Document wgKZgrBD68Q24GqQ5z5d3qbV6

r.'lli The Environment and Disease: ^Association or Causation? by Sir Austin Bradford Hill cbe dsc FRCP<hon) frs (Frofe.tsor Emeritus ofMedical Statistics, Unirersity ofLondon) Amongst the objects ofthis newly-founded Section of Occupational Medicine are firstly `to provide a -means, not readily afforded elsewhere, whereby physicians and surgeons with a special knowledge of the relationship between sickness and injury and conditions of work may discuss their prob lem, not only with each other, but also with colleagues in other fields, by holding joint meet ings with other Sections of the Society'; and, secondly, 'to make available information about the physical, chemical and psychological hazards of occupation, and in particular about those that are rare or not easily recognized': At this first meeting of the Section and before, with however laudable intentions, we set about instructing our colleagues in other fields, it will be proper to consider a problem fund-- mental to our own. How in the first place do we detect these relationships between sickness, injury and -conditions of work? How do we determine what are physical, chemical and psychological hazards of occupation, and in particular those that are rare and not easily recognized? There are, of course, instances in which we can reasonably answer these questions from the general body of medical knowledge. A particular, and perhaps extreme, physical environment can not fail to be harmful; a particular chemical is 'known to be toxic to man and therefore suspect on the factory floor. Sometimes, alternatively, we may be able to consider what might a par.ticular environment do to man, and then see whether such consequences arc indeed to be found. But more often than not we have no such guidance, no such means of proceeding; more often than not we are dependent upon our observation and enumeration of defined events for which we then seek antecedents. In other words we see that the event B is associated with the environmental feature A, that, to take a specific example, some form of respiratory illness . * associated with a dust in the environment. In "what circumstances can we pass from this MeetingJanuary 141965 President's Address Notir-e-T1..' ';2:---na|rr^vf.,?, by copy,-ie.-,> (jUi9 observed association to a verdict of causation? Upon what basis should we proceed to do so? I have no wish, nor the skill, to embark upon a philosophical discussion, of the meaning of `causation*. The `cause' of illness may be imme diate and direct, it may be remote and indirect underlying the observed association. But with the aims of occupational, and almost synony mously preventive, medicine in mind the decisive question is whether the frequency of the un desirable event B will be influenced by a change in the environmental feature A. How such a change exerts that influence may call for a great deal of research. However, before deducing 'causation' and taking action we shall not invariably have to sit around awaiting the results of that research. The whole chain may have to be unravelled or a few links may suffice. It will depend upon circumstances. Disregarding then any such problem in semantics we have this situation. Our observa tions reveal an association between two variables, perfectly clear-cut and beyond what we would care to attribute to the play of chance. What aspects of that association should we especially consider before deciding that the most likely interpretation of it is causation? (I) Strength. First upon my list I would put the strength of the association. To take a very old example, by comparing the occupations of patients with scrotal cancer with the occupations of patients presenting with other diseases. Percival Pott could reach a correct conclusion because of the enormous increase of scrotal cancer in the chimney sweeps. `Even as late as the second decade of the twentieth century*, writes Richard Doll (1964), 'the mortality of chimney sweeps from scrotal cancer was some 200 times that of workers who were not specially exposed to tar or mineral oils and in the eighteenth century the relative difference is likely to have been much greater.' R E c EI V E,* * JT., '*fiv ' * V- " JUN 51980 Shirley D, Conners * To take a more modern and more general example upon which 1 have now reflected for over fifteen years, prospective inquiries into smoking have shown that the death rate from cancer of the lung in cigarette smokers is nine to ten times the rate in non-smokers and the rate in heavy cigarette smokers is twenty to thirty times -g-SbE'" * .i -- wesES ucc 033123 r -., ^nV.Vi.rn Sum.I tir"',-1' '-*1 inw -| nar^rf^--' ''* ------------- ` 296 Proceedings ofthe Royal Society ofMedicine as great. On the other hand the death rate from coronary thrombosis in smokers is no more than twice, possibly less, the death rate in nonsmokers. Though there is good evidence to support causation it is surely much easier in this case to think of some features of life that may go hand-in-hand with smoking - features that might conceivably be the real underlying cause or, at the least, an important contributor, whether it be lack of exercise, nature of diet or other factors. But to explain the pronounced excess in cancer of the lung in any other environmental terms requires some feature of life so intimately linked with cigarette smoking and with the amount of smoking that such a feature should be easily detectable. If we cannot detect it or reasonably infer a specific one, then in such circumstances I think we are reasonably entitled to reject the vague contention of the armchair critic `you can't prove it, there may be such a feature*. Certainly in this situation I would reject the argument sometimes advanced that what matters is the absolute difference between the death tales of our various groups and not the ratio of one to other. That depends upon what we want to know. If we want to know how many extra deaths from cancer of the lung will take place through smok ing (i.e. presuming causation), then obviously we must use the absolute differences between the death rates - 0-07 per 1,000 per year in non smoking doctors, 0-57 in those smoking 1-14 cigarettes daily, 1-39 for 15-24 cigarettes daily and 2-27 for 25 or more daily. But it does not follow here, or in more specifically occupational problems, that this best measure ofthe effect upon mortality is also the best measure in relation to tetiology. In this respect the ratios of 8, 20 and 32 to 1 are far more informative. It does not, of course, follow that the differences revealed by ratios are of any practical importance. Maybe they are, maybe they are not; but that is another point altogether. We may recall John Snow's classic analysis of the opening weeks of the cholera epidemic of 1354 (Snow 1355). The death rate that he recorded in the customers supplied with the grossly polluted water of the Southwark and Vauxhall Company was in truth quite low - 71 deaths in each 10,000 houses. What stands out vividly is the fact that the small rate is 14 times the figure of 5 deaths per 10,000 houses supplied with the sewage-free water of the rival Lambeth Company. In thus putting emphasis upon the strength of an association we must, nevertheless, look at the obverse of the coin. We must not be too ready to disnu'ss a cause-and-effcct hypothesis merely on the grounds that the observed association appears to be slight. There are many occasions in medicine when this is in truth so. Relatively few persons harbouring the meningococcus fall sick of meningococcal meningitis. Relatively few persons occupationally exposed to rat's urine contract Weil's disease. (2) Consistency: Next on my list of features to be specially considered I would place the consistency of the observed association. Has it been repeatedly observed by different persons, in different places, circumstances and times? This requirement may be of special importance for those rare hazards singled out in the Section's terms of reference. With many alert minds at work in industry today many an environmental association may be thrown up. Some of them on the customary tests of statistical significance will appear to be unlikely to be due to chance. Never theless whether chance is the explanation or whether a true hazard has been revealed may sometimes be answered only by a repetition of the circumstances and the observations. Returning to my more genera] example, the Advisory Committee to the Surgeon-General of the United *ates Public Health Service found the association of smoking with cancer of the lung in 29 retrospective and 7 prospective inquiries (US Department of Health, Education &, Welfare 1964). The lesson here is that broadly the same answer has been reached in quite a wide variety of situations and techniques. In other words we can justifiably infer that the association is not due to some constant error or fallacy that permeates every inquiry. And we have indeed to be on our guard against that. * Take, for instance, an example given by Heady (1958). Patients admitted to hospital for opera tion for peptic ulcer are questioned about recent domestic anxieties or crises that may have pre cipitated the acute illness. As controls, patients admitted for operation for a simple hernia are similarly quizzed. But, as Heady points out, the two groups may not be in pari materia. If your wife ran off with the lodger last week you still have to take your perforated ulcer to hospital without delay. But with a hernia you might prefer to stay at home for a while - to mourn (or celebrate) the event. No number of exact repeti tions would remove or necessarily reveal that fallacy. We have, therefore, the somewhat paradoxical position that the different results of a different inquiry certainly cannot be held to refute the > l | ucc 033129 IV Section ofOccupational Medicine 297 'n in W <A 1C "C \ i'V I cc f ai al rjr IN of of id \c 'n Iv If f f >n it u> u t l. t) ;I ii v. t .1 .tl It c t X l 1 original evidence; yet the same results from pre cisely the same form of inquiry will not invariably prcatly strengthen the original evidence. I would myself put a good deal of weight upon similar results reached in quite different ways, e.g. pros pectively and retrospectively. Once again looking at the obverse of the coin there will be occasions when repetition is absent or impossible and yet we should not hesitate to draw conclusions. The experience of the nickel refiners of South Wales is an outstanding example. I quote from the Alfred Watson Memorial Lecture that I gave in 1962 to the Institute of Actuaries: The population at risk, workers and pensioners, numbered about one thousand. During the ten years 1929 to 1938. sixteen of them had died from cancer of the lung, elesen of them had died from cancer of the nuat sinuses. At the age specific death rates of Lnpland and Wales at that time, one might have anticipated one death from cancer of the lung (to compare with the 16), and a fraction of a death from cancer of the nose (to compare with the 11). In all oiler bodily sites cancer had appeared on the death certificate 11 times and one would have expected it to do so 10-11 times. There had been 67 deaths from all other causes of mortality and over the ten years' period 72 would have been expected at the national death rales. Finally division of the population at risk in relation to their jobs showed that the excej" of cancer of the lung and nose had fallen wholly e jon the workers employed in the chemical processes. "More recently my colleague, Dr Richard Doll, has brought this story a stage further. In the nine years 1948 to 19S6 there had been, he found, 48 deaths from cancer of the lung and 13 deaths from cancer of the nose. He assessed the numbers expected at normal rates of mortality as, respectively 10 and 0T. 'In 1923, long before any special hazard had been recopnized, certain changes in the refinery took piace. No case of cancer of the nose has been observed in any man who first entered the works after that Jear, and in these men there has been no excess of mneer of the lung. Fn other words, the excess in both sues is uniquely a feature in men who entered the refinery in, roughly, the first 23 sears of the present century, "No causal agent of these neoplasms has been """`lied. Until recently no animal experimentation "d given any clue or any support to this wholly tiListica) evidence. Yet I wonder if any of us would haitate to accept it as proof of a grave industrial "izd?' (Hill 1962). In relation to my present discussion I know of no parallel investigation. We have (or certainly . * to make up our minds on a unique event; -nd ^*ere is no difficulty in doing so. (3) Specificity: One reason, needless to say, is the specificity of the association, the third character istic which invariably we must consider. If, as here, the association is limited to specific workers and to particular sites and types of disease and there is no association between the work and other modes of dying, then clearly that is a strong argument in favour of causation. We must not, however, over-emphasize the importance of the characteristic. Even in my present example there is a cause and effect rela tionship with two different sites of cancer - the lung and the nose. Milk as a carrier of infection and, in that sense, the cause of disease can pro duce such a disparate galaxy as scarlet fever, diphtheria, tuberculosis, undulant fever, sore throat, dysentery and typhoid fever. Before the discovery of the underlying factor, the bacterial origin of disease, harm would have been done by pushing too firmly the need for specificity as a necessary feature before convicting the dairy. Coming to modern times the prospective investigations of smoking and cancer of the lung have been criticized for not showing specificity in other words the death rate of smokers is higher than the death rate of non-smokers from many causes of death (though in fact the results of Doll & Hill, 1964, do not show that). But here surely one must return to my first characteristic, the strength of the association. If other causes of death are raised 10, 20 or even 50% in smokers whereas cancer of the lung is raised 900-1,000% we have specificity - a specificity in the magnitude of the association. We must also keep in mind that diseases may have more than one cause. It has always been possible to acquire a cancer of the scrotum without sweeping chimneys or taking to mule spinning in Lancashire, One-to-one relationships are not frequent. Indeed I believe that multi causation is generally more likely than single causation though possibly if we knew all the answers wc might get back to a single factor. In short, if specificity exists we may be able to draw conclusions without hesitation; if it is not apparent, we arc not thereby necessarily left sitting irresolutely on the fence. (4) Temporality: My fourth characteristic is the temporal relationship of the association - which is the cart and which the horse? This is a question which might be particularly relevant with diseases of slow development. Does a particular diet lead to disease or do the early stages of the disease lead to those peculiar dietetic habits? Does a ucc 033130 298 Proceedings ofthe Royal Society ofMedicine lo particular occupation or occupational environ in short, the association we observe may be ment promote infection by the tubercle bacillus one new to science or medicine and we must not or are the men and women who select that kind dismiss it too light-heartedly as just too odd. As of work more liable to contract tuberculosis Sherlock Holmes advised Di Watson, `when you whatever the environment - or, indeed, have they have eliminated the impossible, whatever remains, \ already contracted it? This temporal problem however improbable, must be the truth.* may not arise often but it certainly needs to be remembered, particularly with selective factors (7) Coherence: On the other hand the cause-and- at work in industry, effect interpretation of our data should not seriously conflict with the generally known facts (5) Biological gradient: Fifthly, if the association of the natural history and biology of the disease is one which can reveal a biological gradient, or - in the expression of the Advisory Committee dose-response curve, then we should look most to the Surgeon-General it should have coherence. carefully for such evidence. For instance, the fact that the death rate from cancer of the lung Thus in the discussion of lung cancer the rises linearly with the number of cigarettes Committee finds its association with cigarette smoked daily, adds a very great deal to the smoking coherent with the temporal rise that has . simpler evidence that cigarette smokers have a taken place in the two variables over the last, higher death rate than non-smokers. That com generation and with the sex difference in parison would be weakened, though not neces mortality - features that might well apply in an sarily destroyed, if it depended upon, say, a much occupational problem. The known urban/rural . heavier death rate in light smokers and a lower ratio of lung cancer mortality does not detract rate in heavier smokers. We should then need to from coherence, nor the restriction of the effect envisage some much more complex relationship to tt ; lung. to satisfy the cause-and-effect hypothesis. The clear dose-response curve admits of a simple Personally, I regard as greatly contributing to explanation and obviously puts the case in a coherence the histopathological evidence from clearer light. the bronchial epithelium of smokers and the isolation from cigarette smoke of factors car The same would clearly be true of an alleged cinogenic for the skin of laboratory animals. dust hazard in industry. The dustier the environ Nevertheless, while such laboratory evidence can ment the greater the incidence of disease we enormously strengthen the hypothesis and, would expect to see. Often the difficulty is to indeed, may determine the actual causative agent, secure some satisfactory quantitative measure of the lack of such evidence cannot nullify the the environment which will permit us to explore epidemiological observations in man. Arsenic this dose-response. But we should invariably can undoubtedly cause cancer of the skin in man seek it. but it has never been possible to demonstrate such an effect on any other animal. In a wider (6) Plausibility: It will be helpful if the causation field John Snow's epidemiological observations on we suspect is biologically plausible. But this is a the conveyance or cholera by the water from the feature I am convinced we cannot demand. What Broad Street pump would have been put almost ' is biologically plausible depends upon the bio beyond dispute if Robert Koch had been then logical knowledge of the day. around to isolate the vibrio from the baby's nappies, the well itself and the gentleman in To quote again from my Alfred Watson delicate health from Brighton. Yet the fact that. . Memorial Lecture (Hill 1962), there was Koch's work was to be awaited another thirty years did not really weaken the epidemiological *. . . no biological knowledge to support (or to refute) Pott's observation in the 18th century of the excess of cancer in chimney sweeps. It was lack of biological case though it made it more difficult to establish against the criticisms of the day - both just and unjust. knowledge in the 19th that led a prize essayist writing on the value and the fallacy of statistics to conclude, amongst other "absurd" associations, that "it could be no more ridiculous for the stranger who passed the night in the steerage of an emigrant ship to ascribe the typhus, which he there contracted, to the vermin with which bodies of the sick might be infected". And coining to nearer times, in the 20th century there was no biological knowledge to support the evidence (8) Experiment: Occasionally it is possible to appeal to experimental, or semi-experimental, evidence. For example, because of an observed association some preventive action is taken. Does it in fact prevent? The dust in the workshop is reduced, lubricating oils are changed, persons stop smoking cigarettes. Is the frequency of the . against rubella." associated events affected? Here the strongest ..-1. ,~.-.'r-v ~--f -V- ;: -- J- - ~ " I '-'~-z. ...4.* . -- -.v! ~ +- tr;:I*V -`..'r.'-\r r . J-'- t*. ' -- .* j ucc 033131 'C.' 7/ Section ofOccupational Medicine 299 support for the causation hypothesis may be revealed. (9) Analogy: In some circumstances it would be fair to judge by analogy. With the effects of thalidomide and rubella before us we would surely be ready to accept slighter but similar evidence with another drug or another viral disease in pregnancy. Here then are nine different viewpoints from all of which we should study association before we cry causation. What I do not believe - and this has been suggested - is that we can usefully lay down some hard-and-fast rules of evidence that must be obeyed before we accept cause ard effect. None of my nine viewpoints can bring indisputable evidence for or against the causeand-effect hypothesis and none can be required as a sine qua non. What they can do, with greater or less strength, is to help us to make up our minds on the fundamental question - is there any other way of explaining the set of facts before us, is there any other answer equally, or more, likely than cause and effect? Tests ofSignificance No formal tests of significance can answer those questions. Such tests can, and should, reirhd us of the effects that the play of chance can ..reate, and they will instruct us in the likely magnitude of those effects. Beyond that they contribute nothing to the `proof' of our hypothesis. Nearly forty years ago, amongst the studies of occupational health that I made for the Industrial Health Research Board of the Medical Research Council was one that concerned the workers in the cotton-spinning mills of Lancashire (Hill 1930). The question that I had to answer, by the use of the National Health Insurance records of that time, was this: Do the workers in the cardroom of the spinning mill, who tend the machines that clean the raw cotton, have a sickness experi ence in any way different from that of other operatives in the same mills who are relatively unexposed to the dust and fibre that were features of the cardroom? The answer was an unqualified `Yes'. From age 30 to age 60 the cardroom workers suffered over three times as much from respiratory causes of illness whereas from non-respiratory causes their experience was not different from that of the other workers. This pronounced difference with the respiratory causes was derived not from abnormally long periods of sickness but rather from an excessive number of repeated absences from work of the cardroom workers. All this has rightly passed into the limbo of forgotten things. What interests me today is this: My results were set out for men and women separately and for half a dozen age groups in 36 tables. So there were plenty of sums. Yet I cannot find that anywhere I thought it necessary to use a test of significance. The evidence was so clear-cut, the differences between the groups were mainly so large, the contrast between respiratory and nonrespiratory causes of illness so specific,'that no formal tests could really contribute anything of value to the argument. So why use them? Would we think or act that way today? I rather doubt it. Between the two world wars there was a strong case for emphasizing to the clinician and other research workers the importance of not overlooking the effects of the play of chance upon their data. Perhaps too often generalities were based upon two men and a laboratory dog while the treatment of choice was deduced from a difference between two bedfuls of patients and might easily have no true meaning. It was there fore a useful corrective for statisticians to stress, and to teach the need for, tests of significance merely to serve as guides to caution before draw ing a conclusion, before inflating the particular to the general. 1 wonder whether the pendulum has not swung too far - not only with the attentive pupils but even with the statisticians themselves. To decline to draw conclusions without standard errors can surely be just as silly? Fortunately I believe we have not yet gone so far as our friends in the USA where, 1 am told, some editors of journals, will return an article because tests of significance have not teen applied. Yet there are innumerable situations in which they are totally unnecessary because the difference is grotesquely obvious, because it is negligible, or because, whether it be formally significant or not, it is too small to be of any practical importance. What is worse the glitter of the t table diverts attention from the inadequacies of the fare. Only a tithe, and an unknown tithe, of the factory personnel volunteer for some procedure or interview, 20% of patients treated in some particular way are lost to sight, 30% of a randomly-drawn sample are never con tacted. The sample may, indeed, be akin to that of the man who, according to Swift, `had a mind to sell his house and carried a piece of brick in his pocket, which he showed as a pattern to en courage purchasers'. The writer, the editor and the reader are unmoved. The magic formula: are there. Of course I exaggerate. Yet too often I suspect we waste a deal of time, we grasp the shadow and T~'i ' / - I-'.;- M M .-yk. .m M ii'?}- if CJTjEt ''.Ssswfca* YJS:- x. ` .T IJCC rmi 32 300 Proceedings ofthe Royal Society ofMedicine ... lose the substance, we weaken our capacity to interpret data and to take reasonable decisions whatever the value of P. And far too often we deduce `no difference* from `no significant difference*. Like fire, the x* test is an excellent servant and a bad master. The Casefor Action Finally, in passing from association to causation I believe in `real life' we shall have to consider what flows from that decision. On scientific grounds we should do no such thing. The evi dence is there to be judged on its merits and the judgment (in that sense) should be utterly independent of what hangs upon it - or who hangs because of it. But in another and more practical sense we may surely ask what is involved in our decision. In occupational medicine our object is usually to take action. If this be opera tive cause and that be deleterious effect, then we shall wish to intervene to abolish or reduce death or disease. While that is a commendable ambition it almost inevitably leads us to introduce differen tial standards before we convict. Thus on relatively slight evidence we might decide to restrict the use of a drug for early-morning sick ness in pregnant women. If we are wrong in deducing causation from association no great harm will be done. The good lady and the pharmaceutical industry will doubtless survive. On fair evidence we might take action on what appears to be an occupational hazard, e.g. we might change from a probably carcinogenic oil to a non-carcinogenic oil in a limited environment and without too much injustice if we are wrong. But we should need very strong evidence before we made people burn a fuel in their homes that they do not like or stop smoking thecigarettes and eating the fats and sugar that they do like. In asking for very strong evidence I would, however . repeat emphatically that this does not imply, crossing every *t*, and swords with every critic, before we act. All scientific work is incomplete - whether it be observational or experimental. All scientific work is liable to be upset or modified by advancing knowledge. That does not confer upon us a free-. dom to ignore the knowledge we already have, or.' to postponetheaction that it appears todemund at. a given time. _; Who knows, asked Robert Browning, but the world may end tonight? True, but on available evidence most of us make ready to commute on,: the 8.30 next day. - REFERENCES Doll R (1964) la: Mtdial Sur\*y* and Clinical Trial*. Ed, L J Witij. 2nd ad. London; p Doll R & Hill A B (1964) Brit. wrf. 7, j, 1399,1460 H*idy J A (1958) Me4, IVorU, Lo*4.89.905 Hill A B (1930) Sickf u amongst Operate es in Lancashire Spinning Mills. Industrial I -aalth Research Board Report No, 59. HMSO, Londoa (1962)7. /*#, Actu. 88.178 Snow 3 (1855) On the Mode of Communication of Cholera. 2nd cd. London (Reprinted 1936. New York) VS Department of Health, Education it Welfare (1964) Smoking and Health. Public Health Service Publication No. 1103. Washing ton 0331