1 alcohol and cancer nai-chieh yuko you, m.s., ph.d. - epi 242 cancer epidemiology, nov 16, 2009 -
TRANSCRIPT
1
Alcohol and Cancer
Nai-chieh Yuko You, M.S., Ph.D.
- EPI 242 Cancer Epidemiology, Nov 16, 2009 -
2
Outlines Introduction
Health effect
Epidemiologic studies
Alcohol and Cancer
Current interests and issues of alcohol and cancer research
3
Introduction
4
Alcohol Beverages
Drinks made by fermenting fruit juices, sugars, and fermentable carbohydrates with yeast to form alcohol.
The predominant types of commercially produced alcoholic beverages are
beer, wine and spirits.
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.
5
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
6
Trends in Ethanol Consumption in the US, 1960-97
Source: NIAAA, NIH
1960 1970 1980 1990 20000.1
1
10
Total
Wine
Spirits
Beer
5
3
0.5
0.3
Per
capit
a c
onsum
pti
on (gallons)
Year
7
Percent Drinking Alcohol (1984 and 1995)
01020304050607080
WhiteMale
BlackMale
WhiteFemale
BlackFemale
% D
rin
kin
g
1984
1995
Caetano and Clark, J Stud Alcohol, 1998
8
Prevalence of Alcohol Use 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.
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).
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).
9
Health Effect
10
Health Effect 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
11
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 overviewJürgen Rehm , Robin Room , Kathryn Graham , Maristela Monteiro , Gerhard Gmel & Christopher T. Sempos Addiction ; Volume 98 Issue 9 Page 1209 - September 2003
12
Global Mortality Burden (deaths in thousands) Attributable to Alcohol by Major Disease Categories – 2000
Eur Addict Res 2003;9:157–164Global Burden of Disease Attributable to AlcoholJürgen Rehma, Robin Room, Maristela Monteiro, Gerhard Gmel, Kathryn Graham, Nina Rehn, Christopher T. Sempos, David Jernigan
13
Alcohol-Attributable Deaths (in thousands) in 2000 by Disease and Subregion
Eur Addict Res 2003;9:157–164Global Burden of Disease Attributable to AlcoholJürgen Rehma, Robin Room, Maristela Monteiro, Gerhard Gmel, Kathryn Graham, Nina Rehn, Christopher T. Sempos, David Jernigan
14
Global burden of disease (DALYs in thousands) attributable to alcohol by major disease categories – 2000
Eur Addict Res 2003;9:157–164Global Burden of Disease Attributable to AlcoholJürgen Rehma, Robin Room, Maristela Monteiro, Gerhard Gmel, Kathryn Graham, Nina Rehn, Christopher T. Sempos, David Jernigan
15
Alcohol-related disease burden in DALYs (in thousands) by disease category and region
Eur Addict Res 2003;9:157–164Global Burden of Disease Attributable to AlcoholJürgen Rehma, Robin Room, Maristela Monteiro, Gerhard Gmel, Kathryn Graham, Nina Rehn, Christopher T. Sempos, David Jernigan
16
Alcohol and Cancer 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.
17
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 compounds6. Catalyze the metabolic activation of some compounds
into carcinogens 7. Affect hormonal status 8. Increase cellular exposure to oxidants 9. Suppress immune function
18
Selected Chemical Compounds in Alcoholic beverage which have been found to be carcinogenic
compound Identified in IARC evaluation
Beer Wine Spirits human animal Overall
Aflatoxin + + S S 1
Arsenic + S L 1
Asbestos + + + S S 1
Benzene + + S S 1
Chromium + S S 1
Nickle + S S 1
Benz(a)anthracene + ND S 2A
Benzo(a)pyrene + ND S 2A
Cadmium + L S 2A
Formaldehyde + + + L S 2A
N-Nitrosodiethylamine + + + ND S 2A
N-Nitrosodimethylamine + + + ND S 2A
S=Sufficient; L=Limited; I=Inadequate; ND=No data
19
IARC Group 1: The agent (mixture) is carcinogenic to humans.
The exposure circumstance entails exposures that are carcinogenic to humans
Group 2 Group 2A: The agent (mixture) is probably carcinogenic to humans.
The exposure circumstance entails exposures that are probably carcinogenic to humans.
Group 2B: 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.
20
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 compounds6. Catalyze the metabolic activation of some compounds
into carcinogens 7. Affect hormonal status 8. Increase cellular exposure to oxidants 9. Suppress immune function
21
Alcohol Metabolism
Source: Klaassen,CD (1998) Casarett & Doull's Toxicology: The basic science of poisons, fifth edition
22
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 acetaldehyde-derived 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 Brooks PJ et al. PLoS Med. 2009 Mar 24;6(3):e50
23
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
24
Other Possible Mechanisms Direct toxic effect due to highly concentrated alcoholic beverage on
the epithelium
Enhance reflux
Decrease several other phase II enzyme levels, included liver glutathione and SAM level
Inhibit the activity of DNA methylase found in animal studies, but can’t confirm in human.
25
Animal & Human researches
Animal studies
Correlation Studies
Cohort and Case-Control Studies
26
Animal Study 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.
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)
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.
Most of animal studies were expected to find HCC, however, they found the rate of extra hepatic tumor increased, especially UADT.
27
Correlation Studies 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).
Time trends was found in per capita alcohol consumption and mortality from esophageal and laryngeal cancer (Tuyns et al, 1976), and colorectal cancer (McMichael et al, 1979).
28
Cohort/Case Control Studies
Oral and pharyngeal cancerEsophageal cancerStomach cancerLiver cancerColorectal cancerLung cancerBreast cancer
29
Cancers of Upper Aerodigestive Tract (UADT)
Alcohol strong risk factor for cancers of the oral cavity and pharynx, esophagus, and larynx
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
Earliest “association”, an excess of esophageal cancer among alcoholics in Paris in 1910
25-80% are attributable to alcohol
Smoking also strong risk factor; risk greatest for heavy drinkers and smokers
30
Cancer of Oral Cavity and Pharynx
The mucosa of the oral cavity and pharynx (excluding the nasopharynx) comes into close contact with alcohol upon ingestion.
Biological plausible that alcohol directly affect carcinogenesis in these sites via physiochemical or metabolic effects.
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.
31
Relative Risks of Alcohol Consumption for Oral Cancer
Bagnardi et al , British Journal of Cancer 2001
1
2
3
4
5
6
RR
25 50 100
Number of grams (drinks) per day
320 10 20 30 40 50 60
0.1
1
10
Male Female
5
Odd
s R
atio
s
Number of drinks per week
Alcoholic Beverage Use and Risk of Oral Cancer in Puerto Rico by Gender
Subjects – Puerto Rican men and women, aged 21-79
Cases - 286 males, 249 females
Controls - 417 males, 614 females
ORs adjusted for tobacco, diet, education, age
Hayes et al., Cancer Causes Control, 1999
33
Liquor Use and Risk of Oral Cancer in Puerto Rico by Concentration
Huang et al., Am J Epidemiol, 20030 10 20 30 40 50 60 70 80 90 100
0.1
1
10
50
5
Diluted Straight
Odd
s R
atio
s
Number of drinks per week
34
RR Of Oral Cancer According to Daily Consumption of Tobacco and Alcohol
Alcohol Consumption(ethanol/day)
Tobacco Consumption (in g per day)
0 <20 20-39 40+
0 1.00 1.63 1.62 3.40
<0.4oz(9.5g) 1.66 1.89 3.29 3.35
0.4-1.5(9.5-36g) 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
35
Cancer of Esophagus 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.
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.
However, alcohol does not appear to be an important risk factor for adenocarcinoma of esophagus.
36
Pooled RR for Esophageal Cancer Associated with Intake of Alcohol
1
2
3
4
5
6
RR
25 50 100
Number of grams (drinks) per day
Bagnardi et al., Br J Cancer, 2001
37
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
1970 1980 1990 2000
0.1
1
10
20
1970 1980 1990 2000
0.1
1
10
20
0.5
Year of diagnosis
Rat
e pe
r 10
0,00
0 pe
rson
-yea
rs 5 5
0.5
Rat
e pe
r 10
0,00
0 pe
rson
-yea
rs
White BlackSCCE ACE
Male
Female
Year of diagnosis
38
Alcoholic Beverage Use and Risk of SCCE in US Men by Race
0 10 20 30 40 50 60 70 80 90 100
0.1
1
10
50
5
Whites Blacks
Odd
s R
atio
s
Number of drinks per week
Black rate=19.4; white rate=3.6 in 1986
Subjects - black & white men, 30-79
Cases - 124 white, 249 black
Controls - 750 white, 614 black ORs adjusted for tobacco, diet, income, age, area
Brown et al., JNCI, 1994
39
RR of Esophageal Cancer According to Daily Consumption of Tobacco and Alcohol
Alcohol Consumption(g ethanol/day)
Tobacco Consumption (in g per 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
Number of cases 78 58 308
Tuyns et al, 1977
40
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 InternationalHead and Neck Cancer Epidemiology consortium pooled data
Hashibe et al, J Natl Cancer Inst, 2007
41
Cancer of Stomach Stomach is exposed directly to ingested ethanol 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
In view of the overall lack of excess risk for stomach cancer in the cohort studies, the inconsistent results of the case-control 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.
42
Relative Risks of Alcohol Consumption for Each Cancer Site
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 1.3 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
43
Cancer of Liver There have been reports over many decades of
associations between chronic alcohol abuse, alcoholic liver cirrhosis and primary liver cancer.
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.
441970 1980 1990 2000
1
10
100
200
50
5
White BlackMale Female
Rat
e pe
r 10
0,00
0 pe
rson
-yea
rs
Year of diagnosis
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
45
Pooled RR for Liver Cancer Associated with Intake of Alcohol
1
1.2
1.4
1.6
1.8
2
2.2
2.4
RR
25 50 100
Number of grams (drinks) per day
Bagnardi et al., Br J Cancer, 2001
46
Cancer of Colorectum 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
Since ethanol absorbed efficiently from within the stomach and upper intestine, it is unlikely that ethanol has direct effect upon the large bowel.
However, some researches suggested alcohol consumption behavior may modified the colorectal cancer risk
Colorectal cancer is common in developed countries; modest increases in risk can have important public health implications
47
Trends in colorectal cancer incidence rates* in 9 SEER areas in the US by gender and race from 1973-1975 through 1996-2000
1970 1980 1990 2000
1
10
100
200
50
5
White BlackMale Female
Rate
per
100,0
00 p
ers
on-y
ears
Year of diagnosis
*Age standardized to 2000 US population
48
Pooled RR for colorectal cancer associated with intake of alcohol
1
1.1
1.2
1.3
1.4
1.5
RR
Number of grams (drinks) per day
Colon 1.03 1.07 1.15
Rectum 1.04 1.07 1.15
25 (2) 50 (4) 100 (8)
Moskal et al, 2007
49
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
50
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
51
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
52
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
53
Cancer of Female Breast Many epidemiologic studies have identified chronic alcohol
consumption as a risk factor for breast cancer. Previous meta-analyses have shown a positive association
between alcohol intake and breast cancer 4% of breast cancers in developed countries may be attributable
to use of alcohol
54
Individual Study Estimates of Crude Odds Ratios (log scale) ofthe Risk of Breast Cancer Associated with Drinkers versus Non-Drinkers and 95% CI
Key et al, Cancer Causes and Control, 2006
55
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
1970 1980 1990 2000
1
10
100
200
5
50
White BlackFemale
Rat
e pe
r 10
0,00
0 pe
rson
-yea
rs
Year of diagnosis
56
Pooled RR for Breast Cancer Associated with Median Alcohol Intake
11.11.21.31.41.51.61.71.81.9
2
RR
8 18 29 39 58
Number of grams per day (1 drink=12 g of alcohol)
Collaborative group on hormonal factors in breast cancer, Br J Cancer, 2002
57
Cancer of Pancreas
Most epidemiologic studies have found little or no support for a causal relationship between light and moderate alcohol use and risk of pancreatic cancer
58
Trends in Pancreas Cancer Incidence Rates* in 9 SEER Areas in the US by Gender and Race from 1973-1975 through 1996-2000
1970 1980 1990 2000
1
10
100
200
5
50 White Black
Male Female
Rat
e pe
r 10
0,00
0 pe
rson
-yea
rs
Year of diagnosis*Age standardized to 2000 US population
59
Pooled RR for Pancreas Cancer Associated with Intake of Alcohol
1
1.1
1.2
1.3
1.4
1.5
RR
25 50 100
Number of grams (drinks) per day
Bagnardi et al., Br J Cancer, 2001
60
Alcoholic Beverage Use and risk of pancreas cancer in US by Race and Gender
0 10 20 30 40 50 60 70
0.1
1
10
White male White female Black male Black female
5
Odd
s R
atio
s
Number of drinks per weekSilverman et al., Cancer Res, 1995
61
Cancer of Lung 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.
62
Alcohol consumption (g/d) and lung cancer by histologic type: pooled multivariate-adjusted relative risks (RR)
Freudenheim et al, Am J Clin Nutr, 2005
63
Summary of the Studies Included in the Meta-Analysis
1.73
1.351.51
1.07 1.2 1.14 1.111.31
2.77
1.83
2.21
1.151.41
1.21 1.17
1.67
5.75
3.24
4.23
2.24
1.83
1.32 1.32
2.71
0
1
2
3
4
5
6
7
oral
cavit
y
laryn
x
esop
hage
al
stomac
hliv
erco
lon
rectu
mbr
east
Cancer sites
Pool
ed R
R
25g
50g
100g
Bagnardi et al., Br J Cancer, 2001
64
Current issues of alcohol and cancer research
65
Current issues of alcohol and cancer research
Measurement of alcohol drinking Personal susceptibility Moderate drinking Under-age drinking Gene/environmental-environmental interaction
66
Estimate of Alcohol Drinking
NIAAA suggests that the estimates of alcohol drinking should prepared taking into account of: Volume of drinking
Pattern of drinking
67
What is “a Drink”?
Despite the differences in concentration, the average intake of ethanol per drink is approximately constant across beverage types.
A standard drink is: One 12-ounce bottle of beer* or wine cooler One 5-ounce glass of wine 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)
68
Current Issues of Alcohol and Cancer Research
Measurement of alcohol drinking Personal susceptibility Moderate drinking Under-age drinking Gene/environmental-environmental interaction
69
Ethanol is eliminated from the body by oxidation to acetaldehyde
and then to acetate, reactions catalyzed by alcohol
dehydrogenase, and ALDH2, respectively
ADH: alcohol dehydrogenase
CYP2E1: Cytochrome p450 2E1
NQO1:NAD(P)H:quinone oxidoreductase 1
ALDH2 : Aldehyde dehydrogenase 2
Alcohol metabolism
Alcohol
(R-OH)
Aldehyde
(R-CHO)
Acetic acid
(R-COOH)
ADH ALDH2
CYP2E1NQO1
70
ALDH2 in Alcohol Metabolism
When the individuals with ALDH2*2 (Lys487 or rs671 A) gene
drink, the inactive enzyme fails to promptly metabolize
acetaldehyde, and leads to its excessive accumulation after
drinking
The enzyme activity of ALDH2 polymorphisms
1-1 70-100%
1-2 6-20%
2-2 close to 0
In ALDH2 2-2 and ALDH2 1-2, blood acetaldehyde concentration
are approximately 19 and 6 times that in ALDH2 1-1, respectively
71
ALDH2 in Alcohol Metabolism The Ethanol Metabolic Pathway and the Role of the ALDH2
Variants in Acetaldehyde Accumulation
Brooks PJ et al. PLoS Med. 2009 Mar 24;6(3):e50.
72
Alcohol flushing (Asian glow) predominantly due to an inherited deficiency in the enzyme ALDH2
Facial flushing in a 22-year-old ALDH2 heterozygote before (left) and after (right) drinking alcohol. [Brooks PJ et al. PLoS Med. 2009 Mar 24;6(3):e50. ]
73
Based on ~480 College Students in Japan
After a glass of beer(0.5L)
ALDH2 1-1
ALDH2 1-2
ALDH2 2-2
Takashita et al (1999) on Alcoholisms
74
Alcohol Flushing and Cancer A study in Japanese alcoholics showed that the amount of
mutagenic acetaldehyde-derived DNA adducts in white blood cells was significantly higher in ALDH2-deficient heterozygotes than in individuals with active ALDH2. In this study, while the two groups were matched for alcohol consumption, the ALDH2-deficient group consumed slightly less alcohol on average than the controls. (Matsuda et al, Chem Res Toxicol, 2006)
Also, ALDH2 heterozygotes who drank alcohol had higher levels of white blood cells with chromosomal damage than drinkers with active ALDH2 (Ishikawa et al, Mutat Res , 2007)
the 2007 IARC Working Group on alcohol and cancer specifically noted the above evidences supporting a causal role for acetaldehyde in alcohol-related esophageal
75
ALDH2*2 Gene Frequency in Different Populations
Caucasoid Mongoloid
Finns 0 Chinese 0.159
German 0 Chinese (Taiwan) 0.24
Hungarians 0.013 Filipinos 0.006
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
76
ALDH2*2 Gene Frequency in Different Populations
Negroid Other
African 0 Aurocanians (South Chile) 0
Australian Aborigines 0
Caboclos (Brazil) 0.174
Indians Eskimos (Alaska) 0
North American 0-0.2 Mestizos (Mexico) 0
Northwest coast 0.2 Mexican American 0
Pima Indians 0.044 Papua New Guineans 0.04
South American 0.4 Swedish Lapps 0
77
Current Interests of Alcohol and Cancer Research
Measurement of alcohol drinking Personal susceptibility Moderate drinking Under-age drinking Gene/environmental-environmental interaction
78
ALDH2 Deficiency Increases the Risk of Alcohol-Related Squamous Cell Esophageal Cancer
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 low-activity ALDH2 heterozygotes, with odds ratios (ORs) ranging from 3.7 to 18.1 after adjustment for alcohol consumption.
Most studies show ORs of over 10 for increased risk in heterozygotes who are heavy drinkers.
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 ALDH2 heterozygous individuals.
Brooks PJ et al. PLoS Med. 2009 Mar 24;6(3):e50.
79
Moderate Alcohol Drinking Many of these studies have evaluated dose response relationships with
levels of ethanol consumption and the various outcomes of interest. U-shape or J-shape were found in alcohol intake and several disease incidence.
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).
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
80
Complication individual differences – BAC and metabolism
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
Confounding and modification by lifestyle variables also could be a factor in the observed health differences between drinkers and nondrinkers
Drinking pattern and size is different through out countries and occasions
Also, depend on outcome of interest, co-morbid conditions, age, gender, family history, or specific health condition.
81
Recommendations
Government dietary guidelines : 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.
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”.
82
Moderate drinking and cancer 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.
1 Allen NE et al. Moderate alcohol intake and cancer incidence in women. J Natl Cancer Inst. 2009 Mar 4;101(5):296-305. Epub 2009 Feb 24.
83
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
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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 Mar 4;101(5):296-305. Epub 2009 Feb 24.
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Measurement of alcohol drinking Personal susceptibility Moderate drinking Under-age drinking Gene/environmental-environmental interaction
Current Issues of Alcohol and Cancer Research
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FACT!! 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
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.
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%.
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
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Under-Age Drinking and Cancer Researchers start to look into the issues regarding under age
drinking
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.
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Measurement of alcohol drinking Personal susceptibility Moderate drinking Under-age drinking Gene/environmental-environmental interaction
Current Issues of Alcohol and Cancer Research
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Conclusion
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IARC evaluation
Alcoholic beverages are carcinogenic to humans– group 1 carcinogen (1988, revision 2007).
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IARC Group 1: The agent (mixture) is carcinogenic to humans.
The exposure circumstance entails exposures that are carcinogenic to humans
Group 2 Group 2A: The agent (mixture) is probably carcinogenic to humans.
The exposure circumstance entails exposures that are probably carcinogenic to humans.
Group 2B: 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.
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Questions?