Ethanol

Carcinogenicity

Description of key information

Rats: No effect level >3000mg/kg

Mice (B6C3F1):Females: NOAEL>44000mg/kg (cancer), Males: NOAEL>4250mg/kg (based on historic control data), Males BMDL10=1400mg/kg (based on concurrent control data)

Justification for classification or non-classification

The only significant findings in animals are of low concern for the following reasons:

- tumour type is known to have a high background incidence in the species coupled with significantly low incidence in concurrent control compared to historic control.

- lack of progression to malignancy at 'lower' exposure levels (bearing in mind context of very high doses anyway, well above normal limit dose values).

- single sex response.

- single species response.

It should be noted that the International Life Sciences Institute published an extensive review of the health issues relating to alcohol consumption (“Health issues relating to alcohol consumption”, ILSI, 1999) and concluded that ethanol is not a carcinogen by standard laboratory tests using animals.

In humans, the only epidemiology data that could be relevant to the hazard presented through the use of ethanol as a chemical substance at the workplace and in consumer products is that relating to breast cancer. However, the available data shows that, at the doses feasible from such uses, even over a lifetime, there is no sound evidence of any breast cancer hazard. Even the studies that do conclude a risk suggest that the increased rate is small and that has to be put into context of the relatively high rate of breast cancer incidence in the female population and the likelihood of other factors possibly confounding the findings.

Overall, there is no significant evidence to warrant a classification of ethanol for cancer in the context of the relevant classification and labelling regulations for chemical substances.

Additional information

ANIMAL DATA

A significant number of carcinogenicity studies have been identified, but the majority of these are only partial studies designed to look at aspects of the carcinogenic hazard resulting from drinking ethanol containing beverages and are judged unreliable for assessing the cancer hazard of ethanol as a chemical substance. Only two studies were identified as reliable.

In a study to assess the carcinogenic potential of ethanol, groups of rats were exposed to ethanol at concentrations of 1% and 3% in a liquid semi-synthetic diet for a period of 2 years, approximately equivalent to 1 and 3g/kg respectively. Each dose group used a control matched for caloric content using glucose. From the data it was possible to conclude that ethanol did not cause any treatment related increase in tumours and the no effect level was identified as > 3g/kg.

In a study designed and conducted to determine the long-term toxicity and carcinogenicity of urethane in ethanol, groups of mice were exposed to ethanol at concentrations up to 5% in drinking water for a period of 2 years, with control groups consuming drinking water alone. The only significant cancer finding was a dose related increase in the rate of hepatocellular adenomas for male mice in comparison with the concurrent controls. The species of mouse used in this study is known to have a high spontaneous incidence of these tumours. In comparison to historic controls, the incidence rate in the ethanol dosed animals was not high and the controls were significantly lower (although it should be noted that no historic control information was available for animals on the study diet used.) Analysis of the data using the Benchmark dose approach showed a BMDL10 of 1400mg/kg for liver adenomas in males. There was no significant increase in tumour rates (including mammary tumours) in females. Synopsis: Females: NOAEL>44000mg/kg (cancer), Males: NOAEL>4250mg/kg (based on historic control data), Males BMDL10=1400mg/kg (based on concurrent control data).

Based on a review by Pelucchi (2011) of human data (see also below), it is possible to reverse extrapolate and predict that the no effect level in rats would be in excess of 1000mg/kg, the normal limit dose used in animal test for a chemical substance in a safety assessment programme.

HUMAN DATA

Introduction

IARC concluded that there is evidence that consumption of alcoholic beverages is causally related to cancer in the oral cavity, pharynx (excluding nasopharynx), larynx, oesophagus and liver (IARC monographs on the evaluation of carcinogenic risks to humans. Alcohol Drinking”, volume 44, 1988). More recently they have added breast cancer and colorectal cancer to this list (IARC monographs on the evaluation of carcinogenic risks to humans. Consumption of Alcoholic beverages and ethyl carbamate (urethane)”, volume 96, 2007) They reported no conclusive evidence of a link with cancer in any other organ. It is notable that, with the exception of the liver and breast cancers, the susceptible tissues are those that would be in direct contact with alcoholic beverage resulting from consumption. Direct contact was noted by IARC as likely to cause local irritation.  It is reasonable to postulate that the mode of action is likely to proceed through exposure to high local concentrations of ethanol and its metabolites leading to persistent irritation, and eventually hyperplasia and finally tumour formation. Such a mechanism would not be relevant to exposure via other routes. The exception to this is the liver and breast, which would not be in direct contact with beverages. However, the liver is the primary site of metabolism, does see high concentrations of ethanol and its metabolites.

The UK Committee on the Carcinogenicity of Chemicals in Food, Consumer Products and the Environment reviewed the 1988 IARC monograph with the objective of estimating the relative risks of developing the cancers identified as causally associated with alcohol drinking (Sensible Drinking”, Report by the UK department of Health, 1995). The committee estimated the level of alcohol drinking which produced convincing evidence of an increase in the relative risk of cancer at susceptible sites. The group concluded that there is no convincing evidence that the carcinogenic effects of alcoholic beverages in humans occurs as a result of the mutagenic effect of ethanol, acetaldehyde or other beverage constituents. For the oral cavity, pharynx, larynx and oesophagus, alcohol consumption in excess of 30-40g per day is necessary before there is a convincing increase in the relative risk of cancer.  In a large recent prospective cohort epidemiology study across a number of European study centres, no association was found between alcohol consumption and the risk of pancreatic cancer. Most prospective and case-controlled investigations support the conclusion that only heavy drinking (>80g/day) is associated with hepatocellular carcinoma. The overall conclusion of this review was that consumption of between 3-4 units of alcohol per day (21-28g ethanol) per day does not accrue significant health risks. The German MAK commission have also reviewed the data on ethanol and agreed that carcinogenisis of the mouth, throat, larynx and gullet are as a result of local irritancy effects. They also concluded that there is no convincing evidence that ethanol can produce hepatocellular tumours alone and that cirrhosis as a pre-cancerous lesion probably plays a casual role.

Recent meta-analysis and reviews of the wealth of available cancer studies, have concluded that there is no link between light to moderate alcohol consumption and the following cancers: prostate, ovarian, pancreatic, stomach, liver, brain, thyroid, kidney, lung, bladder, uterine and haematological cancers. There appears to be a negative correlation between alcohol consumption and the risk of endometrial or lymphomas (both non-Hodgkins and Hodgkin's types.) The only positive correlation between light and moderate alcohol consumption and cancer, other than site of contact cancers such as oral cancers, which are only relevant for direct and repeated oral consumption and not therefore relevant, is with melanomas and breast cancer. For the former, it is postulated that there could be confounding due to uncorrected correlations between alcohol consumption, socioeconomic status and sun exposure. The only finding that needs further consideration is breast cancer.

Both the European Chemicals Bureau (classification proposal ECBI/22/06 -2006) and the Dutch Expert Committee on Occupational Standards (Ethanol -an evaluation of the health effects from occupational exposure, Health Council of the Netherlands, 06OSH/2006) reasonably concluded that breast cancer is the most sensitive cancer end point. For this reason, only the available epidemiology data that has looked at the link between drinking and breast cancer has been summarised here.

The available toxicokinetic data suggests that continuous exposure to ethanol vapour at 1000ppm for 8 hours is likely to lead to a similar cumulative exposure as a single strong beverage containing 10g ethanol. Higher exposures over such a duration are unlikely due to the discomfort effects of ethanol at high concentrations on the mucous membranes of the respiratory system and eyes. (Resultant blood ethanol levels will of course be orders of magnitude lower from inhalation exposure compared to oral consumption due to the different timescales involved.) Exposure by dermal absorption of ethanol is negligible. Therefore, by extrapolation, to assess the relevant hazard from ethanol inhalation, this is the sort of consumption range that should be examined.

The analysis of a two large prospective cohorts in the USA of the risk of all cancers from beverage consumption lead to the conclusion that for men, light to moderate drinking (up to 15g;/day) is not associated with any significant increased risk of overall cancer. For women, the most sensitive end point was breast cancer where there does appear to be an elevated risk for drinking 5 -15g/day (but not 1 -5g/day) based on the difference in the risk of all cancers versus cancers excluding breast cancer. For men, there was no significantly elevated risk until until above 15g/day. Curiously, for women, excluding breast cancer, there was no significantly elevated riks until above 30g/day. The pattern of drinking does not appear to affect risk, which seems to be dependent on cumulative amount drunk. Overall, there does not appear to be any evidence that light drinking is associated with any increased risk of cancer and that moderate drinking is only associated with a possible elevated risk of breast cancer in women (Cao, 2015).

A prospective cohort study in Canada examined the individual and synergistic effects of alcohol consumption and smoking on overall and site-specific cancer risk. 26,607 males and females participated in the study and there were 2370 incidents of cancer during the follow up period. There were no statistically significant associations between total alcohol consumption and cancer risk for any site, including breast cancer.  When alcohol was analyzed as a continuous variable, a moderate, non-linear, and positive association was observed between alcohol and all cancer risk in males and the entire cohort with no association observed among females.  A moderate and positive association was observed for alcohol consumption and colon cancer incidence in the male population (Ptrend < 0.05 for both the age-adjusted, and multivariable-adjusted models), however, this effect was attenuated when using the latency multivariable- adjusted model (Ptrend = 0.12), not significant when absolute values compared and not significant at any time for women. The banding of beverage consumption of none, 1 drink or more than 1 drink per day is not useful to ascertain dose response information but overall the study did not provide convincing evidence for any cancer link other than at site of contact (Viner, 2019).

A study was carried out to assess the effect of light-to-moderate alcohol consumption on all cancer risk and mortality amongst a cohort of professional workers in South Korea. The authors of the study concluded that alcohol consumption was significantly, and positively associated with an increased risk of cancer mortality in a dose-dependent manner, beginning with light drinkers but the data presented did not seem to support this concusively if light drinking is considered as 10g alcohol/day or less and therefore cannot be extrapolated to routes of exposure other than deliberate alcohol consumption. For such a group, there was no statistically significant association when males and females were considered separately (and no significant association was seen with males for any dose group.) Analysis of both sexes together did show a small but statistically significant increase in hazard ratio for mortality via cancer at 0 -10g alcohol per day, but this was far lower than see for former drinkers, showing that the study duration may have been too short (one of the weaknesses conceded by the authors) (Ko, 2021).

A study was carried out to investigate the link between alcohol consumption and cancer of unknown primary (CUP) -  a metastasised malignancy with no identifiable tumour origin, using a large, existing cohort. The authors of the study concluded that alcohol consumption was significantly and positively associated with an increased risk of CUP but the data presented did not seem to support this for consumption of 30g alcohol/day or less and therefore cannot be extrapolated to routes of exposure other than deliberate alcohol consumption. Below 30g/day, there was no statistically significant elevated risk in any of the banded alcohol consumption groups of 0 -5, 5 -15 and 15 -30g/day. This conclusion remained whether the sexes were analysed separately or combined. The study did report a significant trend but this was only the case when the highest band with significant association was included (Hermans, 2021)

There appears to be no convincing evidence that the data linking the consumption of alcoholic beverages to cancer has any relevance to the use of ethanol as a chemical substance. The only exception is breast cancer, which needs further consideration.

 

Breast cancer data

This summary of available epidemiology data on breast cancer is drawn from the robust study summaries included in the IUCLID chapter 7.10.2. It should be noted that all epidemiology data is generated to assess the hazard from the deliberate consumption of alcoholic beverages. In this assessment, the results are extrapolated as far as possible to assess the conceivable hazards that could result from other forms of exposure to ethanol.

 

To examine the association between drinking patterns of alcoholic beverages, particularly wine, and breast cancer, a case-control study was conducted among 437 newly-diagnosed breast cancer cases and 922 residence and age-matched controls. Details on drinking patterns were obtained by questionnaire. Women who reported an average consumption of less than 1.5 drinks per day, primarily as wine, (equivalent to 10 - 15 g ethanol/day) had a lowered risk of breast cancer when compared to non-drinkers (Bessaoud, 2008).

 

A retrospective case-control study was conducted between 1991 - 1994 involving 989 women with breast cancer and 1350 (non-cancer) hospital controls. Alcohol consumption was associated with an increased breast cancer risk; for women who reported consuming <13.8 g ethanol/day compared with non-drinkers, with an increased risk for those consuming at least 13.8 g ethanol/day. There was a stronger association between alcohol consumption and breast cancer for oestrogen receptor positive (ER+) cancers than for oestrogen receptor negative (ER-) ones, with a dose-response relationship for ER+ tumours, but not for ER- (Deandrea, 2008).

 

A cohort study among 70,033 women, 2829 of whom developed breast cancer, found no significant increase in breast cancer risk for those consuming <1 drink/day versus lifelong alcohol abstainers. A small but significant and increasing risk was found for those consuming 1 -2 drinks/day and >=3 drinks/day. Increased breast cancer risk was concentrated in women with oestrogen receptor positive tumours. The investigators concluded that a hormone-related mechanism is responsible for the increased risk of breast cancer with alcohol drinking, with a threshold in the broad 1 - 2 drinks/day range (Li, 2009).

 

A meta-analysis of 53 epidemiologic studies was performed involving 153,582 participants (58,515 cases and 95,067 without the disease), to examine the association between alcoholic beverage consumption (and tobacco use) and invasive breast cancer risk. This analysis was said to represent over 80% of the relevant information worldwide on alcohol and tobacco consumption and breast cancer at the time of the study. There was no statistically significant increased risk of breast cancer with a reported median daily intake of alcohol below about 8 g, with high consumption of 15-24g/day only becoming associated with increased risk (Beral, 2002).

 

A meta-analysis of 42 epidemiologic studies (published prior to 2000) providing data on 41,477 incident cases of breast cancer and quantifiable alcohol consumption data were assessed to examine the dose-response relation between alcohol consumption and incident breast cancer risk, and to assess whether this risk differed according to beverage type and various study characteristics. Overall, there was a small, but statistically significant, monotonic increase in the adjusted relative risk (RR) of incident breast cancer for increments of reported alcohol consumption of 6 g/day (RR 1.05, CI 95% 1.03-1.07), 12 g/day (about one drink/day) (RR 1.10, CI 95% 1.06-1.14) and 24 g/day (RR 1.21, CI 95% 1.13-1.3), when compared to non-drinkers. However, the investigators noted that the “question of causality remains unclear”, and that, given the modest size of the relation between alcohol consumption and breast cancer risk, “is likely to remain controversial because, in this instance, it is beyond the resolution of epidemiologic methods, as the possibility of confounding or other bias seems difficult to exclude”. This cautionary note becomes even more relevant if you consider that, for the purposes of extrapolation to the occupational and/or consumer exposure situation, the primary concern is with data from the lower exposures where causality is even less clear and exposure measurements even more variable (Ellison, 2001).

 

The risk of invasive breast cancer was assessed in relation to total daily alcohol consumption among 66,561 postmenopausal women. Multivariate relative risks (RR) and 95% confidence intervals (CI) for categories of daily alcohol intake and risk of incident breast cancer were not statistically significantly increased in postmenopausal women consuming less than 15 g alcohol per day, compared to non-drinkers. Only in the highest category of alcohol consumption (at least 15 g/day),was the risk of incident breast cancer was statistically significantly increased, and this was only just significant (Feigelson, 2003).

 

In a US Study involving over 100,000 women aged 25-42 years, the risk of invasive breast cancer was assessed in relation to total daily alcohol consumption during the past year, and the number of alcoholic beverages consumed per week during different time periods and over the participants lifetime. Less than 5% of the women drank more than one alcoholic beverage/day, and 97% of the cohort were premenopausal at baseline. Multivariate relative risks (RR) and 95% confidence intervals (CI) for categories of daily alcohol intake and risk of invasive breast cancer were not statistically significantly increased in women consuming alcohol in the year before joining the cohort ("previous year") at any intake level up to and including the highest consumption group (>20 g/day), compared to non-drinkers. When assessing the relationship of alcoholic beverage consumption in each of four time periods during the patients lives, no statistically significant increases in breast cancer risk were seen in those women reportedly consuming at least 5 drinks per week at ages 15-17, 18-22, and 31-40 years, or in women consuming less than 5 drinks per week (ingesting up to 10 g alcohol/day) in any of the four time periods, compared to non-drinkers. Only those women who reported consuming either 5-6 drinks/week or more than 6 drinks/week between the ages of 23-30 showed a marginally statistically significantly increased risk of invasive breast cancer, compared to non-drinkers. For average lifetime alcohol consumption (assessed as number of alcoholic beverages per week), no statistically significant increases in breast cancer risk were seen in any category of intake, including at up to at least 10 alcoholic beverages per week, compared to non-drinkers (Garland, 1999).

 

The risk of invasive breast cancer associated with total daily alcoholic beverage consumption, and the influence of drinking patterns (frequency) and age at starting to drink were assessed. in 103,460 “at-risk” Californian teachers (and administrators), aged under 85 years. Multivariate relative risks (RR) and 95% confidence intervals (CI) for categories of total daily alcohol intake through drinking alcoholic beverages and risk of invasive breast cancer were not statistically significantly increased in those women consuming less than 20 g/alcohol day in the year before joining the cohort ("past year"), compared to non-drinkers and no clear pattern was seen for consumption during earlier periods of life. A marginally statistically significant increase in breast cancer risk was observed in those who reported consuming at > 20 g alcohol/day in the "past year. Sporadic drinkers (consuming alcohol on 4 or less days/week) were not associated with an increased risk of breast cancer, compared to non-drinkers (Horn-Ross, 2004).

 

To assess the risk of invasive breast cancer associated with total and beverage-specific alcohol consumption, and to assess whether certain (dietary and non-dietary) factors modify the association, the results from seven prospective studies were pooled. The studies included a total of 322,647 women (aged 34 to 93 years of age) evaluated for up to 11 years, and included 4335 participants diagnosed with incident invasive breast cancer. Of these breast cancer cases, 2873 consumed alcoholic beverages (at varying amounts), and 1462 were described as current non-drinkers. In the four categories in which the women were consuming on average less than 30 g alcohol/day, no statistically significant increase in breast cancer risk was seen, compared to the non-drinkers. Only in those who consumed between 30 to 60 g alcohol/day compared to the non-drinkers was a significant association found. For alcohol intakes less than 60 g/day, breast cancer risk increased linearly with increasing alcohol intake but this relationship only reached statistical significance at above about 15 g alcohol/day (Smith-Warner, 1998).

In a prospective cohort study, a total of 445 primary breast cancer cases were diagnosed from 23,778 postmenopausal Danish women in the nearly 5 year follow-up period. Adjusted relative risks (RR) and 95% confidence intervals (CI) for breast cancer were not statistically significantly increased in women who self-reported consuming less than 24 g alcohol/day, compared to the "reference group" (who reported ingesting up to 6 g alcohol/day). However, in those consuming between 24 and 60 g alcohol/day showed a statistically significant increased risk of breast cancer. Although the trend between total alcohol intake (when treated as a continuous variable) and breast cancer showed a statistically significant increase in risk per 10 g/day increment in alcohol consumption, this does not appear to apply at low levels of consumption. Indeed, abstainers and those reporting only "occasional" drinking appeared to be at slightly increased risk compared to those who reported regularly consuming up to 6 g/day. Drinking frequency was without a significant impact on breast cancer risk in this cohort (Tjonneland, 2003).

 

A combined total of 5048 women were selected from the original Framingham (Massachusetts) Study and the Offspring Cohort, and a total of 287 incident breast cancer cases were diagnosed in the more than 40, and up to 24, years of follow-up, respectively. When combining the two cohorts, adjusted rate ratios (RR) and 95% confidence intervals (CI) for average daily alcohol intake and risk of incident breast cancer were not statistically significantly increased in women who reported consuming alcohol at any of the three categories assessed (<5 g/day, 5 to <15 g/day, and≥15 g/day), compared to non-drinkers. Of the women who reported alcohol consumption in the highest category (≥15 g/day), the median intake was 24 g alcohol/day (about two typical drinks). The findings suggest that the light consumption of alcohol or any type of alcoholic beverage is not asociated with increased breast cancer risk (Zhang, 1999).

A population-based case control epidemiologystudy conducted examined 1000 breast cancer cases with controls matched on age, region, and health care system. In-person interviews were conducted to assess breast cancer risk factors and recent diet, including alcoholic beverage consumption, using a food frequency questionnaire. The authors reported that the study provided evidence that any alcohol intake increases risk of breast cancer. However, the data presented does not appear to provide sound evidence for this. With full correction for confounding factors an adjusted OR=1.25, 95% CI=0.99–1.58 was obtained for 'any lifetime use' of alcohol versus total abstention. Of the 12 parameters for which odds ratios were calculated, only two produced positive correlations across the whole confidence limit range, and one of these was not consistent with the trend of related parameters. The only parameter that showed a statistically significant correlation was of questionable biological likelihood ('one drink per month for more than one year') and, in the context of one positive finding out of 12, could be down to a chance. The study did not provide evidence for any likely hazard relating to the use of ethanol by workers or in consumer based products (Beasley, 2010).

In a prospective cohort study based on the Japanese population, no significant link was found between between moderate alcohol consumption (<150g/week) and drinking 3/4 times per week and breast cancer. This would suggest that there is no hazard from exposure to ethanol by inhalation or dermal exposure or any feasible exposure likely to occur through the use of ethanol or ethanol containing products other than by deliberate consumption of alcoholic beverages (Suzuki, 2010.)

In a case controlled retrospective epidemiology study of a large cohort of African American women who had developed invasive breast cancer, no link with recent alcohol consumption was established with ethanol consumption up to >28g/week and early age drinking seemed to reduce risk (Chandran, 2013).

In a study to investigate the association between recent and lifetime alcohol intake on breast cancer risk amongst American Asians, a small but statistically significant elevated risk was seen for Japanese women and those born in the USA, but not for Chinese or Filipino women or those born outside the USA. No link was seen between recent alcohol intake and breast cancer rate; in fact, some of the sub-groups showed a statistically significant reduction in risk. On the whole, the biological plausibility of the findings is questionable and, coupled with the small magnitude of increased and reduced risk seen, the conclusions of the study should be given a low weighting in the overall hazard assessment (Wu, 2012).

In a large study to examine the associations between alcohol consumption and breast cancer risk a significant positive trend association was found but the data indicated no significant findings for doses at or below 5g/day alcohol intake. In fact, the data for individual dose groups was not significant for all dose groups up to 15g/day intake except for ER+/PR+ status women. The data did not indicate a significant risk at low alcohol daily intake (Liu, 2013).

In a prospective cohort study to investigate the association between alcohol consumption and risk of postmenopausal breast cancer in a large multiethnic population, a positive association was established. However, the data suggested a lack of dose response; a positive association was only statistically apparent for the lowest and highest dose groups with an apparent inverse dose response up to 30g/day alcohol consumption. A significant risk increase was only clearly established for consumption of >30g ethanol/day (Park, 2014).

In a study to obtain an overview of the associations between alcohol consumption and breast cancer risk at adulthood, by type of alcohol and subtype of breast cancer. A significant positive trend in breast cancer risk with increasing alcohol intake in the overall population was reported but this seems reliant on the data for women who consumed more than two standard drinks per day (>20g alcohol per day) which resulted in a significant 19% increase in risk [HR=1.19 (1.04–1.36)]. However, for consumption levels less than this the hazard ratios were not significantly less than one for the all three dose groups up to 2 drinks per day. There was no significant effect of alcohol on breast cancer ratees for premenopausal women and the effects were more pronounced with beer (significant increased risk for all dose groups for postmenopausal women) than for wine (only a significant increased risk at highest dose levels) For spirits, there was no significant increased risk for any dose group. The results suggest that consumption levels of alcohol need to be more than 20g/day for there to be an increased risk and that increased risk may not result from ethanol exposure alone (Fagherazzi, 2014).

A case-control study conducted among West African women with invasive breast cancer, a link with alcohol consumption was determined. However, there was no dose response relationship between daily alcohol consumption or cumulative consumption and relative risk. This suggests at least the magnitude of effect reported for light drinking, if not the results as a whole, should be interpreted with caution (Qian, 2014).

A study was caried out to examine the relation between alcohol intake and the risk of breast cancer using prospective observational data from the European Prospective Investigation into Cancer and Nutrition. Alcohol intake at baseline and average lifetime alcohol intake were calculated from country-specific dietary and lifestyle questionnaires. During an average of 11.0 years of follow-up of 334,850 study participants, the study documented 11,576 incident breast cancer cases (mean age 59.4). Alcohol intake showed a significant positive dose-response relation with breast cancer. However, the increase was only barely significant at up to 15g/day. It was also noticeable that abstainers had an increased rate, albeit not quite statistically significant. Bearing in mind the marginal difference in apparent elevated risk for non drinkers compared to drinkers of up to 15g/day, caution is required in interpreting these results as significant for alcohol consumption below 15g/day (Romeiu, 2015).

A prospective observational study was carried out to evaluate the association of breast cancer with alcohol consumption during adult life, including quantity, frequency, and age at consumption. Increasing alcohol consumption was associated with increased breast cancer risk that was statistically significant at levels of 5.0-9.9 gm/day (equivalent to 3-6 drinks/week) but not below. After controlling for cumulative alcohol intake, binge drinking, with a 21% in breast cancer for adult binge drinkers compared with nondrinkers, after controlling for cumulative alcohol consumption. Frequency of drinking, was not associated with enhanced breast cancer risk. The results suggest that concentration rather than cumulative quantity is an important determinant of breast cancer risk (Chen, 2011).

In an extensive review of the evidence for breast cancer being caused by drinking, the authors concluded there is no solid evidence associating moderate alcohol consumption with an increased incidence of breast cancer (Zakhari, 2015).

An analysis of 22,338 women (5,108 cases of invasive breast cancer) from the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium was carried out. This covered the results from three prospective cohort studies and a case controlled study. The association between number of alcoholic drinks per week (dpw) and breast cancer was estimated using logistic regression, adjusting for potential confounders, and stratifying by breast cancer subtype. The data from women who reported current drinking of≥14 drinks per week (dpw) suggested that they had an elevated risk of breast cancer compared with light drinkers (>0–<4 dpw) [adjusted OR (ORadj), 1.33; 95% confidence interval (CI), 1.07–1.64]. Risks for those drinking between 4 and 14 units per week were slightly elevated also compared to light drinkers but not to statistically significant levels. However, this should be put into context of the fact that the risk was elevated for non-drinkers to significant levels (OR=1.12, CI 1.03-1.22). There was no significant difference seen for the results stratified according to receptor sub-type for each of the different drink intake groups compared to the overall data. Overall, the data does not appear to show a statistically significant elevated risk until alcohol consumption exceeds 14dpw and even here, it is uncertain from this study whether risk are indeed elevated since there is not comparison between this group and the ‘never drinkers’, which is contrary to the conclusions of the authors (Williams, 2017)

A population-based case-control study evaluated the association between alcohol consumption and risk of invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), and invasive ductal-lobular carcinoma (IDLC) of the breast, overall and by estrogen receptor (ER) status, among women aged 55–74 years of age. Current alcohol use was moderately associated with risk of ILC (odds ratio = 1.25, but with a 95% confidence interval 0.99, 1.58 this was barely statistically significant. Whilst there was a positive dose-response relationship based on average number of drinks, this did not reach statistical significance for dose except for >7drinks/week (OR=1.52, CI=1.11-2.07). It should be noted that exposure measures were drinks per week which provides no data on the exposure pattern within a week. (Binge drinking exposure is significantly different to exposure spread throughout the week.) The results also suggested that the increased of breast cancer associated with alcohol is largely limited to ER+ ILC and ER+ IDC and not other types. The data does not provide statistically significant evidence of an increased risk with consumption <7 drinks per week (Baglia, 2017)

In the prospective Nurses’Health Study cohort, a study evaluated alcohol consumption and breast cancer risk by individual tumor marker expression (i.e., ER, progesterone receptor [PR], AR, and IR) while controlling for other markers. The authors reported that each increment in one drink per day was associated with 10 % (95 % confidence interval [CI]=4 %, 15 %) and 9 % (95 % CI=4 %, 15 %) increased risk of AR-positive and ER-positive breast cancer, respectively, while no increased risk was observed among AR-negative or ER-negative tumors, suggesting that the alcohol and breast cancer association may be more pronounced among ER-positive and/or AR-positive breast tumors. However, based on the cumulative average daily intake, there was no absolute increased of breast cancer for any tumour type at a beverage consumption of less than 30g intake per day. The data does not suggest any increase in breast cancer risk from any exposure to alcohol other than deliberate beverage consumption (Wang, 2015)

A prospective cohort study amonst Danish women was used to test the hypothesis that postmenopausal women who increase their alcohol intake over a five year period have a higher risk of breast cancer and a lower risk of coronary heart disease compared with stable alcohol intake. Information on alcohol intake was assessed by questionnaire in terms of weekly number of drinks consumed. The study authors concluded that the study showe women who increased their alcohol intake over the five year period had a higher risk of breast cancer and a lower risk of coronary heart disease than women with a stable alcohol intake with a statistically significant trend. However, the OR ratios quoted did not show a clear dose response with the intermediate drink categories showing no statistically significant difference to the no drinking and 1 -7 drinks/week categories. For coronary heart disease, there was a clear trend towards the highest risk being for non-drinkers even compared to the highest drinking group of >28 drinks/week. The data does not seem to provide compelling evidence of a progressive increase in risk of breast cancer from drinking at low to moderate levels and nothing that can be extrapolated to exposures by other means than drinking of beverages. (Dam, 2017)

A prospective cohort study looked at the effects of height, weight gain since age 20, physical activity and alcohol intake on breast cancer risk. The study found a statistically significant increase of breast cancer risk in both pre and post-menopausal women, but only at ethanol consumption above 15g/day. The study showed that weight gain since the age of 20 in post-menopausal women was a a at least a similar risk factor compared drinking. Based on this study, other studies that do not consider weight gain of postmenopausal women could omit a confounding contributing factor to breast cancer risk. Exposures to ethanol at 15g/day or more can only come from deliberate beverage consumption (Nitta, 2016).

A study to examine the relationship between alcohol use and breast cancer risk by the four major subtypes of breast cancer found no statistical elevation in risk from light to moderate drinking (1 -7 drinks per week).  The study therefore implied a threshold, exposures above which can only come from drinking (Gago-Dominquez, 2016).

A restrospective case study was carried out to explore the association of low-to-moderate levels of alcohol consumption with risk of breast cancer subtypes defined by tumor hormone receptor status. Alcohol consumption was assessed by a question about the frequency/quantity of the use of the alcoholic beverages spirits, wine, and beer. The authors reported an increased odds ratio of breast cancer of 1.75 (95% confidence interval [CI]: 1.21–2.53) in women who consumed <=5 drinks/week, and 3.13 (95% CI: 1.81–5.43) in women who consumed >5 drinks/week, both compared with non-drinkers for >=10 years, after adjustment for age and other confounders. When splitting the results by tumour type, the OR remained statistically similar for postmenopausal women but became statistically non-significant for pre-menopausal women, at all consumption levels.  The association of alcohol intake was only statistically significant for estrogen receptor positive breast cancer and not with estrogen receptor-negative (OR per 1 category increase  2.05 (95% CI: 1.49–2.82) and 1.29 (95% CI: 0.85–1.94 respectively) and, again, when splitting further it was only statistically significant for postmenopausal and not pre-menopausal women. No differences were found with PR receptor status. There was no evidence of an interaction between alcohol intake and menopausal status (P = 0.19) in the overall group; however, it was significant in estrogen receptor positive breast cancer (P = 0.04). Overall, this study demonstrated a statistical link between low level alcohol consumption and ER+ tumours in postmenopausal women but with pre-menopausal women or other tumour types (Strumylaite (2015).

 

A prospective cohort study was performed alongside a wider lifestyle and health study of ~50,000 women in Sweden to estimate the effect of alcohol consumption on breast cancer risk and to test whether overweight and obesity modifies this association. Participants were asked about alcohol consumption frequency and the amount of consumption on one occasion for low alcohol beer, beer, white wine, red wine, dessert wine, and spirits. No statistically significant association was found between alcohol intake and breast cancer risk after adjustment for confounding, with an estimated relative risk (RR) of 1.01 (95 % CI: 0.98–1.04) for an increment in alcohol consumption of 5 g/day. Ths included all analysis but tumour sub-type.  A statistically significant elevated breast cancer risk associated with higher alcohol consumption was found only among women with Body mass index ≤25 (RR 1.03, 95 % CI 1.0–1.05 per 5 g/day increase), although it should be borne in mind that such a 3% increase is quite small and was not seen in the absolute comparisons between groups, only with trend analysis nor with in the analysis for the same group (BMI<25) by tumour sub-type. There was also a significant increase OR (1.95, CI 1.01 -3.76) for the abstainer group for those with a BMI>25 compared to the main control group. Whilst the authors noted the competing effects of obesity and alcohol consumption on circulating sex hormone levels may explain the results it shows that obesity can be a confounding effect that needs to be controlled for in studies examining the link between alcohol and breast cancer, particularly at lower doses (Shin, 2015).

A study was carried out to investigate the associations between cumulative average alcohol intake and risk of breast cancer by molecular subtype among 105,972 women in the prospective Nurses’ Health Study cohort, followed from 1980 to 2006. Alcohol consumption was ascertained from a semiquantitative food frequency questionnaire updated every 2–4 years.   Alcohol consumers had an increased risk of luminal A breast cancers per 10 g/day increment (HR=1.10,  95% CI 1.05–1.15), and an increased risk was suggestively stronger for HER2-type breast cancer (HR =1.16, 95%CI 1.02–1.33.  There was no observed statistically significant associations between alcohol and risk of luminal B, basal-like or unclassified breast cancer incidence.  However, when comparing the dose groups to the abstinent controls, luminal A breast cancer was only statistically significant at consumption levels >10g/day (multivariate HR=1.29, CI 1.10-1.52) and none of the others reached statistical significance compared to controls, even at >20g/day (eg for Her2 type, multivariate HR=1.63, CI 0.91-2.91). The study clearly shows a threshold below which there does not appear to be any statistically relevant findings linking alcohol consumption to breast cancer (Hirko, 2015).

A case controlled study was carried out to examine the evidence for a link between alcohol consumption and breast cancer amongst white and black African American women. African Americans who reported drinking >7 drinks per week had an elevated risk of ER- type tumours compared to light drinkers [OR 2.17, (95% CI 1.25-3.75)] and triple negative tumours [OR 2.12  (95% CI 1.12 - 4.04)] but not ER+ or luminal A and B types.  There was no association with lower levels of beverage consumption either.  There was no statistically significant association by OR for white women with any type of breast cancer.  Curiously, there appeared to be a reduction in risk with drinking for triple negative type tumours, which showed p for trend <0.05, although the ORs never reached statistical significance [OR 0.51 (95% CI 0.23 - 1.15)] (Williams, 2106).

A meta-analysis of a large number of cohort studies examined the risks of cancer incidence and mortality from light to moderate consumption of alcoholic beverages. With respect to breast cancer, the authors did report a significant, albeit slightly elevated risk of incidence but with a shallow dose response curve (very light drinking RR=1.04, CI 1.01-1.07, light drinking RR, 1.09; 95% CI, 1.06-1.12, moderate drinking RR, 1.13; 95% CI, 1.11-1.15.) Curiously, however, whilst increasing the incidence of female breast cancer, mortality from female breast cancer was reduced with light drinking (RR, 0.79; 95% CI, 0.64-0.97). Complicating matters was the fact that the authors reported that the indicence of a number of other cancers that result from systemic transport of ethanol, thyroid, kidney and lung appear to be significantly reduced by light to moderate alcohol consumption (Choi, 2017).

A detailed review examined the link between alcohol consumption and breast cancer. Breast cancer is a multifactorial disease. Taking into account all of the non-modifiable and modifiable primary risk factors, the odds ratios contribution for alcohol consumption compared to the other risk factors is estimated to be not statistically significant regarding invasive breast cancer risk. There is no consistent evidence of a link between the metabolite acetaldehyde, estrogen levels and breast cancer. Estimation of alcohol intake remains a weakness of all epidemiology studies. The authors concluded that, generally, the available epidemiological studies do not meet all of the Bradford-Hill criteria that would establish causality of breast cancer from moderate alcohol consumption and finally that the negative consequences of light or moderate drinking are minimal, even in the majority of studies that show a detectable odds ratio for cancer or other diseases at these lower levels.  This conclusion can be extrapolated to exposure to ethanol by other routes which result in even lower levels of exposure (Zakhari, 2019).

A 2 year prospective cohort study was carried out to assess the increased risk of breast cancer from alcohol consumption and to assess how the association may be modified by single nucleotide polymorphisms in alcohol dehydrogenase isoenzymes ADH1B and ADH1C. The study also looked at any association with cancer subtypes by estrogen (ER) and progesterone receptor (PR) status. Exposure assessment was by self administered questionnaires that grouped exposures into four bands plus abstention as a control. The authors concluded that the study shows drinking alcohol is associated with increased breast cancer risk. However, significance of the conclusion is primarly due to the clear positive increased risk from consumption of more than 30g alcohol per day. Excluding these results, there is no significant positive association and there would be no significant trend either. The study does not support the hypothesis that low to moderate alcohol consumption significantly increases the risk of breast cancer and by inference does not provide any support to a hazard from exposure to alcohol by any route other than deliberate consumption (Hahn, 2018)

A prospective cohort study involving approximately 17,000 women and 1000 breast cancer cases found no link between consumption of alcoholic beverages and the overall risk of breast cancer overall or by sub-type (Zeinomar, 2019)

A retrospective study of a cohort of Danish nurses examined the separate and combined risk of tobacco and alcohol use and the incidence of breast and gynecological cancers and overall cancers in women. A total of 16,106 nurses aged 44 years and over were followed for a period of 23 years. Alcohol consumption was banded into none, light (1 -7units/week(, moderate (7 -14 units/week) and excessive (>14 units/week.). No significant difference was seen between the abstinence, low and moderate consumption groups.  However excessive alcohol consumption >14 weeks did increase in overall cancer risk (1.19; CI 1.10-1.28), alcohol related cancer risk (1.25; CI 1.12-1.4) and breast cancer risk (1.18; CI 1.10-1.26).  There was no significant link between alcohol consumption and the risk of gynacological cancers (Herberg, 2019).

A Mendelian randomization (MR) study was performed to test the hypothesis of a causal relationship between alcohol use and risk of breast and ovarian cancer by using summary level genetic data from genome- wide association studies (GWAS) conducted on alcohol consumption, breast and ovarian cancer. Genetic variants associated with alcohol consumption were used as variables (eg variant at gene ALDH2 (aldehyde dehydrogenase 2) as these have been positively associated with alcohol consumption (due to link with alcohol tolerance) by other researchers.  The study examined correlation with three different alcohol intake exposures, drinks per week (drinks/week), alcohol use disorder (AUD) and age-adjusted alcohol use disorder identification test (AUDIT-C). .  Statistics for outcome were extracted from the largest genome- wide association studies of breast (122,977 cases/105,974 controls) and endothelia ovarian cancer (25,509 cases/40,941 controls). The study did not find any evidence to support  a causal association between alcohol consumption and risk of breast cancer using any of the methods of analysis: OR drinks/week values = 1.01 (0.85–1.21); OR AUD = 1.04 (95%CI: 0.89–1.21); OR AUDIT-C = 1.07 (0.90–1.28)]; neither with its subtypes including ER-positive and ER- negative breast cancer, using any of the three alcohol-related exposures. For ovarian cancer, there wwa a significantly reduced risk with alcohol consumption, where a borderline significance was found for AUDIT-C but not for drinks/week or AUC [OR drinks/week = 0.83 (0.63–1.10); OR AUD = 0.92 (0.83–1.01); OR AUDIT-C = 0.83 (0.71–0.97)]. The study authors concluded there was no compelling evidence in support for a causal relationship between geneti-cally predicted alcohol consumption and risk of breast or ovarian cancer, consistent across three different alcohol related exposures (Zhu (2020). One strength of this study is that the assessment of alcohol intake by using genetic phenotypes that cause alcohol intolerance, overcomes one of the weaknesses in alcohol intake assessment when correlating to cancer outcomes.

A metaanalysis of 22 existing cohort studies was carried out with the aim to provide a dose-response estimation between different alcohols and breast cancer risk. The analysis showed that current drinkers for ER+ breast cancers had an increased risk compared with never drinkers. There was no link with PR type. The publication reported a statistically significant linear trend with breast cancer risk increasing gradually by total alcohol and wine dose (but not beer and spirit use), but the way this was reported made it difficult to check the accuracy of the conclusions. Of the 22 studies covered, half reported a significant correlation and half did not (Sun, 2020).

A case controlled study was carried out to assess the association between light to moderate alcohol consumption and cancer incidence in Japan. This hospital based study examined 126,464 individuals (63,232 cancer cases and 63,232 controls).

The study reported that a was significantly elevated cancer risk, including for Breast cancer, for 'ever consumption' of alcoholic beverages. The risk increase was relatively low with an OR of 1.24 (CI 1.11 -1.38). When the results were analysed using a 'drink-year' variable, the risk remained statistically elevated at around 25% across all exposure groups but there was no dose response and for two of the four dose response groups was not even statistically sigificant. As for all of these types of studies, the weakness is the estimation of alcohol consumption, which is too imprecise to establish if there is any hazard from low level drinking or by extrapolation, from exposure by routes other than deliberate beverage consumption (Zaitsu et al, 2020).

A retrospective case controlled study examined whether breast volumetric density modifies and/or mediates the alcohol-breast cancer association. The study reported that alcohol intake was associated with breast for all women (OR1.22, 95% CI  1.05 to 1.42) for 2 drinks or more per day.  On a drinks per day risk increase, the baseline figure was 1.11 (1.04 to 1.20). However, the study did not report findings for the lowest levels of consumption, therefore it is difficult to draw conclusions from the study for the effects of modest alcohol consumption (~1 drink/day) and the results cannot be extrapolated to other routes of consumption.  Note that for pre-menopausal women, the OR increase was not statisically significant (OR, drinks per day: CI 1.12 (0.97 to 1.29)) (Rustagi, 2021).

A Mendelevian randomisation study was carried out to determine if alcohol consumption is causally associated with the risk of female hormone-dependent cancers. The study used by using summary level genetic data from genome- wide association studies (GWAS) conducted on alcohol consumption and breast and ovarian cancer. The study drew on a large database of 1.2 million individuals of European ancestry. The study did not find any compelling evidence in support for a causal relationship between genetically predicted alcohol consumption and risk of breast (overalll or stratified for ER+ and ER- tyes) or ovarian cancer. Such studies avoid biases present in observational studies but may not be powerful enough to detect weak causal relationships and no individual level data to eliminate confounders (Zhu, 2020).

A prospective cohort study was carried out to examine the association between these lifestyle factors (physical activity and alcohol consumption and breast cancer risk and the interaction with general risk of developing breast cancer. The study found an overall increase in the risk of breast cancer with alcohol consumption (ER+ but not ER- type) but not at consumption levels up to 10g/day, which is the intake level that might be relevant to routes of exposure other than deliberate consumption of alcoholic beverages (Rainey, 2020).

Using a mendelian randomisation design to assess existing cancer data, no evidence was found supporting a relationship between alcohol consumption and overall or site-specific cancer risk (breast, ovarian or prostate) (Larsson, 2020).

Conclusion on breast cancer data

 

In one study which found a small but significant correlation between breast cancer and alcohol consumption, the investigators note that the “question of causality remains unclear”, and that, given the modest size of the relation between alcohol consumption and breast cancer risk, “is likely to remain controversial because, in this instance, it is beyond the resolution of epidemiologic methods, as the possibility of confounding or other bias seems difficult to exclude”. This cautionary note becomes even more relevant if you consider that, for the purposes of extrapolation to the occupational and/or consumer exposure situation, the primary concern is with data from the lower exposures where causality is even less clear and exposure measurements even more variable and imprecise. Using such data to extrapolate from one hypothesis (oral consumption of alcoholic beverages causes breast cancer) to another fundamentally different one (exposure of workers to industrial ethanol or to consumers from the use of ethanol containing products) is a massive leap of faith with a very unsound scientific basis. Even so, the data does conclusively indicate that exposure to small amounts of ethanol does not cause a significant increase in breast cancer incidence. Cumulative exposure to ethanol from inhalation or dermal exposure could not reach the high exposure levels where there is some evidence for increased risk of effects in humans. This is without even considering the evidence suggesting that breast cancer may be hormone mediated and therefore likely to involve a threshold mechanism, in which case blood ethanol concentrations are likely to be more important rather than cumulative exposure. This is supported by epidemiological evidence suggesting that patterns of alcohol consumption (e.g. binge drinking) have an important influence on risk rate. There is also evidence to suggest that obsesity is a confounding factor in breast cancer risk.

This conclusion was summed up in two extensive reviews by Zakhari (2015, 2019), who concluded that there is no solid evidence associating moderate alcohol consumption with an increased incidence of breast cancer. The authors concluded that whilst many epidemiological studies suggest that there is an adverse relationship between alcohol use history and the risk for developing breast cancer, the nature of that relationship remains poorly characterized in terms of cause and effect. They advocate caution for the following reasons:

• All studies rely on self-reporting to determine the amount and type of alcoholic beverage consumed, which introduces recall bias. The apparent increased risk of cancer among light-moderate drinkers seen in studies may be substantially due to underreporting of intake, which would over emphasise effects at apparent low doses. This may explain why epidemiological studies produce contradictory associations between the amount of alcohol consumed and risk for breast cancer. (This underreporting and hence over-estimation of risk has been noted by others (Stockwell, 2014; Zeisser, 2017; Ferraguti, 2017).
• The modest size of the association, the shallow dose response, and variation in results across studies leave the causal role of alcohol in question.
• Breast cancer develops over decades. Correlations between alcohol consumption and breast cancer cannot be determined in epidemiological studies with windows of alcohol exposure that captures current or recent alcohol intake after clinical diagnosis.
• There are at least 20 recognized risk factors that can affect the onset and outcome of breast cancer and the overall risk depends on the interactions of all these factors, including those that have not yet been identified. The contribution from particularly moderate alcohol consumption is estimated to be negligible.
• Discrepancies exist between epidemiological and molecular studies which attempt to explain the mode of action, including the role that acetaldehyde plays

In two separate publications that examined the evidence for elevated breast cancer risk from alcohol consumption, Chu et al (2020a & 2020b) examined some specific shortcomings in the published studies on this end point. He carried out both a sensitivity (vibration) analysis and examined the degree with which potential cofounders were properly taken into account in observational studies assessing the risk of breast cancer from alcohol consumption. Around 100 studies were assessed for each issue, The authors concluded that most observational studies evaluating the impact of alcohol on breast cancer report relative effect estimates for the same associations that diverge by >2-fold and that observational studies should estimate the vibration of effects to provide insight regarding the stability of findings.  They also concluded that a substantial proportion of observational study results published need for more adequate consideration of the potential impact of residual confounding to more soundly assess the impact of alcohol consumption on the risk of breast cancer.

Although the use of ethanol in alcoholic beverages is outside the scope of REACH, these data can provide some insight into any risks that might be associated with industrial or other consumer use of ethanol (primarily involving the inhalation or dermal routes), using route to route extrapolation. Whilst breast cancer appears to occur via a systemic exposure pathway, available data supports the hypothesis that ethanol is extremely unlikely to pose any breast cancer risk at the levels of exposure encountered through industrial or other consumer use.