Evidence Report/Technology Assessment 

Number 197 

Alcohol Consumption and Cancer Risk: 

Understanding Possible Causal Mechanisms 

for Breast and Colorectal Cancers 

Prepared for: 

Agency for Healthcare Research and Quality 

U.S. Department of Health and Human Services 

540 Gaither Road 

Rockville, MD 20850 

www.ahrq.gov 

Contract No. 290-2007-10063-I 

Prepared by: 

ECRI Institute Evidence-based Practice Center, Plymouth Meeting, PA 

Investigators 

Olu Oyesanmi, M.D., M.P.H.
 

David Snyder, Ph.D.
 

Nancy Sullivan, B.A.
 

James Reston, Ph.D., M.P.H.
 

Jonathan Treadwell, Ph.D.
 

Karen M. Schoelles, M.D., S.M., F.A.C.P.
 

AHRQ Publication No. 11-E003 

November 2010 
This report is based on research conducted by the ECRI Institute Evidence-based Practice 

Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), 

Rockville, MD (Contract No. 290-2007-10063-I). The findings and conclusions in this 

document are those of the author(s), who are responsible for its content, and do not 

necessarily represent the views of AHRQ. No statement in this report should be construed as 

an official position of AHRQ or of the U.S. Department of Health and Human Services. 

The information in this report is intended to help clinicians, employers, policymakers, and 

others make informed decisions about the provision of health care services. This report is 

intended as a reference and not as a substitute for clinical judgment. 

This report may be used, in whole or in part, as the basis for the development of clinical 

practice guidelines and other quality enhancement tools, or as a basis for reimbursement and 

coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of 

such derivative products may not be stated or implied. 
Suggested Citation 
 

This document is in the public domain and may be used and reprinted without permission except 

those copyrighted materials noted for which further reproduction is prohibited without the 

specific permission of copyright holders. 

Oyesanmi O, Snyder D, Sullivan N, Reston J, Treadwell J, Schoelles KM. Alcohol Consumption 

and Cancer Risk: Understanding Possible Causal Mechanisms for Breast and Colorectal Cancers. 

Evidence Report/Technology Assessment No. 197 (prepared by ECRI Institute Evidence-based 

Practice Center under Contract No. 290-2007-10063-I). AHRQ Publication No. 11-E003. 

Rockville, MD: Agency for Healthcare Resarch and Quality. November 2010. 

No investigators have any affiliations or financial involvement (e.g., employment, 

consultancies, honoraria, stock options, expert testimony, grants or patents received or 

pending, or royalties) that conflict with material presented in this report. 

ii 
 

Preface 

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based 

Practice Centers (EPCs), sponsors the development of evidence reports and technology 

assessments to assist public- and private-sector organizations in their efforts to improve the 

quality of health care in the United States. The Centers for Disease Control and Prevention 

(CDC) requested and funded this report. The reports and assessments provide organizations with 

comprehensive, science-based information on common, costly medical conditions and new 

health care technologies. The EPCs systematically review the relevant scientific literature on 

topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to 

developing their reports and assessments. 

To bring the broadest range of experts into the development of evidence reports and health 

technology assessments, AHRQ encourages the EPCs to form partnerships and enter into 

collaborations with other medical and research organizations. The EPCs work with these partner 

organizations to ensure that the evidence reports and technology assessments they produce will 

become building blocks for health care quality improvement projects throughout the Nation. The 

reports undergo peer review prior to their release. 

AHRQ expects that the EPC evidence reports and technology assessments will inform 

individual health plans, providers, and purchasers as well as the health care system as a whole by 

providing important information to help improve health care quality. 

We welcome comments on this evidence report. They may be sent by mail to the Task Order 

Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, 

Rockville, MD 20850, or by E-mail to epc@ahrq.gov. 

Carolyn M. Clancy, M.D. Jean Slutsky, P.A., M.S.P.H. 

Director Director, Center for Outcomes and Evidence 

Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality 

Thomas R. Frieden, M.D., M.P.H. Stephanie Chang, M.D., M.P.H. 

Director Director and Task Order Officer 

Centers for Disease Control and Prevention EPC Program 

Center for Outcomes and Evidence 

Agency for Healthcare Research and Quality 

Mary White Sc.D., M.P.H. 

Branch Chief, Epidemiology and Applied 

Research Branch 

Division of Cancer Prevention and Control 

Centers for Disease Control and Prevention 

iii 
 

 

 

Acknowledgments 

The Evidence-based Practice Center would like to thank Eileen Erinoff, MSLIS, and 

Helen Dunn for providing literature retrieval and documentation management support; 

Lydia Dharia and Kitty Donahue for their assistance with the final preparations of the report; 

Mary White, Sc.D., M.P.H., of the Centers for Disease Control and Prevention; and 

Stephanie Chang, M.D., M.P.H., of the Agency for Healthcare Research and Quality, for advice 

as our Task Order Officer. 

Technical Expert Panel 

Philip Brooks, Ph.D. 

Molecular Neurobiologist, Laboratory of Neurogenetics 

National Institute of Alcohol Abuse and Alcoholism 

Bethesda, MD 

Joanne Dorgan, M.P.H., Ph.D. 

Member, Division of Population Studies 

Fox Chase Cancer Center 

Philadelphia, PA 

Joel Mason, M.D. 

Scientist I and Director, Vitamins and Carcinogenesis Laboratory 

Jean Mayer USDA Human Nutrition Research Center on Aging 

Tufts University 

Boston, MA 

Mikko Salaspuro, M.D., Ph.D. 

Professor, Research Unit of Substance Abuse Medicine 

University of Helsinki 

Helsinki, Finland 

Helmut Seitz, M.D., Ph.D. 

Director, Department of Medicine 

Salem Medical Center and Laboratory of Alcohol Research 

Heidelberg, Germany 

AHRQ Contacts 

Stephanie Chang, M.D., M.P.H. 

Director and Task Order Officer 

Evidence-based Practice Center Program 

Agency for Healthcare Research and Quality 

Rockville, MD 

Karen Lohmann Siegel, P.T., M.A. 

CAPT, U.S. Public Health Service 

Associate Director 

Evidence-based Practice Center Program 

Agency for Healthcare Research and Quality 

Rockville, MD 

iv 
 

 

 

 

 

 

 

Structured Abstract 

Objectives: The purpose of this report is to systematically examine the possible causal 

mechanism(s) that may explain the association between alcohol (ethanol) consumption and the 

risk of developing breast and colorectal cancers. 

Data Sources: We searched 11 external databases, including PubMed and EMBASE, for studies 

on possible mechanisms. These searches used Medical Subject Headings and free text words to 

identify relevant evidence. 

Review Methods: Two reviewers independently screened search results, selected studies to be 

included, and reviewed each trial for inclusion. We manually examined the bibliographies of 

included studies, scanned the content of new issues of selected journals, and reviewed relevant 

gray literature for potential additional articles. 

Results: 

Breast Cancer. Five human and 15 animal studies identified in our searches point to a connection 

between alcohol intake and changes in important metabolic pathways that when altered may 

increase the risk of developing breast cancer. Alterations in blood hormone levels, especially 

elevated estrogen-related hormones, have been reported in humans. Several cell line studies 

suggest that the estrogen receptor pathways may be altered by ethanol. Increased estrogen levels 

may increase the risk of breast cancer through increases in cell proliferation and alterations in 

estrogen receptors. Human studies have also suggested a connection with prolactin and with 

biomarkers of oxidative stress. Of 15 animal studies, six reported increased mammary 

tumorigenesis (four administered a co-carcinogen and two did not). Other animal studies 

reported conversion of ethanol to acetaldehyde in mammary tissue as having a significant effect 

on the progression of tumor development. Fifteen cell line studies suggested the following 

mechanisms: 

increased hormonal receptor levels 

increased cell proliferation 

a direct stimulatory effect 

DNA adduct formation 

increase cyclic adenosine monophosphate (cAMP) 

change in potassium channels 

modulation of gene expression. 

Colorectal Cancer. One human tissue study, 19 animal studies (of which 12 administered a cocarcinogen and seven did not), and 10 cell line studies indicate that ethanol and acetaldehyde 

may alter metabolic pathways and cell structures that increase the risk of developing colon 

cancer. Exposure of human colonic biopsies to acetaldehyde suggests that acetaldehyde disrupts 

epithelial tight junctions. 

v 
 

 

 

Among 19 animal studies the mechanisms considered included: 

mucosal damage after ethanol consumption 

increased degradation of folate 

stimulation of rectal carcinogenesis 

increased cell proliferation 

increased effect of carcinogens. 

Ten cell line studies suggested: 

folate uptake modulation 

tumor necrosis factor modulation 

inflammation and cell death 

DNA adduct formation 

cell differentiation 

modulation of gene expression. 

One study used a combination of animal and cell line and suggested intestinal cell proliferation 

and disruption of cellular signals as possible mechanisms. 

Conclusions: Based on our systematic review of the literature, many potential mechanisms by 

which alcohol may influence the development of breast or colorectal cancers have been explored 

but the exact connection or connections remain unclear. The evidence points in several directions 

but the importance of any one mechanism is not apparent at this time. 

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Contents 

Executive Summary................................................................................................................................... 1
 

Evidence Report ....................................................................................................................................... 7
 

Chapter 1. Introduction.............................................................................................................................. 9
 

Scope ..................................................................................................................................................... 9
 

Ethanol Metabolism............................................................................................................................. 9
 

Alcohol and Cancer ........................................................................................................................... 10
 

Breast Cancer ..................................................................................................................................... 14
 

Colorectal Cancer .............................................................................................................................. 14
 

Chapter 2. Methods .................................................................................................................................. 15
 

Technical Expert Panel ..................................................................................................................... 15
 

Peer Review and Public Commentary ............................................................................................ 15
 

Key Questions .................................................................................................................................... 15
 

Analytical Framework....................................................................................................................... 16
 

Identification of Clinical Studies ..................................................................................................... 17
 

Electronic Database Searches .......................................................................................................... 17
 

Study Selection ................................................................................................................................. 18
 

Criteria for Inclusion/Exclusion of Studies in the Review.......................................................... 18
 

Literature Review Procedures .......................................................................................................... 18
 

Data Abstraction and Data Management........................................................................................ 19
 

Disposition of the Documents Identified by Literature Searches................................................ 19
 

Assessing the Evidence for Each Key Question............................................................................ 21
 

Assessment of Internal and External Validity .............................................................................. 21
 

Data Synthesis................................................................................................................................... 22
 

Assessment of Internal Validity of Breast and Colorectal Studies.................................................. 22
 

Assessment of External Validity of Breast and Colorectal Studies................................................. 23
 

Chapter 3. Results .................................................................................................................................... 25
 

Evidence Base Describing Possible Mechanisms Connecting Alcohol Consumption and 

Evidence Base for Describing Possible Mechanisms Connecting Alcohol Consumption 

Breast Cancer Risk ............................................................................................................................ 25
 

Human Studies .................................................................................................................................. 25
 

Animal Studies.................................................................................................................................. 26
 

Cell Line Studies............................................................................................................................... 27
 

and Colorectal Cancer Risk.............................................................................................................. 28
 

Human Studies .................................................................................................................................. 28
 

Animal Studies.................................................................................................................................. 28
 

Cell Line Studies............................................................................................................................... 29
 

Combination Study (Animal, Cell Line) ....................................................................................... 30
 

Systematic Reviews and Narrative Reviews of Epidemiology Studies...................................... 30
 

Reported Mechanisms in the Epidemiology Literature ................................................................ 41
 

Ongoing Clinical Trials..................................................................................................................... 43
 

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Chapter 4. Discussion .............................................................................................................................. 45
 

Breast Cancer ..................................................................................................................................... 45
 

Alcohol-related Changes in Circulating Hormones ..................................................................... 46
 

Cell Proliferation and Tumor Progression..................................................................................... 46
 

Polymorphism in Ethanol Metabolism .......................................................................................... 46
 

DNA Adduct Formation .................................................................................................................. 46
 

Other Potential Mechanisms ........................................................................................................... 47
 

Colorectal Cancer .............................................................................................................................. 49
 

Excluded Studies................................................................................................................................ 53
 

Future Research Goals ...................................................................................................................... 53
 

Conclusions ........................................................................................................................................ 53
 

Limitations.......................................................................................................................................... 56
 

References and Included Studies ..................................................................................................... 59
 

List of Acronyms/Abbreviations ..................................................................................................... 81
 

Figures 

Figure 1. Three stages of carcinogenesis ................................................................................... 12
 

Figure 2. Analytical framework for breast cancer ..................................................................... 16
 

Figure 3. Analytical framework for colorectal cancer ............................................................... 17
 

Figure 4. Disposition of the documents identified by literature searches.................................. 20
 

Tables 

Table 1. Systematic reviews/meta-analyses for breast cancer epidemiology studies .......... 31-35
 

Table 2. Systematic reviews/meta-analyses for colorectal cancer epidemiology studies.... 36-40
 

Table 3. Breast cancer epidemiology studies............................................................................ 41
 

Table 4. Colorectal cancer epidemiology studies ..................................................................... 41
 

Table 5. Hypothesis-generating breast cancer studies .............................................................. 42
 

Table 6. Hypothesis-generating colorectal cancer studies ........................................................ 43
 

Table 7. Overall results from human breast cancer studies ...................................................... 48
 

Table 8. Overall results from animal breast cancer studies ...................................................... 49
 

Table 9. Overall results from human colorectal cancer study................................................... 51
 

Table 10. Overall results from animal colorectal cancer studies ................................................ 52
 

Table 11. Reported mechanisms in human breast cancer studies............................................... 54
 

Table 12. Reported mechanisms in animal breast cancer studies............................................... 54
 

Table 13. Reported mechanisms in cell line breast cancer studies ............................................. 55
 

Table 14. Reported mechanisms in human colorectal cancer study ........................................... 56
 

Table 15. Reported mechanisms in animal colorectal cancer studies......................................... 56
 

Table 16. Reported mechanisms in cell line colorectal cancer studies....................................... 56
 

Table 17. Reported mechanisms in combination (animal, cell lines) colorectal cancer study ... 56
 

viii 
Appendixes 

Appendix A: Exact Search Strings 

Appendix B: Sample Data Abstraction Forms 

Appendix C: Evidence tables 

Appendix D: List of Excluded Studies 

Appendix E: Peer Reviewers 

Appendixes and Evidence Tables for this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/alccan/alccan.pdf. 

ix 
 

 

 

 

 

 

 

Executive Summary 

Alcohol Consumption and Cancer Risk: 

Understanding Possible Mechanisms for Breast 

and Colorectal Cancers 

The purpose of our assessment of alcohol and cancer induction is to explore the possible 

underlying causal mechanism(s) of the association between alcohol consumption and breast and 

colorectal cancers. Therefore, we developed four Key Questions that address the potential 

mechanism(s) by which alcohol might be involved in the development of breast and colorectal 

cancers. The primary evidence base to address these questions consisted of experimental studies 

of humans, animals, and cell lines where alcohol exposure could be controlled. In addition to this 

evidence base we also considered epidemiology studies where alcohol exposure was not 

controlled (including those in patients with or without cancer) and hypothesis-generating studies 

that examined potential metabolic pathways connecting alcohol to cancer risk. These studies 

were considered in a separate evidence base that did not directly address the Key Questions. 

Methods 

The following Key Questions will be addressed in this report: 

1.	 What are the likely causal mechanisms by which alcohol contributes to the development of 

breast cancer? Which of the possible mechanisms (e.g., induction of P450 cytochromes and 

carcinogen metabolism, effects on blood hormone concentrations, effect of acetaldehyde or 

other alcohol metabolite on apoptosis and DNA repair, interactive effects on other 

nutritional factors, or others) are likely to be most important in breast cancer development? 

2.	 For the most likely mechanisms of action involving alcohol and the development of breast 

cancer, how might other factors modify the effect of alcohol on breast cancer (for example, 

age, latency of effect, intensity, duration, and recency of exposure, presence of cocarcinogens, presence of threshold effect)? Do the causal mechanisms vary by cell type or 

other tumor characteristics? 

3.	 What are the likely causal mechanisms by which alcohol contributes to the development of 

colorectal cancer? Which of the possible mechanisms (e.g., induction of P450 cytochromes 

and carcinogen metabolism, effects on blood hormone concentrations, effect of acetaldehyde 

or other alcohol metabolite on apoptosis and DNA repair, interactive effects on other 

nutritional factors, or others) are likely to be most important in colorectal cancer 

development? 

4.	 For the most likely mechanisms of action involving alcohol and the development of 

colorectal cancer, how might other factors modify the effect of alcohol on colorectal cancer 

(for example, age, latency of effect, intensity, duration, and recency of exposure, presence of 

co-carcinogens, presence of threshold effect)? Do the causal mechanisms vary by cell type 

or other tumor characteristics? 

To address these Key Questions we searched electronic databases for information on ethanol 

consumption and the possible risks for breast and colorectal cancers. Thirty-five breast cancer 

1
 
 

 

 

 

 

 

 

 

studies (five in humans, 15 in animals, and 15 in cell lines) and 31 colorectal cancer studies (one 

in humans, 19 in animals, 10 in cell lines, and one combination [animal and cell lines]) were 

included in the report. Information on study design and conduct was used to judge individual 

study internal validity. Data on experimental model, mechanism(s) examined, amount and 

duration of ethanol exposure, cancer formation, and intermediate outcomes were abstracted and 

tabled for review and discussion. 

Evidence for Alcohol Consumption and Cancer Risk: 

Understanding Possible Mechanisms for Breast and 

Colorectal Cancers
 

Breast Cancer Studies 

Human studies. We included five studies to evaluate the possible mechanisms for alcohol 

consumption and breast cancer risk: the first study examined effects of alcohol on estradiol, 

estrone, estrone sulfate, testosterone, androstenedione, progesterone, dehydroepiandrosterone 

(DHEA), DHEA sulfate (DHEAS), and androstenediol; the second study examined the effects of 

alcohol on plasma and urinary hormone concentrations in premenopausal women; a third study 

examined the effect of alcohol on prolactin levels in menopausal women using estradiol 

replacement; a fourth study examined the effects of alcohol on estrogen levels in postmenopausal 

women; and a fifth study examined the relationship of alcohol consumption with antioxidant 

nutrients and biomarkers of oxidative stress. Although none of these five studies reported direct 

evidence of cancer, we included them given that alcohol was administered to assess possible 

hormonal mechanism(s) and biomarkers of oxidative stress. 

Animal studies. We included 15 studies using animal models to evaluate the possible mechanisms 

for alcohol consumption and breast cancer risk. Outcomes measured varied across studies. Of the 15 

included studies, 14 reported on the type of mechanism(s) examined and one did not. The type of 

mechanisms examined in the 14 studies included elevated levels of estrogen and or progesterone, 

biotransformation to acetaldehyde, formation of deoxyribonucleic acid (DNA) adducts, elevation of 

serum prolactin, suppression of cellular immunity, enhancement of rate of tumor progression, and effect 

on DNA synthesis. Administration and duration of ethanol exposure varied across all studies. Studies also 

varied on whether a carcinogen was administered to induce carcinogenesis. Of the 15 studies, 10 reported 

the use of a carcinogen to induce cancer: 

dimethylene (a) anthracene [DMBA] (five studies) 

N-methyl-N-nitrosurea [MNU] (two studies) 

N-nitrosodimethylamine [NMDA] and 4-methylnitrosoamino-1-3-pyridyl-1-butanone 

[NNK] (one study) 

MADB106 [one study] 

bittner virus [one study]. 

Cell line studies. We included 15 studies using cell lines to evaluate the possible 

mechanisms for alcohol consumption and breast cancer risk. Twelve studies administered 

ethanol alone, and two studies administered ethanol combined with acetaldehyde. Cell lines 

examined in the studies included: 

MCF-7 (six studies) 

2
 
 

 

 

 

 

 

 

 

MCF-10F (two studies)
 

T4TD (one study)
 

MM46 tumor cells (one study)
 

MCF-7 + T47D (one study)
 

MCF-7 + T84 (one study)
 

MDA-MB-453 (one study)
 

MCF-7 + T47D + MDA-MB-231 (one study)
 

MCF-7 +ZR75.1 + BT-20 + MDA-MB-231 (one study). 

Various mechanisms were reported by these studies: hormonal-related, DNA-adduct 

formation, inflammation and cell death, cell differentiation, increase cyclic adenosine 

monophosphate (cAMP), change in potassium channels, and modulation of gene expression. 

Colorectal cancer studies. 

Human study. We included one study using human tissues to evaluate the possible 

mechanism for alcohol consumption and colorectal cancer risk. The study exposed colonic 

mucosa to acetaldehyde vapor. Although the study did not report direct evidence to show 

causation of cancer, the authors concluded that acetaldehyde may cause an increase in risk of 

colon cancer via loss of cell-cell adhesion. 

Animal studies. We included 19 studies using animal models to evaluate the possible 

mechanisms for alcohol consumption and colorectal cancer risk. Outcomes varied across all 

studies. Of the 19 included studies, 17 reported on the type of mechanism(s) examined and two 

did not. The type of mechanisms examined in the 17 studies included: 

cytochrome system expression 

generation of acetaldehyde 

DNA methylation 

effect of folate metabolism 

cell proliferation 

formation of acetaldehyde by human colonic bacteria 

local mucosal effect 

effect on various phases of carcinogenesis. 

Administration and duration of ethanol exposure varied across all animal studies. Studies 

also varied on whether a carcinogen was administered to induce carcinogenesis. Of the 19 

studies, 12 reported the use of a carcinogen to induce cancer: 

1,1-dimethylhydrazine (DMH) (six studies) 

methylazoxymethanol (MAM) acetate (one study) 

acetoxymethyl-methylnitrosamine (AMMN) (one study) 

AMMN + cyanamide (CY) (one study) 

azoxymethane (AOM) (three studies). 

3
 
 

 

 

 

 

 

 

 

Cell line studies. We included 10 studies using cell lines to evaluate the possible 

mechanisms for alcohol consumption and colorectal cancer risk. Cell lines examined in the 

studies included: 

Caco-2 (six studies)
 

HT-29 (one study)
 

colonic mucosa cells (one study)
 

Caco-2 + HT-29 (one study)
 

HT-29 + SW-1116 + HCT-15 (one study). 

Various mechanisms were reported by these studies: 

folate uptake modulation 

tumor necrosis factor modulation 

inflammation and cell death 

formation of crosslinks with DNA 

cell differentiation 

modulation of gene expression. 

Amount and duration of ethanol and/or acetaldehyde varied across all studies. Seven studies 

administered ethanol alone, while three studies administered ethanol combined with 

acetaldehyde. 

Combination study (animal, cell line).We included one study that used a combination of 

animal (mice) and cell line (Caco-2) to evaluate the possible mechanisms for alcohol 

consumption and colorectal cancer risk. Intestinal cell proliferation as a result of 

phosphatidylethanol accumulation was the examined mechanism. The animal study administered 

ethanol, and the cell line study administered either ethanol or acetaldehyde. The primary 

outcome reported was disruption of cellular signals. 

Discussion 

The relationship between alcohol consumption and the risk of breast and colorectal cancers 

has been assessed in several systematic reviews and epidemiology studies (cohort and casecontrol studies). In this report, we looked at the potential mechanism(s) connecting both breast 

and colorectal cancers with alcohol consumption, under the assumption that there is a causal 

relationship. Our report did not focus on such a causal relationship reported in epidemiology 

literature where alcohol consumption was not under experimental control, but rather on potential 

mechanism(s) in studies that administered either alcohol or acetaldehyde in the absence of 

cancer. Only the human studies that actually administered ethanol regardless of experimental 

model were abstracted and included in the primary evidence base to assess possible 

mechanism(s). In addition, given that acetaldehyde is a metabolite of ethanol, we included 

animal studies that administered either alcohol and/or acetaldehyde in our evidence base. In 

humans, acetaldehyde levels in the blood are either very low or undetectable following alcohol 

consumption. Epidemiology studies that administered survey questionnaires to assess alcohol 

consumption and cancer risk and hypothesis-generating studies that examined potential pathways 

connecting alcohol to cancer risk were included as a separate evidence base. 

The majority of the animal studies that chemically induced tumors through the administration 

of both alcohol and a carcinogen reported an increase in the carcinogenic effect; however, 

these studies can only offer indirect evidence of a connection between alcohol consumption and 

4
 
 

 

 

 

 

 

increased cancer risk in humans. Most of these studies varied in terms of quantity of ethanol and 

timing of administration relative to the carcinogen that was used in the study to induce 

carcinogenesis. Though some of the possible mechanisms identified in this report have been 

evaluated in a variety of experimental models (i.e., human, animals, cell lines), others have 

simply been examined as hypothesis generating and as such may call for future research. 

Breast cancer. Both human and animal studies included in our primary evidence base point 

to a connection between alcohol intake and changes in blood hormone levels, especially elevated 

levels of estrogen and androgens in humans. Several cell line studies also suggest that estrogen 

receptor pathways may be altered by ethanol. Increased estrogen levels may increase the risk of 

breast cancer through increases in cell proliferation and alterations in estrogen receptors. 

Elevation in prolactin levels were also examined in human and animal studies. While not as 

extensive as the estrogen-related studies, these studies give some indication that alcohol 

consumption may alter prolactin levels and increase the risk of developing breast cancer. In order 

to report the role of oxidative stress in breast cancer, one human study measured changes in the 

levels of serum biomarkers. 

The formation of acetaldehyde after ethanol consumption and its involvement in breast 

cancer has been examined in human epidemiology studies of enzyme polymorphism. 

Polymorphism in the enzymes that metabolize ethanol may increase an individual’s exposure to 

toxic metabolites such as acetaldehyde and influence cancer risk if acetaldehyde is involved in 

breast cancer development. In animal studies, conversion of ethanol to acetaldehyde in mammary 

tissue has been reported to have a significant effect on the progression of tumor development. 

Events downstream from acetaldehyde are likely being altered by the presence of acetaldehyde 

and may lead to enhanced tumor development. 

Enhancement of cell proliferation and tumor progression related to ethanol consumption and 

conversion to acetaldehyde were examined in animal and cell line studies. The findings of these 

studies suggest that alterations in cell proliferation due to alcohol exposure may be a possible 

mechanism increasing breast cancer risk. 

Colorectal cancer. One human study reported that acetaldehyde disrupts epithelial tight 

junctions and cell adhesion. Several animal studies also looked at the effects of acetaldehyde in 

the colon and reported the following: mucosal damage after ethanol consumption, increased 

degradation of folate, stimulation of rectal carcinogenesis, and an increased effect of carcinogens 

in the presence of acetaldehyde. In cell line studies, acetaldehyde exposure was reported to 

influence the initial steps of colonic carcinogenesis and later tumor development and decrease 

the activity of some brush border enzymes. Finally, a study using human tissue, animal tissue, 

and a cell line found evidence that acetaldehyde stimulates cell proliferation in intestinal crypt 

cells and therefore acetaldehyde may act as a cocarcinogen in the colon. These studies (human, 

animal, and cell line) combine to suggest that acetaldehyde production in the colon may provide 

a potential causal mechanism by which alcohol contributes to the development of colon cancer. 

An effect of ethanol consumption on cell proliferation in the colon was investigated in a 

combination study (animal and cell line). In this study, chronic alcohol exposure resulted in 

disruption of signals that normally restrict proliferation in highly confluent intestinal cells, 

thereby facilitating abnormal intestinal proliferation. Several animal studies reported enhanced 

growth of mucosal tissue after chronic ethanol consumption. Cell studies indicate that exposure 

to ethanol and acetaldehyde increases cell proliferation and damages DNA which may contribute 

to cancer development. Together these studies suggest that ethanol and acetaldehyde exposure in 

5
 
 

 

the colorectal mucosa may increase cell proliferation and be a potential mechanism connecting 

alcohol consumption to colorectal cancer risk. 

Conclusions 

Based on our systematic review of the literature, many potential mechanisms by which 

alcohol may influence the development of breast or colorectal cancers have been explored but 

the exact connection or connections remain unclear. The evidence points in several directions but 

the importance of any one mechanism is not apparent at this time. Several mechanisms have 

been proposed and human, animal, and cell line studies have provided evidence in support of 

several mechanisms, but the findings have been inconsistent. The diversity of experimental 

protocols among the studies included in this report could have contributed to the lack of 

consistency. Furthermore, variation across included studies for both the route of administration 

and amount of ethanol may have influenced results. Based on animal studies alone, researchers 

may be inclined to infer a causal link between alcohol and the risk of breast or colorectal cancers. 

In addition, although a majority of the epidemiology studies reported that alcohol increased the 

risk of both breast and colorectal cancers, we cannot discount uncontrolled confounding by diet 

and related lifestyles. 

6
 
 Evidence Report
 

7
 

 

 

 

 

 

 

 

 

Chapter 1. Introduction 

Scope 

The purpose of this report is to systematically and objectively synthesize evidence from the 

basic science literature to clarify the possible causal mechanisms by which alcohol may 

contribute to cancer risk, focusing on the induction and development of breast cancer and 

colorectal cancer under the assumption that there is a causal relationship. Therefore, the primary 

evidence base for this report consists of studies that administer ethanol or acetaldehyde to 

humans, animals, tissues, or cells and then look for the development of breast or colorectal 

cancer, or for changes in metabolic pathways and cellular structures that may increase the risk 

for developing these cancers. Case-control and other epidemiology studies are not included in the 

primary evidence base for assessment of possible mechanisms. However, such studies may 

provide insight into the dose/response relationship between alcohol consumption and cancer risk. 

Apart from alcohol (i.e., ethanol) and water, the exact composition of most alcoholic 

beverages (e.g., beer, wine, or distilled spirits) on the market remains confidential proprietary 

information.1 Therefore, the scope of this report is limited to ethanol. Other compounds (or 

contaminants) found in various alcoholic beverages that may play a role in the development of 

breast and colorectal cancers are outside the scope of this report. These compounds include 

nitrosamines, aflatoxins, polyphenols, ethyl carbamate (urethane), asbestos, and arsenic 

compounds.1-4 

In addition, studies that evaluated tumor progression or metastatic spread of either breast or 

colorectal cancer during alcohol consumption are outside the scope of this report because they 

are not examining the mechanisms underlying the association of alcohol and the risk of 

developing cancer. 

Ethanol Metabolism 

Orally-ingested ethanol from an alcoholic drink is rapidly and almost completely absorbed by 

the stomach, small intestines, and colon. The bioavailability of ethanol, the fraction of the 

ingested dose that reaches the systemic circulation, is about 80%.5 Therefore a large portion of 

ingested ethanol reaches the circulation (i.e., blood alcohol concentration) and is distributed to all 

body tissues including the breast, colon, and rectum. Blood alcohol concentration, however, may 

vary depending on the rate of gastric emptying and degree of metabolism during this first pass 

via the stomach and liver (i.e., first-pass metabolism of ethanol).6-8 

Ethanol is metabolized in the body by two pathways (i.e., oxidative and nonoxidative).8 

However, the nonoxidative pathway is minimal compared to the oxidative pathway.8 The liver 

is the major organ for the oxidative metabolism of ethanol.9,10 Ethanol is converted into 

acetaldehyde by cytosolic alcohol dehydrogenase (ADH).9-11 Due to variation in gene encoding 

there are multiple isoenzymes of ADH that vary in their enzyme activity (ADH1A, ADH1B*1, 

2,3,9,11-17 ADH1B*2, ADH1B*3, ADH1C*1, ADH1C*2, ADH4, ADH5, ADH6, and ADH7).

The ADH1B*2 is lower in frequency amongst Caucasians and higher among Asians and is about 

40 times more active compared to the ADH1B*1 in the conversion of ethanol to acetaldehyde.18 

ADH1C*1 is very common in Asians, and metabolizes ethanol 2.5 times faster compared to 

18,19 ADH1C*2. Among individuals who consume alcohol, ADH1C*1, a fast-acting metabolizer 

9
 
 

 

 

 

 

 

 

 

 

 

of ethanol, results in accumulation of acetaldehyde. As a result of increased levels of 

acetaldehyde, these individuals may experience uncomfortable side effects, and may well have a 

18,19 tendency to consume less alcohol. The genetic polymorphism of ADH leads to differences in 

individual ethanol metabolism and individual differences in the susceptibility to alcohol-related 

tissue damage.8,18 

Acetaldehyde, a metabolite of ethanol, is further metabolized to acetate primarily by 

mitochondrial aldehyde dehydrogenase (ALDH2).9,11 ALDH2 accounts for the greater part of 

acetaldehyde breakdown and exists as ALDH2*1 and ALDH2*2. Individuals with ALDH2*2 

have blood acetaldehyde levels 20 times higher compared to those with ALDH2*1.18 

Acetaldehyde is a highly toxic metabolite that binds to many cellular proteins and may be 

responsible for damage in the liver as well as other body tissues.8 It binds to deoxyribonucleic 

acid (DNA), resulting in the formation of a DNA adduct which may influence cancer 

development.3,11 Presence of a DNA adduct is a sign of exposure to specific cancer-causing 

3,11,13 agent, and is indicative of growing damage to the DNA. Acetaldehyde is a cancer-causing 

agent in animals.14 

During each oxidative process, nicotinamide adenine dinucleotide (NAD+) is reduced to 

NADH. In the liver, ethanol metabolism also involves microsomal cytochromes P450 2E1 

(CYP2E1).11 This pathway produces reactive oxygen species (ROS) such as superoxide anions 

2,8,11 and hydroxyl radicals which may increase the risk of tissue damage.

Nonoxidative metabolism of alcohol involves two pathways.8 One pathway results in the 

formation of fatty acid ethyl esters and the other the formation of phosphatidyl ethanol.8,9 

ADH is present in the human colonic mucosa as well as in the microflora inhabiting the 

20,21 colon, and ethanol is metabolized to acetaldehyde by ADH in both of these locations.

ADH activity is significantly higher in the mucosa of the rectum than the colon.21 Aldehyde 

dehydrogenase activity is much greater in the liver than in the colonic mucosa, which favors the 

20 10 accumulation of acetaldehyde in the colon. Breast tissue contains ADH and CYP2E1. Breast 

tissue converts ethanol to acetaldehyde which is then metabolized to acetate by xanthine 

oxidoreductase. 

Alcohol and Cancer 

Fewer than 10% of cancers can be attributed to an inherited genetic abnormality.22 The 

majority of cancers are the result of changes in the gene structure due to the loss of control 

mechanisms that prevent cancer development.22 Control mechanisms that may be altered during 

cancer development are: 1) tumor suppressor genes that lose their function causing a disruption 

in cellular adhesion and abnormal cell cycle progression, 2) DNA repair enzymes that become 

nonfunctional due to distorted methylation, and 3) proto-oncogenes that mutate into oncogenes.22 

The course by which normal cells are transformed into cancer cells is termed carcinogenesis 

(see Figure 1).3,14 When administered in combination with a recognized carcinogen, ethanol or 

its metabolite (acetaldehyde) produces reactive oxygen species (ROS).10 ROS may increase the 

transformation of normal cells into cancerous cells in various organs by inhibition of DNA 

3,10,14,23,24 methylation as well as by interacting with metabolism of retinoids. Alcohol and its 

metabolites have been implicated in all three stages of cancer formation (see the asterisks in 

3,9,11,13,14,24,25 Figure 1): 

10
 
 

 

initiation stage by impact on DNA repair 

promotion stage by altered gene expression, enhanced cell division, suppression of 

immune response, and change in metabolism of vitamin A 

progression stage by expression of oncogenes, exchange of DNA between chromosomes, 

and additional mutations. 

11
 
Figure 1. Three stages of carcinogenesis 

Microsomal enzymes Normal cellDamaged cell

Preinitiated cell

Initiated cell

Benign tumor cell

Cancer cell

*Detoxification of 

reactive molecules

*Altered gene expression

*Vitamin A metabolism

*Suppressed immune response

*Enhanced cell division

*Exchange of DNA 

 between chromosomes

*Expression of oncogenes

*Additional mutations

Carcinogen *Formation of reactive molecules

*Formation of DNA adducts *Repair of 

DNA 

damage

Cell division INITIATION

PROMOTION

PROGRESSION

*Source from http://www.niaaa.nih.gov/resources/graphicsgallery/immunesystem/lieb.htm26 

12
 
 

 

 

 

 

 

 

 

 

 

 

Alcohol consumption is highly prevalent in the general U.S. population. The 2008 prevalence 

and trends data from the Behavioral Risk Factor Surveillance System indicate that about 54% of 

U.S. adults consumed alcohol within the past 30 days.27 Though moderate alcohol consumption 

may have some potential health benefits, alcohol consumption has been identified as one of the 

major worldwide risks for burden of disease.28 In the U.S., a standard drink is 12 fl oz (beer), 

29-32 8 fl oz of malt liquor, 5 fl oz (wine), and 1.5 fl oz (80% proof distilled spirit). Each is 

29-32 equivalent to 0.6 fluid ounces (12-14 g) of ethanol. Moderate daily alcohol consumption in 

29-32 the U.S. for men is two drinks and for women is one drink. However, variations have been 

reported worldwide in the definition of what is moderate for men and women.29 

Several epidemiology studies have reported moderate to strong associations between the 

level of alcohol consumption and the incidence of cancers of the mouth, pharynx, larynx, 

2,24,33-35 esophagus, and liver. Although the association between alcohol and breast and colorectal 

cancer is comparatively less strong than the association with these other cancers, given the high 

prevalence and incidence of breast and colorectal cancer, reducing the effect of any contributing 

3,24,33,34,36-41 factor may have a large overall impact on cancer incidence and prevalence. Observed 

associations of alcohol consumption and cancer, however, can be confounded by other risk 

factors for cancer, such as age, smoking, family history, obesity and physical activity, race or 

14,36,42-44 ethnicity, and nutrition. Because of the high prevalence of alcohol consumption, 

exploring the potential underlying mechanism(s) of the association between alcohol consumption 

and breast and colorectal cancers, if any, is essential in developing primary preventive measures. 

In view of the fact that alcohol consumption is a modifiable behavior,45 recommending and 

promoting changes in behavior and appropriate preventive interventions may help reduce cancer 

risks in the general population. 

Breast Cancer 

According to the US National Cancer Institute (NCI), breast cancer is the most common 

cancer among women. 46 In 2009, it was anticipated that of the 192,370 women who were 

diagnosed, 40,170 would die of breast cancer.46 Risk factors include family history, age at first 

birth, obesity in post menopausal women, dietary factors, alcohol consumption, early menarche, 

18,46 hormonal replacement therapy, low-dose irradiation, and lactation. Estrogen-induced breast 

cancer may result from cell proliferation, activation of cytochrome P450, and DNA damage.10 

Cell proliferation is significant in the maintenance of normal and healthy breast tissue and these 

risk factors may alter cell proliferation in a direction that favors cancer development. 

Furthermore, enzyme polymorphism affects alcohol metabolism and could influence the effect of 

alcohol consumption on hormonal levels, thereby resulting in an increased risk of breast 

47-50 cancer. Among patients diagnosed with breast cancer, unregulated breast epithelial cell 

growth has been reported.51 Alcohol consumption has been investigated as a risk factor in the 

development of breast cancer. In a 2006 meta-analysis of 98 studies of alcohol and breast cancer, 

Key et al. reported that each additional 10 g ethanol/day resulted in a 10% increase in the odds 

ratio (OR) of risk of breast cancer associated with alcohol consumption.52 

13
 
 

 

 

Colorectal Cancer 

Of the estimated 75,590 men and 71,380 women diagnosed with colorectal cancer, 

49,920 men and women were expected to die of the disease in 2009.53 Among adults with 

cancer, colorectal cancer is the second most common cause of death.54 Risk factors 

13,14,53-58 include:

age 

smoking 

low fiber diet 

high red meat/low fish intake 

inadequate intake of folate, B6 and retinoids 

obesity 

lack of physical activity 

low calcium intake 

alcohol (heavy consumption) 

an increase in colonic acetaldehyde level concentration 

chronic ulcerative colitis 

granulomatous colitis 

adenomatous polyps 

In addition, following alcohol consumption, intracolonic ethanol is metabolized by colonic 

mucosal cells and intracolonic microbes. The risks of colorectal cancer development associated 

with alcohol consumption have been examined in epidemiology studies. In a 2004 meta-analysis 

of eight studies, Cho et al. reported that daily consumption of more than 45 g of alcohol 

increased the risk of colorectal cancer by 45%.36 In addition, Homann et al. in a 2009 study 

reported that individuals with ADH1C1*1 homozygosity and consumption of more than 30 g of 

alcohol per day have significant increase risk of colorectal cancer.19 

14
 
 

 

 

 

 

Chapter 2. Methods 

Technical Expert Panel 

ECRI Institute, in consultation with AHRQ, recruited a technical expert panel (TEP) to give 

input on key steps including the selection and refinement of the questions to be examined. Broad 

expertise and perspectives were sought. Divergent and conflicted opinions are common and 

perceived as healthy scientific discourse that results in a thoughtful, relevant systematic review. 

Therefore, in the end, study questions, design and/or methodologic approaches do not necessarily 

represent the views of individual technical and content experts. The expert panel membership is 

provided in the front matter of this report. 

ECRI Institute created a protocol for developing the evidence report. The process consisted 

of working with AHRQ and the TEP to outline the report’s objectives and to finalize Key 

Questions for the review. These Key Questions are presented in the Scope and Key Questions 

section of the Introduction. Upon AHRQ approval, the draft protocol was posted on the AHRQ 

Web site at http://www.ahrq.gov/clinic/tp/alccantp.htm. 

Peer Review and Public Commentary 

A draft of the completed report was sent to the peer reviewers and the representatives of 

AHRQ. In response to the comments of the peer reviewers, revisions were made to the evidence 

report, and a summary of the comments and their disposition was submitted to AHRQ. Peer 

reviewer comments on a preliminary draft of this report were considered by the EPC in 

preparation of this final report. Synthesis of the scientific literature presented here does not 

necessarily represent the views of individual reviewers. 

Key Questions 

The purpose of our assessment of the basic science literature concerning alcohol and cancer 

induction is not to determine the extent to which alcohol is a risk factor for breast and colorectal 

cancers, but instead to explore the evidence suggesting possible underlying causal mechanism(s) 

of the association between alcohol consumption and breast and colorectal cancers (see broken 

arrows from alcohol to cancer induction in Figure 2 and Figure 3). Therefore, we developed four 

Key Questions that address the potential mechanism(s) by which alcohol might be involved in 

the development of breast and colorectal cancers. 

Key Question 1. What are the likely causal mechanisms by which alcohol contributes to the 

development of breast cancer? Which of the possible mechanisms (e.g., induction of P450 

cytochromes and carcinogen metabolism, effects on blood hormone concentrations, effect of 

acetaldehyde or other alcohol metabolite on apoptosis and DNA repair, interactive effects on 

other nutritional factors, or others) are likely to be most important in breast cancer 

development? 

Key Question 2. For the most likely mechanisms of action involving alcohol and the 

development of breast cancer, how might other factors modify the effect of alcohol on breast 

cancer (for example, age, latency of effect, intensity, duration, and recency of exposure, presence 

of co-carcinogens, presence of threshold effect)? Do the causal mechanisms vary by cell type or 

other tumor characteristics? 

15
 
Key Question 3. What are the likely causal mechanisms by which alcohol contributes to the 

development of colorectal cancer? Which of the possible mechanisms (e.g., induction of P450 

cytochromes and carcinogen metabolism, effects on blood hormone concentrations, effect of 

acetaldehyde or other alcohol metabolite on apoptosis and DNA repair, interactive effects on 

other nutritional factors, or others) are likely to be most important in colorectal cancer 

development? 

Key Question 4. For the most likely mechanisms of action involving alcohol and the 

development of colorectal cancer, how might other factors modify the effect of alcohol on 

colorectal cancer (for example, age, latency of effect, intensity, duration, and recency of 

exposure, presence of co-carcinogens, presence of threshold effect)? Do the causal mechanisms 

vary by cell type or other tumor characteristics? 

Analytical Framework 

Figure 2 for breast and Figure 3 colorectal cancer portray analytical framework that visually 

describe the potential links in a chain of evidence that connect alcohol to breast and colorectal 

cancers. Contained within the framework are the Key Questions being addressed by this report 

and the potential areas of study (humans, animals, tissues, cells, ethanol and its metabolites) that 

can be manipulated to examine the assumed connection between alcohol consumption and an 

increased risk of developing breast or colorectal cancer. 

Figure 2. Analytical framework for breast cancer 

Human or Animal 

Isolated Organs and Cells Alcohol Alcohol 

metabolites

Other risk 

factors Cancer induction, 

promotion or 

progression Whole 

Human or 

Whole 

Animal

Cell lines

Breast 

Cancer KQ 1 

KQ 2 

KQ: Key Question

KQ 1: effect of alcohol on stages of carcinogenesis 

KQ 2: effect of alcohol and other risk factors on stages of carcinogenesis 

16
 
Figure 3. Analytical framework for colorectal cancer 

Human or Animal 

Isolated Organs and Cells Alcohol Alcohol 

metabolites

Other risk 

factors Cancer induction, 

promotion or 

progression Whole 

Human or 

Whole 

Animal

Cell lines

KQ 3 

KQ 4 

KQ: Key Question

Colorectal 

Cancer

KQ 3: effect of alcohol on stages of carcinogenesis 

KQ 4: effect of alcohol and other risk factors on stages of carcinogenesis 

Identification of Clinical Studies 

The studies included in the primary evidence base for this technology assessment were 

identified using a multi-staged study selection process, and were based on inclusion criteria that 

were determined a priori, after the creation of the Key Questions and before any detailed 

examination of the literature base. Use of a priori inclusion criteria reduces the risk of bias 

because the decision to include or exclude each study is independent of the results of the study. 

In the first stage of the selection process, we performed a comprehensive literature search using 

broad criteria. In the second stage, we retrieved all articles that appeared to meet the a priori 

inclusion criteria, based on their published abstracts. In the final stage of the study selection, we 

reviewed the full text of each retrieved article, assessed its internal validity, and verified whether 

or not it met the a priori inclusion criteria. 

Electronic Database Searches 

We searched 11 external databases, including PubMed and EMBASE, for studies on possible 

mechanisms of alcohol and breast and colorectal cancer development (i.e., initiation, promotion, 

and progression) to identify evidence relevant to the Key Questions 1-4 using Medical Subject 

Headings and free text words. Additionally, we used some of the search terms and sources that 

were suggested by the Technical Expert Panel members on October 28, 2009. Two reviewers in 

the investigative team independently screened search results, selected studies to be included and 

reviewed each trial for inclusion. To supplement the electronic searches, we manually examined 

the bibliographies of included studies, scanned the content of new issues of selected journals, and 

reviewed relevant gray literature for potential additional articles. Gray literature includes reports 

and studies produced by local government agencies, private organizations, educational facilities, 

and corporations that do not appear in the peer-reviewed literature. Although we examined gray 

literature sources to identify relevant information, we only consider published, peer-reviewed 

literature in this report. During the peer review process, any new studies or data recommended 

17
 
 

 

 

 

 

 

 

were subjected to the same inclusion and exclusion criteria. A complete list of the databases 

searched and the search strategy used to identify relevant studies are presented in Appendix A. 

Study Selection 

Use of explicit inclusion criteria, decided upon before any data have been extracted from 

studies, is a vital tool in preventing reviewer biases. Some of the a priori criteria are based on 

study design, and other criteria ensure that the evidence is not derived from unusual patients or 

interventions, and/or outmoded technologies. We developed the same inclusion criteria for each 

Key Question that this report addresses. 

Criteria for Inclusion/Exclusion of Studies in the Review 

We used the following formal criteria to determine which studies were included in the 

primary evidence base that addresses each Key Question. These studies are primarily 

experimental studies where the exposure to ethanol or acetaldehyde could be controlled and 

precise biochemical measurements could be made. 

1.	 Any study, regardless of design, that provides data on the possible causal mechanism(s) 

of any association between alcohol consumption and the development of breast and 

colorectal cancers in any population setting, including humans, animals, and in vitro 

experimental studies. 

2.	 In order to assess the outcome measure of carcinogenesis, there must be no breast or 

colorectal cancer present in human and animal studies prior to the start of the study. 

3.	 Cell lines should be appropriate to the study of breast and colorectal cancers in humans. 

4.	 Studies that report on metastatic lesions or tumor invasion were excluded because they 

do not discuss the likely causal mechanism(s) of the tumor at the primary site (breast or 

colorectal). 

5.	 When the same study was published more than once, we used the data from the most 

recent publication. However, if the older report had provided data that was not provided 

by the most recent report, we included such data. 

6.	 Studies must have administered ethanol. Studies that administered alcoholic beverages 

such as beer or malt liquor were excluded given that the exact composition of such drinks 

remains confidential. 

Studies that did not specifically control alcohol exposure were also considered in this report 

but were not included in the primary evidence base addressing the Key Questions. Hypothesisgenerating studies examining metabolic pathways that may connect alcohol to cancer risk and 

epidemiology studies of alcohol exposure (including those in patients with or without cancer) 

were incorporated into the report in order to review and discuss this literature for comparison 

with our primary evidence base from experimental studies. 

Literature Review Procedures 

The abstracts for all identified documents were downloaded into the Mobius Analytics SRS 

4.0 Web-based system for conducting systematic reviews. Using this system, we assessed 

abstracts in order to either include or exclude identified documents based on our inclusion 

18
 
 

 

 

 

 

 

 

 

 

 

criteria. If the abstract was missing or had insufficient information to make a decision on 

inclusion we ordered the full article. Full articles were then retrieved for review and 

categorization using Web-based forms. The Web-based system provided a structured framework 

to build and manage the numerous documents identified by our searches. 

The review process underwent four levels: 

Level 1 – Abstract Review 

Level 2 – Full Document Review 

Level 3 – Background Document Review 

Level 4 – Evidence Base Document Review. 

Each level has an electronic form for capturing data about each document identified in our 

searches (see Appendix B for sample data abstraction forms). 

Data Abstraction and Data Management 

All documents that were identified as belonging in the evidence base of the report underwent 

data abstraction using EXCEL spreadsheets. Table B-1 in Appendix B provides a list of the data 

abstracted from each study and placed in to a separate column in the spreadsheet. Some of the 

columns were modified depending on whether a study examined humans, animals, or cell lines. 

The information in the spreadsheets was later used to create the evidence tables in this report. 

Disposition of the Documents Identified by Literature Searches 

The SRS Web-based system allowed us to track all identified documents along with their 

complete citation. Literature searches were updated periodically and the new documents were 

added to the system and reviewed. Using the information contained in the SRS database we were 

able to create Figure 4 to illustrate an attrition diagram as well as separate tables that show the 

disposition of the documents identified by our literature searches. A total of 819 documents were 

identified by our searches. After review of the abstracts and then full documents, we included 

264 documents for discussion within the report. Of these 264 documents, 66 met the 

requirements for the primary evidence base because they addressed one of the Key Questions. 

An additional 197 documents were included because they addressed issues related to alcohol and 

breast or colorectal cancer risk. 

19
 
Figure 4. Disposition of the documents identified by literature searches 

66 Studies addressing the Key Questions, this constitutes the primary evidence base of the report: 6 Human studies (5 breast cancer, 1 colorectal cancer)

 34 Animal exposure (15 breast cancer, 19 colorectal cancer)

 25 Human cell lines (15 breast cancer, 10 colorectal cancer)

 1 Combination [animal/cell line] on colorectal cancer

Abstracts 

screened 359 Documents 

excluded at the 

abstract level 460 Full documents retrieved

Full documents 

reviewed

264 documents to be 

included in the report

819 Documents identified

196 Documents 

excluded at the full 

document level

Full documents 

for inclusion in the 

evidence base

198 Documents that examined 

alcohol and cancer risk but did not 

specifically address the key 

questions:

14 Systematic reviews

(8 breast cancer, 6 colorectal cancer)

165 Epidemiology studies of alcohol 

and cancer

(47 breast cancer, 118 colorectal 

cancer) 

19 Hypothesis generating studies

(8 breast cancer, 11 colorectal cancer)

20
 
 

 

 

 

 

 

Assessing the Evidence for Each Key Question
 

Assessment of Internal and External Validity 

A critical part in the process of creating a systematic review is assessing the validity of the 

results reported in each included study in the review. The validity of individual study results is 

determined in the context of the Key Questions these studies address. Internal validity is the 

extent to which a study’s design and conduct are likely to have prevented bias and produced 

results that describe a true relationship.59 

The members of the Technical Expert Panel proposed several methods for evaluating the 

internal validity of studies using animals, tissues, or cells as the primary experimental model. 

Evidence from experimental studies offer the most compelling evidence that a 

mechanism/pathway is directly involved in increasing cancer risk with alcohol intake. 

Use of alcohol concentration levels in animal studies that far exceed levels that occur 

in humans are considered of low applicability. 

Cell lines should be appropriate to the study of breast and colorectal cancer in 

humans. 

To ultimately establish the presence of a contributory cause between alcohol consumption 

and breast or colorectal cancer, the following criteria have to be fulfilled: association, exposure 

14,60-63 prior to the association, and demonstration that changing the cause alters the effect.

Other supportive criteria such as strength of association, consistency of association, biological 

60-63 plausibility, and a dose-response relationship can be used to establish contributory cause.

For this systematic review, we applied the “direct” vs. “indirect” evidence concept.64 Direct 

assessment measures are those which provide direct evidence that alcohol causes either breast or 

colorectal cancer. Such evidence as shown in Figure 1 may confirm the steps during cancer 

formation and possible sites of action of alcohol thus demonstrating a contributory cause. 

Indirect measures typically focus on predictors that are correlated to carcinogenesis, but 

do not measure actual causation. Some of the most common indirect assessment measures 

3,10,13,14,18,41,55,65-81 include:

increased androgen and estrogen concentration 

inactivation of the BRCA1 gene 

formation of new capillaries (angiogenesis) 

depletion of s-adenosylmethionine (SAM) 

low iron levels, low folate and vitamin B12 levels 

induction of epidermal growth factor 

increase in tumor necrosis factor-alpha receptor 

acetaldehyde formation by colonic bacteria 

induction of CYP2E1 

impairment of retinoic acid 

21
 
 

 

 

 

 

 

 

generation of reactive oxygen species and reactive nitrogen species 

immune suppression (effects on peripheral T- and B-lymphocytes) 

increase in cell membrane permeability 

interference with DNA repair (acetaldehyde-DNA adducts) 

increased levels of biomarkers of oxidative stress. 

Because of the focus on the how and why of causation of cancer, indirect measures are 

critical in our efforts to improve the evidence of direct causation in ongoing and future research 

of possible causal mechanisms explaining the increased risk of breast and colorectal cancer with 

alcohol consumption. 

For this report, experimental studies that show direct evidence were treated as stronger 

evidence than studies of association which only showed indirect evidence. The strength of 

evidence supporting each proposed mechanism relating alcohol intake to the development of 

breast or colorectal cancer were categorized as either “Sufficient” or ”Insufficient.” Three 

domains were evaluated: the potential risk of bias, or “internal validity” of the evidence base, the 

size of the evidence base (number of studies examining any one proposed mechanism), and the 

consistency of the findings (agreement across studies examining the same proposed mechanism). 

External validity is the extent to which the findings and conclusions from a study or report 

can be translated to a specific setting or population (i.e., generalizability).59 Generalizability is 

always strongest when results are collected in the specific setting or population of interest. 

However, clinical studies often cannot be conducted in such a setting or population, and results 

are instead collected from a more rigidly defined and less generalizable patient population. 

Human studies have more external validity than animal or cell line studies. 

Data Synthesis 

No meta-analyses were planned for this report. Given that this systematic review is 

hypothesis-summarizing and generating, we present a narrative summary of the findings based 

on the number of different mechanisms proposed and the studies showing support or lack of 

support for each mechanism. 

Assessment of Internal Validity of Breast and Colorectal 

Studies 

Internal validity, especially in the context of clinical studies, is the extent to which a study’s 

59,82 design and conduct are likely to have prevented bias. However, in the context of this report, 

which is assessing the results of human, animal and in vitro studies, we defined internal validity 

as the extent to which a direct relationship can be seen between the result of a given study and an 

increase in the risk of developing breast or colorectal cancer following ethanol consumption. 

Although we believe that the included studies are valid in design and outcomes measured for 

their intended purpose, we needed a measure of internal validity that was relevant to the 

connection between study results and cancer risk in humans. Therefore we considered human 

studies that administered alcohol having a higher internal validity than animal or in vitro studies. 

Animal studies that administered alcohol and did not use any known co-carcinogen were 

considered as having a higher internal validity (more direct relationship to an increase in cancer 

risk) than studies that administered a carcinogen. Studies that administered acetaldehyde or 

22
 
 

 

known carcinogens were considered as having lower internal validity and a less direct 

relationship with an increase in cancer risk in humans who consume alcohol. 

Assessment of External Validity of Breast and Colorectal 

Studies 

In our report we did not identify any studies using human subjects that directly assessed the 

possible mechanism(s) associated with risk of breast cancer following alcohol consumption. 

However, we did identify one human study that indirectly reported on colorectal cancer risk 

association with alcohol consumption: exposure of colonic biopsy tissues to acetaldehyde.83 

For the animal studies, generalizability may be compromised by administering ethanol 

concentrations that far exceed levels suitable for human consumption, by administering 

73,82,84 acetaldehyde, and by co-administering a known carcinogen. Therefore, the results of these 

studies may not be directly applicable to human settings. 

23
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chapter 3. Results 

Evidence Base Describing Possible Mechanisms Connecting 

Alcohol Consumption and Breast Cancer Risk 

Human Studies 

We included five studies (see Table C-1 in Appendix C) that evaluated the possible 

mechanisms connecting alcohol consumption and breast cancer risk: the first study examined 

effects of alcohol on estradiol, estrone, estrone sulfate, testosterone, androstenedione, 

progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and androstenediol;85 

the second study86 examined the effects of alcohol on plasma and urinary hormone 

concentrations in premenopausal women; the third study87 examined the effect of alcohol on 

prolactin levels in menopausal women using estradiol replacement; the fourth study88 examined 

the effects of alcohol on estrogen levels in postmenopausal women; and the fifth study76 

examined the relationship of alcohol consumption with antioxidant nutrients and a biomarker of 

oxidative stress. Although none of these five studies reported direct evidence of cancer, we 

included them because alcohol was administered to examine alterations in hormonal 

mechanism(s) and biomarkers of oxidative stress that have been suggested to be linked to the 87-90 development of breast cancer. Four studies reported increased serum hormonal levels and 

one study76 reported an increase in isoprostane levels, a biomarker of oxidative stress. Table C-1 

in Appendix C provides a summary of study design, mechanisms examined, amount and duration 

of ethanol or acetaldehyde exposure, study results, and authors’ conclusions. 

In the study by Dorgan et al., 51 healthy postmenopausal women consumed 15 or 30 grams 

of alcohol per day or an alcohol-free placebo beverage through three 8-week dietary periods. 

Each dietary period was preceded by a 2- to 5-week washout period when participants did not 

consume any alcohol. The results showed an increase in serum levels of both estrone sulfate and 

DHEAS. While this study did not report any direct evidence to show causation of cancer, Dorgan 

et al. concluded that results suggest a possible mechanism by which consumption of one or two 

alcoholic drinks per day by postmenopausal women could increase their risk of breast cancer.85 

In the second study Reichman et al. examined 34 premenopausal women who consumed 30 g of 

ethanol daily for three menstrual cycles and no alcohol during three other cycles.86 The results 

showed an increase in plasma DHEA sulfate, plasma estrone, plasma estradiol, and urinary 

estradiol. Reichman et al. concluded that these results suggest a possible mechanism between 

alcohol consumption and risk of breast cancer again because of changes in hormone levels.86 

In the third study, Ginsburg et al.87 conducted two randomized, crossover studies in post 

menopausal women: study 1 administered ethanol (1 mL/kg, 95% ethanol) vs. isocaloric drink; 

study 2 was similar to study 1 except authors removed transdermal estradiol patches after 

administration of either ethanol or isocaloric drink. In both crossover studies, Ginsburg et al.87 

reported an increase in serum prolactin levels. In the fourth study Ginsburg et al.88 administered 

ethanol (pineapple juice and 40% ethanol at a dose of 2.2 mL/kg of body weight [0.7 g/kg of 

body weight] in a total volume of 300 mL) vs. placebo to 24 postmenopausal women and 

reported a 3-fold increase in circulating estradiol levels in women on estrogen replacement 

therapy (ERT). In the fifth study Hartman et al.76 administered a controlled diet plus each of 

three treatments (15 or 30 g alcohol/day or no-alcohol placebo beverage) to 53 postmenopausal 

women, during three 8-week periods in random order and reported that moderate alcohol 

consumption increased isoprostane, a biomarker of oxidative stress by 4.9%. 

25
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Animal Studies 

We included 15 studies using animal models to evaluate possible mechanisms connecting 

alcohol consumption with breast cancer risk (see Table C-2 in Appendix C). Of the 15 included 

studies, 14 reported on the mechanism(s) and one91 did not. The mechanisms examined in the 

14 studies were: 

92-94 elevated levels of estrogen and or progesterone

biotransformation to acetaldehyde95 

formation of DNA adducts96 

97,98 elevation of serum prolactin

suppression of cellular immunity99 

100-103 enhancement of rate of tumor progression

104,105 effect on DNA synthesis

Administration and duration of ethanol exposure varied across studies. Studies also varied on 

whether a carcinogen was co-administered to induce carcinogenesis. Of the 15 studies, 

10 reported the use of a known carcinogen to induce cancer: 

dimethylene (a) anthracene [DMBA] (five studies) 

N-methyl-N-nitrosurea [MNU] (two studies) 

N-nitrosodimethylamine [NMDA] and 4-methylnitrosoamino-1-3-pyridyl-1-butanone 

[NNK] (one study) 

MADB106 [one study] 

bittner virus [one study]. 

Table C-2 in Appendix C provides a summary of mechanisms examined, amount and 

duration of ethanol or acetaldehyde exposure, carcinogen use, study results, and authors’ 

conclusions. 

Outcomes measured varied across studies. Overall, six studies reported increased cancer 92,93,103 91,97 formation (four studies co-administered a carcinogen and two studies did not ). 

The reported results of intermediate outcomes included: 

biotransformation of ethanol to acetaldehyde95 

increase in the formation of DNA adducts96 

94,104,105 increase in terminal-end bud density and a decrease in alveolar bud structures

a reduction in blood natural killer cytotoxicity99 

Three studies reported no changes in outcomes and concluded that their findings did not 100-102 support a link between alcohol consumption and the risk of breast cancer.

26
 
 

 

 

 

 

 

 

 

 

 

 

 

 

Cell Line Studies 

We included 15 studies using cell lines to evaluate possible mechanisms connecting alcohol 

consumption with breast cancer risk (see Table C-3 in Appendix C). Cell lines examined in the 

studies included: 

MCF-7 (six studies) 

MCF-10F (two studies) 

T4TD (one study) 

MM46 tumor cells (one study) 

MDA-MB-453 (one study) 

MCF-7 + T47D (one study) 

MCF-7 + T84 (one study) 

MCF-7 + T47D + MDA-MB-231 (one study) 

MCF-7 + ZR75.1 + BT-20 + MDA-MB-231 (one study). 

Various types of mechanism were reported by these studies: 

65,67-69,106 hormonal-related

107,108 DNA adduct formation

51,109,110 effect on cell proliferation

increase cAMP111 

change in potassium channels112 

mammary gland mucin upregulation113 

smooth muscle up-regulation during transcription114 

Amount and duration of ethanol and/or acetaldehyde exposure varied across all studies. 

Ten studies administered ethanol alone, and two studies administered ethanol combined with 

acetaldehyde. Table C-3 in Appendix C provides a summary of mechanisms examined, amount 

and duration of ethanol or acetaldehyde exposure, study results, and authors’ conclusions. 68,106,113,115 Five studies reported an increase in the expression of mRNA, two studies reported 107,108 an increase in the formation of DNA adducts, two studies reported an increase in cell 

65,69 3 51,110 proliferation, two studies reported enhancement of H-thymidine uptake, one study 114 109 reported up-regulation of smooth muscle myosin alkali light chain, and one study reported 

reduction in the expression ribosomal protein L7a. 

27
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Evidence Base for Describing Possible Mechanisms 

Connecting Alcohol Consumption and Colorectal Cancer
 

Risk
 

Human Studies 

We included one study (see Table C-4 in Appendix C) using human tissues to evaluate the 

possible mechanism connecting alcohol consumption with colorectal cancer risk. The study 

exposed colonic mucosa to acetaldehyde vapor.83 Although no direct evidence to show a 

connection between acetaldehyde exposure and cancer risk was reported, the authors concluded 

that acetaldehyde may cause an increase in risk of colon cancer via loss of cell-cell adhesion.83 

Table C-4 in Appendix C provides a summary of study design, mechanisms examined, amount 

and duration of acetaldehyde exposure, study results, and authors’ conclusions. 

Animal Studies 

We included 19 studies using animal models to evaluate the possible mechanisms for alcohol 

consumption and colorectal cancer risk (see Table C-5 in Appendix C). Of the 19 included 

116,117 studies, 17 reported on the mechanism(s) examined and two did not. The mechanisms 

examined in the 17 studies included: 

118,119 cytochrome system expression

70,120-123 generation of acetaldehyde

DNA methylation124 

125-127 cell proliferation

128,129 local mucosal effect

73,130,131 effect on various phases of carcinogenesis

Administration and duration of ethanol exposure varied across all studies. Studies also varied 

on whether a carcinogen was co-administered. Of the 19 studies, 12 reported the use of a known 

carcinogen to induce cancer: 

1,1-dimethylhydrazine (DMH) (six studies) 

methylazoxymethanol (MAM) acetate (one study) 

acetoxymethyl-methylnitrosamine (AMMN) (one study) 

AMMN + cyanamide (CY) (one study) 

azoxymethane (AOM) (three studies). 

Table C-5 in Appendix C provides a summary of mechanisms examined, amount and 

duration of ethanol or acetaldehyde exposure, carcinogen use, study results, and authors’ 

conclusions. 

Outcomes measured varied across studies. Among the studies that co-administered a 

73,123,126,128,129,132 131 carcinogen, six reported increased cancer formation, one reported suppression 

28
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

116,117 of cancer formation, and two reported no effect. Another study that did not co-administer a 

carcinogen reported an increase in cancer formation.121 The reported results of intermediate 

outcomes include: 

118,122,125,127 increase in the number of aberrant crypt foci

increase in microsomal ethanol-oxidizing system activity120 

increase in acetaldehyde level resulting in folate degradation70 

undermethylation of DNA124 

increase in the expression of CYP2E1119 

decrease in the formation of DNA adducts130 

Cell Line Studies 

We included 10 studies using cell lines to evaluate possible mechanisms connecting alcohol 

consumption with colorectal cancer risk (see Table C-6 in Appendix C). Cell lines examined in 

the studies included: 

Caco-2 (six studies) 

HT-29 (one study) 

colonic mucosa cells (one study) 

Caco-2 + HT-29 (one study) 

HT-29 + SW-1116 + HCT-15 (one study). 

Various mechanisms were reported by these studies: 

folate uptake modulation133 

75,133 tumor necrosis factor modulation

inflammation and cell death134 

formation of crosslinks with DNA135 

136,137 initiation of cancer

cell differentiation138 

modulation of gene expression139 

Amount and duration of ethanol and/or acetaldehyde varied across all studies (seven studies 

administered ethanol alone, three studies administered ethanol combined with acetaldehyde). 

Table C-6 in Appendix C provides a summary of mechanisms examined, amount and duration of 

ethanol or acetaldehyde exposure, study results, and authors’ conclusions. 

Outcomes varied across all studies. Reported results included: 

inhibitory effect on both 3H-folic and 3H-methotrexate uptake140 

increase in tumor necrosis factor-alpha receptor-175 

inflammation resulting in increased phosphatidylserine production134 

increase in mRNA expression74 

29
 
 

 

 

 

 

 

 

 

 

 

 

 

dual effect on cell proliferation (acute acetaldehyde exposure inhibitory and chronic 

acetaldehyde exposure stimulating)136 

137,138 increase in sucrase and maltase activity

increase in alkaline phosphatase and sucrose activities, limited cytotoxicity133 

damage to DNA strands135 

lack of effect on the expression of HLA class 1 antigens139 

Combination Study (Animal, Cell Line) 

We included one study141 that used a combination of animal (mice) and cell line (Caco-2) to 

evaluate the possible mechanisms connecting alcohol consumption with colorectal cancer risk 

(see Table C-7 in Appendix C). Intestinal cell proliferation as a result of phosphatidylethanol 

accumulation was the examined mechanism. The animal study administered ethanol and the cell 

line study administered either ethanol or acetaldehyde. Outcome reported was disruption of 

cellular signals. Chronic alcohol exposure resulted in an increase of maximal intestinal 

density.141 

Systematic Reviews and Narrative Reviews of 

Epidemiology Studies
 

We identified and summarized the reported results and conclusions from 13 systematic reviews 

of epidemiology studies looking for an association between alcohol intake and cancer risk (seven 

on breast cancer [see Table 1], six on colorectal cancer [see Table 2]). While these studies were not 

considered part of our primary evidence base addressing the key questions of this report, they do 

provide important evidence connecting alcohol intake with breast and colorectal cancer risk in 

humans and provide a context for discussing the findings of the studies included in our primary 

evidence base. The tables provide the review objectives, the resources searched, inclusion criteria, 

a summary of results, and the authors’ conclusions. Key areas examined by the systematic reviews 

of breast cancer included: 

alterations in estrogen-dependent pathways 

polymorphisms in one-carbon metabolism pathways 

interaction with dietary folate intake 

dose-response relationships between alcohol intake and cancer risk. 

Key areas examined by the systematic reviews of colorectal cancer include differences in 

Japanese versus western populations, and amount of alcohol intake and cancer risk. 

30
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 1. Systematic reviews/meta-analyses for breast cancer epidemiology studies 

Conclusions 

Resources Searched and as Reported by
 

Study
 Objective Inclusion Criteria Results Study Authors 

Suzuki et al. To quantitatively assess Eligible studies were The risk of developing breast Estrogen-dependent 142 2008 the accumulated evidence identified by searching the cancer was statistically significant pathway alone cannot 

on the association between MEDLINE database from comparing the highest vs. lowest account for the 

alcohol intake and the risk January 1, 1970 through consumption categories for detected positive 

of estrogen receptor (ER) April 20, 2007 for relevant developing: associations with 

and progesterone receptor epidemiology studies of alcohol for ER+PR+ ER+ tumors 27% (1.17-1.38), (PR)– defined breast alcohol consumption in and ER-PR+ tumors. all ER- tumors 14% (1.03-1.26), cancer subtypes and to relation to the risk of breast ER+PR+ tumors 22% (1.11-1.34), evaluate whether the cancer defined by ER/PR ER+PR- tumors 28% (1.07-1.53), observed association without any language but not ER-PR- tumors. differs across ER/PR restriction. 

An increase in alcohol status. Evidence base: consumption of 10 g of ethanol 

Nineteen studies per day was associated with 

(4 prospective cohort studies statistically significant increased 

and 16 case-control studies) risks for: 

all ER+ 12% (8%-15%), 

all ER- 7% (0%-14%), 

ER+PR+ 11% (7%-14%) and 

ER+PR- 15% (2%-30%), 

but not ER-PR-. 

Lissowska et al. To examine the role of Epidemiology studies of There was no significant Study did not support 143 2007 genetic polymorphisms in methylenetetrahydrofolate association of breast cancer risk association between 

the one-carbon metabolism gene (MTHFR A222V and with nutrients involved in one polymorphisms in the 

pathway and breast cancer E429A) polymorphisms and carbon metabolism (i.e., folate, one-carbon 

risk. breast cancer risk published vitamins B2, B6, B12, methionine) metabolism pathway 

through August 2006 were or with alcohol intake. and the risk of breast 

identified through a PubMed cancer. 

search. 

31
 
 

 

 

Conclusions 

Resources Searched and as Reported by 

Study Objective Inclusion Criteria Results Study Authors 

Lewis et al. To summarize the available MEDLINE and ISI Web of Only two studies used the same There is no 

2006144 evidence from observational knowledge databases for cut off points for alcohol intake. association between a 

studies on this issue and a relevant studies that were Therefore, evidence for interaction lack of dietary folate 

meta-analysis of the published through between alcohol and folate intakes intake and breast 

association between a May 31, 2006. with respect to risk of breast cancer risk. 

common polymorphism in Evidence base: cancer was inconclusive. 

the 5,10-methylenetetrahydrofolate reductase 19 studies (13 case-control 

(MTHFR) gene. studies and 9 cohort studies) 

of which seven cohort 

studies and one case-control 

study examined the 

interaction between alcohol 

and folate intakes with 

respect to risk of breast 

cancer. 

32
 
 

 

 

 

Conclusions 

Resources Searched and as Reported by 

Study Objective Inclusion Criteria Results Study Authors 

Key et al. 

200652 

To give an up-to-date 

assessment of the 

MEDLINE, EMBASE, 

Pascal (BIDS), Science 

association of alcohol with Citation Index (BIDS), 

female breast cancer, Social Sciences Citation 

addressing methodological Index (BIDS), Index to 

issues and shortfalls in Scientific and Technical 

previous overviews. Proceedings (via BIDS), 

Biological Abstracts 

(BIOSIS), Biological 

Sciences, AIDS and Cancer 

Research Abstracts, 

Biology Digest, Conference 

Papers Index, Cochrane 

Library, NHS National 

Research Register (NRR), 

SIGLE (System for 

Information on Grey 

Literature), NTIS (National 

Technical Information 

Service), TOXLINE. 

Evidence base: 

98 studies (75,728 drinkers 

vs. 60,653 non-drinkers) 

Excess risk associated with alcohol Association between 

consumption was 22% (9%-37%). 

Each additional 10 g ethanol per 

day increases breast cancer risk 

by 10% (5%-15%). 

alcohol and breast 

cancer may be causal. 

Estimated population attributable 

risk in the U.S.A. and U.K. were, 

1.6% and 6.0%, respectively. 

33
 
 

 

 

 

 

 

 

 

Conclusions 

Resources Searched and as Reported by 

Study Objective Inclusion Criteria Results Study Authors 

Hamajima et al. A collaborative reanalysis Resources searched were The average consumption of Caution is needed to 

200234 of individual data from not reported by study alcohol reported by controls from interpret the effect of 

53 epidemiology studies, authors. developed countries was 6.0 g per alcohol on risk of 

including 58,515 women Evidence base: day, i.e., about half a unit/drink of breast cancer. 

with breast cancer and alcohol per day; greater in ever95,067 women without the 53 studies (51 published, smokers than never-smokers, 

disease. 2 unpublished) (8.4 g per day and 5.0 g per day, 

respectively). 

Compared with women who 

reported no alcohol, relative risk 

(RR) of breast cancer was 

1.32 (1.19-1.45, p <0.00001) for an 

intake of 35-44 g per day alcohol, 

and 1.46 (1.33-1.61, p <0.00001) 

for ≥45 g per day alcohol. 

For each additional 10 g per day 

intake of alcohol, the relative risk of 

breast cancer increased by 7.1% 

(5.5%-8.7%, p <0.00001). 

Corrao et al. 

145 1999

To compare the strength of 

the evidence provided by the 

epidemiology literature on 

the association between 

alcohol consumption and 

the risk of six cancers 

(oral cavity, esophagus, 

colorectum, liver, larynx, 

breast). 

MEDLINE from 1966 up to 

and including 1998, 

articles reported by other 

bibliographic databases 

available at the University of 

Miami (Current Contents 

from 1996, EMBASE from 

1980, CAB abstracts from 

1973, and Core Biomedical 

Collection from 1993). 

Evidence base: 

200 epidemiology studies 

(29 breast). 

RR for dose of alcohol intake for 

breast cancer in the Mediterranean 

region* were: 

1.6 (1.6-1.7) for 25 g per day, 

2.7 (2.4-2.9) for 50 g per day, and 

7.1 (5.8-18.6) for 100 g per day. 

RR for dose of alcohol intake in 

other areas* were: 

1.2 (1.1-1.3) for 25 g per day, 

1.5 (1.2-1.8) for 50 g per day, and 

2.1 (1.4-3.1) for 100 g per day. 

*strata by region 

Based on weak doseresponse relationship, 

there is need for 

well-conducted 

epidemiology studies. 

34
 
 

 

 

Conclusions 

Resources Searched and as Reported by 

Study Objective Inclusion Criteria Results Study Authors 

Smith-Warner et al. To assess the risk of 

199839 invasive breast cancer 

associated with total and 

beverage-specific alcohol 

consumption and to evaluate 

whether dietary and 

nondietary factors modify the 

association. 

Resources searched were 

not reported by study 

authors. 

Evidence base: 

6 prospective studies that 

had at least 200 incident 

breast cancer cases, 

assessed long-term intake of 

food and nutrients, and used 

a validated diet assessment 

instrument. 

For alcohol intake less than 60 g 

per day breast cancer risk 

increased linearly with increasing 

intake. 

Pooled multivariate RR for an 

increment of 10 g per day of 

alcohol (about 0.75-1 drink) was 

1.09 (1.04-1.13). 

Multivariate-adjusted RR for total 

alcohol intake of 30 to <60 g per 

day (about 2-5 drinks) vs. 

nondrinkers was 1.41 (1.18-1.69). 

Limited data suggested that 

alcohol intake of at least 60 g per 

day were not associated with 

further increased risk. 

The specific type of alcoholic 

beverage did not strongly influence 

risk estimates. 

The association between alcohol 

intake and breast cancer was not 

modified by other factors. 

Alcohol consumption 

is associated with a 

linear increase in 

breast cancer 

incidence in women 

over the range of 

consumption reported 

by most women. 

Among women who 

consume alcohol 

regularly, reducing 

alcohol consumption is 

a potential means to 

reduce breast cancer 

risk. 

Longnecker 

1993146 

To evaluate the association 

between alcohol 

consumption and risk of 

breast cancer. 

MEDLINE from 1996 through 

September 1992, all 

abstracts presented at the 

society for Epidemiology 

Research from 1989-1994. 

RR of breast cancer following daily 

alcohol consumption were 

1.11 (1.07-1.16) for one drink, 

1.24 (1.15-1.34) for two drinks, and 

1.38 (1.23-1.55) for three drinks. 

Causal role of alcohol 

remains uncertain. 

Evidence base: 

38 epidemiology studies 

35
 
 

 

 

 

 

Table 2. Systematic reviews/meta-analyses for colorectal cancer epidemiology studies 

Conclusions 

Resources Searched and as Reported by
 

Study
 Objective Inclusion Criteria Results Study Authors 

Mizoue et al. To examine the Population-based cohort studies that In men, multivariate-adjusted pooled hazard When compared to 147 2008 association were conducted in Japan, started ratios for alcohol intake of 23-45.9 g per day, Western populations, 

between alcohol between the mid-1980s and the 46-68.9 g per day, 69-91.9 g per day, and alcohol-colorectal 

consumption and mid-1990s, included more than 30,000 >92 g per day, compared with nondrinkers, cancer association 

colorectal cancer participants, obtained information on were 1.42 (1.21-1.66), 1.95 (1.53-2.49), seems to be more 

in Japanese. diet, including alcohol intake, using a 2.15 (1.74-2.64), and 2.96 (2.27-3.86), evident in Japanese. 

validated questionnaire or a similar one respectively (p for trend <0.001). 

at baseline, and collected incidence The association was evident for both the data for colorectal cancer during the colon and the rectum. A significant positive follow-up period. association was also observed in women. 

Evidence base (5 cohort studies): Twenty-five percent of colorectal cancer 

cases were attributable to an alcohol The Japan Public Health Center- consumption of >23 g per day. based Prospective Study (JPHC) 

The Japan Collaborative Cohort 

Study (JACC) 

The Miyagi Cohort Study 

The Takayama Study 

o	 According to the authors, 

the JPHC was treated as two 

independent studies (JPHC I 

and JPHC II) because of a 

difference in the dietary 

questionnaires used; thus, data 

from a total of five studies were 

analyzed. 

36
 
 

 

 

 

 

 

 

Conclusions 

Resources Searched and as Reported by 

Study Objective Inclusion Criteria Results Study Authors 

Moskal et al. 

148 2007

To examine if 

current alcohol 

intake is 

associated with 

risk of colon and 

rectal cancer 

by summarizing 

the results of 

published 

prospective cohort 

studies with 

meta-analytic 

techniques. 

Prospective cohort studies in MEDLINE High alcohol intake was significantly Lifestyle 

published in English between 1990 and associated with increased risk of colon 1.50 recommendations for 

June 2005; (iii) referenced in MEDLINE. (1.25-1.79) and rectal cancer 1.63 (1.35- prevention of 

Since studies on specific types of 1.97). This was comparable to a 15% colorectal cancer 

alcohol (beer, wine, and liquor) were increase of risk of colon or rectal cancer for should consider 

limited, the authors restricted the meta- an increase of 100 g of alcohol intake per limiting alcohol intake. 

analyses to total alcohol consumption week. The association did not change 

on colorectal cancer risk. Studies in significantly by anatomical site (colon, 

particular populations (i.e., cohorts of rectum). 

alcoholics or brewery workers) were not 

included. 

Evidence base: 

Sixteen prospective cohort studies 

MEDLINE from 1965 to 2005 A moderate or strong positive association was Among the Japanese 

Inclusion criteria: observed between alcohol drinking and colon population, alcohol 

cancer risk in all large-scale cohort studies, consumption perhaps Epidemiology studies on the with some showing a dose-response may increase the risk 

association between alcohol drinking relationship, and among several case-control of colorectal cancer. 

and colorectal cancer incidence or studies. Association with 

mortality among Japanese. 

Evidence base: 

Eighteen studies (5 cohort studies and 

13 case-control studies). 

A positive association with rectal cancer was 

also reported, but it was less consistent, and 

the magnitude of the association was 

generally weaker compared with colon 

colon cancer is 

probable, and that for 

rectal cancer is 

possible. 

cancer. 

The RR of colon or colorectal cancer 

increased even among moderate drinkers 

consuming <46 g of alcohol per day, levels 

at which no material increase in the risk was 

observed in a pooled analysis of Western 

studies. 

Mizoue et al. 

2006149 

To review 

epidemiology 

findings regarding 

the association 

between alcohol 

drinking and 

colorectal cancer 

among the 

Japanese 

population. 

37
 
 

 

 

 

Conclusions 

Resources Searched and as Reported by 

Study Objective Inclusion Criteria Results Study Authors 

Cho et al. 

200436 

To examine the 

relationship of total 

The authors reported a pooled analysis 

of primary data from 8 cohort studies in 

Increased risk for colorectal cancer was 

limited to persons with an alcohol intake of 

alcohol intake and 5 countries. 30 g/day or greater (approximately >2 drinks 

intake from per day), a consumption level reported by 

specific beverages 4% of women and 13% of men. 

to the incidence of 

colorectal cancer 

and to evaluate 

whether other 

potential risk 

factors modify the 

association. 

Compared with nondrinkers, the pooled RR 

were 1.16 (0.99-1.36) for persons who 

consumed 30 to <45 g per day and 

1.41 (1.16-1.72) for those who consumed 

≥45 g per day (p for trend <0.001). 

Evident for cancers of the proximal colon, 

distal colon, and rectum. No clear difference 

in relative risks was found among specific 

alcoholic beverage. 

There was a 

correlation between a 

single determination 

of alcohol 

consumption and a 

modest relative 

elevation in the rate 

of colorectal cancer, 

mostly at the highest 

levels of 

consumption. 

38
 
 

 

 

Conclusions 

Resources Searched and as Reported by 

Study Objective Inclusion Criteria Results Study Authors 

Corrao et al. 

145 1999

To compare the 

strength of the 

evidence provided 

by the 

epidemiology 

literature on the 

association 

between alcohol 

consumption and 

the risk of six 

cancers (oral 

cavity, esophagus, 

colorectum, liver, 

larynx, breast). 

MEDLINE from 1966 up to and 

including 1998, articles reported by
 

other bibliographic databases available 

at the University of Miami (Current 

Contents from 1996, EMBASE from
 

1980, CAB abstracts from 1973, and 

Core Biomedical Collection from 1993).
 

Evidence base:
 

200 epidemiology studies
 

(16 colon [12 case-control, 4 cohort], 

14 rectum [11 case-control, 3 cohort]).
 

Colon studies** 

RR for dose of alcohol intake in colon studies 

(case-control) were 1.0 (1.0-1.1) for 25 g per 

day, 1.1 (1.0-1.2) for 50 g per day, and 1.1 

(1.0-1.3) for 100 g per day. 

RR for dose alcohol intake in colon studies 

(cohort studies) were 1.4 (1.1-1.7) for 25 g 

per day, 1.9 (1.3-2.9) for 50 g per day, and 

3.6 (1.6-8.5) for 100 g per day. 

**Reported results were stratified by study 

design 

Rectum studies*** 

RR for dose of alcohol intake in rectum 

studies among men were 1.1 (1.0-1.2) for 

25 g per day, 1.2 (1.1-1.5) for 50 g per day, 

and 1.5 (1.2-2.2) for 100 g per day. 

RR for dose of alcohol in rectum studies 

among women were 2.3 (1.3-4.0) for 25 g per 

day, 5.0 (1.6-16.4) for 50 g per day, and 25.7 

(2.5-267.6) for 100 g per day. 

***Reported results were stratified by gender 

Based on weak doseresponse relationship, 

there is need for wellconducted 

epidemiology studies. 

39
 
 

 

 

Conclusions 

Resources Searched and as Reported by 

Study Objective Inclusion Criteria Results Study Authors 

Evidence base: 

La Vecchia 

Franceschi and To evaluate 

alcohol 34 studies (15 cohort, 19 case-control). 150 1994 consumption and 

the risk of cancers 

of the stomach 

and colon-rectum. 

Among the 15 cohort studies: seven studies Epidemiology 

were not very informative; and overall evidence regarding a 

evidence from 8 studies showed colon cancer causal role of 

RR estimates varying within a narrow range alcoholic beverage 

of 1.0-1.7 [ranging between 1.1-1.3 in most consumption and 

studies], and rectal cancer 1.0-2.5 [ranging colorectal 

between 1.0-1.7 in most studies]. carcinogenesis 

remains inconclusive. Among the 19 case-control studies: five 

studies were totally negative, and showed 

no evidence of association; 3 other studies 

showed overall significant associations; and 

remaining 11 studies showed no consistent 

overall association. 

40
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Reported Mechanisms in the Epidemiology Literature 

A search of the literature identified the following mechanisms reported in breast and 

colorectal cancer epidemiology studies that were not included in our primary evidence base 

(see Table 3 and Table 4, respectively). These studies investigated the association between 

alcohol consumption and increased cancer risk primarily by administering questionnaires to 

study dietary behavior and amount of alcohol consumption and correlated these findings 

with cancer incidence. Some of these studies looked at different alcoholic beverages, for 

example wine, beer, and other spirits. However, none of these studies controlled alcohol 

exposure. 

Our searches of the literature identified hypothesis-generating studies that provide indirect 

evidence of potential mechanisms. These studies examined various metabolic pathways that 

have been proposed as potential connections between alcohol exposure and increased breast 

or colorectal cancer risk (see Table 5 and Table 6, respectively). 

These hypothesis-generating studies and epidemiology studies were incorporated into this 

report in order to review and discuss this literature base in comparison with our primary evidence 

base. 

Table 3. Breast cancer epidemiology studies 

Proposed Mechanism References 

Changes in circulating hormone levels 37,151-158 

DNA-adduct formation 159 

Changes in levels of insulin-like growth factor 160 

Changes in levels of biomarkers of inflammation 77-81 

Cytochrome P450 polymorphism 161,162 

Methylenetetrahydrofolate reductase polymorphism/Dietary/Vitamins 38,163-173 

Alcohol dehydrogenase/Acetaldehyde dehydrogenase polymorphism 45,47-50,174-178 

Other types of polymorphism 179-184 

Table 4. Colorectal cancer epidemiology studies 

Proposed Mechanism References 

DNA repair polymorphisms 90,166,185-234 

Hyperproliferation of rectal mucosa 141,235 

Colonic microbial metabolism resulting in the generation of acetaldehyde 55,56 

Cytochrome P450 polymorphism 236-240 

Alcohol dehydrogenase and acetaldehyde dehydrogenase polymorphism 19,241-252 

Changes in levels of insulin-like growth factor 253-256 

Impact of C-reactive protein and Inflammation 257,258 

Methylenetetrahydrofolate reductase polymorphism/Dietary/Vitamins 189,259-263 

Other types of polymorphism and mechanisms 259,264-294 

41
 
 

 

 

 

Table 5. Hypothesis-generating breast cancer studies 

Study Reported Mechanism 

Marietta et al. 

2009295 

Stimulation of Fanconi anemia–breast cancer associated (FANC–BRCA) DNA 

damage response network by acetaldehyde 

Taibi et al. 

2009296 

Low levels of both xanthine dehydrogenase and cellular retinol binding protein 

Jin et al. 

2008297 

Activation of BRCA2 transcription by estrogen receptor-beta 

Maciel et al. 

2004298 

Inhibition of bioactivation of ethanol to acetaldehyde by folic acid 

Jordao et al. 

2004299 

Increased lipid peroxidation 

Stevens et al. 

2000300 

Change in estrogen levels 

Colantoni et al. 

2000301 

Increased levels of malondialdehyde 

Jones et al. 

1998302 

Response of MCF-7 cells to potential estrogens and non-estrogenic substances 

42
 
 

 

Table 6. Hypothesis-generating colorectal cancer studies 

Study Reported Mechanism 

Jelski et al. 

200415 

Alcohol dehydrogenase and aldehyde dehydrogenase polymorphisms 

Vincon et al. 

2003303 

Generation of free radicals. 

Leuratti et al. 

2002304 

DNA adduct formation 

Parlesak et al. 

2000305 

Inhibition of retinol oxidation 

Koivisto et al. 

1996306 

Alcohol dehydrogenase polymorphism 

Jokelainen et al. 

199657 

Generation of acetaldehyde by human colonic bacteria 

Seitz et al. 

199621 

Alcohol dehydrogenase polymorphism 

Nosova et al., 

1996307 

Generation of acetaldehyde by human colonic bacteria 

Rosenberg et al. 

1994308 

Induction of cytochrome P450 

Jokelainen et al. 

1994309 

Generation of acetaldehyde by human colonic bacteria 

Shimizu et al. 

1990310 

Induction of cytochrome P450 

Ongoing Clinical Trials 

A search of the clinicaltrials.gov (http://clinicaltrials.gov/) Web site did not identify any 

ongoing trials related alcohol consumption and possible causal mechanisms for breast and 

colorectal cancers. 

43
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chapter 4. Discussion
 

Breast Cancer 

Key Question 1. What are the likely causal mechanisms by which alcohol contributes to the 

development of breast cancer? Which of the possible mechanisms (e.g., induction of P450 

cytochromes and carcinogen metabolism, effects on blood hormone concentrations, effect of 

acetaldehyde or other alcohol metabolite on apoptosis and DNA repair, interactive effects on 

other nutritional factors, or others) are likely to be most important in breast cancer 

development? 

Alcohol-related Changes in Circulating Hormones 

Changes in circulating hormone levels due to chronic alcohol intake have been demonstrated 

in several epidemiology studies (see Table 3). Our searches identified eight epidemiology studies 

37,151-157 151-157 that looked at this connection. Seven studies made specific reference that moderate 

alcohol consumption may be responsible for increasing breast cancer risk by influencing 

hormonal levels and estrogen receptors and one study37 reported light-to-moderate alcohol 

consumption was not associated with increase breast cancer risk. The findings from these seven 

studies suggest that alcohol interferes with estrogen pathways, thereby causing changes in 

hormonal levels and estrogen receptors. This may then have a direct effect on breast tissue and 

cancer risk. Given this apparent connection between alcohol intake and alterations in circulating 

hormones seen in the epidemiology literature, we looked for hypothesis-generating studies that 

examined this connection. 

A majority of the human and animal studies identified in our searches and included in our 

primary evidence base also point to a connection between alcohol intake and changes in 

blood hormone levels, especially elevated levels of estrogen-related hormones in humans (see 

Table C-1 in Appendix C) and animals (see Table C-2 in Appendix C). Several cell line studies 

also suggest that estrogen receptor pathways may be altered by ethanol (see Table C-3 in 

Appendix C). Increased estrogen levels may increase the risk of breast cancer through increases 

in cell proliferation and alterations in estrogen receptors. Suzuki et al.142 looked at the possible 

connection between estrogen receptor (ER) alterations, alcohol intake, and the risk of breast 

cancer in a meta-analysis of epidemiology studies (see Table 1.). The highest versus the lowest 

alcohol consumption categories were analyzed for their association with all ER+ and ERsubtype tumors. Meta-analysis of all studies using relative risk (RR) indicated a statistically 

significant 27% higher risk of developing ER+ tumors (95% CI: 1.17 to 1.38) and a 14% higher 

risk for developing ER- tumors (95% CI: 1.03 to 1.26) in the high consumption group. The 

authors concluded that they had “found support for a positive relationship between alcohol 

consumption and the development of all ER+ tumors.” The authors also concluded that “The 

results from these meta-analyses suggest that the biological mechanism for development of 

breast cancer due to alcohol intake could be explained not only through ER-mediated classical 

estrogen-dependent pathway but also through other mechanisms” such as DNA damage or 

increased expression of other signaling pathways leading to cell proliferation. These studies 

(human, animal, and cell line) combine to suggest that estrogen-related mechanisms may be 

altered by alcohol consumption and provide a potential causal mechanism by which alcohol 

affects the estrogen receptors thereby contributing to the increased risk of development of breast 

cancer. 

45
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Elevation in prolactin levels was examined in one human study. Ginsburg et al.87 reported 

that serum prolactin levels increased in menopausal women during acute ethanol ingestion. 

In animal studies, ethanol-induced hyperprolactinemia in mice was associated with the 

97,98 development of mammary tumors. While not as extensive as the estrogen-related studies, 

these studies give some indication that alcohol consumption may alter prolactin levels and 

increase the risk of developing breast cancer. 

Cell Proliferation and Tumor Progression 

Although we did not identify any epidemiology study that reported on hyperproliferation 

as a possible mechanism, enhancement of cell proliferation and tumor progression related to 

ethanol consumption and conversion to acetaldehyde and its connection to breast cancer has been 

examined in numerous animal (Table C-2 in Appendix C) and cell line studies (Table C-3 in 

93,94 Appendix C). Several of the animal studies used carcinogens such as MNU or 

100,101,105 DMBA. However, the DMBA studies were not as consistent in showing a relationship 

between ethanol and mammary tumorigenesis as the MNU studies (see Table C-2 in 

Appendix C). The effect of ethanol on cell proliferation in cell lines was examined in three 

studies included in this report. Izevbigie et al.51 reported that ethanol stimulated cell proliferation 

in the MCF-7 cell line, Zhu et al.109 reported that ethanol induced changes that could promote 

cancer development in the T4TD cell line, and Przylipiak et al.110 reported that ethanol had direct 

growth stimulatory effects on the MCH cell line. Enhancement of cell proliferation and tumor 

progression as a potential causal mechanism linking ethanol and breast cancer has some support 

but human subject studies are needed to further explore this connection. According to 

Dumitrescu and Shields, estrogen-induced breast cancer may be as a result of cell proliferation, 

activation of CYP2E1, and DNA damage.10 

Polymorphism in Ethanol Metabolism 

Our searches identified a number of epidemiology studies proposing that both genetic and 

enzyme polymorphisms contribute to the promotion of breast cancer development in individuals 

who consume alcohol (see Table 3). Polymorphisms examined in these studies include 

161,162 38,163-173 cytochrome P450, methylenetetrahydrofolate reductase, and alcohol 

45,47-50,174-178 dehydrogenase and acetaldehyde dehydrogenase. The majority of these studies 

reported enzyme polymorphism as a risk marker for breast cancer following moderate 

alcohol consumption. Our searches did not identify any experimental studies in humans or 

animals that examined this issue. 

DNA Adduct Formation 

DNA adduct formation was examined in an epidemiology study by Rundle et al.159 The 

authors investigated the association between alcohol consumption and DNA adduct levels in 

breast tissue in women diagnosed with ductal carcinoma in situ and invasive ductal or lobular 

cancer (i.e., cases) vs. women with benign conditions without atypia (i.e., controls). In tumor and 

nontumor tissue from cases, adduct levels were increased among drinkers compared to 

nondrinkers. However, among controls, no increase in adduct levels were found regardless of 

drinking status.159 

We identified no experimental human studies that examined this mechanism. We did identify 

experimental studies using animals that suggest intake of ethanol does increase adduct formation 

and could contribute to breast cancer risk.96 Cell line studies also suggested that the formation of 

107,108 DNA adducts increases after incubation with ethanol.

46
 
 

 

 

 

 

 

 

 

Other Potential Mechanisms 

A single human study by Hartman et al.76 reported on increased level of biomarkers of 

oxidative stress such as α-tocopherol and isoprostane after alcohol consumption (see Table C-1 

77-81 in Appendix C). Our searches identified five epidemiology studies that also postulated a 

connection between biomarkers of inflammation, alcohol intake, and risk of breast cancer. 

77,79 81 Increased levels of biomarkers such as malondialdehyde, isoprostanes, and catalase 

78,80 activity were reported. We did not identify any experimental studies using animal or cell line 

models that examined other potential mechanisms. 

Key Question 2. For the most likely mechanisms of action involving alcohol and the 

development of breast cancer, how might other factors modify the effect of alcohol on breast 

cancer (for example, age, latency of effect, intensity, duration, and recency of exposure, presence 

of co-carcinogens, presence of threshold effect)? Do the causal mechanisms vary by cell type or 

other tumor characteristics? 

For this Key Question, we looked for studies that evaluated factors that modify the 

association of alcohol with biomarkers of risk of breast cancer. The human studies of alcohol 

consumption and hormone changes were performed in pre- and postmenopausal women but an 

actual age effect was not examined in these studies. The duration of consumption was relatively 

short; long term effects could not be calculated in these studies. However, we did identify one 

human study that examined biomarkers of oxidative stress and risk of carcinogenesis. Hartman et 

al. reported that in postmenopausal women who consumed 30 g alcohol per day, α-tocopherol 

decreased by 4.6% and isoprostane levels increased by 4.9%.76 This study provides a possible 

link between oxidative stress and risk of breast cancer formation. 

Table 7 and Table 8 contain an overview of the breast cancer studies included in this report 

in terms of study design and reporting issues that determined whether the study provides 

evidence of a direct or an indirect association between alcohol consumption and breast cancer. 

Route of administration, rate of absorption and metabolism, formulation and quantity of ethanol, 

and timing of the intervention, however, may reduce the generalizability of animal studies to a 

clinical setting. Although we evaluated cell line studies as part of our overall evidence 

evaluation, we did not include them in this table given that events such as confounding exposure, 

control for other risk factors, and cancer formation are not applicable to this model. 

47
 
 

 

Table 7. Overall results from human breast cancer studies 

Study 

*Confounding 

Exposure 

Cancer 

Formation 

Surrogate 

Outcome 

Measure 

Authors Reported 

on Causal 

Mechanism 

Number of 

Links in the 

Pathway of 

Carcinogenesis 

Hartman et al. 

200576 

N N Y Y 1 

Dorgan et al. 

200185 

Same as 311 

N N Y Y 1 

Ginsburg et al. 

199688 

N N Y Y 1 

Ginsburg et al. 

199587 

N N Y Y 1 

Reichman et al. 

199386 

N N Y Y 1 

*Confounding exposure: did study administer a carcinogen and /or acetaldehyde? 

Y: there was confounding exposure 

N: there was no confounding exposure 

48
 
 

 

 

 

 

Table 8. Overall results from animal breast cancer studies 

Study 

*Confounding 

Exposure 

Cancer 

Formation 

Surrogate 

Outcome 

Measure 

Authors Reported 

on Causal 

Mechanism 

Number of 

Links in the 

Pathway of 

Carcinogenesis 

Hilakivi-Clarke et al. 

200492 

Y Y N Y 1 

Castro et al. 

200395 

N N Y Y 1 

Chhabra et al. 

200096 

Y N Y Y 1 

Watabiki et al. 

200097 

N N Y Y 1 

Holmberg et al. 

199591 

N Y N N 0 

Singletary et al. 

199593 

Y N Y N 0 

Singletary and 

McNary 199494 

Y N Y Y 1 

Taylor et al. 

199399 

Y N Y Y 1 

McDermott et al. 

1992101 

Y Y N N 0 

Hackney et al. 

1992102 

N Y N N 0 

Singletary and 

McNary 1994104 

N N Y Y 1 

Singletary et al. 

1991105 

Y N Y Y 1 

Rogers and Conner 

1990100 

Y Y N N 0 

Grubbs et al. 

1988103 

Y Y N N 1 

Schrauzer et al. 

197998 

Y N Y Y 1 

*Confounding exposure: did study administer a carcinogen and /or acetaldehyde? 

Y: there was confounding exposure 

N: there was no confounding exposure 

Colorectal Cancer 

Key Question 3. What are the likely causal mechanisms by which alcohol contributes to the 

development of colorectal cancer? Which of the possible mechanisms (e.g., induction of P450 

cytochromes and carcinogen metabolism, effects on blood hormone concentrations, effect of 

acetaldehyde or other alcohol metabolite on apoptosis and DNA repair, interactive effects on 

other nutritional factors, or others) are likely to be most important in colorectal cancer 

development? 

49
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Acetaldehyde production in the colon. Exposure of colon mucosa to acetaldehyde from 

microbial metabolism of ethanol has been postulated as a mechanism for increasing the risk of 

55,56 developing colorectal cancer in two epidemiology studies (see Table 4) and three 

57,307,309 experimental studies (see Table 5). According to study authors, individual variations in 

human colonic flora may contribute to the risk of alcohol-related colorectal cancer,55 and 

increased activity of intracolonic bacterial alcohol dehydrogenase may also play a role in 

56,57,307,309 increasing cancer risk.

Experimental human studies examining this subject are few (see Table C-4 in Appendix C). 

A study by Basuroy et al.83 suggests that acetaldehyde disrupts epithelial tight junction and cell 

adhesion and through this mechanism increases the risk of colon cancer. Several animal studies 

also looked at the effects of acetaldehyde in the colon (see Table C-5 in Appendix C). These 

120 70 studies showed mucosal damage after ethanol consumption, increased degradation of folate,

stimulation of rectal carcinogenesis,122 and an increased effect of carcinogens in the presence of 

acetaldehyde.123 In cell line studies acetaldehyde exposure was reported to influence the initial 

steps of colonic carcinogenesis and later tumor development136 and decrease the activity of some 

brush border enzymes.137 Finally, a study using animal and cell line tissue found evidence that 

acetaldehyde stimulates cell proliferation in animal intestinal crypt cells and therefore 

acetaldehyde may act as a cocarcinogen in the colon.141 These studies suggest that acetaldehyde 

production in the colon may provide a potential causal mechanism by which alcohol contributes 

to the development of colon cancer. 

Cell proliferation. Hyperproliferation of rectal mucosa after exposure to alcohol was 

postulated as a mechanism for increasing the risk of developing colorectal cancer in an 

epidemiology study by Simanowski et al.235 The authors examined rectal biopsies for 

proliferation markers such as histone H3 and Ki67 in 44 heavy drinkers and 26 controls. Heavy 

drinkers showed an increase in cell proliferation markers in the rectal mucosa compared to 

controls.235 

An effect of ethanol consumption on cell proliferation in the colon was investigated in both 

animal and cell line studies in our primary evidence base. Several animal studies reported 

125-127 enhanced growth of mucosal tissue after chronic ethanol consumption. Cell studies 

74,136 indicated that exposure to ethanol and acetaldehyde increases cell proliferation and damages 

DNA which may contribute to cancer development.135 Together these studies suggest that 

ethanol and acetaldehyde exposure in the colorectal mucosa may increase cell proliferation and 

be a potential mechanism connecting alcohol consumption to colorectal cancer risk. 

DNA repair polymorphism. We identified 52 epidemiology studies that assessed DNA 

repair polymorphism and alcohol consumption. The majority of these studies suggested that 

DNA repair polymorphism may influence the risk of colorectal cancer. 

Enzyme polymorphism. We identified 19 studies that assessed enzyme polymorphism in 

epidemiology studies: 13 examined alcohol and acetaldehyde dehydrogenase 

19,241-252 236-240 polymorphism; five examined cytochrome P450 polymorphism; and six 

189,259-263 examined methylenetetrahydrofolate reductase polymorphism. The majority of 

these studies reported enzyme polymorphism as a risk marker for colorectal cancer 

following moderate alcohol consumption. 

Other potential mechanisms. Ethanol may also influence carcinogenesis in the colon and 

rectum through an interaction with carcinogens. Animal studies suggest that ethanol exposure in 

the colon increases the chances of tumor development,132 but other studies found no association 

between ethanol ingestion and colorectal carcinogenesis or instead reported inhibition of 

50
 
 

 

 

 

 

 

73,130,131 tumorigenesis. Other possible mechanisms reported in animal studies include alcohol’s 

70 124 inhibition of folate metabolism and DNA hypomethylation.

Key Question 4. For the most likely mechanisms of action involving alcohol and the 

development of colorectal cancer, how might other factors modify the effect of alcohol on 

colorectal cancer (for example, age, latency of effect, intensity, duration, and recency of 

exposure, presence of co-carcinogens, presence of threshold effect)? Do the causal mechanisms 

vary by cell type or other tumor characteristics? 

For this Key Question, we looked for studies that evaluated factors that modify the 

association of alcohol with biomarkers of colorectal cancer risk. Few studies are available that 

examined factors that modify the effects of ethanol consumption on the risk of developing 

colorectal cancer. The study in human subjects in which biopsy samples were examined for 

damage after exposure to acetaldehyde did not report the influence of personal factors on the 

degree of damage generated.83 

Table 9 and Table 10 contain an overview of the colorectal cancer studies included in this 

report in terms of study design and reporting issues that determined whether the study provides 

evidence of a direct or an indirect association between alcohol consumption and colorectal 

cancer. Route of administration, rate of absorption and metabolism, formulation and quantity of 

ethanol, and timing of the intervention however may reduce the generalizability of animal studies 

to a clinical setting. Although we evaluated cell line studies as part of our overall evidence 

evaluation, we did not include them in this table given that events such as confounding exposure, 

control for other risk factors, and cancer formation are not applicable to this model. 

Table 9. Overall results from human colorectal cancer study 

Study 

*Confounding 

Exposure 

Cancer 

Formation 

Surrogate 

Outcome 

Measure 

Authors 

Reported on 

Causal 

Mechanism 

Number of 

Links in the 

Pathway of 

Carcinogenesis 

Basuroy et al. 

200583 

Y N Y Y 1 

*Confounding exposure: did study administer a carcinogen and/or acetaldehyde? 

Y: there was confounding exposure 

N: there was no confounding exposure 

51
 
 

 

Table 10. Overall results from animal colorectal cancer studies 

Study 

*Confounding 

Exposure 

Cancer 

Formation 

Surrogate 

Outcome 

Measure 

Authors 

Reported on 

Causal 

Mechanism 

Number of 

Links in the 

Pathway of 

Carcinogenesis 

Hayashi et al. 

2007118 

Y N Y Y 1 

Perez-Holanda et al. 

200573 

Y N N N 0 

Pronko et al. 

2002120 

N N Y Y 1 

Roy et al. 

2002121 

N N Y N 1 

Homann et al. 

200070 

N N Y N 1 

Choi et al. 

1999124 

N N Y Y 1 

Hakkak et al. 

1996119 

N N Y Y 1 

Simanowski et al. 

1994125 

N N Y Y 1 

Niwa et al. 

1991126 

Y N Y Y 1 

Seitz et al. 

1990122 

Y N Y Y 1 

McGarrity et al. 

1988129 

Y N Y Y 1 

Hamilton et al. 

1988130 

Y N Y Y 1 

Garzon et al. 

1987128 

Y Y N Y 1 

Hamilton et al. 

1987132 

Y N Y Y 1 

Hamilton et al. 

1987131 

Y N Y Y 1 

Simanowski et al. 

1986127 

N N Y Y 1 

Nelson et al. 

1985116 

Y N N N 0 

Seitz et al. 

1985123 

Y N Y Y 1 

Howarth et al. 

1984117 

Y N N N 0 

*Confounding exposure: did study administer a carcinogen and/or acetaldehyde? 

Y: there was confounding exposure 

N: there was no confounding exposure 

52
 
 

 

 

 

 

 

 

Excluded Studies 

Because this is a systematic review using specific inclusion and exclusion criteria with the 

creation of specific Key Questions, the report is directed at evidence that addresses each 

Key Question. None of the excluded studies (see Table D-1 in Appendix D) were left out for 

quality, design, conduct, integrity, or inaccuracy but rather because they did not address these 

Key Questions. 

Future Research Goals 

Our examination of the epidemiology literature correlating alcohol consumption with cancer 

risk has suggested many areas in which experimental research may provide insight into the actual 

mechanisms connecting cancer risk and alcohol consumption. For breast cancer these potential 

mechanisms are changes in circulating hormone levels and changes in hormone receptors, 

DNA-adduct formation, and various enzyme polymorphisms related to alcohol metabolism. 

For colorectal cancer these areas are DNA repair polymorphisms, mucosal cell proliferation, and 

various enzyme polymorphisms related to alcohol metabolism. Experimental studies in humans, 

animals, or cell lines have provided basic information on some but not all of these potential 

mechanisms. 

The connection between alcohol intake and changes in estrogen levels and breast cancer risk 

has been studied in human, animal, and cell line studies. Future research in this area would seem 

to be warranted to determine the exact level of risk imposed by this pathway. A connection 

between cell proliferation and tumor progression in breast cancer has been suggested by animal 

studies but not in human studies and human-based studies in this area would seem to be 

warranted. Enzyme polymorphism in ethanol metabolism as well as in other metabolic pathways 

that may be influenced by alcohol may require more human-based studies as opposed to animal 

studies where polymorphism is not a factor. DNA adduct formation has not been well studied in 

human or animal studies and research in this area should be expanded. Oxidative stress and 

inflammation associated with alcohol consumption have been postulated as risk factors in 

epidemiology studies but not studied to any extent in hypothesis-generating studies. Oxidative 

stress and inflammation should be examined with better experimentally controlled studies. 

Experimental human studies examining the connection between alcohol intake and colorectal 

cancer are few. Many potential mechanisms related to acetaldehyde production in the colon, 

cell proliferation due to ethanol or acetaldehyde exposure, alterations in DNA repair 

mechanisms, and the influence of carcinogens and alcohol in the colon need to be examined in 

human-based studies. Animal studies are also needed to examine the influence of bacterial flora, 

the effects of ethanol and acetaldehyde on the colon, especially changes in cell proliferation and 

DNA, and the interaction between carcinogens and ethanol and acetaldehyde. 

Conclusions 

Based on our systematic review of the literature, many potential mechanisms by which 

alcohol may influence the development of breast or colorectal cancers have been explored but 

the exact connection or connections remain unclear. The evidence points in several directions but 

the importance of any one mechanism is not apparent at this time. 

Table 11 through Table 13 summarizes the mechanisms on alcohol consumption and the risk 

of breast cancer as presented in studies identified in this report. Six human, five animal and 

five cell line studies reported on changes in hormonal levels as the potential causal mechanism 

53
 
 

 

 

 

by which alcohol consumption may contribute to the development of breast cancer. Our findings 

are comparable to the most commonly reported mechanisms in most of the breast cancer 

epidemiology studies summarized in Table 3. 

Table 11. Reported mechanisms in human breast cancer studies 

Number 

of 

Mechanism Reported by Study Authors Studies References 

Change in levels of estrogen, progesterone, and DHEA 2 85,311 

Change in level of estrogen 1 88 

Elevation of prolactin 1 87 

Elevation of estrogens and DHEA 1 86 

Table 12. Reported mechanisms in animal breast cancer studies 

Number 

of 

Mechanism Reported by Study Authors Studies References 

Change in level of estrogen 3 92-94 

Biotransformation of ethanol to acetaldehyde 1 95 

Formation of DNA adducts 1 96 

Elevation of prolactin 2 97,98 

Effects on DNA synthesis 2 104,105 

Suppression of cellular immunity 1 99 

54
 
 

 

Table 13. Reported mechanisms in cell line breast cancer studies 

Number 

of 

Mechanism Reported by Study Authors Studies References 

Effect on estrogen receptor- α expression 5 65,67-69,106 

Effect on peroxisome proliferator-activated receptor (PPAR)-α and PPAR-β 

transactivation 

1 115 

Formation of DNA adducts 2 107,108 

Disruption and modulation of cell proliferation 2 51,109 

Upregulation of transcription of smooth muscle myosin alkali light chain 1 114 

Upregulation of mammary gland mucin 1 113 

Direct growth stimulatory effect by enhancement on 3H-thymidine 1 110 

Change in potassium channels 1 112 

Increase cAMP levels 1 111 

Table 14 through Table 17 summarizes the mechanisms of alcohol consumption and the risk 

of colorectal cancer as presented in studies identified in this report. One human study exposed 

colonic mucosa biopsies to vapor-phase acetaldehyde and reported an effect of acetaldehyde on 

cell adhesion as the most likely causal mechanisms by which alcohol consumption may 

contribute to the development of colorectal cancer. In contrast, nine animal studies reported a 

local toxic effect of acetaldehyde resulting in mucosal damage as the most likely causal 

mechanism by which alcohol consumption may contribute to development of colorectal cancer. 

Other mechanisms identified in this report include: 

increase in cytochrome P4502E1 expression (two animal studies) 

effect on DNA synthesis and methylation (two animal studies, two cell line studies) 

effect on cell proliferation (two cell line studies) 

apoptotic cell death (three cell line studies) 

effect on various stages of carcinogenesis (two animal studies) 

changes in polyamine content (one animal study) 

effect of acetaldehyde on brush border enzymes (one cell line study) 

modulation of gene expression (one cell line study). 

Our findings are comparable to some of the most common mechanisms (e.g., colonic 

microbial production of acetaldehyde, effect on DNA methylation and synthesis) reported by the 

colorectal cancer epidemiology studies summarized in Table 4. 

55
 
 

 

 

 

 

 

 

 

 

 

 

Table 14. Reported mechanisms in human colorectal cancer study 

Mechanism Reported by Study Authors 

Number of 

Studies References 

Effect of acetaldehyde on cell to cell adhesion 1 83 

Table 15. Reported mechanisms in animal colorectal cancer studies 

Mechanism Reported by Study Authors 

Number of 

Studies References 

Local toxic effect of acetaldehyde resulting in mucosal damage and cell 

proliferation 

9 70,120-123,125-

128 

Increase cytochrome P4502EI expression 2 118,119 

DNA methylation and synthesis 2 132,139 

Effect on various stages of carcinogenesis 2 130,131 

Changes in polyamine content 1 129 

Table 16. Reported mechanisms in cell line colorectal cancer studies 

Mechanism Reported by Study Authors 

Number of 

Studies References 

Effect on DNA methylation and synthesis 2 134,140 

Apoptotic cell death 3 75,133,134 

Effect on cell proliferation 3 74,136,138 

Effect of acetaldehyde on brush border enzyme 1 137 

Modulation of gene expression 1 139 

Table 17. Reported mechanisms in combination (animal, cell lines) colorectal cancer study 

Mechanism Reported by Study Authors 

Number of 

Studies References 

Effect on cell proliferation 1 141 

Limitations 

The evidence base for the report included 66 studies: 

six human studies (five breast cancer, one colorectal cancer) 

34 animal studies (15 breast cancer, 19 colorectal cancer) 

25 cell line studies (15 breast cancer, 10 colorectal cancer) 

56
 
 

 

 

 

 

 

one combination study (animal, cell line) on colorectal cancer. 

Therefore the evidence in support of any potential mechanism connecting alcohol intake to 

cancer development is based largely on animal models. Animal models are important tools for 

understanding disease mechanisms but they have limitations when predicting the actual course of 

events in humans.82 Reviews of animal studies have shown that there is a tendency to publish 

studies with positive results and not to publish studies that suggest no difference in measured 

outcomes (i.e., publication bias). Therefore studies that could possibly rule out mechanisms 

connecting alcohol and cancer may not be published. Positive results in animal studies may not 

translate to a clinical setting because carcinogens were administered in a controlled setting that is 

not characteristic of human conditions. Most experimental animals are young and rarely have 

comorbidities, a situation that may also limit generalizability of animal studies to clinical 

studies.312 

Few human studies met the inclusion criteria for this report and this limited the comparisons 

that could be made between the findings of animal studies and those in human studies. Exact 

alcohol exposure can be controlled in animal studies but few human studies have done the same. 

While the four breast cancer human studies actually administered and quantified the amount of 

ethanol, the only colorectal cancer study administered acetaldehyde to biopsied colonic mucosa. 

Because of the limited number of human studies in our evidence base, we did look at potential 

mechanisms suggested in epidemiology studies and compared them to mechanisms examined in 

animal and cell line studies. 

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Cancer Res 1985 Aug;45(8):3415-43. Giannini A, Biggeri A, Gee J, Przybylska K, 

PMID: 3926298 Cheynier V, Dolara P. Effect of polyphenolic 

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malignant melanoma promoted by alcohol- on 1,2-dimethylhydrazine-induced colon 

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417.	 Hall CN, Badawi AF, O’Connor PJ, Saffhill R. 

The detection of alkylation damage in the DNA 

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role in breast carcinogenesis? An unresolved 

hypothesis. Cancer Causes Control 2007 

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419.	 Kabat GC, Miller AB, Jain M, Rohan TE. 

Dietary iron and heme iron intake and risk of 

breast cancer: a prospective cohort study. 

[erratum appears in Cancer Epidemiol 

Biomarkers Prev. 2007 Nov;16(11):2519]. 

Cancer Epidemiol Biomarkers Prev 2007 

Jun;16(6):1306-8. PMID: 17548704 

420.	 Lagiou P, Samoli E, Lagiou A, Georgila C, 

Zourna P, Barbouni A, Gkiokas G, Vassilarou D, 

Tsikkinis A, Sfikas C, Sekeris CE, Hsieh CC, 

Adami HO, Trichopoulos D. Diet and expression 

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421.	 Etique N, Chardard D, Chesnel A, Flament S, 

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422.	 Linz AL, Xiao R, Parker JG, Simpson PM, 

Badger TM, Simmen FA. Feeding of soy protein 

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suppresses formation of aberrant crypt foci in 

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fetal alcohol exposure. J Carcinog 2004 

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423.	 Luceri C, Caderni G, Sanna A, Dolara P. 

Red wine and black tea polyphenols modulate the 

expression of cycloxygenase-2, inducible nitric 

oxide synthase and glutathione-related enzymes 

in azoxymethane-induced f344 rat colon tumors. 

J Nutr 2002 Jun;132(6):1376-9. PMID: 12042461 

424.	 Moon YJ, Wang X, Morris ME. Dietary 

flavonoids: effects on xenobiotic and carcinogen 

metabolism. Toxicol In Vitro 2006 

Mar;20(2):187-210. PMID: 16289744 

425.	 Morris JJ, Seifter E. The role of aromatic 

hydrocarbons in the genesis of breast cancer. 

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PMID: 1513270 

426.	 Nozawa H, Yoshida A, Tajima O, Katayama M, 

Sonobe H, Wakabayashi K, Kondo K. Intake of 

beer inhibits azoxymethane-induced colonic 

carcinogenesis in male Fischer 344 rats. 

Int J Cancer 2004 Jan 20;108(3):404-11. 

PMID: 14648707 

427.	 Nozawa H, Tazumi K, Sato K, Yoshida A, 

Takata J, Arimoto-Kobayashi S, Kondo K. 

Inhibitory effects of beer on heterocyclic amineinduced mutagenesis and PhIP-induced aberrant 

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Environ Mutagen 2004 Apr 11;559(1-2):177-87. 

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428.	 Nozawa H, Nakao W, Zhao F, Kondo K. 

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Aug;49(8):772-8. PMID: 15968705 

429.	 Peluso M, Airoldi L, Munnia A, Colombi A, 

Veglia F, Autrup H, Dunning A, Garte S, 

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Clavel-Chapelon F, Linseisen J, Boeing H, 

Trichopoulou A, Palli D, Krogh V, Tumino R, 

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4-aminobiphenyl-haemoglobin adducts and diet 

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430.	 Reddy BS, Wang CX, Samaha H, Lubet R, 

Steele VE, Kelloff GJ, Rao CV. 

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dietary perillyl alcohol. Cancer Res 1997 

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431.	 Robson EJ, Khaled WT, Abell K, Watson CJ. 

Epithelial-to-mesenchymal transition confers 

resistance to apoptosis in three murine mammary 

epithelial cell lines. Differentiation 2006 

Jun;74(5):254-64. PMID: 16759291 

432.	 Schrauzer GN, Hamm D, Kuehn K, 

Nakonecny G. Effects of long term exposure to 

beer on the genesis and development of 

spontaneous mammary adenocarcinoma and 

prolactin levels in female virgin C3H/St mice. 

J Am Coll Nutr 1982;1(3):285-91. 

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433.	 Takechi R, Hiramatsu N, Mamo JC, Pal S. 

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intestinal CaCo-2 cells. Biofactors 2004;22(1-

4):181-3. PMID: 15630279 

434.	 Wulf G, Garg P, Liou YC, Iglehart D, Lu KP. 

Modeling breast cancer in vivo and ex vivo 

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435.	 Yamagishi M, Natsume M, Osakabe N, 

Nakamura H, Furukawa F, Imazawa T, 

Nishikawa A, Hirose M. Effects of cacao liquor 

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Sevanian A, Haile RW. Role of lipid 

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437.	 Gaudet MM, Gammon MD, Santella RM, 

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Bensen JT, Schroeder J, Olshan AF, Neugut AI, 

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pro- and anti-oxidant environmental modifiers, 

and breast cancer among women on Long Island, 

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of colorectal polyps. Tech Coloproctol 2004 

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Wargovich MJ, Fina MF, Roufail WM, 

Geisinger KR. Polymorphism of the cyclin D1 

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440.	 Orita S, Hirose M, Takahashi S, Imaida K, Ito N, 

Shudo K, Ohigashi H, Murakami A, Shirai T. 

Modifying effects of 1’-acetoxychavicol acetate 

(ACA) and the novel synthetic retinoids Re-80, 

Am-580 and Am-55P in a two-stage 

carcinogenesis model in female rats. 

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441.	 Schatzkin A, Freedman L, Schiffman M. 

An epidemiologic perspective on biomarkers. 

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442.	 Visapaa JP, Jokelainen K, Nosova T, 

Salaspuro M. Inhibition of intracolonic 

acetaldehyde production and alcoholic 

fermentation in rats by ciprofloxacin. 

Alcohol Clin Exp Res 1998 Aug;22(5):1161-4. 

PMID: 9726290 

79 

 

 

 

 

 

 

List of Acronyms/Abbreviations
 

ADH: alcohol dehydrogenase 

ALDH: aldehyde dehydrogenase 

AJ: adherens junctions 

AMMN: acetoxymethyl-methylnitrosamine 

AOM: azoxymethane 

BPDE: benzo[a]pyrene diolepoxide 

BRCA1: breast cancer type 1 

cAMP: cyclic adenosine monophosphate 

CM: colonic mucosa 

CY: cyanamide 

CYP2E1: cytochromes P450 2E1 

DHEA: dehydroepiandrosterone 

DHEAS: DHEA sulfate 

DMBA: dimethylene (a) anthracene 

DMH: 1,1-dimethylhydrazine 

DNA: deoxyribonucleic acid 

EGFR: epidermal growth factor receptor 

ER: estrogen receptor 

ERT: estrogen replacement therapy 

FCS: fetal calf serum 

HLA: human leukocyte antigen 

H2O2: hydrogen peroxide 

H2O: water 

JACC: Japan Collaborative Cohort Study 

JPHC: Japan Public Health Center-based Prospective Study 

MAA: mutagenic malondialdehyde-acetaldehyde 

MAM: methylazoxymethanol 

MEOS: microsomal ethanol-oxidizing system 

MLC: myosin alkali light chain 

MNU: N-methyl-N-nitrosurea 

NAD: nicotinamide adenine dinucleotide 

NADH: reduced nicotinamide adenine dinucleotide 

NMDA: N-nitrosodimethylamine 

NNK: 4-methylnitrosoamino-1-3-pyridyl-1-butanone 

PK: protein kinase 

PPAR: peroxisome proliferator-activated receptor 

PR: progesterone receptor 

ROS: reactive oxygen species 

rp: ribosomal protein 

SAM: s-adenosylmethionine 

TNF: tumor necrosis factor 

TJ: tight junctions 

81
 
 

 

Appendix A: Exact Search Strings 

Electronic Database Searches 

The following databases have been searched for relevant information: 

Name Date Limits Platform/Provider 

Cancerlit 1935 - September 18, 2009 www.pubmed.gov 

ClinicalTrials.gov Searched February 1, 2009 www.clinicaltrials.gov 

The Cochrane Central Register 

of Controlled Trials (CENTRAL) 

Through 2010, Issue 1 www.thecochranelibrary.com 

The Cochrane Database of 

Methodology Reviews 

(Methodology Reviews) 

Through 2010, Issue 1 www.thecochranelibrary.com 

The Cochrane Database of 

Systematic Reviews 

(Cochrane Reviews) 

Through 2010, Issue 1 www.thecochranelibrary.com 

Database of Abstracts of 

Reviews of Effects (DARE) 

Through 2010, Issue 1 www.thecochranelibrary.com 

EMBASE (Excerpta Medica) 1980 through May 3, 2010 OVID 

Health Technology Assessment 

Database (HTA) 

Through 2010, Issue 1 www.thecochranelibrary.com 

MEDLINE 1965 through May 3, 2010 OVID 

U.K. National Health Service 

Economic Evaluation Database 

(NHS EED) 

Through 2010, Issue 1 www.thecochranelibrary.com 

A-1
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Medical Subject Headings (MeSH), EMTREE, PsycINFO and Keywords 

Conventions: 

OVID 

$ = truncation character (wildcard)
 

exp = “explodes” controlled vocabulary term (e.g., expands search to all more specific 

related terms in the vocabulary’s hierarchy) 

/ = limit controlled vocabulary heading 

.fs. = floating subheading 

.hw. = limit to heading word 

.md. = type of methodology (PsycINFO) 

.mp. = combined search fields (default if no fields are specified) 

.pt. = publication type 

.ti. = limit to title 

.tw. = limit to title and abstract fields 

PubMed 

[mh] = MeSH heading 

[majr] = MeSH heading designated as major topic 

[pt] = publication type 

[sb] = subset of PubMed database (PreMEDLINE, Systematic, OldMEDLINE) 

[sh] = MeSH subheading (qualifiers used in conjunction with MeSH headings) 

[tiab] = keyword in title or abstract 

A-2
 
Topic-specific search terms – alphabetical listing 

Concept Controlled Vocabulary Keywords 

Adrenal Adrenal.hw. 

exp Adrenal gland/ 

exp Adrenal glands/ 

exp Endocrine system/ 

Adrenal 

Aldosterone 

Endocrine gland$ 

Primary hyperaldosteroneism 

Alcohol Alcohol 

Alcohol abstinence 

Alcohol drinking 

exp Alcohol-related disorders 

exp Alcoholic beverage 

exp Alcoholic beverages 

Alcohol metabolism 

Drinking behavior 

Ethanol 

Feeding behavior 

Food habits 

Temperance 

Abstinence 

Alcohol$ 

Beer 

Brandy 

Cocktail$ 

EtOH 

Gin 

Liqueur$ 

Liquor$ 

Mixed drink$ 

Schnapps 

Spirits 

Vodka 

Biochemical Processes Exp biochemical processes/ 

Breast cancer exp breast cancer 

Breast carcinoma 

exp Breast diseases 

exp Breast neoplasms 

Breast$ 

Cancer$ 

Carcinoma$ 

Lesion$ 

Lump$ 

Mammar$ 

Tumo?r$ 

Colorectal cancer Adenomatous polyp 

Colorectal cancer 

Colorectal carcinoma 

Exp colorectal neoplasms 

Cancer$ 

Carcinoma$ 

Colon$ 

Colorectal 

Lesion$ 

Polyp$ 

Rectal 

Rectum 

Tumo?r$ 

Experimental neoplasms Experimental neoplasm/ 

exp Neoplasms, experimental/ 

A-3
 
Concept Controlled Vocabulary Keywords 

Hypothalamic-hypophyseal 

system 

Hypothalamo-hypophyseal system 

Hypothalamus hypophysis system 

Pituitary gland 

Hypothalamus hypophysis 

gonad system 

Microbes Achlorhydria/ 

Bacteria, aerobic 

Candida albicans 

Colon flora 

Intestine flora 

Microbial growth 

Microbiology.fs. 

microorganism 

Bacteria 

Bacteriocolonic 

Flora 

Microb$ 

Microflora 

Yeast$ 

Oncogenesis Breast carcinogenesis 

Chemical carcinogenesis 

Colorectal carcinogenesis 

Malignant neoplastic disease 

exp neoplastic processes 

exp Oncogenesis and malignant 

transformation 

Carcinogenesis 

Oncogenesis 

Tumorigenesis 

Tumorigenic effect 

Potential mechanisms 5,10 methlyenetetrahydrofolate 

reductase (FADH2) 

Acetaldehyde 

Alcohol dehydrogenase 

Aldehyde dehydrogenase 

ALDH2 

Apoptosis 

Calcium signaling 

Cell cycle 

Cell cycle regulation 

Cell division 

Cell membrane permeability 

Cell nucleus 

Cell proliferation 

Cyclin dependent kinase 2 

cyp2E1 

Cytochrome p-450 enzyme system 

cytochrome p450 17 

cytochrome p450 1A1 

cytochrome p450 1A2 

Acetaldehyde$ 

MAPK 

MAPKs 

NFkappaB 

Proto-oncogene 

Reactive oxygen 

A-4
 
Concept Controlled Vocabulary Keywords 

cytochrome P450 1B1 

cytochrome P-450 CYP1A1 

cytochrome P-450 CYP1A2 

cytochrome P-450 CYP2B1 

cytochrome P-450 CYP2D6 

cytochrome P-450 CYP2E1 

cytochrome P-450 CYP3A 

Deamination 

DNA adducts 

exp DNA-binding proteins 

DNA damage 

Down regulation 

Estrogen activity 

Estrogen metabolism 

Estrogen receptor, alpha 

Estrogen receptor beta 

Fas antigen 

Folate metabolism 

exp Folic acid 

Folic acid 

Folic acid deficiency 

Gene control 

exp Gene expression regulation 

Gene function 

Gene mutation 

Genetic code 

Genetic polymorphism 

Genetic variability 

Growth regulation modulation 

hydroxylation 

MAP kinase signaling system 

Metabolism.fs. 

Methionine synthase 

Mitochondria 

exp Mitogen-activated kinases 

Mitogen activated protein kinase 

NF-kappa B 

Oxidative phosphorylation 

Oxidative stress 

A-5
 
Concept Controlled Vocabulary Keywords 

p16 protein human.sn. 

Polymorphism, genetic 

Protein expression 

Protein p16 

Proto oncogene 

Exp reactive nitrogen species 

Reactive oxygen metabolite 

Exp Reactive oxygen species 

Receptor cross talk 

Receptor upregulation 

exp Receptors, estrogen 

exp Receptors, retinoic acid 

Retinoid 

Retinoic acid receptor beta 

exp Signal transduction 

exp Transferases 

Tretinoin 

A-6
 
EMBASE/MEDLINE 

English language, remove overlap 

Set 

Number Concept Search Statement 

1 Alcohol Alcohol drinking/ or exp alcohol-related disorders/ or alcohol metabolism/ 

2 exp alcoholic beverage/ or exp alcoholic beverages/ or alcohol/ or ethanol/ 

or beer or wine or alcohol$ or brandy$ or gin or vodka or schnapps or 

EtOH or liquor$ or liqueur$ or spirits or mixed drink$ or cocktail$ 

3 Drinking behavior/ or food habits/ or feeding behavior/ or temperance/ or 

alcohol abstinence/ or abstinence 

4 Combine sets or/1-3 

Oncogenesis 

5 Carcinogenesis Exp neoplastic processes/ or exp oncogenesis and malignant 

transformation/ or malignant neoplastic disease/ or breast carcinogenesis/ 

or colorectal carcinogenesis/ or chemical carcinogenesis/ or exp 

neoplasms, experimental/ or experimental neoplasms 

6 Carcinogenesis or oncogenesis or tumorigenesis or tumorigenic effect 

7 Combine sets or/5-6 

Potential 

mechanisms 

8 Proto oncogene/ or proto-oncogene or exp DNA-binding proteins/ 

9 Metabolism.fs. or deamination/ 

10 Signaling Receptor cross-talk/ or exp signal transduction/ or calcium signaling/ or 

exp gene expression regulation/ or down regulation/ or protein expression/ 

or receptor upregulation/ or growth regulation modulation/ 

11 Estrogen Estrogen receptor, alpha/ or exp receptors, estrogen/ or estrogen activity/ 

or estrogen metabolism/ or estrogen receptor beta/ 

12 MAPK Exp mitogen-activated kinases/ or MAP kinase signaling system/ or 

mitogen activated protein kinase/ or MAPK or MAPKs 

13 Cytochrome 

P-450 

Cytochrome p-450 enzyme system/ or cyp2E1/ or cytochrome P450 17/ or 

cytochrome P450 1A1/ or cytochrome P450 1A2/ or cytochrome P450 

1B1/ or cytochrome P-450 CYP1A1/ or cytochrome P-450 CYP1A2/ or 

cytochrome P-450 CYP2B1/ or cytochrome P-450 CYP2D6/ or cytochrome 

P-450 CYP2E1/ or cytochrome P-450 CYP3A/ 

14 Dehydrogenases Alcohol dehydrogenase/ or aldehyde dehydrogenase/ or ALDH2/ or 

acetaldehyde$ 

15 Methylation exp Folic acid/ or Folic acid/ or folic acid deficiency/ or folate metabolism/ 

16 DNA methylation/ or RNA methylation/ or DNA hypermethylation/ or DNA 

hypomethylation/ or methylation 

17 Methionine synthase/ 

A-7
 
 

Set 

Number Concept Search Statement 

18 Cyclin dependent kinase 2/ or Fas antigen/ or 5,10 

methlyenetetrahydrofolate reductase FADH2/ or Protein p16/ or p16 

protein human.nm. 

19 Cells Apoptosis/ or cell division/ or cell proliferation/ or cell cycle/ or cell cycle 

arrest/ or cell cycle regulation/ or cell membrane permeability/ or cell 

nucleus/ 

20 Misc. genetic 

concepts 

Gene control/ or gene function/ or gene mutation/ or genetic code/ or 

genetic polymorphism/ or genetic variability/ or polymorphism, genetic/ 

21 DNA DNA adducts/ or DNA damage/ or mitochondria/ or exp DNA-binding 

proteins/ 

22 Oxidation Reactive oxygen metabolite/ or oxidative stress/ or hydroxylation/ or exp 

reactive oxygen species/ or oxidative phosphorylation/ or reactive oxygen 

or exp reactive nitrogen species/ 

23 Retinoic acid Retinoid/ or retinoic acid receptor beta/ or exp receptors, retinoic acid/ or 

tretinoin/ 

24 NF-kappa B/ or NFkappaB 

25 Exp transferases/ 

26 Acetaldehyde Exp acetaldehyde/ or acetaldehyde$ 

27 Biochemical 

processes 

(includes DNA 

repair) 

Exp biochemical processes/ 

28 Adrenal Exp Adrenal gland/ or exp adrenal glands/ or adrenal.hw. or adrenal.tw. or 

aldosterone or primary hyperaldosteroneism or exp endocrine system/ or 

endocrine gland$ 

29 Hypothalamic Hypothalamo-hypophyseal system/ or hypothalamus hypophysis system/ 

or Hypothalamus hypophysis gonad system or pituitary gland/ 

30 Microbial Microflora or microbiology.fs. or microb$.ti. or achlorhydria/ or bacteria, 

aerobic/ or candida albicans/ or colon flora/ or intestine flora/ or microbial 

growth/ or microorganism/ or bacteria or bacteriocolonic or flora or 

Microflora or yeast$ 

31 Combine sets 

(mechanisms) 

or/8-30 

32 Breast cancer exp Breast neoplasms/ or exp breast diseases/ or exp breast cancer/ or 

breast carcinoma/ 

33 (breast or mammar$) and (tumo?r$ or lesion$ or cancer$ or carcinoma$ or 

lump$) 

34 Combine sets 

(breast cancer) 

or/32 -33 

A-8
 
 

 

Set 

Number Concept Search Statement 

35 Colorectal 

cancer 

Exp colorectal neoplasms/ or adenomatous polyp/ or colorectal cancer/ or 

colorectal carcinoma/ 

36 (colon$ or rectal or rectum or colorectal) and (tumo?r$ or lesion$ or 

cancer$ or carcinoma$ or polyp$) 

37 Combine sets 

(colorectal 

cancer) 

or/35-36 

38 Combine sets 

Alcohol, 

oncogenesis & 

breast cancer 

4 and 7 and 34 

39 Combine sets 

Alcohol, 

mechanisms & 

breast cancer 

4 and 31 and 34 

40 Combine sets 

Alcohol, 

oncogenesis & 

colorectal cancer 

4 and 7 and 37 

41 Combine sets 

Alcohol, 

mechanisms & 

colorectal cancer 

4 and 31 and 37 

42 Combine sets 38 or 39 or 40 or 41 

43 Limit to English 42 and English 

44 Non-English 42 not 43 

45 Eliminate 

overlap 

Remove duplicates from 43 

A-9
 
 

 

Submit Data Submit Data

 

Submit Data

 

Submit Data

Appendix B: Sample Data Abstraction Forms 

Level 1 – Abstract Review: At this review level abstracts were examined to determine if a 

document should be retrieved for further review. Checking the inclusion boxes in the form 

automatically led to retrieval of the full article. All documents selected for inclusion at this level 

fell to the next level for evaluation. 

Keywords: 

Abstract: 

1. Include or Exclude document 

Include 

Exclude 

Include: Non-English Language 

Clear Selection 

Level 2 – Full Document Review: At this level we made the final determination as to whether 

the document was to be excluded or included in the report. The reason for exclusion was noted in 

a separate box on the form. All documents selected for inclusion at this level fell to the next level 

for evaluation. 

Keywords: 

1. Is this document included in the Report (includes 

Abstract: 

Background and Evidence)? 

Include in Report 

Exclude 

Clear Selection 

2. Reason for Exclusion 

Enlarge Shrink 

B-1
 
 

 

 

Level 3 – Background Document Review: At this level we determined if the document will appear 

in the Background section of the report or in the Evidence section of the report. If the document 

was to be used as background material this form was used to indicate which area in the 

Background section the document belonged. All documents selected for inclusion in the evidence 

report at this level fell to the next level for evaluation. 

Submit Data

1. Is this document included in the Background only or the Evidence Report? 

Include in Evidence Report 

Include in Background Only 

Clear Selection 

2. If Included for Background only, which of the following apply? 

Basic cancer mechanisms 

Breast cancer mechanisms 

Colorectal cancer mechanisms 

Alcohol metabolism 

Epidemiology of alcohol and cancer 

Other components of alcoholic drinks 

B-2
 
 

 

Submit Data

Level 4 – Evidence Base Document Review: Only documents that were used in the evidence 

report appeared at this level. Information recorded at this level was used to organize the 

documents into specific areas of study depending on study design. 

Submit Data

1. Which of the following apply to this document? 

Human studies - breast 

Animal models - breast 

Animal tissues - breast 

Cell lines - breast 

Human studies - colorectal 

Animal models - colorectal 

Animal tissues - colorectal 

Cell lines - colorectal 

B-3
 
 

 

 

Table B-1. Data abstraction and data management 

Document ID#: internal ECRI Institute ID number 

Article Citation 

Country where study was completed 

Year in which the study was performed 

Experimental Model: type of animal model or cell line 

Primary Mechanism examined: mechanism being tested for relationship between alcohol intake and 

cancer risk 

Secondary Mechanism examined: for studies that explore multiple mechanisms 

Amount of Alcohol Exposure: levels of alcohol exposure depending on the design of the experiment 

and the experimental model 

Mode of Administration: mode of administration of alcohol depending on the design of the experiment 

and the experimental model 

Duration of Alcohol Exposure: duration of alcohol exposure depending on the design of the 

experiment and the experimental model 

Use of a Carcinogen: the carcinogenic agent, if any, being examined in the study along with alcohol 

Use of other non-carcinogen agents: nutritional or other interventional agents utilized to show the 

relationship between alcohol intake and cancer risk 

Description of subject characteristics in human studies: age, male/female ratio, smoking, 

comorbidities, race/ethnicity, alcoholism 

Study design: explains the type of study design 

Duration of the study 

Direct or Indirect Association: explains evidence of carcinogenesis 

Results for Intermediate Outcomes: usually molecular, biochemical, or histological outcomes which 

may be indicative of a direct or indirect relationship between alcohol intake and cancer risk 

Results for Clinical Outcomes: typically broader organ measurements that correlate to a direct or 

indirect relationship between alcohol intake and cancer risk 

Results for Patient Oriented Outcomes: entries in this column are only for human studies 

Conclusions: did the study present evidence for or against the proposed mechanism 

B-4
 
 

 

 

Appendix C: Evidence Tables 

Evidence Base for Breast Cancer 

Table C-1. Summary of results from human studies on breast cancer 

Study Model Study Design Mechanism Examined 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure Results 

Conclusions as 

Reported by 

Study Authors 

Hartman et al. 

200576 

53 postmenopausal 

women 

Case control Increase levels of 

biomarkers of 

oxidative stress 

Controlled diet 

plus each of 

three treatments 

(15 or 30 g 

alcohol per day 

or no-alcohol 

placebo 

beverage), during 

three 8-week 

periods in 

random order 

After adjusting for 

body mass index 

(all models) and 

total serum 

cholesterol 

(tocopherol and 

isoprostane 

models), there was 

a 4.6% decrease 

(p = 0.02) in 

α-tocopherol and a 

4.9% increase 

(p = 0.07) in 

isoprostane levels 

when women 

consumed 30 g 

alcohol/day 

(p = 0.06 and 0.05 

for overall effect of 

alcohol on atocopherol and 

isoprostanes, 

respectively). 

Moderate 

alcohol 

consumption 

increases some 

biomarkers of 

oxidative stress 

in 

postmenopausal 

women. 

C-1
 
 

 

 

Study Model Study Design Mechanism Examined 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure Results 

Conclusions as 

Reported by 

Study Authors 

Dorgan et al. 

200185 

Same as 311 

51 healthy 

postmenopausal 

women not using 

hormone 

replacement 

therapy 

Three-period 

crossover 

design 

Elevated serum levels of 

estradiol, estrone, 

estrone sulfate, 

testosterone, 

androstenedione, 

progesterone, 

dehydroepiandrosterone 

(DHEA), DHEA sulfate 

(DHEAS), and 

androstenediol 

15 g or 30 g of 

alcohol per day 

or an alcohol-free 

placebo 

beverage through 

a three 8-week 

dietary period. 

Alcohol was 

supplied as 

95% ethanol in 

12 oz orange 

juice. Each 

dietary period 

was preceded by 

a 2- to 5-week 

washout period 

when participants 

did not consume 

any alcohol. 

15 g of alcohol/day 

resulted in an 

increase of 7.5% 

(95% confidence 

interval [CI]: 

-0.3 to 15.9%; 

p = 0.06) of estrone 

sulfate. 30 g of 

alcohol/day 

resulted in an 

increase of 10.7% 

(95% CI: 

2.7 to 19.3%; 

p = 0.009) 

estrone sulfate 

15 g of alcohol/day 

resulted in an 

increase of 5.1% 

(95% CI: 1.4 to 

9.0%; p = 0.008) 

DHEAS. 30 g of 

alcohol/day 

resulted in an 

increase of 7.5% 

(95% CI: 3.7 to 

11.5%; p <0.001) 

DHEAS 

Results suggest 

a possible 

mechanism by 

which 

consumption of 

one or two 

alcoholic drinks 

per day by 

postmenopausal 

women could 

increase their 

risk of breast 

cancer. 

C-2
 
 

 

 

 

 

 

Study Model Study Design Mechanism Examined 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure Results 

Conclusions as 

Reported by 

Study Authors 

Ginsburg et al. 

199688 

12 postmenopausal 

women receiving 

oral estrogen 

(estradiol, 

1 mg/day) and 

progestin 

(medroxyprogesterone 

acetate) 

replacement 

therapy were 

compared with 

12 postmenopausal 

women who were 

not using estrogen 

replacement 

therapy (ERT). 

Randomized, 

double-blind, 

placebocontrolled 

crossover study 

Effects of alcohol 

ingestion on estrogens in 

postmenopausal women 

Pineapple juice 

and 40% ethanol 

at a dose of 

2.2 mL/kg of 

body weight 

(0.7 g/kg of body 

weight) in a total 

volume of 

300 mL over 

15 minutes 

Within 50 minutes 

of alcohol ingestion 

in postmenopausal 

women on ERT, 

there was a 

3-fold increase in 

estradiol levels 

from 297 to 

973 pmol/L 

(p <0.001) 

No changes in 

estradiol following 

alcohol ingestion in 

postmenopausal 

women not on ERT 

Acute alcohol 

ingestion may 

lead to 

significant and 

sustained 

elevations in 

circulating 

estradiol. 

Ginsburg et al. 

199587 

14 menopausal 

women using 

transdermal 

estradiol 

Two randomized 

crossover 

studies 

Effect of acute ethanol 

ingestion on prolactin in 

menopausal women 

using estradiol 

replacement 

Ethanol (1 mL/kg, 

95% ethanol) 

over 20 minutes 

Alcohol when 

compared to 

isocaloric 

carbohydrate drink 

ingestion resulted 

in increased serum 

prolactin levels in 

both study 1 

(p <0.03) and study 

2 (p <0.001) 

There was an 

increase in 

serum prolactin 

levels. 

C-3
 
 

 

Study Model Study Design Mechanism Examined 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure Results 

Conclusions as 

Reported by 

Study Authors 

Reichman et al. 

199386 34 premenopausal women with a 

history of regular 

menstrual cycle 

Randomized, 

diet-controlled 

crossover 

intervention 

The effects of alcohol 

consumption on plasma 

and urinary hormone 

(DHEA, estrogens) 

concentrations in 

premenopausal women 

30 g of ethanol 

daily for three 

menstrual cycles 

and no alcohol 

for the other 

three 

Plasma DHEAS 

levels increased by 

7.0% (p = 0.05) in 

the follicular phase 

Plasma estrone 

levels increased by 

21.2% (p = 0.01) in 

the peri-ovulatory 

phase 

Plasma estradiol 

increased by 27.5% 

(p = 0.01), urinary 

estradiol increased 

by 31.9% 

(p = 0.009) in the 

peri-ovulatory 

phase 

At the luteal phase, 

urinary estrone 

increased by 15.2% 

(p = 0.05), estradiol 

levels increased by 

21.6% (p = 0.02), 

and estriol levels 

increased by 29.1% 

(p = 0.03) 

Results suggest 

a possible 

mechanism 

between alcohol 

consumption 

and risk of 

breast cancer. 

C-4
 
 

 

Table C-2. Summary of results from animal studies on breast cancer 

Study 

Mechanism 

Examined Experimental Model 

Amount and Duration 

of Ethanol and/or 

Acetaldehyde 

Exposure Use of Carcinogen Results 

Conclusions as Reported 

by Study Authors 

Hilakivi-Clarke 

et al. 200492 

Elevated levels of 

estrogen 

receptors 

Rats Amount in study 

groups: 

0 g/kg ethanol 

vs. 

16 g/kg ethanol 

vs. 

25 g/kg ethanol 

Duration of Exposure: 

12 days 

Dimethylene(a)anthra 

cene (DMBA) 

Latency to the 

appearance of first 

tumor [weeks, mean 

([s.e.m)] was 9.7 (0.6) 

in the control, 8.4 

(0.5) in the 16 g 

alcohol group, and 

8.6 (0.5) in the 25 g 

alcohol group. 

Tumor incidence and 

tumor multiplicity were 

higher in the alcohol 

groups compared to 

control. 

Tumor growth rate 

was similar in all three 

groups. 

Maternal alcohol intake 

increased offspring’s

mammary tumorigenesis. 

Castro et al. 

200395 

Biotransformation 

of ethanol to 

acetaldehyde 

Rats Amount in study group: 

0.21M ethanol 

Duration of exposure: 

1 hour 

None Biotransformation of 

ethanol to 

acetaldehyde 

occurred in mammary 

tissue microsomes. 

Result could have a 

significant effect in some 

stages of the process of 

breast tumor promotion by 

ethanol. 

Chhabra et al. 

200096 

Formation of DNA 

adducts 

Rats Amount in study group: 

1.6 g/kg ethanol 

Duration of exposure: 

14 days 

Nnitrosodimethylamine 

(NDMA), 

4­

(methylnitrosamino)­

1-(3-pyridyl)-1­

butanone (NNK) 

There was a 10-fold 

increase in O6 -

methylene adducts 

from NDMA in 

mammary gland 

following cotreatment 

with ethanol. 

Nitrosamines and ethanol 

are contributors to mammary 

cancer risk and perinatal 

carcinogenesis. 

C-5
 
 

Study 

Mechanism 

Examined Experimental Model 

Amount and Duration 

of Ethanol and/or 

Acetaldehyde 

Exposure Use of Carcinogen Results 

Conclusions as Reported 

by Study Authors 

Watabiki et al. 

200097 

Ethanol-induced 

hyperprolactinemia 

and/or mammary 

tumor virus 

increased by the 

hyperprolactinemia 

Rats Amount in study 

groups: 

10% ethanol 

vs. 

15% ethanol 

vs. 

tap water 

Duration of exposure: 

25 months 

None In the ethanol-treated 

group, tumor 

occurrence was 

reported in 9 (45%) of 

the 20 rats at 8 to 

24 months. There no 

occurrence of tumor in 

the control. 

The murine model may be 

useful to study the role of 

ethanol in mammary 

tumorigenesis. 

Holmberg et al. 

199591 

None reported Rats Amount in study 

groups: 

1 ethanol 

vs. 

3% ethanol 

Duration of exposure: 

2 years 

None Following the 

administration of low 

amounts of ethanol, 

there was an increase 

in mammary gland 

fibroma, 

fibroadenoma or 

adenoma. 

The finding seems not to be 

consistent in terms of a 

dose-response relationship 

or in their interrelation and 

may thus be regarded as an 

unspecific phenomenon. 

C-6
 
 

Study 

Mechanism 

Examined Experimental Model 

Amount and Duration 

of Ethanol and/or 

Acetaldehyde 

Exposure Use of Carcinogen Results 

Conclusions as Reported 

by Study Authors 

Singletary et al. 

199593 

Influence on 

initiation and 

promotion stages 

of carcinogenesis 

through change in 

blood estrogen 

and progesterone 

Rats Amount in study 

groups: 

Diet containing ethanol 

at 0% calories 

vs. 

15% calories 

vs. 

20% calories, 

vs. 

30% calories 

Duration of exposure: 

22 days 

N-methyl-Nnitrosourea (MNU) Ethanol consumption 

at 15% caloric intake 

resulted in an 

increase during either 

the initiation or 

promotion stages. 

Ethanol consumption 

at 20% caloric intake 

resulted in increase 

during the promotion 

stage 

There was no effect 

on either stage in the 

group that received 

ethanol at 30% caloric 

intake. 

Ethanol at specific intakes 

can enhance the initiation 

and promotion stages of 

MNU-induced mammary 

tumorigenesis. However, 

there was not a consistent 

and proportionate increase 

in mammary tumor 

development with increasing 

intakes of ethanol. 

Singletary and 

McNary 199494 

Effect on serum 

estradiol and 

progesterone 

Rats Amount in study 

groups: 

Diet containing ethanol 

at 0% calories 

vs. 

20% calories, 

vs. 

30% calories 

Duration of exposure: 

35-39 days 

MNU Ethanol consumption 

at 20% caloric intake 

resulted in a 

19% increase in 

rat mammary gland 

terminal-end bud 

(TEB) density and 

49% decrease 

in alveolar bud (AVB) 

structures. 

Ethanol consumption 

at 30% caloric intake 

resulted in a 

45% increase in 

rat mammary gland 

TEB density and 

44% decrease in AVB 

structures. 

Ethanol consumption can 

lead to an increase in the 

quantity of and the rate of 

cell proliferation of 

mammary gland terminalend bud (TEB) structures. 

C-7
 
 

Study 

Mechanism 

Examined Experimental Model 

Amount and Duration 

of Ethanol and/or 

Acetaldehyde 

Exposure Use of Carcinogen Results 

Conclusions as Reported 

by Study Authors 

Taylor et al. 

199399 

Suppression of 

cellular immunity 

(T cell activation 

and proliferation, 

and on natural 

killer [NK] 

cytotoxicity) 

Rats Acute ethanol exposure 

of 2.5-3.5 g/kg 

body weight 

1 hour before tumor 

inoculation 

vs. 

chronic consumption of 

liquid diet containing 

ethanol for 2 weeks 

before and for 3 weeks 

after tumor inoculation. 

Study authors only 

reported 

“Tumor inoculation” 

by MADB106 

Blood NK cytotoxic 

activity was reduced 

in ethanol treated rats. 

Number of blood large 

granular lymphocytes 

(LGL) per NK cells at 

2 hours post ethanol 

administration 

dropped to 86% of 

control group and at 

5 hours post ethanol 

administration: 

dropped to 74% of 

control group. 

Alcohol exposure during 

fetal or adult life has 

profound 

immunopathological effects. 

McDermott et 

al. 1992101 

The aim of the 

study was to test 

the hypothesis 

that dietary 

alcohol intake 

increases the 

incidence of 

experimental 

mammary 

carcinoma 

Rats Amount in study 

groups: 

4.4 g/kg/day ethanol 

vs. 

tap water 

Duration of exposure: 

10 days 

DMBA Mean time (days, [SD] 

to first tumor 

appearance in the 

alcohol group was 

63 (16.3) and 

67.3 (19) in the 

control. 

Mean number of 

tumors/animal in the 

alcohol group was 

3.2 (2.2) and 2.9 (2.7) 

in the control. 

Tumor rate growth 

(mm3/day) in the 

alcohol group was 

30.7 (17.7) and 

25.5 (11.8) in the 

control. 

This study failed to support 

the hypothesis that dietary 

alcohol intake increases the 

incidence of mammary 

carcinoma. 

C-8
 
Study 

Mechanism 

Examined Experimental Model 

Amount and Duration 

of Ethanol and/or 

Acetaldehyde 

Exposure Use of Carcinogen Results 

Conclusions as Reported 

by Study Authors 

Hackney et al. 

1992102 

Enhancement of 

the rate of 

mammary tumor 

development 

Rats Amount in study 

groups: 

4 g/kg/day ethanol 

vs. 

15 g/kg/day ethanol 

vs. 

20 g/kg/day ethanol 

Duration of exposure: 

65 weeks 

None There was 

no difference among 

study groups 

(p = 0.10) in 

development of 

mammary tumors. 

Findings do not support the 

hypothesis that ethanol 

augments the risk of breast 

cancer. 

Singletary and 

McNary 

1994104 

Effect on 

mammary gland 

structural 

development, 

DNA synthesis, 

and decrease in 

serum 

progesterone 

Rats Amount in study 

groups: 

Diet containing ethanol 

at 0% 

vs. 

15% 

vs. 

20% 

vs. 

25% of calories 

Duration of exposure: 

Experiment 1: 32 days 

Experiment 2: 28 days 

Experiment 3: 33 days 

None In experiment 1, TEB 

increased for rats fed 

ethanol at 20% and 

30% caloric intake 

and density of AVB 

decreased at all 

ethanol 

concentrations. 

In experiment 2, TEB 

density of ethanol-fed 

rats increased 64%. 

In experiment 3, there 

was no change in 

serum estradiol. 

However, serum 

progesterone: 

decreased by 56% 

and 51% compared to 

pair-fed control and 

ad lib-fed control rats, 

respectively. 

Cancer risk in humans may 

be proportional to both cell 

number and rate of cell 

division within a target 

tissue. 

C-9
 
Study 

Mechanism 

Examined Experimental Model 

Amount and Duration 

of Ethanol and/or 

Acetaldehyde 

Exposure Use of Carcinogen Results 

Conclusions as Reported 

by Study Authors 

Singletary et 

al. 1991105 

Effect on 

mammary gland 

structural 

development and 

DNA synthesis 

Rats Amount in study 

groups: 

Diet containing ethanol 

at 0% 

vs. 

15% 

vs. 

20% 

vs. 

30% of calories 

Duration of exposure: 

29 days 

DMBA Rats that consumed 

ethanol at 10% and 

20% of calories 

exhibited a significant 

increase in TEB 

density and a 

significant decrease in 

AVB density. 

Rats that consumed 

ethanol at 20% of total 

calories prior to 

DMBA administration 

exhibited a significant 

54-74% increase in 

tumor incidence 

compared with rats 

fed the control diet. 

78%, 82%, and 91% 

of tumor-bearing rats 

possessed 

adenocarcinomas for 

rats fed the diets 

containing 0%, 10%, 

and 20% of calories 

as ethanol, 

respectively. 

For rats fed ethanol at 

30% of calories, tumor 

incidence was 

identical to that for 

rats fed the control 

diet until 12 weeks 

following DMBA 

dosing. 

Specific quantities of ethanol 

can enhance the initiation 

and the promotion stages of 

DMBA-induced mammary 

tumorigenesis. 

C-10
 
Study 

Mechanism 

Examined Experimental Model 

Amount and Duration 

of Ethanol and/or 

Acetaldehyde 

Exposure Use of Carcinogen Results 

Conclusions as Reported 

by Study Authors 

Rogers and 

Conner 

1990100 

Enhancement of 

carcinogenesis 

Rats Amount in study 

groups: 

Diet providing 10% 

vs. 

20% 

vs. 

50% of calories as 

ethanol 

Duration of exposure: 

Exp 1: 10% of ethanol 

for 1 week, 

20% of alcohol for 

3 weeks. 

Exp 2: 10% of ethanol 

for 4 days, 20% for the 

remainder of the 

experiment. 

Exp 3: 10% of ethanol 

for 4 weeks, at the 

beginning of the 

4th week the rats were 

given a single dose of 

50% ethanol. 

DMBA In all experiments, 

there was 

no detectable effect 

on mammary tumor 

latency, incidence, 

number, weight or 

histology. 

There was no effect of 

ethanol on mammary gland 

tumorigenesis induced by 

DMBA. 

Grubbs et al. 

1988103 

Enhancement of 

mammary cancer 

initiation 

Rats Amount in study 

groups: 

7.0 g/kg ethanol 

vs. 

3.5 g/kg ethanol 

Duration of exposure: 

DMBA group: 3 weeks 

MNU group: 8 weeks 

DMBA 

MNU 

Mammary cancer 

initiation by DMBA 

was increased by both 

dose levels of ethanol. 

Mammary cancer 

initiation by MNU was 

increased by high 

dose of ethanol. 

Ethanol enhances mammary 

cancer initiation. 

C-11
 
 

Study 

Mechanism 

Examined Experimental Model 

Amount and Duration 

of Ethanol and/or 

Acetaldehyde 

Exposure Use of Carcinogen Results 

Conclusions as Reported 

by Study Authors 

Schrauzer et 

al. 197998 

Change in 

prolactin levels 

Mice Amount in study 

groups: 

12% ethanol 

vs. 

table wine with an 

alcohol content of 

11.5% 

Duration of exposure: 

6 weeks 

Bittner virus Mean serum prolactin 

levels (ng/ml [SD]) in 

the alcohol group was 

23 (9) and 52 (23) in 

the control. 

Tumor incidence, 

growth rates and 

latency in the alcohol 

group occurred in 

8 animals that 

developed 

adenocarcinoma, the 

first at the age of 

6 months 

(after 5 months of 

exposure), the last 

at 11 months 

(median: 8). The 

tumor incidence was 

73%. 

Among the control, 

animals developed 

mammary tumors 

between 12 and 

16 months of age 

(median: 14.2). Tumor 

incidence was 82% 

* difference in latency 

times was 

significant 

(p <0.001) 

Long-term exposure to 

ethanol significantly reduced 

the latency period in the 

genesis of spontaneous 

mammary adenocarcinoma. 

C-12
 
 

 

 

 

 

 

 

 

Table C-3. Summary of results from cell line studies on breast cancer 

Study Mechanism Examined 

Experimental 

Model 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure Results 

Conclusions as Reported by 

Study Authors 

Etique et al. 

2009106 

Cross-talk between 

A2A Adenosine 

receptor (A2A AR) and 

the estrogen receptoralpha 

MCF-7 Amount in study 

groups: 

0.3% ethanol 

vs. 

0.1% ethanol 

Duration of 

exposure: 

24 hours 

There was an increase in the 

level of progesterone receptor 

mRNA following 24 hours of 

treatment with 1uM CGS21680 

(a selective agonist). Antagonist 

(MSX-3) induced a dosedependent inhibition of an 

ethanol-induced increase in 

progesterone receptor 

expression. 

Although results demonstrate 

cross-talk between A2A AR and 

estrogen receptor-alpha in the 

ethanol action on MCF-7 cells, 

the link between ethanol and 

A2A AR remains to be 

determined. 

Venkata et al. 

2008115 Relationship between ethanol and its 

metabolite 

acetaldehyde on 

peroxisome 

proliferator-activated 

receptor (PPAR)alpha 

and PPAR(beta) 

transactivation 

MCF-7 Amount in study 

groups: 

0 mM ethanol 

vs. 

10 mM ethanol 

vs. 

30 mM ethanol 

vs. 

100 mM ethanol 

vs. 

300 mM ethanol 

Duration of 

exposure: 

24 hours 

Over a range of ethanol 

concentrations up to 300mM, 

ethanol was able to dose 

dependently and significantly 

increase the expression of 

PPAR(alpha) mRNA in MCF-7 

cells. Ethanol also modestly 

increased the mRNA for 

PPAR(beta) with a significant 

increase seen at 30 and 300mM, 

although not at 100mM. The 

increased expression for 

PPAR(beta) mRNA was only in 

the order of two-fold in contrast to 

the approximately sevenfold 

increase seen for PPAR(alpha) 

compared with the absence of 

ethanol. 

There is likely to be a complex 

interplay in the way ethanol 

and/or acetaldehyde acts via the 

PPARs and other proteins to 

influence tumorigenic relevant 

pathways such as proliferation, 

resistance to apoptosis, and 

invasiveness. 

C-13
 
 

 

 

 

 

 

 

 

 

Study Mechanism Examined 

Experimental 

Model 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure Results 

Conclusions as Reported by 

Study Authors 

Etique et al. 

200768 

Activation of the 

estrogen signaling 

pathway (cyclic AMP 

[cAMP]/protein kinase 

A [PKA]). 

MCF-7 Amount in study 

groups: 

0.1% ethanol 

vs. 

0.3% ethanol 

vs. 

0.5% ethanol 

vs. 

0.7% ethanol 

Duration of 

exposure: 

24 hours 

There was a significant 1.6-fold 

increase in progesterone receptor 

mRNA level for either 0.1 or 0.3% 

ethanol and a 1.3-fold increase in 

pS2 expression for a dose of 

0.3%. 

Ethanol treatment of MCF-7 

breast cells stimulates the 

cAMP/PKA pathway which 

triggers two important events: an 

increase in the expression of 

genes with cAMP response 

element (CRE) in their promoter, 

like aromatase as well as a 

ligand-independent activation of 

estrogen receptor-alpha and 

transcription of target genes. 

Etique et al. 

200465 

Stimulation of cell 

proliferation, estrogen 

receptor-alpha, and 

aromatase expression 

MCF-7 Amount in study 

groups: 

0.0% ethanol 

vs. 

0.1% ethanol 

vs. 

0.3% ethanol 

Duration of 

exposure: 

Up to 6 days 

Ethanol enhanced cell 

proliferation and clonal growth of 

MCF-7 cells. In the presence of 

0.1% ethanol, there was a 

significant increase in cell 

proliferation (11.5%) at day 4 and 

it peaked at 28% at day 6. In the 

presence of 0.3% ethanol, there 

was a significant increase (11%) 

at day 4, and no significant 

change at day 6. 

Study supports data suggesting 

that ethanol is an increased risk 

factor for breast cancer. 

C-14
 
 

 

Amount and 

Duration of 

Ethanol and/or 

Experimental Acetaldehyde Conclusions as Reported by 

Study Mechanism Examined Model Exposure Results Study Authors 

Izevbigie et al. Disruption and 51 2002 modulation of cell 

proliferation 

MCF-7 Ethanol (0.1%­

10%) with or 

without an 

inhibitor of 

mitogen activated 

protein kinase 1 

vs. 

0.3%, 3%, and 

10% ethanol for 

5-, 10-, 20-, and 

40-min time 

course 

experiments. 

Exposure of to 65 mM (0.3% 

ethanol) increased incorporation 

of [3-H] thymidiene into MCF-7 

cells by approximately two-fold 

over control. In contrast to the 

growth stimulatory effect of 

0.3% ethanol, both 3% and 10% 

ethanol significantly inhibited 

cell growth. 

Ethanol stimulates p44/42 

mitogen-activated protein 

kinase’s activity and subsequent 

MCF-7 cell proliferation. 

C-15
 
 

 

 

Study Mechanism Examined 

Experimental 

Model 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure Results 

Conclusions as Reported by 

Study Authors 

Przylipiak et al. 

1996110 Direct growthstimulatory effect on 

cancer cells by 

enhancement of 

3H-thymidine 

MCF-7 Amount in study 

groups: 

0.00001% 

ethanol 

vs. 

0.0001% ethanol 

vs. 

0.001% ethanol 

vs. 

0.01% ethanol 

vs. 

0.1% ethanol 

vs. 

1% ethanol 

vs. 

10% ethanol 

Duration of 

exposure: 

5 hours 

Ethanol enhanced 3H-thymidine 

uptake in cultured human 

mammary carcinoma cell line 

MCF-7. The most effective 

concentration was 0.01% which 

evoked a 202% enhancement of 

3H-thymidine uptake, when 

compared to controls. 

Concentrations of ethanol 

between 0.0001% and 10% 

also significantly enhanced 

3H-thymidine uptake. 

A concentration of 0.00001% 

ethanol did not affect thymidine 

incorporation. 

Ethanol appears to play a role in 

tumor promotion in vivo as a 

result of direct growthstimulatory effect on human 

mammary cancer cells in vitro. 

C-16
 
 

 

 

 

 

 

 

Study Mechanism Examined 

Experimental 

Model 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure Results 

Conclusions as Reported by 

Study Authors 

Singletary et 

al. 2004107 Decreased capacity to remove benzo[a]pyrene 

diolepoxide-DNA 

(BPDE-DNA) adducts 

MCF-10F Amount in study 

groups: 

0 mM ethanol 

vs. 

15 mM ethanol 

vs. 

25 mM ethanol 

Duration of 

exposure: 

48 hours 

Incubation of cells with ethanol 

was associated with a significant 

increase in prevalence of BPDEDNA adducts compared to 

controls. 

Ethanol- and oxidative stressassociated inhibition of 

carcinogen-DNA adduct removal 

in non-neoplastic human 

mammary cells may be another 

biological mechanism to explain 

the increased risk for breast 

cancer among women 

consuming alcohol. 

Barnes et al. 

2000108 

DNA adduct formation 

and enhancement 

carcinogen-induced 

DNA damage in target 

cell DNA 

MCF-10F Amount in study 

groups: 

Ethanol: 0, 5, 15, 

or 25 mM 

vs. 

Aldehyde: 0, 0.5, 

2.5, or 5.0 μM 

Duration of 

exposure: 

6 days 

Exposure of cells to 

physiologically relevant 

concentrations of either ethanol 

or aldehyde prior to dosing with 

B[a]P increased adducts 

formation. 

A possible mechanism by which 

alcohol intake may be 

enhancing breast cancer risk in 

humans may be through an 

ethanol- and aldehydeassociated increase in 

carcinogen-DNA adducts in the 

target mammary epithelial cells. 

Zhu et al. 

2001109 

Modulation of 

expression of 

ribosomal protein L7a 

(rpL7a) 

T4TD Amount in study 

groups: 

100-400 mg/dl 

ethanol 

Duration of 

exposure: 

16 days 

Long-term exposure to ethanol 

(2 weeks) significantly reduced 

the transcript of rpL7a by more 

than 60%. 

Ethanol-induced alteration of 

rpL7a expression may mediate 

the promoting effects of ethanol 

on breast cancer development. 

C-17
 
 

 

 

 

 

 

 

Study Mechanism Examined 

Experimental 

Model 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure Results 

Conclusions as Reported by 

Study Authors 

Dhar and 

Plummer 

2006112 

Protein expression of 

G-protein inwardly 

rectifying potassium 

channels (GIRK) 

MDA-MB-453 Amount in study 

group: 

0.12% ethanol 

Duration of 

exposure: 

16 hours 

Transfection of GIRK1 or GIRK4 

plasmids decreased gene 

expression in MDA-MB-453 

breast cancer cells. 

Functional GIRK channel exists 

in breast cancer cells that are 

involved in cellular signaling. 

Singletary et 

al. 200169 

Proliferation and 

intracellular content of 

cAMP in estrogen 

receptor (ER)-alpha 

expression 

MCF-7, 

ZR75.1, 

BT-20, 

MDA-MB-231 

Amount in study 

groups: 

0-100 mM 

ethanol 

Duration of 

exposure: 

Up to 10 days 

Exposure of ER+ cell lines to 

increasing concentrations of 

ethanol was associated with an 

increase in cell proliferation. 

For example, ethanol added to 

cultures of cells at concentrations 

of 20-50 mM significantly 

stimulated proliferation of MCF-7 

and ZR75.1 cells by 53-91% 

following 7 and 10 days of 

treatment, compared to controls. 

Treatment with ethanol is 

associated with increased 

proliferation of two estrogen 

receptor-positive human breast 

cancer cell lines. 

Zhu et al. 

2001114 Up-regulation of transcription of smooth 

muscle myosin alkali 

light chain (MLC 1sm) 

MCF-7, T47D, 

MDA-MB-231 

Amount in study 

groups: 

50-400 mg/dl 

ethanol 

Duration of 

exposure: 

16 days 

At 400 mg/dl, an ethanolmediated increase was evident at 

6 hours (55% increase), peaked 

at 24 hours (2.7 fold increase) 

following exposure. 

At pharmacologically relevant 

concentrations (e.g., 100 mg/dl), 

ethanol produced a significant 

increase of MLC 1sm expression, 

and progressively higher ethanol 

concentrations resulted in more 

up-regulation. 

Alcohol consumption may 

promote the progression of 

breast cancer in women. 

C-18
 
 

 

 

Study Mechanism Examined 

Experimental 

Model 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure Results 

Conclusions as Reported by 

Study Authors 

Fan et al. 

200067 

Stimulation of the 

estrogen receptor 

signaling 

MCF-7, T47D Amount in study 

groups: 

60 mM-100 mM 

ethanol 

Duration of 

exposure: 

24 hours 

Alcohol partially reverses the 

BRCA1-mediated inhibition of 

estrogen receptor-alpha 

transcriptional activity. Alcohol 

down-regulates BRCA1 and upregulates estrogen receptor-alpha 

expression in MCF-7 cells. 

Inactivation of BRCA1 and 

increased estrogenresponsiveness might contribute 

to alcohol-induced breast 

cancer. 

Verna and 

Davidson 

1999113 

Mammary gland mucin 

(MUC1) upregulation 

MCF-7, T84 Amount in study 

groups: 

0 mM ethanol 

vs. 

50 mM ethanol 

vs. 

100 mM ethanol 

vs. 

150 mM ethanol 

vs. 

200 mM ethanol 

vs. 

250 mM ethanol 

vs. 

500 mM ethanol 

Duration of 

exposure: 

Acute exposure: 

24 hours 

Chronic 

exposure: up to 

4 weeks 

Ethanol enhanced the expression 

of MUC1 mRNA in a dose- and 

time-dependent manner in MCF-7 

cells. 

Ethanol regulates expression of 

the MUC1 gene at the 

transcription level which strongly 

suggests the existence of 

ethanol responsive elements in 

the promoter of the mucin gene. 

C-19
 
 

 

Study Mechanism Examined 

Experimental 

Model 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure Results 

Conclusions as Reported by 

Study Authors 

Cyong et al. 

1978111 

Increase cAMP levels MM46 tumor 

cells 

Amount in study 

groups: 

0% 

vs. 

0.1% 

vs. 

0.5% 

vs. 

1.0% 

vs. 

2.5% 

vs. 

5.0% ethanol 

Duration of 

exposure: 

30 minutes 

Dose-related increases in cAMP 

were observed at ethanol 

concentrations from 0.1% to 

5.0%. 

Results suggest that either 

tumor cell membrane, or its 

membrane-associated defense 

mechanism for detergents, 

may be incomplete. 

C-20
 
 

 

 

 

 

Evidence Base for Colorectal Cancer 

Table C-4. Summary of results from human studies on colorectal cancer 

Study 

Amount and 

Duration of Ethanol Conclusions 

Mechanism and/or Acetaldehyde as Reported by 

Study Design Examined Exposure Results Study Authors 

Basuroy et al. Case series. The effect of Biopsies were exposed Acetaldehyde These may have 83 2005 acetaldehyde on to vapor-phase resulted in epithelial significant Mucosal biopsies tyrosine acetaldehyde, to TJ disruption by implications for the from the left phosphorylation, achieve acetaldehyde inducing tyrosine loss of cell-cell colon (4 forceps immmunofluorescence concentration of phosphorylation and adhesion and biopsies from localization, and 100-600 uM in the dissociation from the increased risk for visibly normal detergent-insoluble buffer bathing the cytoskeleton of TJ colon cancer. area of mucosa fractions of the tight tissue. Briefly, biopsies and AJ proteins. in each subject) junctions (TJ) and in 24-well culture plates were collected adherens junctions were treated with from subjects (AJ). vapor-phase admitted for acetaldehyde by colonoscopy for placing stock the purpose of acetaldehyde solution cancer (0.1%-0.6%) in the surveillance. reservoir wells and 

Authors did not sealing the lid to the
 report patients’
 plate with tapes.
 characteristics
 5 hours and previous
 

alcohol exposure.
 

C-21
 
 

 

 

 

 

 

 

 

Table C-5. Summary of results from animal studies on colorectal cancer 

Study 

Mechanism 

Examined 

Experimental 

Model 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure Use of Carcinogen Results 

Conclusions as 

Reported by Study 

Authors 

Hayashi et al. 

2007118 

Increased 

expression of 

cytochrome 

P4502E1 

(CYP2E1) 

Rats Amount in study 

group: 

Ethanol-containing 

liquid diet (36% of 

total calories, 

5% ethanol v/v) 

Duration of 

exposure: 

36 weeks 

1,1-dimethylhydrazine 

(DMH) 

The number of 

aberrant crypt foci 

(ACF) in colons 

obtained from ethanolfed rats with DMH was 

24, which was 

significantly more than 

that of the other 

treated rats. 

The increased 

expression of CYP2E1 

induced by chronic 

ethanol consumption 

promotes 

the development of 

DMH-induced colon 

cancer. 

Perez-Holanda 

et al. 200573 

Effect of ethanol 

consumption on 

experimental colon 

carcinogenesis 

using a dynamic 

model with 

concomitant 

administration of 

alcohol and 

dimethylhydrazine 

(DMH). 

Rats Amount in study 

group: 

Ethanol at a dose 

of 1.23 g/kg of 

body weight 

Duration of 

exposure: 

24 weeks 

DMH Tumors developed 

only in DMH treated 

groups: 25 rats (89%) 

in the DMH group and 

16 rats (100%) in the 

DMH + ethanol group. 

However, when 

excluding tumor-free 

animals, 

no differences were 

observed in the mean 

number of tumors per 

rat (1.67 in the DMH 

group compared to 

1.60 in the DMH + 

ethanol group). 

Addition of an ethanol 

supplement does not 

modify colorectal 

carcinogenesis using a 

dynamic model of 

tumor induction with 

DMH. 

C-22
 
 

 

 

 

 

 

 

 

 

Amount and 

Duration of 

Ethanol and/or Conclusions as 

Mechanism Experimental Acetaldehyde Reported by Study 

Study Examined Model Exposure Use of Carcinogen Results Authors 

Pronko et al. Activities of Rats Amount in study None MEOS activity in the This mechanism can 

2002120 alcohol 

dehydrogenase 

(ADH), catalase, 

microsomal 

ethanol-oxidizing 

system (MEOS), 

and aldehyde 

dehydrogenase 

(ALDH) 

group: 

Ethanol as 25% of 

calories 

Duration of 

exposure: 

35 days 

alcohol group was 

149% higher 

compared to control 

group (increase not 

statistically significant). 

Effect of acute alcohol 

intoxication in rats 

consuming ethanol 

chronically (control vs. 

ethanol diet) as 

measured by ethanol 

concentrations in the 

colon was 9.1 (0.98) 

vs. 11.1 (1.52) and in 

the rectum was 13.6 

(2.57) vs. 17.9 (2.90). 

Effect of acute alcohol 

intoxication in rats 

consuming ethanol 

chronically (control vs. 

ethanol diet) as 

measured by 

acetaldehyde 

concentrations in the 

colon was 7.93 (1.22) 

vs. 18.5 (3.94)* and in 

the rectum: 18.1 (3.95) 

vs. 30.5 (7.13). 

*p <0.05 

account for the local 

toxicity of ethanol after 

its chronic 

consumption, and 

relates the 

development of 

mucosal damage and 

compensatory hyperregenerative 

processes, and 

possibly 

carcinogenesis, in the 

colonic and rectal 

mucosa of alcoholics to 

the effects of 

acetaldehyde. 

C-23
 
 

 

 

 

 

 

 

 

 

 

 

Study 

Mechanism 

Examined 

Experimental 

Model 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure Use of Carcinogen Results 

Conclusions as 

Reported by Study 

Authors 

Homann et al. 

200070 

Folate deficiency 

via microbial 

acetaldehyde 

production 

Rats Amount in study 

group: 

3 g/kg of ethanol 

Duration of 

exposure: 

2 weeks 

None Alcohol treatment led 

to very high 

intracolonic 

acetaldehyde levels 

(387 [185] mM). 

Erythrocyte, serum 

and small intestinal 

folate levels were 

unaffected by alcohol 

treatment. 

Alcohol administration 

decreased significantly 

colonic mucosal folate 

levels by 48%. 

Alcohol administration 

leads to local folate 

deficiency of colonic 

mucosa in rats, most 

probably via the 

degradation of folate by 

the high levels of 

acetaldehyde 

microbially produced 

from ethanol. 

Choi et al. 

1999124 DNA methylation and methylation of 

p53 tumor 

suppressor gene 

Rats Amount in study 

group: 

Diet containing 

36% of total 

energy as ethanol 

Duration of 

exposure: 

4 weeks 

None Titrated methyl uptake 

by colonic DNA from 

alcohol-fed rats was 

57% less than that in 

control DNA (p <0.05) 

Genomic 

undermethylation of 

colonic DNA was 

observed in the 

alcohol-fed rats 

compared to control 

rats. 

C-24
 
 

 

 

 

Study 

Mechanism 

Examined 

Experimental 

Model 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure Use of Carcinogen Results 

Conclusions as 

Reported by Study 

Authors 

Hakkak et al. 

1996119 

The effects on 

expression of 

CYP2E1 and 

CYP2C7 

Rats Amount in study 

groups: 

8-13 g/kg/day 

ethanol. 

Duration of 

exposure: 

Not reported by 

authors. 

None CYP2E1 was found to 

be present in the colon 

and induced by 

ethanol. Chronic 

ethanol treatment 

increased expression 

of both hepatic 

(p <0.01) and colonic 

(p <0.05) CYP2E1 by 

three-fold. 

CYP2E1 and CYP2C7 

are present in the 

colonic tissue and are 

inducible by ethanol. 

C-25
 
 

 

 

 

 

 

 

 

 

 

Amount and 

Duration of 

Ethanol and/or Conclusions as 

Mechanism Experimental Acetaldehyde Reported by Study 

Study Examined Model Exposure Use of Carcinogen Results Authors 

Simanowski et Effect on rectal Rats Amount in study None While age by itself Hyperregeneration of 

al. 1994125 cell proliferation 

(hyperregeneration) 

group: 

36% of total 

calories as 

ethanol, with an 

additional acute 

intraperitoneal 

dose of 2.5 g/kg 

body weight 

Duration of 

exposure: 

4 weeks 

did not affect colorectal 

cell renewal, chronic 

ethanol consumption 

stimulated rectal, but 

not colonic, crypt cell 

production rate in an 

age dependent 

manner. While no 

significant effect of 

ethanol was noted in 

young animals, cell 

proliferation was 

significantly enhanced 

in middle aged animals 

by 81% (95% CI: 4.1 

(2.7-5.5) v 7.4 (6.0-8.7) 

cells/crypt/hour, 

p <0.001) and in 

old animals by 138% 

(95% CI: 4.5 (3.3-5.6) v 

10.7 (8.9-12.4) 

cells/crypt/hour, 

p <0.001), after 

ethanol ingestion. 

There was a 

significant positive 

correlation between 

crypt cell production 

rate and acetaldehyde 

concentrations 

measured in the distal 

and proximal colon 

after an acute dose of 

ethanol. 

the rectal mucosa after 

alcohol drinking could 

by itself favor 

carcinogenesis, which 

is especially relevant in 

old age. 

C-26
 
 

 

Study 

Mechanism 

Examined 

Experimental 

Model 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure Use of Carcinogen Results 

Conclusions as 

Reported by Study 

Authors 

Niwa et al. 

1991126 Hyperproliferation of rectosigmoidal 

colon 

Rats Amount in study 

groups: 

7.5% ethanol 

vs. 

10% ethanol 

vs. 

15% ethanol 

Duration of 

exposure: 

414 days 

Methylazoxymethanol 

(MAM) acetate 

Incidence of colonic 

cancer (11/17, 85%) 

was higher in the 

group that received 

10% ethanol 

compared to control 

distilled water, 

p = 0.04. 

A relatively short-term 

administration of 

ethanol induced 

significant 

hyperproliferation of the 

colonic, especially 

rectosigmoidal colonic, 

mucosa. 

C-27
 
 

 

 

 

 

 

 

Study 

Mechanism 

Examined 

Experimental 

Model 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure Use of Carcinogen Results 

Conclusions as 

Reported by Study 

Authors 

Seitz et al. 

1990122 Acetaldehyde generation 

Rats Carcinogenesis 

Study 1 with a 

duration of 

exposure of 

15 weeks: 

Liquid diet 

containing 36% of 

total calories as 

ethanol 

vs. 

isocaloric glucose 

Carcinogenesis 

Study II with a 

duration of 

exposure of 3 hrs: 

2.5 ml 0.15 NaCl 

vs. 

2.5 ml 0.15 NaCl + 

cyanamide (CY) 

vs. 

2.5 ml ethanol 

vs. 

2.5 ml ethanol + 

CY 

Acetaldehyde 

Determination in 

Blood and 

Tissues: 

Acute dose of 

ethanol (2.5 g/kg 

body wt) 

Acetoxymethylmethylnitrosamine 

(AMMN) 

CY 

Using metaphasearrest technique, 

administration of 

alcohol induced rectal 

(99.1 [2.0] vs. 9.1 [1.8] 

cells/crypt/hour, 

p <0.01), but not 

caecal (18.9 [1.3] vs. 

22.2 [3.3]] 

cells/crypt/hour, 

p <0.05. 

Mucosal concentration 

of acetaldehyde 

(nmolg/colon)* in the 

rectum was 198 (23) 

and 120 (23) in the 

caecum. 

These values were 

not affected by 

chronic alcohol 

feeding. 

*p <0.05 

Chronic ethanol 

consumption can 

stimulate under certain 

experimental conditions 

chemically induced 

rectal carcinogenesis 

by direct mechanisms 

in the rectal mucosa, 

possibly mediated by 

acetaldehyde. 

C-28
 
 

 

 

 

 

 

Study 

Mechanism 

Examined 

Experimental 

Model 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure Use of Carcinogen Results 

Conclusions as 

Reported by Study 

Authors 

McGarrity et al. 

1988129 Changes in polyamine content 

Rats Amount in study 

group: 

Ethanol as 36% of 

total calories 

Duration of 

exposure: 

16 weeks 

DMH DMH and 

DMH + ethanol groups 

developed 

20 adenocarcinomas: 

with tumors located in 

the proximal colon 

(8 vs. 3), distal colon 

(11 vs. 114) and 

rectum (1 vs. 3) for the 

DMH and 

DMH + ethanol 

groups, respectively. 

No tumors developed 

in the control or 

ethanol treated 

groups. 

Chronic ethanol 

consumption did not 

alter overall tumor 

formation, however 

consumption was 

reported to increase 

putrescine content in 

all 3 regions (proximal, 

distal colon and 

rectum) compared to 

the control liquid diet 

group. Increase in 

tissue putrescine levels 

may possibly reflect 

increased ornithine 

decarboxylase activity 

which has been shown 

to be increased in 

human colon 

adenocarcinomas and 

premalignant 

adenomas. 

Hamilton et al. 

1988130 

Effect on the 

initiation phase of 

carcinogenesis 

Rats Amount in study 

group: 

Ethanol as 33% of 

total calories 

Duration of 

exposure: 

13 weeks 

Azoxymethane (AOM) After 24 hours of 

AOM administration, 

levels of DNA adducts 

O6 -methylguanine and 

7-methylguanine were 

reduced in the clonic 

mucosa of the ethanolfed rats to 14 ±7% and 

61 ±11% of controls. 

Dietary ethanol during 

the preinduction and 

induction phase of the 

AOM model 

dramatically inhibits 

tumorigenesis. 

C-29
 
 

 

 

 

 

 

 

 

 

Study 

Mechanism 

Examined 

Experimental 

Model 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure Use of Carcinogen Results 

Conclusions as 

Reported by Study 

Authors 

Garzon et al. 

1987128 

Local effect of 

ethanol on the 

colorectal mucosa 

Rats Amount in study 

group: 

Liquid diets 

containing 36% of 

total calories as 

ethanol 

Duration of 

exposure: 

10 weeks 

AMMN Significant difference 

in occurrence of 

colorectal tumors 

following chronic 

ethanol feeding at 

weeks 15 (42.1 vs. 

15.8, p <0.05). 

No significant 

difference was 

reported at weeks 18 

and 21. 

Chronic ethanol feeding 

combined with the 

direct acting carcinogen 

AMMN resulted in an 

earlier occurrence of 

colorectal tumors. 

Hamilton et al. 

1987132 

Effect on fecal 

bacterial flora, and 

colonic epithelial 

DNA synthesis 

Rats Amount in study 

groups: 

Liquid diet 

containing 0% 

ethanol 

vs. 

9% ethanol 

vs. 

18% ethanol as 

calories 

Duration of 

exposure: 

25 weeks 

AOM Low ethanol group 

demonstrated a trend 

for higher incidence of 

left-sided colonic 

tumors compared to 

controls (35% vs. 15% 

controls, p = 0.06). 

The total number of 

tumors in the highethanol group 

compared to controls 

was 46% vs. 81%, 

p = 0.002), 

respectively. 

Modulation of 

experimental colonic 

tumorigenesis by 

ethanol consumption 

was due to alcohol 

rather than other 

beverage constituents. 

C-30
 
 

 

 

 

 

 

 

 

Study 

Mechanism 

Examined 

Experimental 

Model 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure Use of Carcinogen Results 

Conclusions as 

Reported by Study 

Authors 

Hamilton et al. 

1987131 

Effect on 

preinduction, 

induction, and 

postinduction 

phases of 

carcinogenesis 

Rats Amount in study 

groups: 

Liquid diet 

containing 

11% ethanol 

vs. 

22% ethanol 

vs. 

33% ethanol as 

calories 

Duration of 

exposure: 

13 weeks 

AOM Suppression of colonic 

tumorigenesis 

occurred in the groups 

with high levels of 

chronic dietary ethanol 

consumption during 

acclimatization and 

AOM administration: 

in the 33% and 22% 

diet groups, the 

prevalence of colonic 

tumors was 3% and 

20% as compared with 

50% in control 

(p <0.001 and p <0.02, 

respectively). 

Chronic dietary ethanol 

effects on experimental 

colonic tumorigenesis 

with AOM are: 

(a) due to mechanisms 

affecting the 

preinduction and/or 

induction phase, 

including carcinogen 

metabolism; 

(b) unrelated to 

postinduction events 

such as tumor 

promotion and 

progression; and 

(c) dependent on 

ethanol dose with a 

threshold for inhibition 

of tumorigenesis which 

is mediated by ethanol 

inhibition of carcinogen 

metabolism. 

C-31
 
 

 

 

 

Study 

Mechanism 

Examined 

Experimental 

Model 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure Use of Carcinogen Results 

Conclusions as 

Reported by Study 

Authors 

Simanowski et 

al. 1986127 

Promotion of cell 

proliferation 

Rats Amount in study 

group: 

Liquid diet 

containing 36% of 

total calories as 

ethanol (6.6% v/v) 

Duration of 

exposure: 

4 weeks 

None Cell proliferation rate 

was 19.1 (2.0) in the 

ethanol fed group vs. 

9.1 (1.8) 

cell/crypt/hour in the 

carbohydrate fed 

group, p <0.005. 

Serum gastrin also 

was elevated in the 

ethanol fed group 

172 (51) vs. 106 (27) 

pmol/l, p <0.01). 

The ethanol dependent 

proliferative changes in 

the rectal mucosa are 

predictive of higher 

susceptibility of this site 

to carcinogenesis, 

supporting 

experimental and 

epidemiology data. 

Increased gastrin 

concentrations may 

partly explain the 

observed rectal 

hyperproliferation. 

Other possible causes 

cannot, however, be 

excluded. 

Nelson et al. 

1985116 

None reported by 

study authors 

Rats Amount in study 

groups: 

95% laboratory 

grade ethanol 

diluted 

vs. 

tap water 

Duration of 

exposure: 

19 weeks 

DMH Number of colonic 

tumors* in the DMH 

group was 77 and 88 

in the DMH + 

ethanol group. 

*p = 0.764 

No augmentation of 

colonic tumor induction 

in rats supplemented 

by dietary ethanol was 

seen. 

C-32
 
 

 

 

 

 

 

 

Study 

Mechanism 

Examined 

Experimental 

Model 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure Use of Carcinogen Results 

Conclusions as 

Reported by Study 

Authors 

Seitz et al. 

1985123 

Generation of 

acetaldehyde 

Rats Amount in study 

groups: 

Ethanol given as 

36% of total 

calories; ethanol 

concentration of 

alcohol diet was 

6.6% (v/v) 

vs. 

isocaloric 

carbohydrates 

Duration of 

exposure: 

4 weeks 

DMH There was a 2.8 fold 

increase in rectal 

tumors on the ethanol 

fed rats compared to 

controls (p <0.02). 

All large intestinal 

tumors were located in 

the rectum in 47% of 

ethanol fed rats vs. 

27% in controls. 

The observed increase 

of ADH activity in the 

distal colorectum after 

chronic ethanol feeding 

may be of relevance 

with respect to the 

cocarcinogenic effect of 

ethanol in the rectum. 

Howarth et al. 

1984117 None reported by study authors 

Rats Amount in study 

groups: 

High-fat diet 

vs. 

Beer 

vs. 

Alcohol (4.8% v/v) 

Duration of 

exposure: 

20 weeks 

DMH Alcohol did not affect 

the incidence of 

intestinal cancers. 

The shift of mean 

tumor distance toward 

the anus was similar in 

ethanol drinkers 

(0.61 [0.33] to 

0.33 [0.23], p <0.05). 

Alcohol had no effect 

in our syngeneic model 

of DMH-induced 

colorectal cancer, while 

a high-fat diet had a 

potent cocarcinogenic 

effect. 

C-33
 
 

 

 

 

Study 

Mechanism 

Examined 

Experimental 

Model 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure Use of Carcinogen Results 

Conclusions as 

Reported by Study 

Authors 

Roy et al. 

2002121 

Effect on cell 

proliferation, 

apoptosis, and 

formation of 

mutagenic 

malondialdehydeacetaldehyde 

(MAA) 

Mice Amount in study 

group: 

Ethanol 

supplementation 

in the drinking 

water (15% 

alternating with 

20% on a daily 

basis) 

Duration of 

exposure: 

10 weeks 

None Ethanol 

supplementation 

resulted in a significant 

increase in tumor 

number (135± 35%, 

p = 0.027 vs. control). 

The induction of 

tumorigenesis by 

ethanol was most 

dramatic in the distal 

small bowel 

(167± 56%, p = 0.001). 

Ethanol consumption is 

a risk factor for 

colorectal cancer. 

C-34
 
 

 

 

 

 

Table C-6. Summary of results from cell line studies on colorectal cancer 

Study 

Mechanism 

Examined 

Experimental 

Model 

Amount and Duration of 

Ethanol and/or Acetaldehyde 

Exposure Results 

Conclusions as Reported by 

Study Authors 

Lemos et al. 

2007140 

Modulation of 

folate uptake 

Caco-2 Amount in study group: 

12% alcohol 

Duration of exposure: 

Not reported 

Ethanol had an acute inhibitory 

effect on both 3H-folic acid and 

3H-methotrexate uptake. 

Alcohol inhibited 3H-folic acid 

uptake in Caco-2 cells. 

Rodriguez et al. 

200475 

Increase in 

tumor necrosis 

factor-alpha 

receptor-1 

(TNF-R1) 

levels 

Caco-2 Amount in study groups: 

25 mM ethanol 

vs. 

50 mM ethanol 

vs. 

100 mM ethanol 

Duration of exposure: 

48 hours 

Caco-2 cells showed a 

significant 80% increase in 

TNF-R1 levels at 200 mM 

ethanol (p <0.05). 

Exposure of intestinal cells to 

pharmacologic concentrations of 

ethanol increases TNF-R1 levels 

and may augment TNF-alphamediated cell injury. 

Asai et al. 

2003134 

Intestinal 

epithelial cell 

death induced 

by acute, low 

concentrations 

of ethanol 

Caco-2 Amount in study groups: 

0% ethanol 

vs. 

5% ethanol 

vs. 

10% ethanol 

Duration of exposure: 

3 hours 

Treatment with 5% and 10% 

ethanol for 3 hours led to a 

gradual increase in 

phosphatidylserine (PS) 

externalization. Caspasemediated CK18 was 

significantly enhanced as early 

as 1 hour after 10% ethanol 

incubation, while DNA 

fragmentation was detected 

from 2 hours onwards. 

Apoptotic cell death in confluent 

Caco-2 cells was induced by 

acute and low concentrations of 

ethanol. These results suggest 

that clinically achievable doses of 

ethanol impair intestinal barrier 

function by induction of apoptosis 

in intestinal epithelial cells. 

Tong et al. 

199974 

Induction of 

epidermal 

growth factor 

receptor 

(EGFR) 

expression and 

mitogenesis 

Caco-2 Amount in study group: 

0.22 mM of ethanol 

Duration of exposure: 

24 hours 

Alcohol affects proliferation of 

Caco-2 cells, elevates EGFR 

expression and raises cyclin 

D1 mRNA and protein 

expression. 

Low blood levels of alcohol may 

stimulate in vivo proliferation of 

colonocytes by elevating 

transcription of a growth factor 

receptor as well as modifying 

expression of a cell cycle 

regulator. 

C-35
 
 

 

 

Amount and Duration of 

Mechanism Experimental Ethanol and/or Acetaldehyde Conclusions as Reported by 

Study Examined Model Exposure Results Study Authors 

Koivisto and Effect of 

Salaspuro 1998136 acetaldehyde 

alone or in 

combination 

with ethanol 

on cell 

proliferation 

rate 

Caco-2 Study 1:
 

Acute exposure: 

cells were exposed to
 

acetaldehyde and/or ethanol
 

for 72 hours.
 

Study 2: 

Chronic exposure: cells were 

grown in the presence of 

acetaldehyde and/or ethanol 

for five passages with daily 

change of media. 

No significant differences were Ethanol-driven or even 

observed between the four endogenous acetaldehyde 

groups in the cytotoxic studies contributes to the initial steps of 

(control vs. 100 mM ethanol vs. colonic carcinogenesis and has 

500 uM acetaldehyde vs. an effect on later tumor 

1,000 uM acetaldehyde) development. 

suggesting that a 72 hour 

treatment with 500 or 1,000 uM 

acetaldehyde, or 100 mM 

ethanol does not have 

cytotoxic effects on these cells. 

In the proliferation studies, the 

acute effect of acetaldehyde on 

the proliferation rate of Caco-2 

cells was strongly inhibitory. 

The duplication time of Caco-2 

cells was also significantly 

increased by acute exposure to 

100 mM ethanol. Concomitant 

presence of ethanol did not, 

however, significantly alter the 

proliferation rate of 

acetaldehyde-treated cells. 

5-week treatment with 500 uM 

acetaldehyde, both alone and 

in combination with 100 mM 

ethanol, significantly 

decreased cell duplication time 

as compared with control. 

A 5-week treatment with 

100 mM alone did not have 

any significant effect on cell 

proliferation rate. 

Acetaldehyde decreased the 

adhesion of Caco-2 cells to 

both collagens 1 & IV in the 

cell adhesion studies. 

C-36
 
 

 

Amount and Duration of 

Mechanism Experimental Ethanol and/or Acetaldehyde Conclusions as Reported by 

Study Examined Model Exposure Results Study Authors 

Koivisto and Effect of 

Salaspuro 1997137 acetaldehyde 

on brush 

border enzyme 

activities 

Caco-2 Amount in study groups:
 

500 uM acetaldehyde
 

vs.
 

500 uM acetaldehyde + 

100 mM ethanol
 

vs.
 

1,000 uM acetaldehyde +
 

100 mM ethanol
 

vs.
 

100 mM ethanol
 

Duration of exposure: 

13 days 

Ethanol alone significantly Acetaldehyde decreases the 

increased the specific activities activities of some, but not all, 

of sucrase and maltase, but brush border enzymes in Caco-2 

no significant effect on lactase cells. 

activity. 

Only ethanol increased alkaline 

phosphatase activity. 

Control cells, as well as cells 

grown in the presence of 

100 mM ethanol alone or 

500 uM acetaldehyde, showed 

a typical pattern of dome 

formation, with a sharp 

increase in the number of 

domes a few days after the 

confluency, followed by a rapid 

decrease and plateau. Cells 

grown in presence of both 

100 mM ethanol and 1,000 uM 

acateladehyde showed 

significantly fewer domes 

4 and 7 days after the 

confluency than control cells. 

The acetaldehyde 

dehydrogenase (ALDH) activity 

of Caco-2 cells, measured 

using 200 uM acetaldehyde as 

substrate was quite similar to 

that of normal colonic mucosa. 

C-37
 
 

 

Study 

Mechanism 

Examined 

Experimental 

Model 

Amount and Duration of 

Ethanol and/or Acetaldehyde 

Exposure Results 

Conclusions as Reported by 

Study Authors 

Vaculova et al. 

2004133 

Modulation of 

the tumor 

necrosis factor 

(TNF)-related 

apoptosisinducing ligand 

(TRAIL)­

induced 

apoptosis 

HT-29 Experiment 1: 

4% ethanol alone or in 

combination for 4 or 24 h in the 

medium with 5% of fetal calf 

serum (FCS). 

Experiment 2: 

Using ethanol (0.1–6%) alone, 

the cells were treated for 

48 hours. 

There was only a limited 

cytotoxicity of TRAIL (100 

ng/ml) in HT-29 cells. After 

24-hour-treatment, the cell 

viability was 82%. However, 

when TRAIL was combined 

with ethanol, only 40% of cells 

remained viable. 

There was no significant 

changes in ethanol-treated 

cells and about two-fold 

enhancement of the number of 

cells with decreased MMP after 

TRAIL treatment (4 hours) 

compared to control were 

detected. 

Ethanol acts as a potent agent, 

sensitizing colon cancer cells to 

TRAIL-induced apoptosis. 

Blasiak et al. 

2000135 

Formation of 

crosslinks with 

DNA 

Colonic 

mucosa (CM) 

cells 

Single exposure study: 

CM cells were exposed to 

ethanol at 10 mm 

vs. 

acetaldehyde at 100 mm for 

1 hour. 

Combined exposure study: In 

combined exposure, the cells 

were subsequently exposed to 

ethanol and acetaldehyde at all 

combinations of the 

concentrations of the agents 

for 1 hour 

Ethanol caused DNA strand 

breaks. The CM cells exposed 

to ethanol at 100 mM were 

able to remove DNA damage 

within time period shorter than 

2 hours. 

Alcohol consumption may lead to 

the damage to DNA of 

gastrointestinal tract, which in 

turn can directly or indirectly 

contribute to the appearance and 

development of cancers of this 

organ. 

C-38
 
 

 

 

 

 

 

Study 

Mechanism 

Examined 

Experimental 

Model 

Amount and Duration of 

Ethanol and/or Acetaldehyde 

Exposure Results 

Conclusions as Reported by 

Study Authors 

Papavassiliou et al. 

1994139 

Modulation of 

human 

leukocyte 

antigen (HLA) 

class I gene 

expression 

HT-29, 

SW-1116, 

HCT-15 

Amount in study group: 

100% ethanol 

Duration of exposure: 

48 hours 

Ethanol had no effect on the 

expression of HLA class 1 

antigens in human colon 

adenocarcinoma cell lines. 

Ethanol (1.7 x 10 -10 M to 1.7 x 

10 -1 M), had no effect on the 

expression of HLA class 1 

antigens on these colonocytes, 

corresponding mRNA levels, or 

the expression of HLA 

constructs. 

These findings do not support the 

hypothesis that ethanol may 

modulate the expression of HLA 

class 1 genes in human colon 

cancer cells. 

Malagolini et al. 

1994138 

Differentiation 

of intestinal 

cells 

Caco-2, 

HT-29 

Amount in study groups: 

0 mM ethanol 

vs. 

50 mM ethanol 

vs. 

100 mM ethanol 

vs. 

200 mM ethanol 

Duration of exposure: 

7 days 

The addition of ethanol in the 

culture medium resulted in a 

significant increment of 

sucrase and alpha 2, 

6-sialyltransferase activities in 

all cell lines, as well as the 

beta 1, 

4-N-acetylgalactosaminyltransferase activity in the 

Caco-2 cells and alkaline 

phosphatase activity in 

HT-29 cells. 

Ethanol in vitro affects the 

differentiation of intestinal cells 

along the enterocytic lineage. 

C-39
 
 

 

 

Table C-7. Summary of results from combination study (animal, cell line) on colorectal cancer 

Study Mechanism Examined 

Experimental 

Model 

Amount and 

Duration of 

Ethanol and/or 

Acetaldehyde 

Exposure 

Use of 

Carcinogen Results 

Conclusions as Reported by 

Study Authors 

Pannequin 

et al. 

2007141 

Accumulation of 

phosphatidylethanol 

resulting in a signal 

change in intestinal cell 

proliferation 

Mice, Caco-2 Animal study: 

2 mol/L (10%) 

ethanol for 

4 months. 

Cell line study: 

10 mmol/L of 

ethanol or 

0.5 mmol/L of 

acetaldehyde 

once daily for 

48 hours. 

None Chronic exposure 

to low doses of 

ethanol 

(10 mmol/L) 

induces an 

increase of 

maximal intestinal 

cell density. 

The disruption of cellular 

signals might facilitate the 

stimulatory role of ethanol 

metabolites such as 

acetaldehyde on the 

proliferation of cells within 

intestinal crypts, thereby 

participating in the wellestablished cocarcinogenic 

role of alcohol consumption in 

the colon. 

C-40
 
Appendix D: List of Excluded Studies 

Table D-1. Excluded full articles 

Study Reason(s) for Exclusion 

Yi et al. 2010313 Cancer mortality study. 

Author(s) not listed 1988103 Clinical meeting article. 

Purohit et al. 200540 Clinical meeting article. 

Scheppach et al. 1999314 Clinical meeting article. 

Seitz et al. 1992315 Clinical meeting article. 

Weisburger 1992316 Clinical meeting article. 

Kleinjans et al. 1996317 Contents of alcoholic beverage. 

Potter et al. 1982318 Correlation analysis study. 

Siegmund et al. 2003319 Description of animal models in gastrointestinal alcohol 

research. 

Aye et al. 2004320 Invasion of breast cancer cells. 

Luo 2006321 Invasion of breast cancer cells. 

Luo and Miller 2000322 Invasion of breast cancer cells. 

Ma et al. 2003323 Invasion of breast cancer cells. 

Meng et al. 2000324 Invasion of breast cancer cells. 

McGarrity and Nelson 1986325 Letter to editor. 

Larsen 1993326 News report publication. 

Colombo et al. 2001327 No outcome of interest. 

Fiala et al. 1987328 No outcome of interest. 

Zedeck 1980329 No outcome of interest. 

Holford 19875 Pharmacokinetic study. 

Weisburger and Wynder 1984330 Review article. 

Agrawal et al. 2007331 Review article. 

Alberts 2002332 Review article. 

Ambrosone 2000333 Review article. 

Arasaradnam et al. 2008334 Review article. 

Author(s) not listed 20001 Review article. 

Author(s) not listed 200827 Review article. 

Author(s) not listed 1994335 Review article. 

Baan et al. 20072 Review article. 

D-1
 
Study Reason(s) for Exclusion 

Bailey 2003336 Review article. 

Blot 1992337 Review article. 

Boffetta and Hashibe 2006338 Review article. 

Bosetti et al. 2002339 Review article. 

Brown 2005340 Review article. 

Campos et al. 2005341 Review article. 

Chhabra et al. 1996342 Review article. 

Correa Lima and Gomes-da-Silva 2005343 Review article. 

Dossus and Kaaks 2008,344 Review article. 

Dumitrescu and Cotaria 2005345 Review article. 

Ferguson et al. 2005346 Review article. 

Filion 2002347 Review article. 

Forman et al. 2004348 Review article. 

Fraumeni 1979349 Review article. 

Gago-Dominguez et al. 2007350 Review article. 

Giovannucci 2002351 Review article. 

Goodwin 2008352 Review article. 

Hamid et al. 2009353 Review article. 

Heavey et al. 2004354 Review article. 

Homann et al. 2005355 Review article. 

Huxley et al. 2007356 Review article. 

Key and Verkasalo 1999357 Review article. 

Key et al. 200442 Review article. 

Kim et al. 2007358 Review article. 

Klatsky 2001359 Review article. 

La Vecchia 1989360 Review article. 

Lands 1998361 Review article. 

Ledermann 1955362 Review article. 

Li and Lai 2009363 Review article. 

Lieber 2000364 Review article. 

Lindhal 1992365 Review article. 

Longnecker 1995366 Review article. 

D-2
 
Study Reason(s) for Exclusion 

Longnecker 1995367 Review article. 

Lowenfels 1990368 Review article. 

Mason and Choi 2005369 Review article. 

Nagy 20049 Review article. 

Nanri et al. 2007370 Review article. 

O’Hanlon 200535 Review article. 

Payne 1990371 Review article. 

Perse and Cerar 200784 Review article. 

Porter 1993372 Review article. 

Porter 1995373 Review article. 

Poschl and Seitz 200424 Review article. 

Poschl et al. 2004374 Review article. 

Pufulete et al. 2003375 Review article. 

Purohit 2000376 Review article. 

Rampersaud et al. 2002377 Review article. 

Rogers and Conner 1986378 Review article. 

Rogers et al. 1993379 Review article. 

Rothman et al. 1995380 Review article. 

Sakar et al. 2001381 Review article. 

Salaspuro 199620 Review article. 

Salaspuro and Mezey 2003382 Review article. 

Schatzkin and Longnecker 199443 Review article. 

Secretan et al. 200917 Review article. 

Seitz and Becker 2007383 Review article. 

Seitz and Homann 2007384 Review article. 

Seitz and Maurer 2007385 Review article. 

Seitz and Poschl 1997386 Review article. 

Seitz et al. 1994387 Review article. 

Seitz et al. 2005369 Review article. 

Seitz et al. 1998388 Review article. 

Siegmund et al. 2006389 Review article. 

Simanowski et al. 1995390 Review article. 

D-3
 
 

 

 

 

 

 

 

Study Reason(s) for Exclusion 

Stoll 1999391 Review article. 

Tan et al. 2006392 Review article. 

Taylor and Rehm 2006393 Review article. 

Thies and Siegers 1989394 Review article. 

Tsigris et al. 2007395 Review article. 

Ulrich 2007396 Review article. 

Walker and Burkitt 1976397 Review article. 

Wang 2003398 Review article. 

Wang 2005399 Review article. 

Weisburger et al. 1981400 Review article. 

Weisburger 1998401 Review article. 

Welsch 1985402 Review article. 

Williams 1976403 Review article. 

Winawer and Shike 1992404 Review article. 

Wright et al. 199925 Review article. 

Wynder 1977405 Review article. 

Wynder 1978406 Review article 

Nozawa et al. 2006407 Study administered freeze-dried beer. 

Martin et al. 2004408 Study administered Resveratrol, a polyphenol found in 

grapes. 

Gierer 1955409 Study did not look at cancer causation. 

Briviba et al. 2002410 Study did not report on consumption/administration of 

ethanol. 

Caderni et al. 2000411 Study did not report on consumption/administration of 

ethanol. 

Cerda et al. 1999412 Study did not report on consumption/administration of 

ethanol. 

Depeint et al. 2006413 Study did not report on consumption/administration of 

ethanol. 

Diergaarde et al. 2003259 Study did not report on consumption/administration of 

ethanol. 

Dolara et al. 2005358 Study did not report on consumption/administration of 

ethanol. 

Farah 2005414 Study did not report on consumption/administration of 

ethanol. 

D-4
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Study Reason(s) for Exclusion 

Femia et al. 2005415 Study did not report on consumption/administration of 

ethanol. 

Gonthier et al. 2003416 Study did not report on consumption/administration of 

ethanol. 

Hall et al. 1991417 Study did not report on consumption/administration of 

ethanol. 

Kabat and Rohan 2007418 Study did not report on consumption/administration of 

ethanol. 

Kabat et al. 2007419 Study did not report on consumption/administration of 

ethanol. 

Lagiou et al. 2009420 Study did not report on consumption/administration of 

ethanol. 

Etique et al. 2004421 Study did not report on consumption/administration of 

ethanol. 

Linz et al. 2004422 Study did not report on consumption/administration of 

ethanol. 

Luceri et al. 2002423 Study did not report on consumption/administration of 

ethanol. 

Maciel et al. 2004298 Study did not report on consumption/administration of 

ethanol. 

Moon et al. 2006424 Study did not report on consumption/administration of 

ethanol. 

Morris and Seifter 1992425 Study did not report on consumption/administration of 

ethanol. 

Nozawa et al. 2004426 Study did not report on consumption/administration of 

ethanol. 

Nozawa et al. 2004427 Study did not report on consumption/administration of 

ethanol. 

Nozawa et al. 2005428 Study did not report on consumption/administration of 

ethanol. 

Peluso et al. 2008429 Study did not report on consumption/administration of 

ethanol. 

Reddy et al. 1997430 Study did not report on consumption/administration of 

ethanol. 

Robson et al. 2006431 Study did not report on consumption/administration of 

ethanol. 

Schrauzer et al. 1982432 Study did not report on consumption/administration of 

ethanol. 

Takechi et al. 2004433 Study did not report on consumption/administration of 

ethanol. 

D-5
 
 

 

 

Study Reason(s) for Exclusion 

Wulf et al. 2004434 Study did not report on consumption/administration of 

ethanol. 

Yamagishi et al. 2002435 Study did not report on consumption/administration of 

ethanol. 

Slattery et al. 200958 Study looked at tumor markers. 

Gago-Dominguez et al. 2005436 Unrelated epidemiology study. 

Gaudet et al. 2005437 Unrelated epidemiology study. 

Giacosa et al. 2004438 Unrelated epidemiology study. 

Lewis et al. 2003439 Unrelated epidemiology study. 

Orita et al. 2004440 Unrelated epidemiology study. 

Schatzkin et al. 1993441 Unrelated epidemiology study. 

Visapaa et al. 1998442 Inhibition of intracolonic acetaldehyde production by 

ciprofloxacin. 

Vogel et al. 2007184 Title correction. 

D-6
 
Appendix E: Peer Reviewers 

List of peer reviewers to be provided by AHRQ. 

E-1