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FILE NAME Kent KNT DATE 1953 Sept 5 DOC KNT130 DOCUMENT DESCRIPTION Journal Article - Bronchial Carcinoma Incidence & Etiology - British Medical Journal RITISH MEDICAL JOURNAL LONDON SATURDAY SEPTEMBER 5. 1953 BRONCHIAL CARCINOMA INCIDENCE AND AETIOLOGY BY RICHARD DOLL M.D. M.R.C.P. Member of the Statistical Research Unit of the Medical Research Council A little over a hundred years ago Dr. Gavin Milroy took an active part in the establishment of the EpidemioNogical Society The object of the Society was to study epidemic and endemic diseases with special reference : to the investigation of a the various external or physical agencies and the different conditions of life which favour their development or influence their character and b the sanitary and hygienic measures best fitted to check mitigate or prevent them In 1850 interest was focused on the great epidemic diseases but the methodsMilroy urged collection of statistical data on the natural history of disease over large areas and over periods of years followed by inductive reasoning , from the observed facts as applicable day to the study of lung cancer as they were then to the study of plague typhus and cholera And the rapid increase which has been recorded in the mortality from lung cancer suggests that it is urgent to determine the " measures best fitted to check mitigate or prevent it Incidence frequent in proportion to other cancers the proportion was 40 Compared with malignant diseases lung cancer was recorded as a more common cause of death in men ; than hypertension or respiratory tubercle but only a third as many deaths were attributed to it as were attributed to coronary artery disease Of all male deaths in 1950 % were attributed to lung cancer ; at ages 45-54 the proportion was 10 There is no reason to suppose that these figures have yet reached their maxima On the contrary the trend in mortality rates suggests that lung cancer will reach an even more prominent position It is difficult to esti- mate the actual number of deaths which will occur Trends do not always continue smoothly For example the trend in male mortality at ages 35 44showed an almost steady increase from 1920 to 1946 when the rate reached the level of 166 deaths per million -- --I n 1950 the rate might have been expected to be about 190 per million whereas in fact it remained the . No figures are available for assessing the incidence of s lung cancer in Britain other than the mortality statistics of the Registrars Because of its great fatality the number of persons dying from it is nearly equal to the number affected and from this point of view mortality statistics provide a reasonable estimate of the inci- dence They are however subject to the inaccuracy inherent in the certification of causes of death . The salient feature of the reported mortality is the extent to which it has increased in the last 50 years particularly in the last 25 years In 1900 the crude ; annual death rate attributed to lung cancer in England and Wales was 8 per million persons by 1925 it had risen to 20 and by 1950 to 278 per million In other words the recorded rate increased two and a half times in the first 25 years and 14 times in the next 25 years in By 1950 12,241 deaths were attributed to lung cancer in one 10,254 in men and 1,987 in women As a site of cancer in both sexes taken together the lung was second in importance to the stomach but it was easily the most important site in giving rise to 28 more deaths than were attributed to cancer of the stomach and to more than double the number attribu- men ted to cancer of the colon Of all cancers in 24 were classified as having arisen in the lung but at ages 45-54 when lung cancer was relatively most same as four years earlier If future experience proves that the mortality in men aged 35-44 has in fact become stable it is to be expected that the increase will also cease in the older age groups but only after progressively longer periods of time have clapsed The maximum mortality from lung cancer unlike that from every other major form of cancer in men is not in the oldest age group At present it lies in the age group 65-74 and in 1931-47 was a decade earlier Fig 1 Over the last 20 years the age distribution bas become somewhat closer to that of the other major forms of cancer If it can be assumed that the death rates under the age of 45 have now become stable and that the trend in the age distribution continues until the distribution is similar to that of say cancer of the . stomach a rough estimate can be made of the number of deaths which will eventually be attributed to lung cancer On such assumptions highly speculative but I think not wholly unreasonable number of deaths for a population of the same age and sex composition as at present will eventually reach 20,000 In fact the future population will almost certainly contain a higher proportion of old persons so that the number recorded in 20 years time may be as great as 25,000 Increase in Incidence Physicians The Milroy Lectures delivered at the Royal Physicians of London on February 10 and 12 1953. By 1952 the rate had reached the level of 321 College of Abridged per million The evidence that lung cancer has become more frequent derives from necropsy studies as well as from vital statistics and clinical series Figures from Leeds General Infirmary 4835 BRONCHIAL CARCINOMA BRITISH MEDICAL JOURNAL TN published by Bonser 1934 and brought up to date by Watkinson personal communication show a rise in the proportion of necropsies at which a bronchial carcinoma was found from 1.4 in 1928-32 to 4.0 in 1949 and from 7.5 of all cancers found at necropsy to 16.9 Figures from St. Mary's St. Bartholomew's and the Glasgow Western Infirmary also show increases over the last 15 years Daff Doll and Kennaway 1951 . The only contrary experience recently 2000- recorded is that of Bryson and Spen- cer 1951 earlier oO\ . reports are pur- posely not consid- MEN 1500- 10,0 PER 1000+ RATE i / | [ / ; \ \ \ 4 J \ 1948-50 1948-50 1945-419475-47 1945-47 ered as they would not seem to be rel- evant to a prob- Iem which has presented itself in an acute since form they only were written Bryson and Spencer's material DEATH 500 ANUAL 200 100 laa 1940-44 \ 1936 - 39 ~ 1931-35 was collected from the necropsy records of the Cen- tral Histological Laboratory of the London County Council over a r 35 45 55 65 75 85 AGE FIG Mortality from lung cancer among men at different ages 1911-50 period when the number of necrop- sies performed in- creased rapidly from 684 to 1,723 a year although the number of patients admitted to the 26 hospitals concerned fell by a quarter It seems likely that in fact the type of subject coming to necropsy changed sputum and diagnostic thoracotomy It would indeed be diagnosis strange if the consequent increased facility in had clini not been reflected in a general recognition of a cally obscure disease It must also be recognized that im provements in therapy of the infectious diseases larly of pneumonia have reduced the number deaths occurring from the early complications of of lung cancer and so allowed a greater proportion the cases to proceed to a readily diagnosable stage In illustration of the close relationship presumed to hold between the lung cancer death rate and the standard of medical diagnosis and certification Rigdon and Kirchoff 1952 have shown that the correlation coefficient between the death rate and the the number of patients per physician in the 48 States of U.S.A. is 0.6:6 that is the fewer the patients per physician the higher the lung cancer death rate . In recent years Willis 1948 in Britain and Clemmesen and Busk 1947 in Denmark have like Steiner 1944 in the U.S.A. expressed the view that the increase is spurious It Kennaway seems however as pointed out by Heady and Kennaway 1949 that Willis based his opinion on evidence collected before 1933 is before the greater part of the increase was recorded while Clemmesen has revised his opinion Clemmesen Nielsen and Jensen 1953 and Steiner has locally been convinced that a real increase has taken place -for example in Los Angeles Steiner Butt and Edmonds son 1950 : Reasons for believing that there has been a real increase ; are : 1 The increase in the recorded death despite the long period which has elapsed drawn to the im- portance of the disease 2 The disease is 500 now so common that had the increase been entirely spurious it would be necessary to postu- 400- PATIO Of 1915 rate still continues since attention was MEN . DATES considerably and this is borne out by finding that the pro- late that 50 years 1925 portion of cancers which arose in the large intestine ago 95 of the fatal 1935 increased from % to 13 If therefore Bryson and Spencer's material suggests that bronchial carcinoma did not increase between 1936 and 1947 it also suggests that cancer of the large intestine which is contrary to the evidence of mortality statistics and to all clinical impression The increase recorded by vital statistics is partly due to the increasing proportion of the population who live to the cancer age This however accounts for only a small part cases were certified wrongly 3 Necropsy examinations conduc- ted under the super- vision of single eminent pathologists at teaching over hospitals where over 90 of 0 '0 1 300300300 PER RATE 2001 20012001 1985 1946 1947 1948 1949 1950 1951 ~ 0 4. 5-1611 F 30 45 69 of the increase If the sex and age distribution of the population in 1950 had 300- PERSONS * CRUDE DEATH DEATH PERSONS 250- RATE PERSONS 1,000,000 1,00,00 200- been the same as it was in 1931 the _ general rate for the population O would have been 236 per million instead of 278 per the died subjects who came to ne- cropsy example St. Mary's London and Lecds General Infirmary - have also shown con- siderable proportions increases in the proportions of bronchial carci- DEATH j i 100- a 501 501 f ad payee at 1910 1800 1920 1910 1920 1930 1950 1940 1950 1,00,00 1,0,0 150; PER "yf million that is ---- there would still have been a five- nomas to cers and necropsies all to can- all FIG Death rates from lung cancer in England and Wales 1900 50 ' PER 100 | RATE RATE x / + DEATH so vA DEATH wk Xxxx Xxxx Xxxx Xxxx . Xxxx 1 1900 1910 1920 1930 1940 DATE ' 1950 FIG Death rate from lung cancer in England and Wales 1900-50 Esti- mated death rate in 1950 with population of age and sex distribution as in 1931. Estimated death rate in 1950 with population of age and sex distribution as in 1901 fold increase in 19 years Fig 2 It has been held that the great increase in the recorded mortality in Britain may be due to the succes- osfive introduction radiography bronchoscopy bronchoscopy p umonectomy cytological cytological exam- ination of the 4 The increase has been persistently greater in men Passey and Holmes 1935 suggested that this might be due to the greater facilities for medical attention available to men under the National Health Insurance Act but in the few years that have 3 * elapsed since the introduction of the National Health Service Act in July 1948 the disparity has become even greater Fig 3 5 The age distribution of lung cancer in men is different from that of all other major types of male cancer and has been changing in form while its incidence has been increasing Korte- : weg 1951 notes that the trends in England and Wales are in occurred conformity with the hypothesis that a real increase has and that successive generations have been exposed to extraneous carcinogens to different extents The same phenomenon has observed 11995533 in Denmark Clemmesen Nielsen and Jensen = Ai] Ss oy ei? BNLY SEPT 5 1953 BRONCHIAL CARCINOMA * BRITISH MEDICAL JOURNAL 523 6 The death rates in town and country have in England and Wales retained the same relation to one another 7 The mortality among doctors who may be presumed to be as carefully investigated as any section of the community has been practically the same as that for the whole population Kemuway and Kennaway 1947 Dublin Spiegelman and Leland 1947 It cannot be said that all workers are agreed on the conclusions to be drawn Rigdon and Kirchoff 1952 for example continue to believe that the increase is wholly spurious At the International Symposium on the Endemiology of Lung Cancer held last year at Louvain however it was agreed that a significant part of this increase is absolute and represents a real increase in the number of people suffering from cancer of the lung Council for International Organizations of Medical Sciences 1953 and the conclusion of the Symposium seems to me to be reasonable -. How much of the increase is real after standardizing for age and sex remains uncertain The extent of the change in the last five years when the importance of the disease has been recognized and facilities for diagnosis have been readily available suggests that the real increase is likely to be large I believe it may well be more than half On the other hand I would think it certain that some of the increase is nosological and some is due to the therapeutic advance which prevents death from pneumonia before the presence . of the underlying growth is evident Possible Explanations of the Increase The importance of the conclusion reached is that it holds out hope for prevention An increase of the rapidity and extent of that presumed to have occurred cannot be accounted for on the basis of a changing inherent con- ' stitution Some potent environmental factor must have become prevalent and therefore when the factor is iden- . lified it may prove possible to reduce its influence Factors which have been considered are 1 atmospheric pollution with a the waste products of domestic chimney and factory smoke b the exhaust fumes of vehicles and c the dust from tarred roads ; 2 the smoking of tobacco ; and 3 the effects of certain respiratory infections - for example influenza of the type associated with the 1918- 19 pandemic and tuberculosis solutions containing methylcholanthrene or dibenzanthracene into the thigh muscles of adult animals and by Lisco and Finkel 1949 by the administration of radioactive cerium Ce,,in the form of an aerosol Substances derived from sources suspected of being implicated in causing human lung cancer have been tested by exposing mice to atmospheres containing the test substance in the form of dust or smoke or by painting McDonald and Woodhouse 1942 found an increased incidence of pulmonary tumours in mice exposed to inhalation of soot collected from the air of an English city and Leiter Shimkin and Shear 1942 produced sarcomas in mice at the site of inoculation with extracts of soot collected from the air of several American towns Campbell 1934 found a greatly increased incidence of pulmonary tumours in mice exposed to an atmosphere heavily laden with the dust from tarred roads and many animals also developed carcinoma of the skin presumably from contact with the dust externally; road dust from which the tar had been extracted also increased the incidence of the tumourbust to a less marked extent Campbell 1937 Mice kept in an atmosphere of tobacco smoke by Campbell 1936 in Britain and by Lorenz Stewart Daniel and Nelson 1943 in America showed no significant increase in the number of tumours In contrast Essenberg 1952 has recorded an increased incidence in mice exposed to high concentrations of cigarette smoke The mice came from a strain with a high spontaneous incidence and tumours were obtained in 21 out of 23 91 in the experimental group against 19 out of 32 60 in the control group It may be significant that the cigarette smoke was drawn directly into the animal box in Essenberg's experiment whereas in the other experiments it was introduced through tubing In no case have the conditions reproduced those to which men are exposed in smoking nor can they do so unless animals are trained to smoke Tar obtained from tobacco burnt at temperatures normally reached in smoking has resulted in the production of carcinomas when applied to the skin both in mice Flory 1941 Graham Wynder and Croninger 1952 and in rabbits Sanders Thomson Cooper and Lamb 1932 The tumours have not been produced easily but there is no doubt that tobacco tar can contain a carcinogenic agent Experiments in which animals have been exposed to the exhaust fumes of cars have proved negative Campbell 1936 Twort 1939 Animal Experiments The effect of these and other factors has been studied ex- lensively lensively in animals Unfortunately although lung tumours have been described in many species there is no laboratory animal which spontaneously develops tumours comparable to the ordinary squamous or anaplastic carcinoma of the bronchus of man For example the common pulmonary fumour of mice which has been the subject of most experiments is a papillary adenocarcinoma and according Grady and Stewart ( 1940 is of alveolar rather than of bronchial origin Many substances when fed to mice painted on the skin injected parenterally increase the incidence of this tumour most effective method generally being intra- Yenous injection Not all strains of mice respond in the ; Name way strains with high and low incidences of spon- faneously occurring pulmonary tumours have becn eparated and different strains react in different ways to application of the same substance though not of the hydrocarbons known to be carcinogenic under urethaneconditions have been shown on testing by these methoduresthane to produce pulmonary tumours The most potent Tumours more like the human type have been produced mice by Andervont 1937 by the insertion of a piece cotton thread impregnated with dibenzanthraImplantation into the lungs by Smith 1950 by the Implantation of lung tissue from embryo mice along with The application of these results to the study of human lung cancer is problematical In the first place the pulmonary tumour of mice is histogenetically different from bronchial carcinoma and tumours which more closely resemble the human type have been produced only by methods which do not appear likely to have any direct counterpart in naturally occurring carcinogenesis The rarity of bronchial carcinoma in animals accords with the theory that the tumour in man commonly arises from some specifically human activity In the second place it is clear that most of the sources suggested as responsible for the production of bronchial atmospheric soot dust from tarred roads and tobacco can be shown by selected methods of application to contain substances which are carcinogenic for some animals Whether they are of importance in the production of the human disease can be determined only by observations on man Incidence in Different Parts of the World It is always difficult to compare vital statistics from different countries and particularly so when they relate to a disease like lung cancer which is not easy to diagnose with certainty by clinical methods Necropsy statistics have the advantage that the diagnoses can be relied on but the populations from which the subjects are drawn are seldom known with accuracy and much bias may be introduced into the figures for this reason without there being any ; evidence of its nature , . 524 SEPT 5. 1953 BRONCHIAL CARCINOMA BRITISH MEDICAL JOURNAL en TABLE Death Rates from Lung Respiratory and respiratory Cancers in Various Countries 1949 Non- Death Rate per 1,000,000 respiratory Cancer 1,584 1,597 Country . ; England and Wales Scotland .. .- | Death Rate per : 1,000,000 | Respiratory Lung Cancer | Cancer Lung Cancer as % of all Cancers Found at Necropsy 288 256 251 228 | 310 214 16-1 | 20.4 1,123 1,652 1,262 1,545 1,256 1,474 1,271 1,041 1,131 1,462 1,152 1,292 988 1,407 666 1,411 809 Uruguay .. Switzerland Holland France U.S.A. W. Germany New Zealand S. Africa .. Canada Denmark Australia .. Eire Italy Iceland Spain Norway .. e Chile an an 151 144 135 131 131 127 10 106 106 103 99 84 80+ 67 63 47t 122 133 112 160 | 16.0 11.3 10-4 " I 58 | 3.1 54 _- 1947. 1948 Necropsy England and Wales St. Bartholomew's 1945-8 St. Mary's 1945-8 Leeds General Infirmary 1945-9 Scotland Western Infirmary Glasgow 1945-8 Holland Amsterdam and Rotterdam Korteweg personal communication U.S.A Los Angeles Kirchoff Steiner Butt and Edmondson 1950 Texas 1945-9 Rigdon and Kirchoff 1951 Iceland Reykjavik 1940-50 Dungal 1950 and personal com-com- munication Not all countries which publish vital statistics separate lung cancer from other cancers of the respiratory system Of those that do the highest rates recorded in 1949 were in England and Wales 251 per million and in Scotland 228 per million the next highest in Holland Switzerland and the U.S.A. all around 110-120 and the lowest in Iceland 58 and in Norway 54 Differences of this size 4 to ) cannot be accounted for by demographic differences If for example the English rates had held for populations of the sex and age distributions of the U.S.A. and Norway the death rates would have been 223 and 239 per million and still much higher than the rates actually recorded in those countries The forms of respiratory cancer other than cancer of the lung have in all probability different aetiologies lung cancer however accounts for such a high proportion of all respiratory cancer that important differences in the mor- The rates for all forms of cancer other than respiratory give an indication of the reliability of the national statistics All forms of cancer may be relatively infrequent in some countries but in view of the great variety of factors responsible for the production of cancer in different sites to conditions favouring a generally low rate are unlikely be common A low rate for all respiratory cancers in conjunction with the low rate for respiratory cancer must arouse the suspicion that many cases are not diag nosed a high rate for all respiratory cancers with low respiratory cancer rate will on the other hand suggest though it does not prove that the respiratory rate is reason ably reliable If necropsy studies in the same country also indicate a low proportion of lung carcinoma the impression will be strengthened With these considerations in mind it would be unwise to attach importance to the low respiratory cancer rates reported from Italy Spain and Chile On the other hand in both Norway and Iceland there is no deficiency of diag nosis of cancer generally and it seems reasonable to believe that the extremely low rates reported for lung cancer are real In Iceland moreover Dungal 1950 found a very low proportion of lung cancers at necropsy at the Uni versity Clinic where necropsy is routinely performed on all patients who die Very low incidences at necropsy have been reported from many parts of the world for which vital statistics are lacking Table II Gharpure 1948 found no case of lung cancer among 4,321 necropsies performed in Bombay during <": 1926-46 and Strachan 1934 found none among 1,901 | necropsies on native South Africans In this context it is of interest that the death rate from lung cancer among the white population of the U.S.A. is of the same order ~* as that among the white population so that the apparent difference found between Europeans and native Africans is - ~ unlikely to be due to heredity The average age at death in . the Indian and South African native cases must have been much less than that in recent European series and this ;alone will have considerably reduced the proportion found 2 to be cancer of the lung Nevertheless an appreciable number of cancers were found in the sites which commonly give rise to cancer among Europeans and it is unlikely that -. no case of bronchial carcinoma should have occurred in such large series if the condition was as common in India and South Africa as it is in Britain TABLE Incidence of Lung Cancer at Necropsy in Different Countries Author Place Period - England average for St. Mary's St. Bartholo mew's and Leeds G.I. . e .e | See Daff Doll and Kennaway 1951 Turkey Istanbul 2. Yugoslavia Ljubljana Shik 1946 te U.S.S.R. Moscow Gharpure Nath and Grewal 1935 Kouwenaar 1950 India Bombay a IndInidaoLneasbiaore Lucknow Chinese Indonesia Javanese .. Patna te and Patna os an Davies 1948 Strachan 1934 E. Africa i - S. Africa Bantus only 1945-8 1945-9 1945-9 1936-43 1926-46 1914-34 - 1931-47 1924-33 Lung Cancer as % of All Necropsies M F M 822811118 822811118 822811118 822811118 822811118 822811118 822811118 822811118 822811118 0.0 2821811118 2821811118 2821811118 2821811118 2821811118 2821811118 2821811118 2821811118 2821811118 2821811118 5.0 2.1 1.1 1-8 - 0.0 0.90.9 0.9 0.1 0.0 Lung Cancer as % of All Cancer Necropsies M F F 29-6 381811118 381811118 381811118 381811118 381811118 381811118 381811118 381811118 0-0 11.0 7.8 3-1 _ 0-0 - _ ~ 0.0 22-8 170 7.1 15.6 0-0 1.5 1. .5 23 14% 60 . tality from respiratory cancer are likely to simulate underlying differences in the mortality from lung cancer Figures for the death rate from respiratory cancer are shown in Table I for all those countries for which the statistics are published Table I also shows the death rates from all forms of cancer other than respiratory and for some countries the death rates from lung cancer alone and the proportion of bronchial carcinomas among all cancers found at necropsy in recent series is in necropsies performed since 1940 The rate for Iceland is for 1948 Attractive though it may be to conclude that a high death rate from lung cancer reffects principally a high standard of diagnosis it is probable that real differences in incidence between different parts of the world do particularly between Britain on the one hand and Norway Iceland and a number of Asiatic and African countries on the other- even though all of some of the recorded differences and some of all of them may be nosological One characteristic however is the same for all countries which have recorded vital statistics of lung or respiratory cancer for any length of time In each one the death rat^' has increased substantially in Norway Fig 4 tt nt ie AAT A STOTT ian etsintet 1 5-19 BUR ET R SE SEU MOE SEPT 5 1953 BRONCHIAL CARCINOMA BRITISH MEDICAL JOURNAL 525 ENGLAND k WALES SCOTLAND U.S. SWITZERLAND SWITZERLAND HOLLAND DENMARK DENMARK _O a 7 NORWAY NORWAY waste s a 1920 T 1925 U 1930 T 1935 T 1940 7 1945 1 1950 FIG Lung cancer Death rate in different countries 192050. Rates for the countries shown in parentheses were close to the rates for the countries with which they are grouped Differences Between Town and Country with carcinoma of the lung and the same number of matched control patients with other diseases that the proportion who had ever lived for any long period in the country was lower among the carcinoma patients irrespective of their present place of residence That is to say among patients residing in Greater London at the time of interview a lower proportion of those with lung carcinoma than of those with other diseases had ever lived for 10 or more years in a rural district similarly for each other place of present residence The differences were small and not statistically significant but they were all in the same direction and provide some support for the belief that the risk of developing lung cancer is in fact lower in the countryside The observation of a town and country difference is not confined to Britain Clemmesen Nielsen and Jensen 1953 have reported an even more pronounced difference between the capital and rural areas of Denmark In their opinion however the difference is not constant but may be explained by the spread of a new carcinogenic factor to the countryside 10 years after it had begun spreading in the capital In Norway the difference between urban and rural areasas definite as in Britain despite the low total incidence also increasing Mortality statistics for which I am grateful to Professor Kreyberg provide the following compari- sons Important differences in incidence have also been noted between sections of the population within individual countries Though mostly less dramatic than the differences between countries they have hitherto been of greater value in elucidating the aetiology of the disease since it has been possible to define more precisely the differences in environment to which the separate groups have been exposed For example differences in mortality have been noted between countrymen and townsmen and between the inbabitants of towns of different sizes According to the Registrar the death rate from lung cancer in 1950 was twice as high among the male inhabitants of Greater London as among men living in rural districts and the difference was more pronounced in the older age group The rates for other parts of the country fell between the Greater London and rural rates in exact order of town size Fig 5 Female rates show the same trends though the differences are less marked and the trends somewhat blurred possibly owing to smaller numbers Comparison of the relative differences at different periods shows that these differences have remained remarkably stable despite the great increase in the recorded mortalities Stocks 1952 has analysed the urban death rates for the period 1946-9 and has demonstrated a progressive increase with the increase in the number of inhabited 35001 Ratio of Death Rate in Town and in Country Men Women oe oe e an 1931-5 1.8 1 11 1946-50 2.5 1.5 It seems therefore as if differences are constantly in the same direction but that there may also be local differences which modify the trends in different countries Three substances known to be carcinogenic under suitable conditions have been identified in town air According to Dawson 1952 radioactive material is present to the extent of 30-100 10-12 curie per m. Activity in the open air of towns is not much greater than in rural areas but within closed rooms the activity may be doubled and in extreme cases as in an underground shelter it was found to be 100 times greater Even this value is however only tenth of the tolerance concentration it proves as it may do that the limit at present accepted is set too high The amount of arsenic varies according to Goulden Kennaway and Urquhart 1952 from 0.04 gof As^ per m in Bristol to 0.16 pg per m at Beckton in London houses Within Greater London he found that the boroughs with the highest mor- talities were situated to the north and east the town's centre This he suggests may be related to the direction of the pre- vailing wind which is from the south and might therefore be expected to shift The area of maximum smoke density to just that part of the town in which the highest mortalities occur : As always when drawing conclusions from vital statistics it must be asked whether the differences can be purely noso- logical whether the factor is nothing more than a greater facility for diagnosis the unlikely larger towns This seems first place it would hardly be ex- pected that diagnostic acumen should be so dependent upon the exact size of closely town town ; secondly there is the stability of the there urban : rural ratio and thirdly is 1952 evidence obtained by Doll and Hill 1952 They found among 1,465 patients 3000- * 0 0'0 0 0 0'0 0 o-- ~* 00'00 2500- ' 838 00- RATE RATE 1500- DEATH GREATER LONDON CONURBATIONS & TOWNS > 100,000 POPULATION 1000ANNUAL ANUAL ANNUAL 500- 0 15 TOWNS 100,000 POPN AURAL DISTRICTS a 25 _=74 ~ $72. gee Leteo* png 2B 7 7 r 45 AGE 65 75 > LONDON GREATER CONURB 100,10000 ,00 00 POPN TOWNS < 100,000 POPULATION RURAL DISTRICTS 1 85 FIG Death rate from lung cancer in different areas of England and Wales 526 SEPT 5 1953 . BRONCHIAL CARCINOMA MEDICAL JOURNAL it is however difficult to ascribe any one value to a town duction of gas For example Gloyne 1951 found as there are considerable variations between stations within towns example the concentration in the air at County Hall London was only a third of that found at Beckton and only slightly greater than that recorded in Bristol The total amount inspired by a town dweller per year is estimated by Kennaway to be 0.5 mg which only tenth of 52 men dying with asbestosis about 20 gave evidence of the presence of a primary lung cancer whereas among men with other forms of pneumoconiosis the proportion % As is shown later there are reasons for believing that the incidence among men with pneumoconiosis is generally close to the average of the amount in the maximum official dose of Fowler's solution 0.5 ml According to Waller 1952 benzpyrene is present in town air in amounts varying from 0.013 gper m.in Bristol to 0.046 gper m. of air in the centre of London Again however variations in the concentration make it necessary for many readings to be obtained before a fair estimate can be made of the content of the air of a town as a whole The evidence of the existence of a risk of lung cance in the handling of inorganic arsenic derives from an investi gation by Hill and Faning 1948 into the causes of death among men employed in a factory making sheep The traced five deaths due to lung cancer among these men whereas they estimated by comparison with the causes death in other workers in the area that there should have been only one i Winter concentrations are three to four times greater than summer concentrations and great increases are obtained during fogs In Waller's opinion the variations in benzpyrene content suggest that most of it is derived from the smoke of domestic fires Some has however been detected in motor exhausts and since the sizes of the particles in exhaust smoke are concentrated over a limited range of small sizes this source could be of greater biological significance than appears from the proportion which it contributes to the total air pollution The existence of special cancer risks in most of thes industries is not surprising since the workers in them have been exposed in the past and in some cases still are ex posed to unusual concentrations of known carcinogens According to Evans 1950 the mean concentration of radon per in the air of the Jachymov mines is about 3 ^ 10 curic m. while the tolerance concentration is at the most 10-1 curie per that is thirtieth of that found in the mines Hueper 1952 has produced sarcomas in mice at the site of injection with suspensions of finely dispersed nickel Occupational Risks The classical method leading to the isolation of chemically pure carcinogens is the observation of specially high cancer risks in specific occupations With lung cancer exceptional risks have been recognized in several unrelated industries These are mining of various ores in Schnee- berg Germany and in Jachymov Czechoslovakia; chro- matc production refining in Clydach S. Wales asbestos manufacture and the production of gas / powder and nickel must be presumed to be deposited in the respiratory passages on the decomposition of nickel carbonyl a gas produced in the refining process at Clydach workers are exposed to coal one of the most prolific sources of carcinogenic hydrocarbons and in- cluding benzpyrene Finally arsenic is known to produce cancer of the skin in man when ingested over long periods and large quantities up to 1,000 gper m were found in the atmosphere of the sheep factory Perry Bowler Buckell Druett and Schilling 1948 i these should probably be added the handling of inorganic No direct evidence is available on the nature of the arsenic and possibly occupations providing excessive carcinogenic factor in the chromate and asbestos indus- exposure to iron dust with or without added exposure to silica : The risks involved have been estimated only for chromate workers and workers Brinton Frasier and Koven 1952 extending the initial observations of Machle and Gregorius 1948 have compared the sickness and mortality experience of insured workers in the seven chromateproducing plants in the U.S.A. with the whole sickness data obtained by the U.S. Public Health Service and the death rates for the U.S. population They found that the The position with regard to workers is obscure Turner and Grace 1938 found that foundry smiths and grinders had a mortality from lung out cancer higher than that of any other occupational group in Sheffield; and Turner and Martin 1949 found that of 32 cancer deaths among grinders with silicosis the lung was the primary site in 19. grinders also suffered a high mortality from lung cancer in Kennaway and Kennaway's 1947 material These observations might be thought to mortality from lung cancer among white males employed in the plants was 14 times the expected and among coloured males it was 80 times the expected According to Bidstrup 1951 the risk is unlikely to be as great in the British chromate industry imply that silicosis predisposed to lung cancer but this has been convincingly shown not to be true Miners Phthisis Medical Bureau 1936 Kennaway and Kennaway 1947 If there is any excess among special groups of metal workers it must be presumed to be due to some other and more = Doll 1952 studied the causes of death among 2,071 male specific industrial hazard pensioners of a London gas company and found that the number of deaths from lung cancer was approximately double that expected by comparison with male inhabitants of London of the same age distribution is 25 deaths against 13.8 Confidence that this small excess is real derives from the observation that for all other causes of death studied the numbers observed were not significantly different from those expected; it is also of the same order as that determined by Kennaway and Kennaway 1947 when they drew attention to the possibility of there being a risk in the gas industry Of the other occupational risks that incurred in the Schneeberg and Jachymov mines is likely to have been the highest as much as 50 to 75 of all deaths among the miners may have been due to lung cancer Haerting and Hesse 1879 Lange 1935 Peller 1939 The risk in the Clydach nickel refinery least till the reorganization of the plant in must also have been considerable Chief Inspector of Factories 1949 In the manufacture of asbestos and arsenical sheep dip the risk is more likely to have been of the same order as that involved in the pro- An attempt has been made to discover whether any other common occupation carries a special risk by interrogating patients with and without bronchial carcinoma about their past occupations The questions were asked as part of a general investigation into the aetiology of bronchial carcinoma which has been described previously Doll and Hill 1950 1952 Altogether 1,357 men with bronchial carcinoma and 1,357 men with other diseases were interviewed Occupations in which the men had been employed for three or more years were recorded no account was taken of time spent in the Services unless the patient had served as a regular and no analysis was made employments under the age of 20 when changes occupation were frequent Many men had worked in: two or more occupations for the minimum of three years so that the number of occupations recorded was greater than the number of men interviewed for the men with lung carcinoma and 2,415 for the same number of men with other diseases Of all the 76 groups into which the occupations were classified there were only two in which the differences between the numbers BRONCHIAL CARCINOMA BRITISH MEDICAL JOURNAL 527 bronchial carcinoma and of control patients who had been employed in them could be considered by the usual statistical criteria to be significant The occupations re- corded of the bronchial carcinoma patients included 80 in mines and 16 in the police forces of the control patients there were 113 in mines and 32 in the police forces In view of its correspondence with the results of the analysis of the national mortality data made by Kennaway and Kennaway 1947 the deficiency of coalminers among the bronchial carcinoma group may reasonably be taken to confirm that miners are subject to a lower incidence of bronchial carcinoma than other industrial groups The deficiency in the cancer group of men who had been employed as policemen may in the absence of other evidence be attributed to chance since there is nothing surprising in finding one difference of this extent when so many groups have been studied difference is however uncertain In this country the mortality statistics of the Registrar gave in 1950 a ratio of 5.2 male deaths to every female death and the proportion has been increasing steadily though slowly from year to year During the first half of 1949 Mackay's 1951 study of patients discharged from a number of selected hospitals mainly teaching hospitals gave a ratio of 5.1 to 1 and the national cancer registration scheme which is believed to cover about half the cases in the country gave in 1946 a ratio of 6.9 to 1 Stocks 1950 Much higher ratios have been recorded in recent clinical varying from 7.3 to 1 to 12.6 to 1 Fulton 1949 Mason 1949 Brooks Davidson Thomas Robson and Smithers 1951 ; Doll and Hill 1952 The inconsistency may be partly due to the inclusion of a proportion of inaccurately diagnosed cases in the nationa The most important excess in the cancer group occurred men who had been directly concerned with the production of gas the cancer group contained 23 such men the control group 14. Other evidence has shown that workers are exposed to a special risk of lung cancer and the present figures are corroborative by themselves not -statistically significant The closeness of the numbers in the two disease groups who had been employed in many of the other occupations is striking This is particularly so for occupations which might have been expected to be disproportionately represented in the carcinoma group if exposure to the dust of tarred roads or to motor exhaust fumes was responsible for many cases of the disease Motor mechanics garage hands ws Drivers of cars lorries or buses . Bus and train conductors Le .. Van drivers horse . - . Other road transport |. . se Roadmen council labourers dustmen Men with Lung Other = Carcinoma ae 19 a Diseases 25 - 105 101 . 10 21 a 33 - 25 . 17 as 25 .. 39 a 39 propor- The failure to find any difference in the relative tions of men employed on the roads or in the service of cars is of interest It accords with the conclusion of Kennaway and Kennaway 1947 that none of the open occupations where there was special exposure to road dust had a high incidence of cancer of the lung The results provide little or no support for the suggestion of Wynder and Graham 1951 that painters and what they describe as " hot metal workers may suffer special risks PERSONS PERSONS 300 PERSONS PERSONS PERSONS ENGLAND I WALES U.S.A DENMARK x 1,00,00 250 1,000,000 1,000,000 1,000,000 1,0 0,0 0 + 200 PEA PEA PEA x 150 150 RATE DEATH DEATH DEATH - 100 SWITZERLAND HOLLAND gq x me] CANCER CANCER So CANCER NORWAY il . a fi Oo 0 LUNG x LUNG = LUNG x a Y t t t 0 : 2 3 4 5 631 RATIO OF MALE TO FEMALE DEATH RATES FIG Lung cancer Ratio of male : female death rates at different levels of incidence in different countries Ratios for the countries shown in parentheses were at each level of incidence similar to the ratios for the countries with which they are grouped Painters Painters and decorators Furnacemen foundrymen Other metal workers and smiths smiths . . Men with Lung Other Carcinoma . 70 a 26 . Diseases 59 23 150 +. 157 ; The evidence from a study of occupational factors is therefore therefore that the development of bronchial carcinoma may result from prolonged exposure to a number of atmospheric carcinogens some of these substances like radon benz- pyrene and arsenic are present in town though in very ; mliukech lower concentrations than occur in industry others nickel are peculiar to specialized industrial processes ; others are as yet undetermined So far as it goes the evidence is against the bypothesis that motor fumes and road dust are responsible agents - Although one occupation refining of nickel also responsible for a high incidence of cancer of the nasal sinuses it is a remarkable fact that none known Cancer to be associated appears to carry with a high any increased dancer It is probable therefore that are responsible for the production of of the occupations incidence of lung risk of laryngeal the factors which carcinoma of the bronchus and for carcinoma of the larynx are independent Sex Ratio According to all reports the incidence of lung cancer is much greater in men than in women The extent of the figures though this should not apply to the cancer registration scheme but it may also be due to the process of selection which to some extent accompanies the collection of any clinical series example through the exclusion of patients the relative exclusion of the very old or the availability of male and female beds Experience of the full and accurate registration scheme which is now operating in Denmark suggests that the true ratio is probably somewhat not higher than that indicated by death certificates and it is reasonable to believe that the true ratio in the United the present time of the order of 6 or 7 to Kingdom 1 is at At the beginning of the century the sex ratio judged by mortality data was as low as 1.3 to 1. In Norway the ratio is to this day not much greater Generally it would that in all countries the higher the incidence of the appear disease the greater the male preponderance see Fig 6 It is notable that the relation between the sex ratio and It the total incidence is not the same in all countries but that in some a given degree of male preponderance is reached at a lower general level of incidence It seems probable therefore that the factor mainly responsible for the increase is one to which men are particularly exposed and that the extent of the relative difference in exposure of men and women varies from country to country ; Part II will appear next week with list of references