Animal Smoking Studies

Some seem to think experiments show smoking causes cancer in animals.  Not so, for mice or rats:

I review the results of a representative selection of chronic inhalation studies with rats and mice exposed to mainstream cigarette smoke. … Smoke-induced epithelial hypertrophy, hyperplasia, and squamous metaplasia were reported in the conducting airways in most of the studies, along with increased numbers of intra-alveolar macrophages that were occasionally associated with alveolar metaplasia. Lung adenomas and adenocarcinomas were reported in only a few of the studies. No statistically significant increase in the incidence of malignant lung tumors was seen. …

The 14 studies reviewed … [showed] significant increases in the numbers of malignant tumors were not produced in the respiratory tracts of rats or mice exposed chronically by inhalation to cigarette smoke.  The studies clearly involved the inhalation of very large amounts of smoke (usually from unfiltered, high-tar cigarettes) …  The results of this work clearly indicate that maximal amounts of smoke were inhaled into the lungs of the animals (blood COHb concentrations very close to those associated with lethality) daily for up to 2 yr with no carcinogenic effect noted.

Nor for hamsters, dogs, or primates:

This paper makes an identical evaluation as before, but, restricting the species being evaluated to representative studies of smoke-exposed hamsters, dogs (both by tracheostomy and by direct inhalation), and nonhuman primates. As was seen previously, no statistically significant increase in the incidence of malignant tumors of the respiratory tract was found in any of the 3 species, even though very long exposures and high doses of smoke were used.

Now the number of animals in these studies is a few thousand at most, and their duration is less than decades, but experimenters did have complete control over making animals smoke heavily.  Yes this review author works for a tobacco firm, but his papers seem professional.

Searching for “animal smoking experiments,” I found many sources admitting we haven’t found much evidence smoking hurts animals, and none saying the opposite.  Here is a ’97 Scientific American article “Animal Research is Wasteful and Misleading”:

In a striking illustration of the inadequacy of animal research, scientists in the 1960s deduced from numerous animal experiments that inhaled tobacco smoke did not cause lung cancer (tar from the smoke painted on the skin of rodents did cause tumors to develop, but these results were deemed less relevant than the inhalation studies).  For many years afterward, the tobacco lobby was able to use these studies to delay government warnings and to discourage physicians from intervening in their patients’ smoking habits.  Of course, human population studies provided inescapable evidence of the tobacco-cancer connection.

In fact, folks blame early animal experiments for distracting from human correlations:

The link between smoking and lung cancer was discovered by the British scientist Sir Richard Doll in the 1950s by means of a study of human lung cancer patients in twenty London hospitals. He used the epidemiological method, i.e. the statistical study of diseases in human populations. The practical application to medicine of this all-important discovery had been hindered and delayed by animal research. Why?

First, because animal experiments had previously failed to demonstrate this link and researchers had ruled it out. Medical researchers were dismissive of Doll’s discovery. They had already tried to trigger cancer in animals using tobacco tar but had failed, they pointed out. Only later was it shown that their experimental procedures contained serious errors.

And then, even after Doll’s theory was published, animal researchers tested it by trying to reproduce the carcinogenic effects of smoking in animals. Some of this animal research was funded (you may guess) by tobacco manufacturers.

And what were those “serious errors” of early animal experiments?

Animal experimentation is by its own very nature unreliable for application to humans.

Bob Unwin points us to a nice history of the early smoking controversy, written by philosophers.  It starts:

The fascinating history of the debates over smoking and lung cancer illustrates the difficulties of causal inference and prediction from policy studies, and also illustrates some common mistakes.  Perhaps no other hypothetical cause and effect relationship has been so thoroughly studied by non-experimental methods or has so neatly divided the professions of medicine and statistics into opposing camps.

It ends:

The real view of the medical community seems to have been that it was just too implausible to suppose that genotype strongly influenced how much one smoked, whether one smoked at all, whether one smoked cigarettes as against a cigar or pipe, whether one was a Mormon or a Seventh day Adventist, and whether one quit smoking or not.  After Cornfield’s survey the medical and public health communities gave the common cause hypothesis more invective than serious consideration.  And finally, in contrast to Burch, who was an outsider and maverick, leading epidemiologists, such as Lilienfeld, seem simply not to have understood that if the relation between smoking and cancer is confounded by one ore more common causes, the effects of abolishing smoking cannot be predicted from the “risk ratios,” that is, from sample conditional probabilities.  The subsequent controlled smoking intervention studies gave evidence of how very bad were the expectations based on uncontrolled observation of the relative risks of lunch cancer in those who quit smoking compared to those who did not.

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  • http://sophia.smith.edu/~jdmiller/resume.pdf James Miller

    Robin has been harshly criticized in the comment section of this blog for questioning the supposed massive negative health effects of smoking. But many smokers have suffered enormous pain in attempts to stop smoking. If indeed their quitting smoking would have minimal health benefits, then false information about smoking has had the effect of needlessly causing the torture of millions of humans, and Robin should therefore be commended for helping inform us about the true health consequences of smoking.

  • http://lesswrong.com/ Eliezer Yudkowsky

    If there is actually a gene which causes people to want to smoke and also causes them to develop lung cancer at 23 times the base, I will buy a hat and eat it.

    • http://lesswrong.com/ Eliezer Yudkowsky

      *base rate

    • http://sophia.smith.edu/~jdmiller/resume.pdf James Miller

      What about a gene that impairs many parts of the mind and body including the lungs and the ability to forgo immediate pleasure.

      • http://lesswrong.com/ Eliezer Yudkowsky

        Why just the lungs, then?

      • http://sophia.smith.edu/~jdmiller/resume.pdf James Miller

        To Eliezer: Smoking is correlated with many types of harm, so the possible gene could do harm to many parts of the body and still be consistent with the evidence. Although it would have to impact the lungs more than other organs, and I can’t offer anything but “it could happen” as a reason.

    • Doug S.
    • loqi
    • http://silasx.blogspot.com Silas Barta

      If there’s a button I can push that would kill every mass murderer, I’d press it.

      Wait, what decision-theoretic problem was all of this isomorphic to, again?

  • http://www.cawtech.freeserve.co.uk Alan Crowe

    This might be an opportunity for thinking about the silliness taboo

    The standard story is that you smoke from 20 years old until you die of lung cancer aged 50. (For my chain smoking aunt it was 60. For my pipe smoking grandfather is was 60 and oesophagal cancer. Perhaps when I say 50 I am hurrying the standard story along a little.)

    So scientists do a controlled trial with 1000 mice smoking the equivalent of 40 cigarettes a day and 1000 mice breathing clean air. During year 30 there are no deaths from lung cancer in either group. The headline in The Onion exclaims: mice no longer at risk of lung cancer after being dead for 28 years. In the body of the article scientists explain their reasoning. The diseases that afflict us in later life are too frightening to contemplate so it is important to research them using short lived animals in order to avoid the risk of learning things that man was not meant to know.

    I do have a sober point to make. When Robin discussed the silly taboo in April 2008 he refered to topics that are unwisely considered silly. The other side to the the silly taboo (and considering both sides might shed some light on this taboo) is that some topics are unwisely considered sensible.

    Consider the following hypothetical. Mouse studies do show that smoking cigarettes cause lung cancer in mice. Because tobacco companies are working with a cheap animal model they are able to track down the problem, identifying arsenic in the tobacco smoke as the cause of lung cancer in mice. They reject tobacco grown on soils subject to industrial pollution and also tobacco grown on soils with naturally occurring arsenic. The new, expensive arsenic-free tobacco doesn’t cause cancer in mice. Humans rejoice and smoke like chimneys.

    How do we expect that to play out? I would expect that 30 years later people would start noticing that lung cancer rates were not declining and would start to question the relevance of mouse studies to humans. Using animals that only live 2 years as a model for human diseases with a 30 year onset delay is just silly. When we see it being taken seriously we learn something interesting about the silly-tabboo: when it should apply, but doesn’t.

  • Daniel Lakeland

    If in some alternative universe you made some 5 to 7 year old humans smoke heavily for 2 years do you really think you’d see much increase in lung cancer on that short a time span especially given that the lung cancer deaths attributed to smoking are typically in the ages 40 to 60’s?

    For animal models of carcinogenesis typically a tumor prone animal is used because the lifespan of the model animal is shorter and the animals are not generally capable of getting cancer in their limited lifespan. Investigations use high doses and tumor prone animals to attempt to accelerate the production of tumors. The treated and un-treated animals are compared to account for the tumor proneness.

    Skimming the article you link, it seems that many of these studies were done in “C57BL” aka “black 6″ mice, which is basically “wild type” without any mutations that make them more susceptible to tumors.

  • http://entitledtoanopinion.wordpress.com TGGP

    The Econ Journal Watch issue discussing funding by tobacco companies is here. Andrew Gelman discusses the issue here.

  • Tanath

    I highly recommend you read the book “Doubt is Their Product.” It should change your mind, and make you more careful.

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  • Ben A

    I found many sources admitting we haven’t found much evidence smoking hurts animals

    A tobacco-smoke exposure model is an industry standard system for evaluating COPD medicines. There is of course concern about the transferability of findings in these systems to the human disease state. But pharmas and biotechs are using these models to direct multi-million dollar development decisions.

    http://chestjournal.chestpubs.org/content/122/6_suppl/301S.full.html

    http://ajplung.physiology.org/cgi/content/full/294/4/L612

    It would be helpful for Robin to clarify what hypothesis he is advancing. Is it:

    1) We do not have reason to believe smoking increases risk for any health problem
    2) We do not have reason to believe smoking increases risk for lung cancer specifically
    3) We have reason to believe both 1 and 2, but the magnitude of the risk is less certain than we imagine

    • http://hanson.gmu.edu Robin Hanson

      Those are interesting, but they don’t seem to be measuring animal mortality, right? We have many conflicting reasons here; I’m trying to sort them out.

      • Ben A

        Right — because you aren’t trying to kill the mice. You’re trying to evoke COPD so you can a) examine the biology, b) see if your test compound has effect. These animals for sure have inflammation and airway pathology suggestive of human COPD.

  • Ben A

    Here’s one well-done observational study on the relationship of smoking to COPD.

    TI Developing COPD: a 25 year follow up study of the general population.
    AU Lokke A; Lange P; Scharling H; Fabricius P; Vestbo J
    SO Thorax. 2006 Nov;61(11):935-9.

    BACKGROUND: Smokers are more prone to develop chronic obstructive pulmonary disease (COPD) than non-smokers, but this finding comes from studies spanning 10 years or less. The aim of this study was to determine the 25 year absolute risk of developing COPD in men and women from the general population. METHODS: As part of the Copenhagen City Heart Study, 8045 men and women aged 30-60 years with normal lung function at baseline were followed for 25 years. Lung function measurements were collected and mortality from COPD during the 25 year observation period was analysed. RESULTS: The percentage of men with normal lung function ranged from 96% of never smokers to 59% of continuous smokers; for women the proportions were 91% and 69%, respectively. The 25 year incidence of moderate and severe COPD was 20.7% and 3.6%, respectively, with no apparent difference between men and women. Smoking cessation, especially early in the follow up period, decreased the risk of developing COPD substantially compared with continuous smoking. During the follow up period there were 2912 deaths, 109 of which were from COPD. 92% of the COPD deaths occurred in subjects who were current smokers at the beginning of the follow up period. CONCLUSION: The absolute risk of developing COPD among continuous smokers is at least 25%, which is larger than was previously estimated.

    http://thorax.bmj.com/content/61/11/935.abstract

  • http://www.abs-usa.com Floccina

    It seems to me that the Animals tested do not live long enough to get lung cancer from smoking. From what I have read, there is almost no increased mortality due to smoking before the age of 30 which generally 10 to 15 years in from starting. So I am not surprised that Animals do not show increased mortality due to smoking.

    • Joe

      Exactly my thoughts.

  • http://pdf23ds.net pdf23ds

    Does COPD include emphysema? I was under the impression that emphysema was an uncontroversial effect of smoking, and almost as deadly as cancer in its extreme forms.

    • Ben A

      Correct. COPD has classically been defined as comprising both emphysema and chronic bronchitis (although now a broader umbrella definition is preferred). My sense is that not many epidemiological studies of COPD have sought to separate out risk factors for the emphysema and chronic bronchitis components, but I am by no means expert in this literature.

      COPD certainly has a significant disease burden. http://www.who.int/mediacentre/factsheets/fs315/en/index.html

  • curious

    Yes this review author works for a tobacco firm, but his papers seem professional.

    this is a riot. good one!

  • http://www.boxerurkabustaiz.es/aboutus.html boxer

    As hamsters, rats and dogs have lifespans much shorter than humans, perhaps they are not exposed to smoke for long enough to produce damage.

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  • Fredrik

    Robin

    I too was suprised to find out that all attempts to create lung cancers had failed in animinal models when I first read about it from looking

    through the evidence given in the McTear case. I was taught at school that

    the tobacco companies had known that animal studies showed tobacco smoke to be carcinogenic but had suppressed the information. Clearly this was utter nonsense. But what is more confusing is that in murine models life expectancy of tobacco smoke exposed animals is increased over controls see the kaplan meier survival curve at the botom of the post in this surreal discussion here. In addition to animal studies causing confusion in the issue of causation, I find it odd that in country such as Sweden that took up smoking some 30 years later than a country such as the USA experiences a lung cancer epidemic at exactly the same time as the US, ~1950, as can be seen on my blog here.

    “Curiouser and curiouser” said Alice.