Page last updated: September 13, 2016
Comment On Alcohol and Cancer - Opinion piece by Byron Sharp, Professor of Marketing Science at the University of South Australia

Does alcohol cause cancer ? Can Good Intentions Corrupt Science?

Recently an article by a Kiwi Professor gained sensational newspaper coverage along the lines of “proof alcohol causes cancer”. I’m very interested in the corruption and abuse of science. Good intentions, moral vanity, together with a single source of funding are a strong cause of bias. That’s what it looks like here*, most likely a case of either seeing what you want to see in the evidence, or perhaps deliberating misusing it to make a political point (‘the ends justifies the means’?).

The scientific evidence suggests alcohol might cause a few cancers, though these are rare and the elevated risk of death is tiny. It’s wrong to misrepresent this evidence, and unethical to scare the public.

I’m going to show how Professor Jennie Connor’s case is incomplete and a bit shoddy, in that she misses out important studies and misrepresents others. She even misses out evidence that helps part of her argument.

Her article isn’t a new study, there is no new data, nor data analysis. It was published in the journal’s “For Debate” section. Its purpose is to examine whether it might be reasonable to consider the (weak) correlations seen in population studies as causal evidence that drinking alcohol increases your risk of cancer.

Connor says alcohol causes some cancers. Her conclusion is based almost entirely on epidemiology studies that show drinkers have slightly higher rates of some specific cancers (and slightly lower rates of some others). In doing so she places great faith in epidemiology, far more than many of her colleagues. A more sober analysis would adopt the epidemiologists’ rule of not considering risk assessments of less than a factor of 3 as indicating any causality (see Taubes, G. 1995. ‘Epidemiology faces its limits.’ Science, 269:5221, 164-69). Unlike smoking, alcohol and cancer studies seldom report risk estimates anywhere near this level.

The key problem with epidemiology studies is that they show correlations that are often not causal, they can be completely spurious due to confounding factors. For example, studies might show that elderly people who get regular exercise live longer, but elderly people who are afflicted with health issues are very likely to exercise less (many will be simply unable to), so it is really health that is determining both the exercise as well as the longevity. Exercise might be doing good here but the risk estimate (for not exercising) is going to be way over-estimated.

The problem with comparing alcohol drinkers, of various levels, to lifetime non-drinkers is that alcohol drinkers tend to smoke more, they also tend to be less rural and wealthier. Moderate drinkers might be people who tend to be adopt other healthy behaviours. Heavy drinkers may be self-medicating because of mental or physical ill-health. There are plenty of reasons for caution in treating a correlation seen in population data as causal. Here are some funny examples of real but non causal correlations.

Connor understands the possibility of confounds producing spurious correlations yet completely refrains from discussing any. Instead she goes off on a tangent discussing possible confounds for the well established link between drinking and much lower risk of heart disease. Here she suddenly loses her faith in epidemiology, i.e. when she doesn’t like the results. To even discuss heart disease is rather odd given that her article is about cancer – it’s truly bizarre given she doesn’t have a section covering confounds for alcohol and cancer.

In the absence of controlled experiments (which for cancer research are pretty much impossible for ethical and practical reasons) we need other evidence to support treating a epidemiology result as causal. Connor’s article makes 3 points :

1. First, Connor says, there is a dose-response relationship between alcohol consumption and some cancers, that is, any increase in drinking is associated with increased cancer risk. However, she then (rightly so) contradicts herself in pointing out that for most of these cancers meta-analysis shows no risk for light drinking. In fact some meta-analyses show risk only for the heaviest level of drinking (which is problematic as this group may contain alcoholics and people drinking as self-medication for health problems).

2. Second, Connor notes “evidence that, for some cancers, the risk associated with alcohol attenuates when drinking ceases”. Now this is what we would expect if there were a causal relationship, however it is odd that in this epidemiological analysis the risk drops so terribly slowly, taking decades before drinking cessation results in the same risk as a nondrinker. This is far longer than the effects of cigarette cessation, suggesting the apparent alcohol risks have more to do with confounding factors than a direct causal relationship (i.e. lifestyle factors that slowly regress to the mean). Besides, this evidence is of poor quality; to quote from one of the meta-analyses that Connor cites “Too few studies have addressed this question and of the studies that have, all have significant limitations” and “the only statistically significant relationship that we observe is that drinkers who recently quit drinking have a higher risk of liver cancer than current drinkers”! It would clearly be wrong to make much of this evidence, the models have huge error margins, and are hardly supportive of a causal link between alcohol and cancer.

3. Third, Connor discusses briefly potential biological mechanisms for alcohol perhaps causing cancer. Alcohol in itself is not carcinogenic to human cells, and the epidemiology shows associations with only some cancers not others (indeed drinking seems to be associated with less of some cancers). As Connor writes: “The mechanisms by which alcohol causes cancer are not well understood, but are thought to depend upon the target organ. Pure ethanol does not act as a carcinogen in animal studies, and evidence that it causes mutations directly in humans is weak”. A possible mechanism is that bacteria in the mouth and digestive tract convert alcohol to acetaldehyde, which is a carcinogen. As Connor notes “Stronger associations and more susceptibility at low doses is seen for the cancers where alcohol and [hence] acetaldehyde come into direct contact with the tissues”. She doesn’t mention, but it is important, that this potential bio-mechanism is supported by the evidence that people with mutated ALDH enzymes (somewhat common in Asia, very rare for West Europeans) and so are slow to break down acetaldehyde, have substantially higher rates of these cancers even though they drink less.

So for oral/throat cancers we have the highest correlations in epidemiology data (though nowhere like the magnitude for smoking), and we have a plausible mechanism (the culprit being acetaldehyde). Plus we can add the evidence that Connor missed, there are much higher rates of oral/throat (aerodigestive) cancer amongst people who do not have the genes to quickly process acetaldehyde. This is by far the best case for making a causal connection between drinking alcohol and a cancer. Though it must be noted that aerodigestive cancers are rare (eg a tiny 0.3% of US deaths are from oral cancers, and most are caused by smoking, age and genes) even though most of the population drinks alcohol.

For the other cancers Connor mentions, the evidence of causality is extremely poor. In comparison, the evidence is vastly more convincing that drinking alcohol reduces heart disease, diabetes, dementia, and overall mortality. In addition to meta-analyses of many many population studies, we have plausible biological mechanisms, supported by lab studies, animal experiments, and hospital trials. Meta-analysis of dozens of experiments shows administering alcohol to subjects leads to rapid changes in biomarkers for heart disease (Brien et al 2011). We also see changes in drinking linked to changes in rates of heart disease, diabetes and overall mortality, e.g. people who increase their drinking lower their risk of heart disease. In sum, this is what a plausible case for causality looks like.

Apart from oral/throat and perhaps liver cancer Connor is wrong, there isn’t evidence to support drinking causing cancer. And even for oral/throat cancer the risk may be confined to smokers, and people with particular ALDH enzyme mutations.

But that’s if we stop with Connor’s superficial analysis. There is more evidence to consider if we are to form a proper judgement about causality. Read on…

Connor concluded that drinking probably was causal for 7 cancers. This has a nice ring about it…. like the ‘7 Deadly Sins’ (Oil of Olay understand this with their ‘fights the 7 Signs of Aging’ slogan). Now, Connor used the old medical convention of labeling cancer according to where the tumour occurs. It’s possible to talk of hundreds if not thousands of different cancers, but more reasonably for this discussion we have (1) oral/throat/oesophagus (aerodigestive cancers) which we have already discussed, (2) liver, (3) colorectal, and (4) breast cancer. It’s this last one that drives most public health forecasts that reductions indrinking could reduce cancer, this is because breast cancer is the most common potentially deadly cancer for women. That said, less than 3% of female deaths in the USA are from breast cancer. 90% of breast cancer is not fatal, due to curative treatment but also because many breast cancer diagnoses are for nonfatal cancer. Over-diagnosis is a very real problem.

Breast cancer is a prime example of how deficient Connor was not to discuss evidence on confounding factors. Meta-analysis shows no link between drinking and breast cancer mortality, nor with recurrence (Gou et al 2013). While a very new study from the Women’s Health Initiative (Lowry 2016) again shows no link between drinking (before or after breast cancer diagnosis) and mortality. Similarly a large study with long follow-up of women with breast cancer (Newcomb et al 2013) showed they had better chances of survival if they were regular drinkers before diagnosis. If they altered their drinking after diagnosis this had no link to their chance of dying from breast cancer, but an increase in drinking was associated with an overall increase in life expectancy (largely due to substantially fewer heart disease deaths among those who increased their alcohol consumption). This is strong causal evidence that alcohol prevents heart disease, and it seriously conflicts with the idea of alcohol causing breast cancer.

Similarly while animal experiments show drinking results in less heart disease, and longer life overall they do not show a link between alcohol consumption and breast cancer (see Hackney et al 1992, Singletary 1997). While alcohol actually reduced the risk of breast cancer metastasis in mice (Vorderstrasse et al 2012).

The (weak) correlation seen in population studies between drinking and breast cancer diagnosis is then probably due to a confounding factor, as so often can happen in population studies. In this case probably simply that drinkers are more likely to screen for breast cancer (shown in Mu and Mukamal 2016) – screening absolutely increases diagnosis (and quite a few of these diagnoses will be false, or non harmful). Land et al 2014, which screened all their subjects (i.e. controlling for screening incidence), showed no link between drinking and breast cancer diagnosis – indeed drinking was associated with slightly less risk of diagnosis (of both breast and colon cancer).

The modest degree of increased risk of colorectal cancer for alcohol drinkers may also be spurious or exaggerated for the same reason – drinkers screen more, which results in more diagnoses. As far as a potential biological mechanism some fecal bacteria have been shown to convert alcohol to acetaldehyde in vitro (Jokelainen et al 1994). While other bacteria have been shown to break down acetaldehyde (Nosova et al 2000) – the flora of the human gut are complex. Acetaldehyde has been shown to exist in the colons of rats but the level was not affected by feeding the rats alcohol (Seitz et al 1990). Research is needed to see if drinking really can increase acetaldehyde levels in the colon. In humans alcohol is absorbed in the stomach and small intestine which makes it harder to explain how alcohol might reach the colon where it could be converted to acetaldehyde by bacteria. Whereas risk of oral cancer is much higher among people without the genes to produce some adetaldehyde processing enzymes this does not appear to be the case for colorectal cancer (Tiemersma et al 2003). So a causal link between drinking alcohol and colorectal cancer remains speculative, and if there is a link it is not strong – non and light drinkers still get colorectal cancer at much the same rate as heavy drinkers.

That leaves us only with liver cancer to discuss. This is a rare but deadly cancer, causing 1% of deaths in the USA, though most cases are due to viral (hepatitis) infection, obesity, diabetes, other disease, and genetics. We perhaps again have the plausible biological mechanism of acetaldehyde but only at high levels of drinking as the liver is very efficient and fast at breaking down acetaldehyde. It’s also very plausible that alcohol, through its effect on liver disease, leads to higher risk of liver cancer. However very few drinkers develop liver disease, so the degree of absolute increase in risk is absolutely tiny and probably only for long-term alcoholics or those unlucky enough to have liver damage from hepatitis, other disease, or obesity.

So it’s plausible that alcohol contributes to some cancer, but only a few rather rare cancers, and its influence can’t be great. So we would not expect drinkers to die much more often from cancer, and this is exactly what is observed. Meta analyses report cancer mortality is barely higher among drinkers than occasional/zero drinkers and confined to the cohort who admit to consumption of more than 50g of alcohol per day (see Jin et al 2012, table 2). In Thun et al 1997 (a study of death among middle class, middle aged and elderly americans) the heaviest drinkers showed higher rates of death from alcoholism and injury, as expected. They were more likely to die from aero-digestive and liver cancer, again as expected, though none of these deaths were common. As expected, they were less likely to die from heart disease, stroke and other circulatory disease – each of which were major causes of death. There was no consistent relationship with rates of drinking and rates of death from colorectal or breast cancer, as expected.

Finally it is worth noting, there is clear way that drinking alcohol (at least to non-alcoholic levels) increases your chance of any cancer, and that is through its effect on living longer. For most cancers age is the dominant risk factor (e.g. half of all colorectal cancers occur in people aged over 70 years old, half of breast cancer is for women aged over 62). Drinkers live longer, largely due to reduced levels of heart disease (also diabetes, and dementia), perhaps it’s also due to drinkers being more social or some other beneficial behaviours – but whatever the cause it means that drinkers will live longer and will therefore have to get more cancer (as everyone has to die from something). This fact alone is enough to produce an association, but not a direct causal one, between drinking and cancer.

*Otago University website describes Connor as having “a long-standing research interest in alcohol related
Thanks to these people for commenting on earlier
Ian Olver, Professor of Translational Cancer Research, Director Sansom Institute for Health Research, University
of South Australia.
Wiemer Snijders, consultant, The Commercial Works.

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All text and images © 2003 Alcohol In Moderation.