Alcohol consumption and the risk of colon cancer by family history of colorectal cancer (original) (raw)

• Journal List
• [Am J Clin Nutr](/pmc/?term=%22Am J Clin Nutr%22[journal])
• PMC3260069

Am J Clin Nutr. 2012 Feb; 95(2): 413–419.

1From the Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (EC, JEL, EBR, and ELG); the Departments of Nutrition (EC, EBR, and ELG) and Epidemiology (EBR and ELG), Harvard School of Public Health, Boston, MA; the Department of Food and Nutrition, Sookmyung Women's University, Seoul, Korea (JEL); and the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA (CSF).

Corresponding author.

2The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

3Supported by research grants AA017693;, CA87969;, and CA55075 from the NIH.

4Address reprint requests and correspondence to E Cho, Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115. E-mail: ude.dravrah.gninnahc@ohc.gnuoynue.

Received 2011 Jun 22; Accepted 2011 Nov 22.

Copyright © 2012 American Society for Nutrition

Abstract

Background: Individuals with a family history of colorectal cancer may be more susceptible to adverse effects of alcohol consumption.

Objective: We investigated whether the association between alcohol consumption and colon cancer risk differed by family history of colorectal cancer.

Design: We conducted prospective studies in women and men in the Nurses’ Health Study and Health Professionals Follow-Up Study, respectively. Alcohol consumption was first assessed in 1980 in women and in 1986 in men.

Results: During a follow-up of 26 y among 87,861 women and 20 y among 47,290 men, we documented 1801 cases of colon cancer (1094 women and 707 men). Higher alcohol consumption was associated with an elevated risk of colon cancer, although the association was significant only for the highest intake category of ≥30 g/d, with no significant linear trend. The association between alcohol consumption and colon cancer risk differed by family history of colorectal cancer; in comparison with nondrinkers, the pooled multivariate RRs for alcohol consumption of ≥30 g/d were 1.23 (95% CI: 0.96, 1.57; NS) among those with no family history and 2.02 (95% CI: 1.30, 3.13) among those with a family history of colorectal cancer (P value test for difference = 0.05). In comparison with nondrinkers with no family history, the RR for colon cancer was 2.80 (95% CI: 2.00, 3.91) for individuals who consumed ≥30 g/d and who had a family history of colorectal cancer.

Conclusion: Reducing alcohol consumption may decrease the incidence of colon cancer, especially among those with a family history of colorectal cancer.

INTRODUCTION

Alcohol consumption is an established risk factor for colorectal cancer (1). However, it is not clear if there are susceptible subpopulations. Genetic susceptibility plays a role in the development in colorectal cancer. A history of colorectal cancer in a first-degree relative (eg, a parent or sibling) elevates an individual's lifetime risk of developing colorectal cancer ∼2-fold (2). In a preliminary study, we found that among women in the NHS5, a positive association between alcohol intake and colon cancer risk was largely restricted to those with a positive family history of colorectal cancer (3). However, the estimates were unstable due to a small sample size among those with a positive family history, and thus the difference in associations by family history was not conclusive. Also, it is of interest whether a similar difference in association exists in men. Therefore, we prospectively examined the relations between alcohol consumption and colon cancer risk by family history of colorectal cancer after doubling the sample size and adding another prospective study in men (4).

SUBJECTS AND METHODS

Study population

The NHS enrolled 121,700 female registered nurses aged 30–55 y in 1976 (5). The HPFS included 51,529 male health professionals aged 40–75 y in 1986. We sent follow-up questionnaires to both cohorts biennially to update information regarding diet and lifestyle and to ascertain new diagnoses of major illnesses. Deaths in the cohorts were ascertained by reports from family members, the postal service, and a search of the National Death Index (6). The overall follow-up rates for these cohorts are >94% (7). In this analysis, we included only participants with plausible energy intakes (600–3500 kcal/d for women and 800–4200 kcal/d for men) and with no diagnosis of cancer (except for nonmelanoma skin cancer), ulcerative colitis, or familial polyposis syndrome at baseline.

The procedures and protocols of the study were approved by the institutional review boards for the Brigham and Women's Hospital and the Harvard School of Public Health.

Alcohol consumption and other exposure assessments

A semiquantitative FFQ with ∼60 food items was sent to members of the NHS cohort in 1980. An expanded FFQ with ∼130 food items was administered to women in 1984, 1986, and every 4 y thereafter. A similar, expanded version of FFQ was administered to men in the HPFS in 1986 and every 4 y thereafter. Participants were asked how often, on average, they had consumed each type of food or beverage, including alcoholic beverages (beer, wine, and liquor), during the past year. Serving sizes were specified for each food in the FFQ. The questionnaire had 9 possible responses, ranging from never or less than once per month to ≥6 times/d. Participants also reported the frequency of alcohol consumption in number of days per week (none; 1–2, 3–4, 5–6, or 7 d/wk) in 1986 in both cohorts.

We determined alcohol intake by multiplying the specific alcoholic beverage by its ethanol content; 12.8 g for a 12-oz can or bottle of beer, 11.3 g for a 12-oz can or bottle of light beer, 11.0 g for a 4-oz glass of wine, and 14.0 g for a standard drink of liquor. The cumulative average of alcohol intakes was calculated. For example, alcohol intake in 1980 was used for analyses of colon cancer diagnosed from 1980 through 1984, and the average alcohol intake through 1980–1984 was used for analyses of colon cancer diagnosed from 1984 through 1986 and so on.

To evaluate the validity of the reported alcohol consumption measured by the FFQ, comprehensive diet records and plasma HDL concentrations were obtained from a subsample of participants in the NHS and HPFS (8). Mean daily intakes of alcohol, as assessed by the questionnaire and by the diet records, were very similar. The Spearman correlation coefficient for alcohol intake measured by the diet records and the questionnaire was 0.90 in women and 0.86 in men. In addition, the difference in plasma HDL concentrations for male abstainers and drinkers of 39 g/d was 11.8 mg/dL based on alcohol intake reported by the FFQ, a magnitude similar to that determined from short-term intervention studies of alcohol (8).

In the NHS, a history of colorectal cancer in a father, mother, or siblings was elicited in 1982 and was updated in 1988, 1992, 1996, and 2000. In the HPFS, colorectal cancer history in a father or mother was elicited in 1986 and that in a father, mother, or siblings was requested in 1990, 1992, and 1996.

Participants provided information on age and height at baseline and smoking history, weight, physical activity (except for 1980–1984, 1990, and 2002 in the NHS), aspirin use (except for 1986 in the NHS and except for 1988 in the HPFS), postmenopausal hormone use, and screening by colonoscopy or sigmoidoscopy as well as the indications for the procedure (except for 1982 in the NHS) biennially unless specified otherwise during the follow-up period. Intakes of total calorie, red meat, calcium, and folate were calculated from the FFQ. Calcium and folate intakes were energy-adjusted by using the nutrient residual method (9).

Assessment of colon cancer

In a previous analysis of these cohorts, a family history of colorectal cancer was associated with an increase in the risk of colon cancer but had no influence on the risk of rectal cancer (10); as a result, we considered only colon cancer in the primary analysis and evaluated colorectal cancer in the secondary analysis.

On each biennial questionnaire we inquired whether colon cancer had been diagnosed and, if so, the date of the diagnosis. When a diagnosis of cancer of the colon was reported we asked the participant or next of kin for permission to obtain medical records and pathology reports pertaining to the diagnosis. A study physician blinded to alcohol consumption information reviewed the records and extracted information on histologic type, anatomic location, and stage. Proximal colon cancers were defined as those from the cecum to and including the splenic flexure, and distal colon cancers were defined as those in the descending and sigmoid colon. Cancers other than confirmed adenocarcinomas were excluded.

Statistical analyses

Alcohol consumption was divided into categories by using prespecified identical cutoffs [nondrinkers; 0.1 to <5, 5 to <10, 10 to <15 (∼1 drink/d), 15 to <30, or ≥30 g/d] across the studies. The number of days per week that alcohol was consumed was evaluated in addition to the amount of alcohol intake.

Participants contributed person-time from the date of return of the baseline questionnaire until the date of diagnosis of colon cancer, death, or end of follow-up (June 2006 for the NHS and January 2006 for the HPFS), whichever came first. Participants were divided into categories according to their alcohol intake. RRs of colon cancer were calculated as the incidence rate for a given category of alcohol consumption as compared with the rate for the nondrinkers. We used Cox proportional hazards regression to account for potential effects of other risk factors for colon cancer. To control as finely as possible for confounding by age, calendar time, and any possible 2-way interactions between these 2 time scales, we stratified the analysis jointly by age in months at start of follow-up and calendar year of the current questionnaire cycle. We conducted an analysis by using the whole population, with adjustment for family history of colorectal cancer in parents and siblings (yes or no) and also conducted a stratified analysis by family history. We also evaluated the associations by subtype of colon cancer (proximal compared with distal). Finally, we further stratified the association of alcohol consumption and family history and colon cancer by folate intake. All covariates were updated in each questionnaire cycle or whenever new data were available.

SAS PROC PHREG (SAS Institute Inc) was used, and the Anderson-Gill data structure (11) was used to handle time-varying covariates efficiently. For all RRs, 95% CIs were calculated. To calculate the P value for the test for trend, participants were assigned the median value of their category of alcohol, and this variable was used as a continuous variable in the study-specific regression models.

To test whether the association between alcohol intake and colon cancer risk was modified by family history of colorectal cancer, comparisons between top categories of alcohol intake were tested by using a Wald test. All P values were 2-sided.

We conducted separate analyses for each cohort, tested for heterogeneity between studies, and used meta-analytic methods with a random-effects model to pool the RRs from the cohorts (12). SAS statistical software package version 9.1 (SAS Institute Inc) was used for all statistical analyses.

RESULTS

During the follow-up of 26 y among 87,861 women in the NHS (2,147,523 person-years) and 20 y among 47,290 men in the HPFS (830,242 person-years), we documented 1801 cases of invasive colon cancer (1094 women and 707 men).

Characteristics of the study participants according to intake of alcohol consumption in 1986 are shown in Table 1. Individuals who consumed higher amounts of alcohol were more likely to eat red meat, to smoke, and to use aspirin in both the NHS and the HPFS. The proportion of participants with a positive family history of colorectal cancer ranged between 8% and 9% across alcohol consumption in the studies.

TABLE 1

Characteristics according to alcohol intake in 1986 in the NHS and the HPFS_1_

Higher alcohol consumption was associated with an elevated risk of colon cancer, although the association was significant only for the highest intake category of ≥30 g/d, with no significant linear trend (Table 2). In sex-specific analysis, although there was a suggestion of a positive association in women, the association was significant only in men (_P_-trend = 0.006). The number of drinking days was not associated with risk of colon cancer; the RRs for colon cancer were 1.07 (95% CI: 0.96, 1.21) for 1–2 drinking days/wk and 1.18 (95% CI: 0.94, 1.48) for ≥5 drinking days/wk, compared with nondrinkers.

TABLE 2

Age-adjusted and multivariate RRs and 95% CIs of colon cancer according to cumulative alcohol intake and family history of colorectal cancer_1_

The association between alcohol consumption and colon cancer risk differed by family history of colorectal cancer (Table 2); compared with nondrinkers, the pooled multivariate RRs were 1.23 (95% CI: 0.96, 1.57) for alcohol consumption of ≥30 g/d among those with no family history and 2.02 (95% CI: 1.30, 3.13) for the same comparison among those with a family history (P value test for difference by family history = 0.05). The results were not significantly different by study (P value test for difference by study > 0.55 for the category). The corresponding RRs for colorectal cancer (n = 2527) were 1.38 (95% CI: 1.13, 1.69) and 1.76 (95% CI: 1.19, 2.61), respectively (P value test for difference by family history = 0.28).

Compared with nondrinkers with no family history, the pooled multivariate RRs for colon cancer were 1.38 (95% CI: 1.06, 1.80) for nondrinkers with a family history and 2.80 (95% CI: 2.00, 3.91) for individuals who drank ≥30 g/d and who had a family history of colorectal cancer (Figure 1). Because part of the association may be mediated by folate, we further stratified the association by folate intake. Compared with nondrinkers with a folate intake of ≥300 μg/d and no family history, the pooled multivariate RRs for colon cancer were 2.09 (95% CI: 1.28, 3.39) for individuals who drank ≥30 g/d, had a folate intake of ≥300 μg/d, and had a family history of colorectal cancer and 3.59 (95% CI: 2.30, 5.62) for those who drank ≥30 g/d, had a folate intake of <300 μg/d, and had a family history of colorectal cancer. The results were similar in women and men; the corresponding RRs were 1.92 (95% CI: 0.70, 5.31; NS) and 3.97 (95% CI: 2.16, 7.29) for women and 2.14 (95% CI: 1.23, 3.71) and 3.19 (95% CI: 1.65, 6.18) for men.

Pooled multivariate RR of colon cancer according to cumulative alcohol intake and family history of colorectal cancer. RR was stratified by age in months at the start of follow-up and calendar year of the current questionnaire cycle and was simultaneously adjusted for the following factors: pack-years of smoking before age 30 y (never smoker; 1–4, 5–10, or ≥11 y of smoking), BMI (in kg/m2; <23, 23 to <25, 25 to <30, 30 to <35, or ≥35), history of endoscopy (yes or no), use of aspirin (never; past; current use of 1–2, 3–5, 6–14, or ≥15 tablets/wk), and intakes of energy (continuous), calcium (continuous), folate (<250, 250 to <400, 400 to <600, 600 to <800, or ≥800 μg/d), and red meat (quintiles). In the NHS, information on menopausal status and use of postmenopausal hormone (premenopausal, never, past, or current) were also adjusted for. The number of cases in each category was 268 for 0 g alcohol/d and no family history, 846 for 0.1–14.9 g alcohol/d and no family history, 152 for 15 to <30 g alcohol/d and no family history, 111 for ≥30 g alcohol/d and no family history, 71 for 0 g alcohol/d and family history, 260 for 0.1–14.9 g alcohol/d and family history, 49 for 15 to <30 g alcohol/d and family history, and 44 for ≥30 g alcohol/d and family history. *RR was significant. NHS, Nurses’ Health Study.

Although there was no significant interaction by family history of colorectal cancer, a positive association with alcohol consumption among those with a positive family history was found for distal colon cancer but not for proximal colon cancer; the pooled multivariate RRs for consumption of ≥30 g alcohol/d were 1.17 (95% CI: 0.76, 1.80; NS) among those with no history and 2.35 (95% CI: 1.05, 5.26) among those with a positive family history for distal colon cancer (P value test for difference by family history = 0.13; Table 3). The corresponding RRs for proximal colon cancer (P value test for difference by family history = 0.98) were 1.05 (95% CI: 0.71, 1.56; NS) and 1.05 (95% CI: 0.65, 1.69; NS).

TABLE 3

Multivariate RRs and 95% CIs of proximal and distal colon cancer according to cumulative alcohol intake and family history of colorectal cancer_1_

DISCUSSION

In our study, higher alcohol intake, especially intakes of >30 g/d, was associated with an elevated risk of colon cancer. The positive association between alcohol intake and colon cancer was stronger among those with a positive family history of colorectal cancer than among those without a history, which was consistent in both cohorts.

Although progress has been made on inherited susceptibility of colorectal cancer (13), the nature of inherited susceptibility and the specific gene or genes responsible for inherited susceptibility to the cancer are not completely understood. Individuals with a family history of colorectal cancer are relatively common, and they may experience morbidity and mortality from colorectal cancer at younger ages than those with no family history. At the same time, this population of those with a family history may be more willing to make lifestyle changes for cancer prevention than would the general population.

Few studies have evaluated the populations with a positive family history of colorectal cancer. A case-control study in Hawaii reported a stronger association between alcohol intake and colorectal cancer among those with a positive family history (14). A case-control study from Australia reported similar findings that those who consumed beer had a higher risk of developing colorectal cancer among those with a family history than among those with no history (15). However, a case-control study from Italy did not find any difference in association between alcohol consumption and colorectal cancer by family history (16). In our preliminary evaluation of colon cancer by family history of colorectal cancer in women in the NHS, a suggestive positive association between alcohol intake and colon cancer was found only among those with a positive family history of colorectal cancer (3). In the present study, we confirmed that the association between alcohol consumption and colon cancer risk was stronger among those with a positive family history, with a much larger sample size, and also found similar associations in men, which reduces the possibility that our findings were due to chance.

Our results may imply that alterations in certain inherited factors involved in the metabolism of alcohol or in other pathways affected by alcohol consumption (eg, one-carbon metabolism) may partly contribute to or interact with the inherited susceptibility (17–20). This may suggest that future studies evaluating genetic susceptibilities of colon cancer should take alcohol consumption into account (eg, stratify by alcohol consumption). We also found that folate deficiency in addition to alcohol consumption and family history further contributed to the elevated risk of colon cancer. It is also possible that shared environment by family members could contribute to the associations we found.

We found that the association between alcohol intake and colon cancer risk was observed primarily for distal but not proximal colon cancers. The association between alcohol and colon cancer may be stronger for distal colon cancer than for proximal colon cancer (21), and alcohol may be metabolized by intestinal bacteria to acetaldehyde, a carcinogen, primarily in the distal colon because the lower pH in the proximal colon inhibits acetaldehyde production (22).

This study had several strengths. The prospective nature of the study avoided some biases (such as recall or selection bias) that may occur in case-control studies. Our study provided a unique opportunity to evaluate alcohol intake and risk of colon cancer by family history of colorectal cancer in large populations of women and men with an adequate number of incident colon cancer cases among those with a positive family history. Because we had repeated measures of dietary intake, we were able to use repeated and updated alcohol consumption, which may reduce measurement error. We also had information on a wide range of potential confounders collected prospectively.

Several potential limitations of our study are important to consider. First, residual confounding is a concern in observational studies. However, adjustment for multiple risk factors made only minimal changes in results, suggesting that residual confounding did not completely explain the associations we found. Second, we had limited numbers of participants with relatively heavy alcohol consumption and were only able to evaluate alcohol consumption of ≥30 g/d as the highest intake category. Thus, it is possible that the association between alcohol consumption and colon cancer risk may be even stronger and the contrast by family history of colorectal cancer may be clearer among populations with heavier alcohol consumption. Third, former drinkers who quit alcohol consumption might be included in the nondrinkers group. However, because we took advantage of multiple assessment of alcohol consumption during follow-up and used the average of intake from the assessments, participants who quit drinking during follow-up were not grouped as nondrinkers. Also, when past drinkers were evaluated separately, past drinking was not associated with colorectal cancer in the HPFS (4).

In conclusion, we found that alcohol consumption was associated with an elevated risk of colon cancer, especially among those with a positive family history. Reducing alcohol consumption may decrease the incidence of colon cancer, especially in this highly susceptible population.

Acknowledgments

The authors’ responsibilities were as follows—EC: study concept and design, drafting of the manuscript, and obtainment of funding; JEL: analysis and interpretation of data, critical revision of the manuscript for important intellectual content, and statistical analysis; EBR: study concept and design and critical revision of the manuscript for important intellectual content; CSF: acquisition of data and critical revision of the manuscript for important intellectual content ; and ELG: study concept and design, acquisition of data, and critical revision of the manuscript for important intellectual content. None of the authors had any personal or financial conflicts of interest.

Footnotes

5Abbreviations used: FFQ, food-frequency questionnaire; HPFS, Health Professionals Follow-Up Study; NHS, Nurses’ Health Study.

REFERENCES

1. World Cancer Research Fund, American Institute for Cancer ResearchFood, nutrition, physical activity, and the prevention of cancer: a global perspective. Washington, DC: American Institute for Cancer Research, 2007 [Google Scholar]

2. Fuchs CS, Giovannucci EL, Colditz GA, Hunter DJ, Speizer FE, Willett WC.A prospective study of family history and the risk of colorectal cancer. N Engl J Med1994;331:1669–74 [PubMed] [Google Scholar]

3. Fuchs CS, Willett WC, Colditz GA, Hunter DJ, Stampfer MJ, Speizer FE, Giovannucci EL.The influence of folate and multivitamin use on the familial risk of colon cancer in women. Cancer Epidemiol Biomarkers Prev2002;11:227–34 [PubMed] [Google Scholar]

4. Thygesen LC, Wu K, Gronbaek M, Fuchs CS, Willett WC, Giovannucci E.Alcohol intake and colorectal cancer: a comparison of approaches for including repeated measures of alcohol consumption. Epidemiology2008;19:258–64 [PubMed] [Google Scholar]

5. Colditz GA, Hankinson SE.The Nurses’ Health Study: lifestyle and health among women. Nat Rev Cancer2005;5:388–96 [PubMed] [Google Scholar]

6. Stampfer MJ, Willett WC, Speizer FE, Dysert DC, Lipnick R, Rosner B, Hennekens CH.Test of the National Death Index. Am J Epidemiol1984;119:837–9 [PubMed] [Google Scholar]

7. Smith-Warner SA, Spiegelman D, Ritz J, Albanes D, Beeson WL, Bernstein L, Berrino F, van den Brandt PA, Buring JE, Cho E, et al.Methods for pooling results of epidemiologic studies: the Pooling Project of Prospective Studies of Diet and Cancer. Am J Epidemiol2006;163:1053–64 [PubMed] [Google Scholar]

8. Giovannucci E, Colditz G, Stampfer MJ, Rimm EB, Litin L, Sampson L, Willett WC.The assessment of alcohol consumption by a simple self-administered questionnaire. Am J Epidemiol1991;133:810–7 [PubMed] [Google Scholar]

9. Willett W, Stampfer MJ.Total energy intake: implications for epidemiologic analyses. Am J Epidemiol1986;124:17–27 [PubMed] [Google Scholar]

10. Wei EK, Giovannucci E, Wu K, Rosner B, Fuchs CS, Willett WC, Colditz GA.Comparison of risk factors for colon and rectal cancer. Int J Cancer2004;108:433–42 [PMC free article] [PubMed] [Google Scholar]

11. Therneau TM.Extending the Cox model. In: Lin DY, Fleming TR, eds. Proceedings of the First Seattle Symposium in Biostatistics: survival analysis. New York, NY: Springer Verlag, 1997:51–84 [Google Scholar]

12. DerSimonian R, Laird N.Meta-analysis in clinical trials. Control Clin Trials1986;7:177–88 [PubMed] [Google Scholar]

13. Barnetson RA, Tenesa A, Farrington SM, Nicholl ID, Cetnarskyj R, Porteous ME, Campbell H, Dunlop MG.Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med2006;354:2751–63 [PubMed] [Google Scholar]

14. Le Marchand L, Wilkens LR, Hankin JH, Kolonel LN, Lyu LC.Independent and joint effects of family history and lifestyle on colorectal cancer risk: implications for prevention. Cancer Epidemiol Biomarkers Prev1999;8:45–51 [PubMed] [Google Scholar]

15. Kune GA, Kune S, Watson LF.The role of heredity in the etiology of large bowel cancer: data from the Melbourne Colorectal Cancer Study. World J Surg1989;13:124–9; discussion 129–31 [PubMed] [Google Scholar]

16. Tavani A, Ferraroni M, Mezzetti M, Franceschi S, Lo Re A, La Vecchia C.Alcohol intake and risk of cancers of the colon and rectum. Nutr Cancer1998;30:213–9 [PubMed] [Google Scholar]

17. Mason JB, Choi SW.Effects of alcohol on folate metabolism: implications for carcinogenesis. Alcohol2005;35:235–41 [PubMed] [Google Scholar]

18. Matsuo K, Ito H, Wakai K, Hirose K, Saito T, Suzuki T, Kato T, Hirai T, Kanemitsu Y, Hamajima H, et al.One-carbon metabolism related gene polymorphisms interact with alcohol drinking to influence the risk of colorectal cancer in Japan. Carcinogenesis2005;26:2164–71 [PubMed] [Google Scholar]

19. Koushik A, Kraft P, Fuchs CS, Hankinson SE, Willett WC, Giovannucci EL, Hunter DJ.Nonsynonymous polymorphisms in genes in the one-carbon metabolism pathway and associations with colorectal cancer. Cancer Epidemiol Biomarkers Prev2006;15:2408–17 [PubMed] [Google Scholar]

20. Stern MC, Siegmund KD, Conti DV, Corral R, Haile RW.XRCC1, XRCC3, and XPD polymorphisms as modifiers of the effect of smoking and alcohol on colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev2006;15:2384–90 [PubMed] [Google Scholar]

21. Cho E, Smith-Warner SA, Ritz J, van den Brandt PA, Colditz GA, Folsom AR, Freudenheim JL, Giovannucci E, Goldbohm RA, Graham S, et al.Alcohol intake and colorectal cancer: a pooled analysis of 8 cohort studies. Ann Intern Med2004;140:603–13 [PubMed] [Google Scholar]

22. Jokelainen K, Roine RP, Väänänen H, Färkkilä M, Salaspuro M.In vitro acetaldehyde formation by human colonic bacteria. Gut1994;35:1271–4 [PMC free article] [PubMed] [Google Scholar]

Articles from The American Journal of Clinical Nutrition are provided here courtesy of American Society for Nutrition