Friday 8 October 2010

Nuns, prostitutes, witches and toads

[A fairly lengthy article about cervical cancer might not sound the most interesting way to spend ten minutes but it provides a good example of epidemiology confusing cause and effect.]

In 1842, the Italian physician Domenico Antonio Rigoni-Stern noticed that nuns in Verona were more susceptible to breast cancer than other women. Ruminating on what aspect of convent living might explain the phenomenon, he concluded that the nuns' corsets were too tight. This explanation was wide of the mark but the initial observation was sound; we now know that having children makes a woman less likely to develop breast cancer.

But the Italian found another association. It seemed that the nuns were less prone to cervical cancer than the rest of society. Furthermore, cervical cancer was unusually common amongst prostitutes. This observation provided the first clue to the real cause of the disease but it would take a further century and a half of confusion and dead-ends before the real truth emerged.

Early myths

The very earliest myth about cervical cancer emerged in early modern Europe where witches were believed to curse their victims with warts which ultimately led to a painful death. As we shall see, even this bizarre notion was not entirely without reason but, by the dawn of the 20th century, medicine had moved on and in 1901 The Lancet observed that cervical cancer was rare amongst Jewish women.

Suspecting that the disease was caused by excess salt, The Lancet correspondent surmised that Jews were less susceptible because they avoided bacon. An alternative explanation was offered when the subject was revisited in 1959, when a doctor speculated that circumcision reduced the risk (1). Neither man was correct about the cause but, again, the association was real.

In the 1970s, epidemiological studies showed that cervical cancer was more common amongst women who had a history of herpes. It was therefore assumed that the cancer was caused by the herpes virus. It was not, but it was becoming clear that the disease was in some way connected with sexual activity. At this point, with the answer now within reach, researchers dived down a blind alley.

Modern myths

The suggestion that cancer of the cervix was caused by smoking was first made in 1977 and, by the end of the 1980s, the belief that passive smoking was also a risk factor had reached the pages of the Journal of the American Medical Association (2). A number of epidemiological studies had shown a small but consistent relationship between tobacco smoke and cervical cancer, and yet something strange seemed to be happening. Studies frequently showed that passive smoking carried as high or higher risk than active smoking. This was completely at odds with the expected dose-response relationship. The association with passive smoking was, as one researcher commented, "almost too strong".

Nevertheless, anti-smoking groups let it be known that smoking doubled a woman's risk of contracting cervical cancer and, with tobacco now firmly in the frame, the earlier observation that the disease was related to sexual activity came under fire. In 1991, the British Journal of Obstetrics and Gynecology published an article by Malcolm Griffiths which flatly stated that Rigoni-Stern's research had been sloppy. There was, said Griffiths, no reason to believe that nuns had a lower rate of cervical cancer than the rest of the female population (3). The implication was obvious: cervical cancer was not related to sexual activity.

Griffith's theory took hold and the became the orthodox view. Still, not everyone was convinced. In 2000, when the British Medical Journal reopened the debate, an exasperated professor wrote to ask:

"We now know, with lots of evidence, that cervical cancer is a venereal disease, the responsible herpes type virus being passed from female to female via male sexual partners. Why is there no comment about this in your letters and no statistics about the number of sexual contacts found in the various studies, which is clearly the most relevant fact in incidence and death from the condition?"

To which a fellow doctor replied:

"I had, until recently, believed that nuns did not get cervical cancer. I accepted the received wisdom since I found it repeated so frequently. I realized how mistaken I was when I encountered the paper on this topic by Griffiths. In his paper Griffiths clearly and persausively demonstrates that the assertion that nuns are not at risk of cervical cancer is based on a mis-reading of Rigoni-Stern's original report of 1842. I hope that if enough of us highlight Dr Griffiths' work often enough this myth will be laid to rest." (4)

But, as was already becoming clear, sexual activity was very closely related to cervical cancer risk. By the end of the millennium, scientific—as opposed to statistical—evidence conclusively proved that the sexually transmitted human papillomavirus (HPV) was implicated in all cases of cervical cancers. HPV did not guarantee the onset of cervical cancer but it was impossible to contract the disease without first being infected with it. With this knowledge, the age-old observation of the nuns and prostitutes made perfect sense.

The truth

Biological evidence indicated that cervical cancer was no more caused by herpes than breast cancer was caused by tight corsets. The rarity of cervical cancer amongst Jewish women was, scientists now realised, due to the protective P53 gene which was far more common amongst Jews than other races. Salt had been a red herring. Even the old myth that cervical cancer was connected to witchcraft had some bearing in fact, since HPV causes warts to grow. In medieval society warts were associated with toads which were, in turn, associated with witches.

Smoking, like herpes, was not the cause of cervical cancer, it was simply more common amongst women who were sexually active and, therefore, more likely to be infected with HPV. Had the Italian doctor looked at tobacco use, he would have observed that smoking was more common amongst prostitutes than amongst nuns. He might also have noted that prostitutes were more likely to drink alcohol, have children and be atheists. But none of these things caused cervical cancer; they were just more common amongst prostitutes. The statistical correlations were real, but they were meaningless until the nature of HPV was understood.

The clues had always been there. For one thing, cervical cancer mortality had fallen by 80% in the second half of the 20th century, at a time when tobacco consumption had never been higher (5). This, in itself, strongly suggested that smoking was not a cause of the disease.

That smoking was correlated with sexual activity had been known for many years. In 1994, an article in the International Journal of Epidemiology had flagged up the issue:

"The correlation between cigarette smoking and sexual activity that exists in most cultures makes evaluation of the potential additional role of smoking difficult." (6)

Indeed it did. One epidemiological study (Nischan, 1988 (7)) had found a relative risk from smoking of 1.5 (ie. a 50% increase in risk), but, as the authors noted, "the risk for smokers depended significantly on number of sexual partners"—a telling observation which warranted closer scrutiny. Indeed, when they adjusted their figures in an effort to account for this mysterious confounder, the risk—already low—fell to just 1.2 (0.8-1.6) and was no longer statistically significant.

The real giveaway was that the risks for passive smokers were as high, or higher, than those found for smokers. Given the vastly lower dose of smoke inhaled by the former, this was a biologically implausible finding which defied both common sense and the expected dose-response relationship. Another study (Scholes 1999 (8)) found a risk of 1.4 for both smokers and passive smokers. The study that attracted the most attention from the press (Slattery 1989 (9)) found a relative risk for smokers of 3.42—much higher than the association found in other studies but still not quite as high as that found in the same study for passive smokers where a 3.43 risk was reported.

To take such findings at face value would require tearing up the toxicological text-book. It was hugely improbable that passive exposure to tobacco smoke in any setting could be as harmful of smoking. What was much more likely was that cervical cancer was not a smoking-related disease at all and that the findings had been skewed by the confounding factor of sexual activity.

The key to the riddle was the human papillomavirus. Once it was shown to be implicated in every case of cervical cancer, the long observed correlation between sexual activity and cervical cancer made sense. And since smokers—as a group—were somewhat less likely to be celibate and somewhat more likely to be promiscuous, the correlation between smoking and cervical cancer had a rational explanation. Correlation did not equal causation. Yes, there was an association between smoking and cervical cancer but the one did not in any way cause the other.

The association with passive smoking was more intriguing and had a unique explanation. Because HPV is carried by men and easily transmitted to women, a woman's risk of catching the virus depends as much on her partner's sexual history as her own. She may be a nonsmoker with no previous lovers but if her partner has slept with many women she remains at high risk. And since the smoking male tends to be have had more sexual partners than his nonsmoking counterpart, the woman who lives with him is at higher risk of contracting HPV and, therefore, cervical cancer. Yes, living with a smoker slightly raises a woman's risk of cervical cancer but not because he smokes. Correlation does not equal causation.

The passive smoking researchers who had adjusted their results for sexual history had made the mistake of only asking questions of the women. They had, of course, made every effort to find out about the man's smoking status but had neglected to enquire about his own sexual history which was far more important, considering his role as the HPV carrier.

As the role of HPV in cervical cancer became known, it became clear that smoking was not independently associated with the disease. HPV was the key and, by 2006, an effective vaccine against it was developed. Immunisation programmes were initiated by governments around the world and the possibility of wiping out cervical cancer within a few generations became a realistic proposition.

It was a rare breakthrough in the war against cancer. It came about thanks to advancements in our understanding of biological science and was facilitated by the development of new drugs. It was, if you will, an 'old-fashioned' way of dealing with a public health problem. It owed nothing to the army of epidemiologists who were dominating popular science, nor to the proponents of the fashionable belief that cancers were caused by tobacco, diet, alcohol and environment. Not only had the social theorists missed the mark, but their preoccupation with smoking had sent researchers on a wild goose chase for more than two decades.

Carry on regardless

And yet, the anti-smoking organisations still had a slew of studies showing an association between smoking and cervical cancer. To admit these studies were worthless would be to accept the failure of their methods. Not only that, but admitting that cervical cancer was not a smoking-related disease would be to lose a weapon in their campaign to dissuade women from smoking. And so they carried on as if nothing had happened.

Today, the American Cancer Society maintains that smoking doubles the risk of cervical cancer (10), based only on the statistical correlation. The fact that the organisation also claims that chlamydia, multiple pregnancies and oral contraceptives are also risk factors shows that the ACS has learnt nothing from the long history of mistaken cause-and-effect that has surrounded cervical cancer over the centuries. Chlamydia, multiple pregnancies and oral contraceptives—like herpes, warts and prostitution—are obviously associated with unprotected sex. It would be a truly extraordinary coincidence if these factors also happened to be independent risk factors from smoking.

At least the ACS no longer claims that passive smoking raises the risk. The same cannot be said of other anti-smoking groups. Rather than accepting that the studies had been flawed because they had failed to adjust for HPV infection, they continue to take them at face value.

As implausible as it is, the idea that passive smoking is more dangerous than smoking holds an appeal to such groups. Recently, a study on breast cancer showed a higher risk for passive smokers than smokers. In truth, smoking of any kind was not a risk factor for breast cancer, as even the American Cancer Society accepted. Nonetheless, ASH released a press release titled 'Secondhand tobacco smoke more dangerous than smoking itself - implications for women especially frightening' (11) and Stanton Glantz described the finding as "the most important scientific development in the last 10 years" (12).

Their motives were obvious. Having banned smoking in virtually all indoor places, their attention turned to the outdoors, but to ban smoking in the open air required persuading the public that secondhand smoke was exceptionally toxic.

Further 'evidence' for this wacky idea appeared in the form of the Helena heart attack study (co-authored by Glantz) which claimed that heart attack incidence fell by a whopping 40% once smoking was banned in bars and restaurants. Not accepting for a minute that this study might also be fatally flawed, anti-smoking groups used it as further evidence that secondhand smoke was far more dangerous than had been previously thought. Glantz also wrote an article titled 'Even a little secondhand smoke is dangerous' (13) and claimed that 30 seconds of exposure could kill.

In 2006, the Surgeon General told the American public that there was "no safe level" of secondhand smoke exposure. Secondhand smoke had become the most deadly entity known to man.

(1) Dunn JE, Buell P. Association of cervical cancer with circumcision of sexual partner. J Natl Cancer Inst 1959;22:7469.
(2) In January 1980, the American Journal of Epidemiology reported that there "an apparent connection, as yet unexplained, between smoking and cancer of the uterine"
(4) 'Screening and mortality from cervical cancer', Rapid responses; BMJ 1999; 319: 642
(5) Cancer Research UK, 'UK Cervical Cancer mortality statistics'
(6) 'Cigarette smoking as a potential cause of cervical cancer; has confounding been controlled?', Andrew Phillips & George Davey Smith, International Journal of Epidemiology, 1994, Vol. 23, No. 1, pp.42-49
(7) 'Smoking and invasive cervical cancer risk: Results from a case-control study', Nischan et al. American Journal of Epidemiology, 1988, vol. 128, No. 1: pp. 74-77
(8)Scholes et al. Cancer Causes & Control, Vol, 10, No. 5, Oct. 1999 pp. 339-344 'The association between cigarette smoking and low-grade cervical abnormalities in reproductive-age women'
(9) JAMA, vol. 261, No. 11, 17/3/89, Slattery et al. 'Cigarette smoking and exposure to passive smoke are risk factors for cervical cancer'
(11) ASH press release, 2005
(12) 'Lecture ties secondhand smoke to breast cancer', Michael Coburn, The Dartmouth News, 7.3.08

[Originally published at in 2009]


Ben said...

Excellent article which shows the limits and at the same time the misuse of epidemiology.
Many epidemiologists don't seem to know much about their own science. But they know for sure that it can be a èowerful weapon in the pursuit of an agenda.

Ann W. said...

"Nonetheless, ASH released a press release titled 'Secondhand tobacco smoke more dangerous than smoking itself - implications for women especially frightening' (11) and Stanton Glantz described the finding as "the most important scientific development in the last 10 years" (12)."

Chris, this is still going on in Canada. So much so that the anti smoker group Physicians for a Smoke-Free Canada have been lobbying to have this made into a new warning on cigarette packs.

"Canadian Expert Panel on Tobacco Smoke and Breast Cancer Risk - April 2009"

And can you guess "who" is part of this expert panel? why Physicians for a Smoke-Free Canada. How self serving!

Active Smoking
Based on the weight of evidence from epidemiologic and toxicological studies and understanding of biological mechanisms, the associations between active smoking and both pre- and postmenopausal breast cancer are consistent with causality.

Secondhand Smoke
The association between SHS and breast cancer in younger, primarily premenopausal women who have never smoked is consistent with causality. The evidence is considered insufficient to pass judgement on SHS and postmenopausal breast cancer.

But Physicians for a Smoke-Free Canada have been trying to scare women with this information for sometime and started looking for their next "Heather Crowe" but the person they wanted won't bite.

An open letter to Wendy Mesley CBC News: Marketplace March 10, 2006
Wendy, unfortunately, we may never know for sure what caused your breast cancer. But you are widely known in Canada as an excellent communicator. You could do great service to breast cancer prevention by clearly communicating to Canadians this important new information about tobacco smoke as a cause of breast cancer. It is now more important than ever that people not smoke and that non-smokers be protected from exposure to tobacco smoke.

DaveA said...

It does not stop Cancer Research from lying. Their website despite admitting that studies say it is not smoking have a whole paragraph inferring causation.

Also HPV has been suggested but not proven, that maybe a cause of lung cancer in non smokers. I have the papers is you want Chris.

"For cigarette smoking there is a strong dose-response relationship. The risk of CIN 3 for women who were HPV positive and smoking 20 or more cigarettes a day was two and a half times that of women who had never smoked. The authors concluded that even though smoking was not a risk factor for HPV, smoking acted with HPV to cause cervical neoplasia (see also Smoking section below).

Smoking and cervical cancer risk

Cigarette smoking has been linked to inactivation in cervical tumours of the fragile histidine triad 6 putative tumour suppressor gene (which is also altered in most tobacco-associated lung cancers).

Smoking may also be associated with a decrease in the number of Langerhans’ immune cells in the cervix epithelium, suggesting a decrease in epithelial cell-mediated immune responses in smokers 7, 8.

The most recent meta-analysis showed that risk of squamous cell cervical cancer is increased by 50% in current smokers. 30

Reduction in early cervical lesion size in women who gave up smoking after diagnosis has been reported 10. Also smokers have been found to have a 3-fold increased risk of treatment failure of CIN compared to non-smokers and therefore require more intensive follow-up after treatment.

Anonymous said...

Where's the control group when studying the effects of SHS? That is, those people who have never been exposed to it whatsoever. If we are led to believe that there is no safe level, what do they compare it with? I would imagine that 100% of most countries' population have been exposed to a lesser or greater extent during their lifetime. This is something that can never be measured with any degree of accuracy.

Unknown said...

"Second hand smoke is more dangerous than smoking."

From that, logic states that one's danger levels can therefore be reduced by being a smoker.


It's unfortunate that 'common sense' is no longer either.