Section ofOccupational Medicine

The Environment and Disease:Association or Causation?by Sir Austin Bradford Hill CBE DSC FRCP(hOn) FRS(Professor Emeritus ofMedical Statistics,University ofLondon)

Amongst the objects ofthis newly-founded Sectionof Occupational Medicine are firstly 'to provide ameans, not readily afforded elsewhere, wherebyphysicians and surgeons with a special knowledgeof the relationship between sickness and injuryand conditions of work may discuss their prob-lems, not only with each other, but also withcolleagues in other fields, by holding joint meet-ings with other Sections of the Society'; and,secondly, 'to make available information aboutthe physical, chemical and psychological hazardsof occupation, and in particular about those thatare rare or not easily recognized'.

At this first meeting of the Section and before,with however laudable intentions, we set aboutinstructing our colleagues in other fields, it willbe proper to consider a problem fundamental toour own. How in the first place do we detectthese relationships between sickness, injury andconditions of work? How do we determine whatare physical, chemical and psychological hazardsof occupation, and in particular those that arerare and not easily recognized?

There are, of course, instances in which wecan reasonably answer these questions from thegeneral body of medical knowledge. A particular,and perhaps extreme, physical environment can-not fail to be harmful; a particular chemical isknown to be toxic to man and therefore suspecton the factory floor. Sometimes, alternatively,we may be able to consider what might a par--ticular environment do to man, and then seewhether such consequences are indeed to befound. But more often than not we have no suchguidance, no such means of proceeding; moreoften than not we are dependent upon ourobservation and enumeration of defined eventsfor which we then seek antecedents. In otherwords we see that the event B is associated withthe environmental feature A, that, to take aspecific example, some form of respiratory illnessis associated with a dust in the environment. Inwhat circumstances can we pass from this

Meeting January 141965

President's Addressobserved 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 aphilosophical discussion of the meaning of'causation'. The 'cause' of illness may be imme-diate and direct, it may be remote and indirectunderlying the observed association. But withthe aims of occupational, and alnost synony-mously preventive, medicine in mind the decisivequestion is whether the frequency of the un-desirable event B will be influenced by a changein the environmental feature A. How such achange exerts that influence may call for a greatdeal of research. However, before deducing'causation' and taking action we shall notinvariably have to sit around awaiting theresults of that research. The whole chain mayhave to be unravelled or a few links may suffice.It will depend upon circumstances.

Disregarding then any such problem insemantics we have this situation. Our observa-tions reveal an association between two variables,perfectly clear-cut and beyond what we wouldcare to attribute to the play of chance. Whataspects of that association should we especiallyconsider before deciding that the most likelyinterpretation of it is causation?

(1) Strength. First upon my list I would put thestrength of the association. To take a very oldexample, by comparing the occupations ofpatients with scrotal cancer with the occupationsof patients presenting with other diseases,Percival Pott could reach a correct conclusionbecause of the enormous increase of scrotalcancer in the chimney sweeps. 'Even as late as thesecond decade of the twentieth century', writesRichard Doll (1964), 'the mortality of chimneysweeps from scrotal cancer was some 200 timesthat of workers who were not specially exposedto tar or mineral oils and in the eighteenthcentury the relative difference is likely to havebeen much greater.'

To take a more modern and more generalexample upon which I have now reflected forover fifteen years, prospective inquiries intosmoking have shown that the death rate fromcancer of the lung in cigarette smokers is nine toten times the rate in non-smokers and the rate inheavy cigarette smokers is twenty to thirty times

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as great. On the other hand the death rate fromcoronary thrombosis in smokers is no more thantwice, possibly less, the death rate in non-smokers. Though there is good evidence tosupport causation it is surely much easier in thiscase to think of some features of life that may gohand-in-hand with smoking - features that mightconceivably be the real underlying cause or, atthe least, an important contributor, whether it belack of exercise, nature of diet or other factors.But to explain the pronounced excess in cancer ofthe lung in any other environmental termsrequires some feature of life so intimately linkedwith cigarette smoking and with the amount ofsmoking that -such a feature should be easilydetectable. If we cannot detect it or reasonablyinfer a specific one, then in such circumstances Ithink we are reasonably entitled to reject thevague contention of the armchair critic 'you can'tprove it, there may be such a feature'.

Certainly in this situation I would reject theargument sometimes advanced that what mattersis the absolute difference between the death ratesof our various groups and not the ratio of one toother. That depends upon what we want to know.If we want to know how many extra deaths fromcancer of the lung will take place through smok-ing (i.e. presuming causation), then obviously wemust use the absolute differences between thedeath rates - 0 -07 per 1,000 per year in non-smoking doctors, 0'57 in those smoking 1-14cigarettes daily, 1 39 for 15-24 cigarettes dailyand 2-27 for 25 or more daily. But it does notfollow here, or in more specifically occupationalproblems, that this best measure of the effect uponmortality is also the best measure in relation toatiology. In this respect the ratios of 8, 20 and 32to 1 are far more informative. It does not, ofcourse, follow that the differences revealed byratios are of any practical importance. Maybethey are, maybe they are not; but that is anotherpoint altogether.

We may recall John Snow's classic analysis ofthe opening weeks of the cholera epidemic of 1854(Snow 1855). The death rate that he recorded inthe customers supplied with the grossly pollutedwater of the Southwark and Vauxhall Companywas in truth quite low - 71 deaths in each 10,000houses. What stands out vividly is the fact thatthe small rate is 14 times the figure of 5 deaths per10,000 houses supplied with the sewage-freewater of the rival Lambeth Company.

In thus putting emphasis upon the strength ofan association we must, nevertheless, look at theobverse of the coin. We must not be too ready todismiss a cause-and-effect hypothesis merely on

the grounds that the observed associationappears to be slight. There are many occasions inmedicine when this is in truth so. Relatively fewpersons harbouring the meningococcus fall sickof meningococcal meningitis. Relatively fewpersons occupationally exposed to rat's urinecontract Weil's disease.

(2) Consistency: Next on my list of features to bespecially considered I would place the consistencyof the observed association. Has it been repeatedlyobserved by different persons, in different places,circumstances and times?

This requirement may be of special importancefor those rare hazards singled out in the Section'sterms of reference. With many alert minds atwork in industry today many an environmentalassociation may be thrown up. Some of them onthe customary tests of statistical significance willappear to be unlikely to be due to chance. Never-theless whether chance is the explanation orwhether a true hazard has been revealed maysometimes be answered only by a repetition ofthe circumstances and the observations.

Returning to my more general example, theAdvisory Committee to the Surgeon-General ofthe United States Public Health Service foundthe association of smoking with cancer of thelung in 29 retrospective and 7 prospectiveinquiries (US Department of Health, Education& Welfare 1964). The lesson here is that broadlythe same answer has been reached in quite a widevariety of situations and techniques. In otherwords we can justifiably infer that the associationis not due to some constant error or fallacy thatpermeates every inquiry. And we have indeed tobe 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 recentdomestic anxieties or crises that may have pre-cipitated the acute illness. As controls, patientsadmitted for operation for a simple hernia aresimilarly quizzed. But, as Heady points out, thetwo groups may not be in pari materia. If yourwife ran off with the lodger last week you stillhave to take your perforated ulcer to hospitalwithout delay. But with a hernia you mightprefer to stay at home for a while - to mourn (orcelebrate) the event. No number of exact repeti-tions would remove or necessarily reveal thatfallacy.

We have, therefore, the somewhat paradoxicalposition that the different results of a differentinquiry certainly cannot be held to refute the

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original evidence; yet the same results from pre-cisely the same form of inquiry will not invariablygreatly strengthen the original evidence. I wouldmyself put a good deal of weight upon similarresults reached in quite different ways, e.g. pros-pectively and retrospectively.

Once again looking at the obverse of the cointhere will be occasions when repetition is absentor impossible and yet we should not hesitate todraw conclusions. The experience of the nickelrefiners of South Wales is an outstandingexample. I quote from the Alfred WatsonMemorial Lecture that I gave in 1962 to theInstitute of Actuaries:

'The population at risk, workers and pensioners,numbered about one thousand. During the ten years1929 to 1938, sixteen of them had died from cancer ofthe lung, eleven of them had died from cancer of thenasal sinuses. At the age specific death rates ofEngland and Wales at that time, one might haveanticipated one death from cancer of the lung (tocompare with the 16), and a fraction of a death fromcancer of the nose (to compare with the 11). In allother bodily sites cancer had appeared on the deathcertificate 11 times and one would have expected it todo so 10-11 times. There had been 67 deaths from allother causes of mortality and over the ten years'period 72 would have been expected at the nationaldeath rates. Finally division of the population at riskin relation to their jobs showed that the excess ofcancer of the lung and nose had fallen wholly uponthe workers employed in the chemical processes.

'More recently my colleague, Dr Richard Doll, hasbrought this story a stage further. In the nine years1948 to 1956 there had been, he found, 48 deaths fromcancer of the lung and 13 deaths from cancer of thenose. He assessed the numbers expected at normalrates of mortality as, respectively 10 and 0 1.

'In 1923, long before any special hazard had beenrecognized, certain changes in the refinery tookplace. No case of cancer of the nose has been observedin any man who first entered the works after thatyear, and in these men there has been no excess ofcancer of the lung. In other words, the excess in bothsites is uniquely a feature in men who entered therefinery in, roughly, the first 23 years of the presentcentury.

'No causal agent of these neoplasms has beenidentified. Until recently no animal experimentationhad given any clue or any support to this whollystatistical evidence. Yet I wonder if any of us wouldhesitate to accept it as proof of a grave industrialhazard?' (Hill 1962).

In relation to my present discussion I know ofno parallel investigation. We have (or certainlyhad) to make up our minds on a unique event;and there is no difficulty in doing so.

(3) Specificity: One reason, needless to say, is thespecificity of the association, the third character-istic which invariably we must consider. If, ashere, the association is limited to specific workersand to particular sites and types of disease andthere is no association between the work andother modes of dying, then clearly that is a strongargument in favour of causation.

We must not, however, over-emphasize theimportance of the characteristic. Even in mypresent example there is a cause and effect rela-tionship with two different sites of cancer - thelung and the nose. Milk as a carrier of infectionand, in that sense, the cause of disease can pro-duce such a disparate galaxy as scarlet fever,diphtheria, tuberculosis, undulant fever, sorethroat, dysentery and typhoid fever. Before thediscovery of the underlying factor, the bacterialorigin of disease, harm would have been done bypushing too firmly the need for specificity as anecessary feature before convicting the dairy.

Coming to modern times the prospectiveinvestigations of smoking and cancer of the lunghave been cr_iticized for not showing specificity -in other words the death rate of smokers ishigher than the death rate of non-smokers frommany causes of death (though in fact the resultsof Doll & Hill, 1964, do not show that). But heresurely one must return to my first characteristic,the strength of the association. If other causes ofdeath are raised 10, 20 or even 50% in smokerswhereas cancer of the lung is raised 900-1,000%we have specificity - a specificity in the magnitudeof the association.

We must also keep in mind that diseases mayhave more than one cause. It has always beenpossible to acquire a cancer of the scrotumwithout sweeping chimneys or taking to mule-spinning in Lancashire. One-to-one relationshipsare not frequent. Indeed I believe that multi-causation is generally more likely than singlecausation though possibly if we knew all theanswers we might get back to a single factor.

In short, if specificity exists we may be able todraw conclusions without hesitation; if it is notapparent, we are not thereby necessarily leftsitting irresolutely on the fence.

(4) Temporality: My fourth characteristic is thetemporal relationship of the association --whichis the cart and which the horse? This is a questionwhich might be particularly relevant with diseasesof slow development. Does a particular diet leadto disease or do the early stages of the diseaselead to those peculiar dietetic habits? Does a

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particular occupation or occupational environ-ment promote infection by the tubercle bacillusor are the men and women who select that kindof work more liable to contract tuberculosiswhatever the environment - or, indeed, have theyalready contracted it? This temporal problemmay not arise often but it certainly needs to beremembered, particularly with selective factorsat work in industry.

(5) Biological gradient: Fifthly, if the associationis one which can reveal a biological gradient, ordose-response curve, then we should look mostcarefully for such evidence. For instance, thefact that the death rate from cancer of the lungrises linearly with the number of cigarettessmoked daily, adds a very great deal to thesimpler evidence that cigarette smokers have ahigher death rate than non-smokers. That com-parison would be weakened, though not neces-sarily destroyed, if it depended upon, say, a muchheavier death rate in light smokers and a lowerrate in heavier smokers. We should then need toenvisage some much more complex relationshipto satisfy the cause-and-effect hypothesis. Theclear dose-response curve admits of a simpleexplanation and obviously puts the case in aclearer light.

The same would clearly be true of an allegeddust hazard in industry. The dustier the environ-ment the greater the incidence of disease wewould expect to see. Often the difficulty is tosecure some satisfactory quantitative measure ofthe environment which will permit us to explorethis dose-response. But we should invariablyseek it.

(6) Plausibility: It will be helpful if the causationwe suspect is biologically plausible. But this is afeature I am convinced we cannot demand. Whatis biologically plausible depends upon the bio-logical knowledge of the day.

To quote again from my Alfred WatsonMemorial Lecture (Hill 1962), there was

'. . . no biological knowledge to support (or to refute)Pott's observation in the 18th century of the excess ofcancer in chimney sweeps. It was lack of biologicalknowledge in the 19th that led a prize essayist writingon the value and the fallacy of statistics to conclude,amongst other "absurd" associations, that "it couldbe no more ridiculous for the stranger who passed thenight in the steerage of an emigrant ship to ascribethe typhus, which he there contracted, to the verminwith which bodies of the sick might be infected". Andcoming to nearer times, in the 20th century there wasno biological knowledge to support the evidenceagainst rubella.'

In short, the association we observe may beone new to science or medicine and we must notdismiss it too light-heartedly as just too odd. AsSherlock Holmes advised Dr Watson, 'when youhave eliminated the impossible, whatever remains,however improbable, must be the truth.'

(7) Coherence: On the other hand the cause-and-effect interpretation of our data should notseriously conflict with the generally known factsof the natural history and biology of the disease- in the expression of the Advisory Committeeto the Surgeon-General it should have coherence.

Thus in the discussion of lung cancer theCommittee finds its association with cigarettesmoking coherent with the temporal rise that hastaken place in the two variables over the lastgeneration and with the sex difference inmortality - features that might well apply in anoccupational problem. The known urban/ruralratio of lung cancer mortality does not detractfrom coherence, nor the restriction of the effectto the lung.

Personally, I regard as greatly contributing tocoherence the histopathological evidence fromthe bronchial epithelium of smokers and theisolation from cigarette smoke of factors car-cinogenic for the skin of laboratory animals.Nevertheless, while such laboratory evidence canenormously strengthen the hypothesis and,indeed, may determine the actual causative agent,the lack of such evidence cannot nullify theepidemiological observations in man. Arseniccan undoubtedly cause cancer of the skin in manbut it has never been possible to demonstratesuch an effect on any other animal. In a widerfield John Snow's epidemiological observations onthe conveyance of cholera by the water from theBroad Street pump would have been put almostbeyond dispute if Robert Koch had been thenaround to isolate the vibrio from the baby'snappies, the well itself and the gentleman indelicate health from Brighton. Yet the fact thatKoch's work was to be awaited another thirtyyears did not really weaken the epidemiologicalcase though it made it more difficult to establishagainst the criticisms of the day - both just andunjust.

(8) Experiment: Occasionally it is possible toappeal to experimental, or semi-experimental,evidence. For example, because of an observedassociation some preventive action is taken. Doesit in fact prevent? The dust in the workshop isreduced, lubricating oils are changed, personsstop smoking cigarettes. Is the frequency of theassociated events affected? Here the strongest

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Section ofOccupational Medicine

support for the causation hypothesis may berevealed.

(9) Analogy: In some circumstances it would befair to judge by analogy. With the effects ofthalidomide and rubella before us we wouldsurely be ready to accept slighter but similarevidence with another drug or another viraldisease in pregnancy.

Here then are nine different viewpoints from allof which we should study association before wecry causation. What I do not believe - and thishas been suggested - is that we can usefully laydown some hard-and-fast rules of evidence thatmust be obeved before we accept cause ardeffect. None of my nine viewpoints can bringindisputable evidence for or against the cause-and-effect hypothesis and none can be requiredas a sine qua non. What they can do, with greateror less strength, is to help us to make up ourminds on the fundamental question - is there anyother way of explaining the set of facts before us,is there any other answer equally, or more, likelythan cause and effect?

Tests ofSignificanceNo formal tests of significance can answer thosequestions. Such tests can, and should, remind usof the effects that the play of chance can create,and they will instruct us in the likely magnitudeof those effects. Beyond that they contributenothing to the 'proof' of our hypothesis.

Nearly forty years ago, amongst the studies ofoccupational health that I made for the IndustrialHealth Research Board of the Medical ResearchCouncil was one that concerned the workers inthe cotton-spinning mills of Lancashire (Hill1930). The question that I had to answer, by theuse of the National Health Insurance records ofthat time, was this: Do the workers in the card-room of the spinning mill, who tend the machinesthat clean the raw cotton, have a sickness experi-ence in any way different from that of otheroperatives in the same mills who are relativelyunexposed to the dust and fibre that werefeatures of the cardroom? The answer was anunqualified 'Yes'. From age 30 to age 60 thecardroom workers suffered over three times asmuch from respiratory causes of illness whereasfrom non-respiratory causes their experience wasnot different from that of the other workers.This pronounced difference with the respiratorycauses was derived not from abnormally longperiods of sickness but rather from an excessivenumber of repeated absences from work of thecardroom workers.

All this has rightly passed into the limbo offorgotten things. What interests me today is this:My results were set out for men and womenseparately and for half a dozen age groups in 36tables. So there were plenty of sums. Yet I cannotfind that anywhere I thought it necessary to use atest of significance. The evidence was so clear-cut,the differences between the groups were mainly solarge, the contrast between respiratory and non-respiratory causes of illness so specific, that noformal tests could really contribute anything ofvalue to the argument. So why use them?

Would we think or act that way today ? Irather doubt it. Between the two world wars therewas a strong case for emphasizing to the clinicianand other research workers the importance of notoverlooking the effects of the play of chance upontheir data. Perhaps too often generalities werebased upon two men and a laboratory dog whilethe treatment of choice was deduced from adifference between two bedfuls of patients andmight easily have no true meaning. It was there-fore a useful corrective for statisticians to stress,and to teach the need for, tests of significancemerely to serve as guides to caution before draw-ing a conclusion, before inflating the particularto the general.

I wonder whether the pendulum has not swungtoo far - not only with the attentive pupils buteven with the statisticians themselves. To declineto draw conclusions without standard errors cansurely be just as silly? Fortunately I believe wehave not yet gone so far as our friends in theUSA where, I am told, some editors of journalswill return an article because tests of significancehave not been applied. Yet there are innumerablesituations in which they are totally unnecessary -because the difference is grotesquely obvious,because it is negligible, or because, whether it beformally significant or not, it is too small to be ofany practical importance. What is worse theglitter of the t table diverts attention from theinadequacies of the fare. Only a tithe, and anunknown tithe, of the factory personnel volunteerfor some procedure or interview, 20% of patientstreated 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 thatof the man who, according to Swift, 'had a mindto sell his house and carried a piece of brick in hispocket, which he showed as a pattern to en-courage purchasers'. The writer, the editor andthe reader are unmoved. The magic formulae arethere.

Of course I exaggerate. Yet too often I suspectwe waste a deal of time, we grasp the shadow and

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lose the substance, we weaken our capacity tointerpret data and to take reasonable decisionswhatever the value of P. And far too often wededuce 'no difference' from 'no significantdifference'. Like fire, the X2 test is an excellentservant and a bad master.

The Casefor ActionFinally, in passing from association to causationI believe in 'real life' we shall have to considerwhat flows from that decision. On scientificgrounds we should do no such thing. The evi-dence is there to be judged on its merits and thejudgment (in that sense) should be utterlyindependent of what hangs upon it - or whohangs because of it. But in another and morepractical sense we may surely ask what is involvedin our decision. In occupational medicine ourobject is usually-to take action. If this be opera-tive cause and that be deleterious effect, then weshall wish to intervene to abolish or reducedeath or disease.While that is a commendable ambition it

almost inevitably leads us to introduce differen-tial standards before we convict. Thus onrelatively slight evidence we might decide torestrict the use of a drug for early-moMing sick-ness in pregnant women. If we are wrong indeducing causation from association no greatharm will be done. The good lady and thepharmaceutical industry will doubtless survive.On fair evidence we might take action on what

appears to be an occupational hazard, e.g. wemight change from a probably carcinogenic oil

to a non-carcinogenic oil in a limited environmentand without too much injustice if we are wrong.But we should need very strong evidence beforewe made people burn a fuel in their homes thatthey do not like or stop smoking thecigarettes andeating the fats and sugar that they do like. Inasking for very strong evidence I would, however,repeat emphatically that this does not implycrossing every 't', and swords with every critic,before we act.

All scientific work is incomplete - whether it beobservational or experimental. All scientific workis liable to be upset or modified by advancingknowledge. That does not confer upon us a free-dom to ignore the knowledge we already have, orto postponethe action that it appears to demand ata given time.Who knows, asked Robert Browning, but the

world may end tonight? True, but on availableevidence most of us make ready to commute onthe 8.30 next day.

REFERENCESDoll R (1964) In: Medical Surveys and Clinical Trials. Ed. L JWitts. 2nd ed. London; p 333Doll R & Hill A B (1964) Brit. med. J. i, 1399, 1460Heady J A (1958) Med. World, Lond. 89, 305Hill A B(1930) Sickness amongst Operatives in Lancashire Spinning Mills.Industrial Health Research Board Report No. 59. HMSO, London(1962) J. Inst. Actu. 88, 178Snow J (1855) On the Mode of Communication of Cholera. 2nded. London (Reprinted 1936, New York)US Department of Health, Education & Welfare (1964) Smokingand Health. Public Health Service Publication No. 1103. Washing-ton