2000 US population 58

Pooled RR for Pancreas Cancer Associated with Intake of Alcohol Bagnardi et al. , Br J Cancer, 2001 59

Alcoholic Beverage Use and risk of pancreas cancer in US by Race and Gender 60 Silverman et al. , Cancer Res, 1995

Cancer of Lung o There is evidence that alcohol can act as a prooxidant in tissues, including lung tissue, and on lipids, including lung membrane lipids. Alcohol can induce the expression of enzymes that are related to carcinogen metabolism, and compounds other than ethanol that are contained in alcoholic beverages may have carcinogenic effects. 61

Alcohol consumption (g/d) and lung cancer by histologic type: pooled multivariate-adjusted relative risks (RR) 62 Freudenheim et al, Am J Clin Nutr, 2005

Summary of the Studies Included in the Meta-Analysis Bagnardi et al. , Br J Cancer, 2001 63

Current issues of alcohol and cancer research 64

Current issues of alcohol and cancer research o o o Measurement of alcohol drinking Personal susceptibility Moderate drinking Under-age drinking Gene/environmental-environmental interaction 65

Estimate of Alcohol Drinking o NIAAA suggests that the estimates of alcohol drinking should prepared taking into account of: n Volume of drinking n Pattern of drinking 66

What is “a Drink”? o Despite the differences in concentration, the average intake of ethanol per drink is approximately constant across beverage types. o A standard drink is: n One 12 -ounce bottle of beer* or wine cooler n One 5 -ounce glass of wine n 1. 5 ounces of 80 -proof+ distilled spirits. * Different beers have different alcohol content. Malt liquor has a higher alcohol content than most other brewed beverages. + 80 -proof== 40% ABV (alcohol by volume) 67

Current Issues of Alcohol and Cancer Research o o o Measurement of alcohol drinking Personal susceptibility Moderate drinking Under-age drinking Gene/environmental-environmental interaction 68

Alcohol metabolism o Ethanol is eliminated from the body by oxidation to acetaldehyde and then to acetate, reactions catalyzed by alcohol dehydrogenase, and ALDH 2, respectively Alcohol (R-OH) ADH CYP 2 E 1 NQO 1 Aldehyde (R-CHO) o ADH: alcohol dehydrogenase o CYP 2 E 1: Cytochrome p 450 2 E 1 o NQO 1: NAD(P)H: quinone oxidoreductase 1 o ALDH 2 : Aldehyde dehydrogenase 2 ALDH 2 Acetic acid (R-COOH) 69

ALDH 2 in Alcohol Metabolism o When the individuals with ALDH 2*2 (Lys 487 or rs 671 A) gene drink, the inactive enzyme fails to promptly metabolize acetaldehyde, and leads to its excessive accumulation after drinking o The enzyme activity of ALDH 2 polymorphisms n 1 -1 70 -100% n 1 -2 6 -20% n 2 -2 close to 0 o In ALDH 2 2 -2 and ALDH 2 1 -2, blood acetaldehyde concentration are approximately 19 and 6 times that in ALDH 2 1 -1, respectively 70

ALDH 2 in Alcohol Metabolism o The Ethanol Metabolic Pathway and the Role of the ALDH 2 Variants in Acetaldehyde Accumulation Brooks PJ et al. PLo. S Med. 2009 Mar 24; 6(3): e 50. 71

Alcohol flushing (Asian glow) o predominantly due to an inherited deficiency in the enzyme ALDH 2 Facial flushing in a 22 -year-old ALDH 2 heterozygote before (left) and after (right) drinking alcohol. [Brooks PJ et al. PLo. S Med. 2009 Mar 24; 6(3): e 50. ] 72

Based on ~480 College Students in Japan After a glass of beer(0. 5 L) o ALDH 2 1 -1 o ALDH 2 1 -2 o ALDH 2 2 -2 Takashita et al (1999) on Alcoholisms 73

Alcohol Flushing and Cancer o A study in Japanese alcoholics showed that the amount of mutagenic acetaldehyde-derived DNA adducts in white blood cells was significantly higher in ALDH 2 -deficient heterozygotes than in individuals with active ALDH 2. In this study, while the two groups were matched for alcohol consumption, the ALDH 2 -deficient group consumed slightly less alcohol on average than the controls. (Matsuda et al, Chem Res Toxicol, 2006) o Also, ALDH 2 heterozygotes who drank alcohol had higher levels of white blood cells with chromosomal damage than drinkers with active ALDH 2 (Ishikawa et al, Mutat Res , 2007) o the 2007 IARC Working Group on alcohol and cancer specifically noted the above evidences supporting a causal role for acetaldehyde in alcohol-related esophageal 74

ALDH 2*2 Gene Frequency in Different Populations Caucasoid Mongoloid Finns 0 Chinese 0. 159 German 0 Chinese (Taiwan) 0. 24 Filipinos 0. 006 Hungarians 0. 013 Native Americans 0 Japanese 0. 23 -0. 46 Siberians (Yakut) 0 Koreans 0. 151 Swedes 0 Malays 0. 034 Turks 0 Mongolian 0. 05 Finns 0 Myanmar 0. 02 Thais 0. 05 75

ALDH 2*2 Gene Frequency in Different Populations Negroid African Other 0 Indians Aurocanians (South Chile) 0 Australian Aborigines 0 Caboclos (Brazil) 0. 174 Eskimos (Alaska) 0 North American 0 -0. 2 Mestizos (Mexico) 0 Northwest coast 0. 2 Mexican American 0 Pima Indians South American 0. 044 0. 4 Papua New Guineans Swedish Lapps 0. 04 0 76

Current Interests of Alcohol and Cancer Research o o o Measurement of alcohol drinking Personal susceptibility Moderate drinking Under-age drinking Gene/environmental-environmental interaction 77

ALDH 2 Deficiency Increases the Risk of Alcohol. Related Squamous Cell Esophageal Cancer o Case control studies in Japan and Taiwan have consistently demonstrated a strong link between the risk of esophageal squamous cell carcinoma and alcohol consumption in lowactivity ALDH 2 heterozygotes, with odds ratios (ORs) ranging from 3. 7 to 18. 1 after adjustment for alcohol consumption. o Most studies show ORs of over 10 for increased risk in heterozygotes who are heavy drinkers. o In the Japanese and Taiwanese studies, a strikingly high proportion (58%– 69%) of the excessive risk for esophageal cancer is attributable to drinking by low-activity ALDH 2 heterozygous individuals. Brooks PJ et al. PLo. S Med. 2009 Mar 24; 6(3): e 50. 78

Moderate Alcohol Drinking o Many of these studies have evaluated dose response relationships with levels of ethanol consumption and the various outcomes of interest. Ushape or J-shape were found in alcohol intake and several disease incidence. o Many studies found “moderate” drinking is the only level of drinking that has been shown to have potential health benefits, however, the level of “moderate” or “heavy” have not been defined consistently across studies (Gaziano et al. , 2000; Klatsky, 2002; NIAAA, 1992). o Further, they are not always consistent with the definition of moderate drinking in the USDA/DHHS Dietary Guidelines (2000) no more than one drink per day for women and no more than two drinks per day for men 79

Complication o individual differences – BAC and metabolism o Intensity & frequency- (3 drinks in one hour will produce a much higher BAC than 3 drinks over the course of 3 hours ), and therefore different effect o Confounding and modification by lifestyle variables also could be a factor in the observed health differences between drinkers and nondrinkers o Drinking pattern and size is different through out countries and occasions o Also, depend on outcome of interest, co-morbid conditions, age, gender, family history, or specific health condition. 80

Recommendations o Government dietary guidelines : n Except for those individuals at particular risk, consumption of 2 drinks a day for men and 1 for women is unlikely to increase health risks. n As risks for some conditions and diseases do increase at higher levels of consumption, men should be cautioned to not exceed 4 drinks on any day and women to not exceed 3 on any day Note: However, “moderate alcohol use” should not be construed as “healthy alcohol use”. 81

Moderate drinking and cancer o Low to moderate alcohol consumption( 3 drink/day) in women increases the risk of certain cancers (oral cavity and pharynx, esophagus, larynx, rectum, breast, and liver, and with a decreased risk for thyroid cancer, non–Hodgkin lymphoma, and renal cell carcinoma ). For every additional drink regularly consumed per day, the increase incidence in developed countries is estimated to 15 cancers per 1000 women up to age 751. Allen NE et al. Moderate alcohol intake and cancer incidence in women. J Natl Cancer Inst. 2009 82 Mar 4; 101(5): 296 -305. Epub 2009 Feb 24. 1

Estimated increase in the relative risk (95% CI) of incident cancer per 10 -g/d increase in alcohol intake (drinkers only). Analyses are adjusted for age, region of residence, SES, BMI, smoking, physical activity, use of OC and HRT Allen NE et al. J Natl Cancer Inst. 2009 83

Relative risk (95% floated confidence interval) of breast cancer by amount and type of alcohol consumed (drinkers only). Analyses are adjusted for age, region of residence, SES, BMI, smoking, physical activity, use of OCs and HRT. (FCI = floated confidence interval. "Other alcoholic drinks" is defined as drinkers of beer and/or spirits exclusively or a mixture of wine, beer, and/or spirits. ) Allen NE et al. Moderate alcohol intake and cancer incidence in women. J Natl Cancer Inst. 2009 84 Mar 4; 101(5): 296 -305. Epub 2009 Feb 24.

Current Issues of Alcohol and Cancer Research o o o Measurement of alcohol drinking Personal susceptibility Moderate drinking Under-age drinking Gene/environmental-environmental interaction 85

FACT!! o A 1996 study of children ages 9 to 11 found that children were more familiar with Budweiser’s television frogs than Kellogg’s Tony the Tiger, the Mighty Morphin’ Power Rangers, or Smokey the Bear o A study of 12 -year-olds found that children who were more aware of beer advertising held more favorable views on drinking and expressed an intention to drink more often as adults than did children who were less knowledgeable about the ads. o A recent economic analysis assessed the effects of alcohol advertising on youth drinking behaviors by comparing federally reported levels of youth drinking with detailed reports on alcohol advertising in local markets during the same years. The analysis concluded that a complete ban on alcohol advertising could reduce monthly levels of youth drinking by 24% and youth binge drinking by about 42%. o The Center on Alcohol Marketing and Youth found that, in 2001, youth in the United States were 93 times more likely to see an ad promoting alcohol than an industry ad discouraging underage drinking. In fact, compared to underage youth, adults age 21 and over were more than twice as likely to see advertising discouraging underage drinking 86

Under-Age Drinking and Cancer o Researchers start to look into the issues regarding under age drinking o So far, very few studies address this on cancer, however, some researchers suspected drinking alcohol in younger age may associated with early onset of certain alcohol-related cancer. 87

Current Issues of Alcohol and Cancer Research o o o Measurement of alcohol drinking Personal susceptibility Moderate drinking Under-age drinking Gene/environmental-environmental interaction 88

Conclusion 89

IARC evaluation o Alcoholic beverages are carcinogenic to humans– group 1 carcinogen (1988, revision 2007). 90

IARC o o Group 1: The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans Group 2 n n o o Group 2 A: The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans. Group 2 B: The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. Group 3: The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans Group 4: The agent (mixture) is probably not carcinogenic to humans. 91

Questions? 92