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Transcript
- EPI 242 Cancer Epidemiology, Nov 16, 2009 -
Alcohol and Cancer
Nai-chieh Yuko You, M.S., Ph.D.
1
Outlines
 Introduction
 Health effect
 Epidemiologic studies
 Alcohol and Cancer
 Current interests and issues of alcohol and cancer
research
2
Introduction
3
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.
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
10
Per capita consumption (gallons)
5
3
Total
Beer
1
Spirits
0.5
Wine
0.3
0.1
1960
Source: NIAAA, NIH
1970
1980
Year
1990
2000
6
% Drinking
Percent Drinking Alcohol (1984 and 1995)
80
70
60
50
40
30
20
10
0
1984
1995
White
Male
Black
Male
Caetano and Clark, J Stud Alcohol, 1998
White
Female
Black
Female
7
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).
8
Health Effect
9
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
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
12David
Jürgen Rehma, Robin Room, Maristela Monteiro, Gerhard Gmel, Kathryn Graham, Nina Rehn, Christopher T. Sempos,
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
13David
Jürgen Rehma, Robin Room, Maristela Monteiro, Gerhard Gmel, Kathryn Graham, Nina Rehn, Christopher T. Sempos,
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
14David
Jürgen Rehma, Robin Room, Maristela Monteiro, Gerhard Gmel, Kathryn Graham, Nina Rehn, Christopher T. Sempos,
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
15David
Jürgen Rehma, Robin Room, Maristela Monteiro, Gerhard Gmel, Kathryn Graham, Nina Rehn, Christopher T. Sempos,
Jernigan
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.
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
2A
Benzo(a)pyrene
+
ND
S
2A
L
S
2A
Cadmium
+
Formaldehyde
+
+
+
L
S
2A
N-Nitrosodiethylamine
+
+
+
ND
S
2A
N-Nitrosodimethylamine
+
+
+
ND
S
2A
S=Sufficient; L=Limited; I=Inadequate; ND=No data
18
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.
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. PLoS Med. 2009 Mar 24;6(3):e50
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

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.
24
Animal & Human researches
 Animal studies
 Correlation Studies
 Cohort and Case-Control Studies
25
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.
26
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).
27
Cohort/Case Control Studies
Oral and pharyngeal cancer
Esophageal cancer
Stomach cancer
Liver cancer
Colorectal cancer
Lung cancer
Breast cancer
28
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
29
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.
30
Relative Risks of Alcohol Consumption for Oral Cancer
6
5
RR
4
3
2
1
25
50
100
Number of grams (drinks) per day
Bagnardi et al , British Journal of Cancer 2001
31
Alcoholic Beverage Use and Risk of Oral Cancer in
Puerto Rico by Gender
10

Subjects – Puerto Rican
men and women, aged 2179

Cases - 286 males, 249
females

Controls - 417 males, 614
females

ORs adjusted for tobacco,
diet, education, age
5
Odds Ratios
Male
Female
1
Hayes et al., Cancer Causes Control, 1999
0.1
0
10
20
30
40
Number of drinks per week
50
60
32
Liquor Use and Risk of Oral Cancer in Puerto Rico by
Concentration
50
10
Odds Ratios
Diluted
Straight
5
1
0.1
Huang et al., Am J Epidemiol, 2003
0
10
20
30
40
50
60
70
Number of drinks per week
80
90
100
33
RR Of Oral Cancer According to Daily Consumption of
Tobacco and Alcohol
Alcohol Consumption
Tobacco Consumption (in g per day)
(ethanol/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
34
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.
35
Pooled RR for Esophageal Cancer Associated with
Intake of Alcohol
6
5
RR
4
3
2
1
25
50
100
Number of grams (drinks) per day
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
20
10
10
5
White Black
SCCE
ACE
1
0.5
0.1
1970
1980
1990
Year of diagnosis
2000
Rate per 100,000 person-years
Rate per 100,000 person-years
Male
20
Female
5
1
0.5
0.1
1970
1980
1990
2000
Year of diagnosis
37
*Age standardized to 2000 US population
Alcoholic Beverage Use and Risk of SCCE in US Men by Race
50
Odds Ratios
10

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

5
Whites

Blacks
1
Brown et al., JNCI, 1994
0.1
0
10
20
30
40
50
60
70
Number of drinks per week
80
90
100
38
RR of Esophageal Cancer According to Daily Consumption of
Tobacco and Alcohol
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
 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.
41
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
42
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.
43
Trends in Liver Cancer Incidence Rates* in 9 SEER Areas in
The US by Gender and Race from 1973-1975 through 1996-2000
200
Rate per 100,000 person-years
100
*Age standardized to 2000 US population
50
White
Black
Male
Female
10
5
1
1970
1980
1990
Year of diagnosis
2000
44
Pooled RR for Liver Cancer Associated with Intake of Alcohol
2.4
2.2
2
RR 1.8
1.6
1.4
1.2
1
25
50
100
Number of grams (drinks) per day
Bagnardi et al., Br J Cancer, 2001
45
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
46
Trends in colorectal cancer incidence rates* in 9 SEER areas in the
US by gender and race from 1973-1975 through 1996-2000
200
Rate per 100,000 person-years
100
*Age standardized to 2000 US population
50
White
10
Black
Male
Female
5
1
1970
1980
1990
Year of diagnosis
2000
47
Pooled RR for colorectal cancer associated with intake of
alcohol
1.5
1.4
1.3
RR
1.2
1.1
1
Colon
Rectum
25 (2)
50 (4)
100 (8)
1.03
1.04
1.07
1.07
1.15
1.15
Number of grams (drinks) per day
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
 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
53
Individual Study Estimates of Crude Odds Ratios (log scale) of
the Risk of Breast Cancer Associated with Drinkers versus NonDrinkers 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
200
Rate per 100,000 person-years
100
50
White
10
5
1
1970
*Age standardized to 2000 US population
Black
Female
1980
1990
Year of diagnosis
2000
55
Pooled RR for Breast Cancer Associated with Median Alcohol Intake
2
1.9
1.8
1.7
1.6
RR 1.5
1.4
1.3
1.2
1.1
1
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
56
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
57
Trends in Pancreas Cancer Incidence Rates* in 9 SEER Areas in
the US by Gender and Race from 1973-1975 through 1996-2000
200
Rate per 100,000 person-years
100
50
Black
10
5
1
1970
*Age standardized to 2000 US population
White
Male
Female
1980
1990
Year of diagnosis
2000
58
Pooled RR for Pancreas Cancer Associated with Intake of Alcohol
1.5
1.4
1.3
RR
1.2
1.1
1
25
50
100
Number of grams (drinks) per day
Bagnardi et al., Br J Cancer, 2001
59
Alcoholic Beverage Use and risk of pancreas cancer in US by Race and
Gender
10
Odds Ratios
5
1
White male
White female
Black male
Black female
0.1
0
10
Silverman et al., Cancer Res, 1995
20
30
40
50
Number of drinks per week
60
70
60
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.
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
7
6
5.75
Pooled RR
5
4.23
4
25g
3.24
3
50g
2.77
2.71
2.24
2.21
2
1.73
1.83
1.83
1.51
1.35
100g
1.071.15
1
1.41
1.2
1.67
1.32
1.141.21
1.32
1.111.17
1.31
Bagnardi et al., Br J Cancer, 2001 Cancer sites
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om
ha
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la
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op
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63
Current issues of alcohol and cancer
research
64
Current issues of alcohol and cancer research





Measurement of alcohol drinking
Personal susceptibility
Moderate drinking
Under-age drinking
Gene/environmental-environmental interaction
65
Estimate of Alcohol Drinking
 NIAAA suggests that the estimates of alcohol drinking should
prepared taking into account of:
 Volume of drinking
 Pattern of drinking
66
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)
67
Current Issues of Alcohol and Cancer Research





Measurement of alcohol drinking
Personal susceptibility
Moderate drinking
Under-age drinking
Gene/environmental-environmental interaction
68
Alcohol metabolism

Ethanol is eliminated from the body by oxidation to acetaldehyde
and then to acetate, reactions catalyzed by alcohol
dehydrogenase, and ALDH2, respectively
Alcohol
(R-OH)
ADH
CYP2E1
NQO1
Aldehyde
(R-CHO)

ADH: alcohol dehydrogenase

CYP2E1: Cytochrome p450 2E1

NQO1:NAD(P)H:quinone oxidoreductase 1

ALDH2 : Aldehyde dehydrogenase 2
ALDH2
Acetic acid
(R-COOH)
69
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
70
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.
71
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. ]
72
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
73
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
74
ALDH2*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
ALDH2*2 Gene Frequency in Different Populations
Negroid
African
0
Indians
Other
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





Measurement of alcohol drinking
Personal susceptibility
Moderate drinking
Under-age drinking
Gene/environmental-environmental interaction
77
ALDH2 Deficiency Increases the Risk of AlcoholRelated 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 lowactivity 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.
78
Moderate Alcohol Drinking

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.

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
79
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.
80
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”.
81
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.
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





Measurement of alcohol drinking
Personal susceptibility
Moderate drinking
Under-age drinking
Gene/environmental-environmental interaction
85
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
86
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.
87
Current Issues of Alcohol and Cancer Research





Measurement of alcohol drinking
Personal susceptibility
Moderate drinking
Under-age drinking
Gene/environmental-environmental interaction
88
Conclusion
89
IARC evaluation
 Alcoholic beverages are carcinogenic to
humans– group 1 carcinogen (1988,
revision 2007).
90
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.
91
Questions?
92