278

AETIOLOGICAL FACTORS IN LUNG CANCERmA REVIEW.

ROBERT CARROLL, ]~'[.B., B.Ch. (N.U.I.); M.R.C.P.I., D.C.P. (Lond.),

Department of Pathology, Postgraduate Medical School of London.

O NE of the phenomena in the history of malignant disease that has become apparent in this century is the rapid increase of deaths in male subjects that has been ascribed to cancer of the lung; this

increase has been most apparent in recent decades. The increase in lung cancer is not entirely due to better diagnostic

methods (Kreybergl'). An abundant cause may be found in the increased exposure to many forms of irritating inhalations. Figuring prominently amongst these are tobacco, coal tar products and dusts of many forms.

Recent studies, notably those of Kreyberg TM in Norway, Daft et al. 5 in three British hospitals and Rosahn 23 have centred on the increased incidence of the disease. Rosahn investigated the incidence in the Yale University School of Medicine between the years 19o.8-1937. He found that primary cancer of the lung represented 11% of all the deaths from malignant disease. This was a 49% increase in this decade as compared with the preceding 10 years. Kennaway and Kennaway ~4 found that cancer of the lung has increased from 361 deaths in 1921 to 5,982 deaths in 1945 in men and from 186 deaths in 1921 to 1,480 deaths in 1945 in women. They also found that cancer of the lung differs from all other forms of cancer, in that the proportion of males is increasing. During the whole period 1921 to 1945 the ratio of female to male deaths changed from 1:1.9 to 1:4.0.

Aetiological Factors. The first intimation that an agent from the external environment might

cause cancer of the lungs came from the experience of the miners in the Schneeberg region of Saxony. Many of the miners in the Schneeberg and Joachimstal areas are known to die in middle age of a pulmonary disease which the miners call "Bergkrankheit " or mountain disease. This was first described as carcinoma of the lung in 1879; and it has now been established (Lorenz TM) that this disease accounts for 50 per cent. of the deaths in these miners. Various reasons were given for the causation of the high incidence of this lung tumour, among which were (1) mechanical irritation of the inhaled dust, (2) fumes or particles from various chemicals mined there (cobalt, arsenic, nickel, silica), (3) radio-active substances. 'In former years pneumoconiosis in com- bination with arsenic and cobalt was assumed to be the primary cause of the cancer; today the radio-activity of the ore and the radium content of the mines are generally considered to be the primary cause.

The atypical bronehiolar proliferation associated with past-influenzal pneumonia was early thought to be a factor predisposing to carcinoma of the lung. Influenza, however, affected both sexes equally, whereas the great increase in carcinoma of the lung has been in the male popu- lation. Iceland, which was badly affected by the influenza epidemic, has shown no increase in lung tumours among the population (Dungall~

The association between active tuberculosis and carcinoma of the

AETIOLOGICAL FACTORS IN LUNG C A N C E R - - A REVIEW 279

lung has been studied by Fried. ~ In his 319 patients with pulmonary tuberculosis 10.6% also had lung cancer. Robbins and Silverman 22 also studied cases of pulmonary carcinoma with active pulmonary tuber- culosis and came to the conclusion that there was no relationship between the two. Woodruff and Nahas 27 and Woodruff et al. 2~ studied 67 cases of carcinoma arising in cases in which there were calcified loci in the lungs and they showed a close connection between the sites of these foci and the sites of origin of carcinoma of the squamous and undifferentiated types. They regard healed pulmonary tuberculosis as an important factor in the aetiology of carcinoma of the bronchus. In summary it must be stated that the relationship between tuberculosis and carcinoma has not been clearly defined, although I might add it may be an impor- tant factor in that it is responsible for pulmonary scarring, and scars are an important site of origin of a group of lung carcinomas.

Arse~dc.

The occurrence of cancer of the skin in patients who had received prolonged arsenical treatment, and in workers exposed to arsenical dusts, and the fact that the latter group were also subject to perforation of the nasal septum suggested that arsenic might be capable of causing respiratol~ ~ cancer. Hill and Faning 1~ reviewed the literature and studied the relationship between arsenical dust and carcinoma of the bronchus. They stated that the fi~t fatal case of lung cancer associated with arsenical dust came to the notice of the British Factory Department in 1939 and since then two further fatal cases were reported in 1940 and a fur ther case ill 1943. These fatalities have been mainly in sheep dip workers. They found that of 22 cancer deaths in an arsenic factory 5 were due to carcinoma of the lung. A survey of the mortality records of an arsenic plant in America (Snegireff et al. ~) showed that out of 72 deaths from all causes in the past 25 years 18 were due to cancer, with 7 cancers of the respiratory system. Ill the age group under 55 there were twice as many cancer deaths as would be expected for the State as a whole. Arsenical dusts are thought to be an important aetiological factor in the causation of lung cancer in barium miners and in workers in the nickel industry. Arsenic as a causative factor in lung cancer must be clearly established because of the common use of arsenic in insecticides. Finished tobacco products have been found to contain considerable amounts of arsenic, a large proportion of which is volatilised in the smoke. I t was thought that this arsenic present in tobacco was due to the spraying of tobacco crops with insecticides. This led to a comparison of the carcinogenic properties of Virginian (which is sprayed with arsenic-containing insecticides and is found to contain a small amount of al~enie) and Turkish tobacco (which contains no arsenic). Daft et a l l showed that there was no difference in the car- cinogenic properties of either type of tobacco and commented on the high incidence of carcinoma of the lung found at necropsy in Istanbul where Turkish cigarettes are obviously much more popular.

I t may be concluded, therefore, that arsenic is capable of producing lung cancer provided it is present in sufficient concentration to produce other signs of chronic arsenic poisoning.

280 IRISH JOURNAL OF MEDICAL SCIENCE

C h r o m i u m . The existence of a specific industrial hazard in the chromium industry

was not realised until Machle and Gregorius 2t reported an increased incidence of carcinoma of the lung in chromium workers in the U.S.A. They investigated all factories producing chromates and found that out of 193 deaths 66 were due to cancer and a large proportion of these (46) were due to carcinoma of the lung. Taking different factories, the ratio of deaths from cancer of the respiratory system varied from 17 to 31 times the normal. They also investigated the incidence of the new growth among various types of workers and found that those handling the monochromates were worst affected. Bidstrup ~ examined 724 workers in the chromium industry radiologically, and found one case of carcinoma of the lung. These people were employed in three British factories, and Bidstrup and Case 2 followed them closely over a period of five years and found that in their series, used for statistical analysis, 12 deaths due to carcinoma of the lung were recorded where only 3.3 were expeoted. They also felt that the hazard lay in the use of the monochromates, but had not absolute proof of this fact.

We may conclude that there is an increased incidence of carcinoma of the lung in workers in the chromium industry, but evidence of the exact nature of the substance responsible for the induction of the disease is conflicting. The ore is a ferrous one (FeO.Crz0~) which contains 40-50 per cent. chromium and small amounts of alumina and silica. No cases have been reported among miners of the ore and Machle and Gregorius found no cases in the one American plant where the exposure was to dichromate and chromic acid. The supposition is, therefore, that the monochromates are the causative agents.

Pneumocanios i s .

The association between pneumoconlosis and pulmonary carcinoma has been studied by Vorwald and Karr. 26 They studied the x-ray films of 57,362 males and autopsy reports on 3,739 patients who had been exposed to occupational dusts: despite a large number of cases of anthracosis and silicosis they found no increased incidence of carcinoma of the lung above that of the general population. As a result of this large survey and also a good deal of experimental work in which only 2 animals out of 3,338 exposed to dust developed tumours (both adeno- mas) they concluded that inhaled dusts, except those containing carcino- genic agents, cannot be regarded as aetiological factors in the develop- ment of primary lung carcinoma.

Homburger ~ studied the association between asbestosis and pulmonary carcinoma. In his review he found 16 cases of primary lung tumours in asbestos workers, 11 of which were squamous carcinomata. In his own series of 4,000 autopsies from 1918 to 1938 he found asbestosis 8 times and silicosis 17 times. Four of his asbestosis cases and two of the silicoties had lung carcinoma. These numbers are small and do not provide a good foundation for regarding asbestosis as an aetiological factor. Lynch and Smyth ~~ reported a case of squamous carcinoma in an asbestos worker and a further case in 1939. They also found a high incidence of squamous metaplasia of the bronchial epithelium in the lungs of asbestos workers. Bonser et al. s reported on carcinoma arising

AETIOLOGICAL FACTORS IN LUNG CANCER~A REVIEW 281

in the pleura, lungs and bronchi of asbestos workers and found this in 26% of males and 8.7% of females. The interesting fact is that they found most of the tumours to be of the adenocareinomatous variety. They also found an increased incidence of adenocarcinoma of the lung in haematite workers. Silica is common to both types of occupation and they suggested it might be the cause. However, carcinoma has not been found in significant numbers in the lungs of silicotics and the extent of fibrosis in the lungs in which carcinoma develops in the asbestos and haematite workers is of a minor degree. Silica itself is not carcino- genic, but the combination of silica and asbestos or silica and iron ore may act as a carcinogen. The final proof that asbestosis predisposes to the development of lung cancer is borne out by Doll's 6 study of the mortality recorded among asbestos workers. He studied 113 men who had worked for 20 or more years in the asbestos industry and found that between 1922 and 1953, 39 died; whereas on the basis of the mor- tali ty rates suffered by men of the same ages in the whole population only 15.4 deaths would have been expected. Of the 39 deaths 11 were due to lung cancer, whereas less than 1 would have been expected. From 1933 onwards precautions were taken to prevent the dissemination of the dust and the incidence of the disease has become progressively less as the number of years during which the men were exposed to the pre-1937 conditions has diminished.

We may conclude, therefore, that carcinoma of the lung is a definite industrial hazard among asbestos workers and I would like to emphasise the prominence of adenocarcinoma of the lung in the more recent studies.

N ic, kel. Doll ~ found that between the years 1938 and 1956, 26 % of all deaths

among nickel workers was attributed to lung cancer and 10% attributed to nasal cancer. This rate is nine times that found in a control series. The British factory used a process of purification in which the gas nickel carbonyl (Ni(CO),) is formed from finely divided nickel and water gas. The gas decomposes very. rapidly and nickel is presumed to be deposited in highly active form when the gas comes into contact with the respiratory mucosa. No cases have been reported from Canada, Germany or U.S.A. and in these countries other processes are used in the refineries.

I t is noteworthy that my consideration of the environmental factors in lung cancer has thus far taken into account only inorganic compounds. Several types of exposure, notably tar and tarry materials, have been considered to present occupational respiratory tract hazards. A greater than expected frequency of lung cancer was attributed to gasworks stokers and coke-oven chargers by Kennaway and Kennaway. 1" They analysed the occupations on the death certificates of men dying of tung cancer between 1921 and 1938. There were 10 occupations in which the employees might be supposed to have special exposure to coal gas and tar. In 9, the estimated mortality from lung cancer was above the average for the whole male population, and 4 of these were among the 5 occupations with the highest mortalities.

The carcinogenic effect of many substances has been studied by the "t issue transplant technique " (Smith~4). Lungs are removed from

282 IRISH JOURNAL OF MEDICAL SCIENCE

mouse embryos, cut fine and implanted into the thigh muscle of adult animals of the same inbred line. When such tissue is implanted with methylcholanthrene, benzpyrene or dibenzanthracene the bronchial epithelium undergoes metaplasia and carcinomas of the squamous type appear.

The evidence for a definite risk of carcinoma of the lung has been established in 5 different industries--nickel refining, mining of radio- active ores, asbestos manufacturing, coal gas and monochromate produc- tion. There is probably also a risk associated with workers in the arsenic industry and haematite miners. Several other substances, namely copper mining, manufacture of isopropanol and the use of beryllium, have fallen under suspicion, but there is not sufficient evidence to in- criminate them definitely.

From the widespread occurrence of lung cancer~ it is clear that many cases of this disease would occur no matter the occupation of its victims. Many isolated cases, therefore, have no doubt been wrongfully attributed to occupation. For scientific advancement the reporting of occasional cases, with implication of occupational aetiology, is not sufficient. This must be replaced by careful statistical evaluation of a large series of occupational groups. Studies of inbred lines of mice have shown that genetically different strains living under normal condi- tions develop tumours of certain tissues with differing and predictable frequencies. The exposure of such animals to carcinogens will increase the frequency and the time of appearance of the tumours to which they are susceptible. Before claims for new occupational factors in human cancer can be considered, evidence of a significant increa~ in the tumour frequency over and above that found in a properly selected control population must be forthcoming.

Smoking. The influence of smoking on cancer of the lung has been studied by

Doll and Hill s 9 in Great Britain and Wynder and Graham ~~ in the U.S.A. Doll and Hill studied the smoking habits of 1,465 people with carcinoma of the lung and 1,465 control patients who were of the same age and sex distribution as the carcinoma group. They found fewer non-smokers among the male and female lung carcinoma patients than among the corresponding control patients (0.5% and 37.0% against 4.5% and 59.5%), and more heavy smokers, i.e., smoking 25 or more cigarettes per day, (25% and 13.4% against 11.1% and 0.9%). More- over, the proportion of lung carcinoma patients to control patients steadily increased as the amount of tobacco smoked increased. The pro- portion of pure pipe smokers (persons who have never regularly smoked cigarettes for as long as 1 year) was lower in the lung carcinoma group than in the control group. The proportion of men who had used a holder and who had smoked filter-tipped cigarettes was also lower in lung carcinoma series. (Holders used 5% against 11.6% and filter- tipped cigarettes 0.6% against 3.2%.) The difference between the two groups is significant, but it may only mean that these less common ways of smoking tobacco are associated with light smoking rather than that they are less likely to produce carcinoma of the lung.

AETIOLOGICAL FACTORS IN LUNG C A N C E R ~ A REVIEW 283

They conclude that the risk increases steadily with age and with the amount smoked so that the risk of dying with lung carcinoma at age 65-74 when smoking an average of more than 50 cigarettes a day is approximately 1% per annum and this is 33 times the risk for a non- smoker of the same age and 20 times the risk for a man smoking the same amount, but 40 years younger.

Wynder and Graham in their survey found no non-smokers among the cancer group while there was 41.1% non-smokers among the control group. 96.5% of these with cancer fell into the moderate heavy to chain smoker group and 51.2% were excessive and chain smokers, while among the patients without cancer 73.7.% and 19.1% fell among these smoking-groups respectively. They also observed that the influence of tobacco was much less on adenocarcinoma than on the other types of bronehogenic carcinoma. If we study the histological types of Doll and Hill 9 we see a confirmation of Wynder and Grahams' finding.

Squamous Oat cell and Adeno- Unclassified carcinoma anaplastic Ca. carcinoma

1,357 men 52% 33% 4% 11% 108 women 23% 48% 13% 16%

A further investigation into the problem of smoking was undertaken by Levin et al. ~8 who agree in substance with the main facts already outlined.

Atmospher ic Pollution. The reason why atmospheric pollution has been regarded as an aetiolo-

gical factor in lung cancer is that the mortality from lung cancer has been consistently lecorded as being higher in urban than in rural areas (Curwen et al. 4, Kreyberg~7.) The British workers also found that in rural areas the male mortality increased in proportion to the density of the population.

There are many factors suggesting that the explanation of the urban- rural difference is not as clear cut as it seems.

(1) The difference between urban and rural mortality is most marked in countries with little pollution--Norway 4 : lhwhereas in Britain the ratio between the male mortality in Greater London and that in the rural districts is slightly less than 2 : 1.

(2) The increase in the mortality in the urban areas seems to have affected the sexes differently, whereas general atmospheric pollution would be expected to affect them equally. In both Norway and Great Britain there has been a greater predominance of male cases in the urban areas with their high mortality than in the rural areas with their low mortality.

Other factors which may contribute to the higher incidence in urban communities are (1) better diagnostic methods, (2) the fact that people in these areas are inclined to smoke more heavily (Doll and Itill, 8 Kreyberg~6).

At the moment, therefore, in spite of intensive work on the subject, it is not possible to reach a definite conclusion as to whether atmospheric pollution can be regarded as a specific aetiological factor in the causa- tion of cancer of the lung.

28~ IRISH JOURNAL OF MEDICAL SCIENCE

C onr~lusions. We have seen from the previous discussion that the aetiological factors

in carcinoma of the lung have taken a definite pattern. We have the various occupations in which the workers are exposed to specific hazards, and where an accurate statistical survey of the mortality figures of people employed in the industry has given proof of the effect of the carcinogen concerned. The most important are nickel refining, mining of radio-active ores, asbestos manufacturing and the production of coal gas and monoehromates. The dangers of accepting single cases or small groups of cases as significant have been mentioned. The figures obtained from the surveys of the smoking population are also indis- putable and the danger, especially from cigarette smoking, is noted. The place of atmospheric pollution is less clear, although what small amount of evidence there is would seem to point to carcinogens in chimney smoke being more important than fumes from motor vehicles.

Other causes must also exist among which the influence of genetic differences must be considered and the possibility of the radio-activity present in the atmosphere. The part played by chronic lung damage and scarring also remains to he elucidated.

Ref erence~ . 1. Bidstrup, P. L. (1951). Br~. J . I ~ t r . Med., 8, 302. 2. Bidstrup, P. L., and Case, R. A. M. (1956). Ibid., 13, 260. 3. Bonser, G. M., Faulds, J. S., and Stewart, M. J . (1955). A m . J . Clan. Path., 25, 126. 4. Curwon, M. P., Kennaway, E. L. and Kennaway, N. M. (1954). Brit. J . Cancer, 8,

181. 5. Daft, M. E., Doll, R., and Kennaway, E. L. (1951). BriL J . Cancer, 5, 1. 6. Doll, R. (1955). BriL. J . I,td~tr. Med., 12, 81. 7. Doll, R. (1958). Ib/d., 15, 217. 8. Doll, R. and Hill, A. B. (1952). Br/$. ~ded. J . , ii, 1271. 9. DolI, R. andHill, A. B. (1954). Ibid., i, 1451.

10. Dungal, N. (1950). Zonc~, 259, 245. 11. Fried, B. M. (1935). Am. J . Can~r, 23, 247. 12. Homburger, F. (1943). Am. J . Pagh., 19, 797. 13. Hill, A. B., and Faning, E. L. (1948). Br~. J . Ind~,s~r. Med., 5, 2. 14. Kennaway, E. L. and Konnaway, N. M. (1947). Br/t. J . Oancer, i, 260. 15. Kreyberg, L. (1954). Brit. J. Cancer, 8, 199 and 599. 16. Kreyberg, L. (1955). Brit. J . Cancer, 9, 495. 17. Kreyberg, L. (1956). Br~. J . IDr~v. aoc. Med., 10, 145. 18. Levin, M. L., Goldstein, H. and Gerhardt, P. P. (1950). J , Am. reed. Assn., 143,

336. 19. Lore~z,E. (1944). J . Nat. Oa~.er Inet,., 5, 1. 20. Lynch, K. M. and Smyth, W. H. (1935). Am. J . C'a~u~er, 24, 56. 21. Machle, W. and Oregorius, F. (1948). P ~ I . HIO~. Rep., 63, 1114. 22. Robbins, E. and S i l v e r , G. (1949). Ga1~ ' , 2, 65. 23. Rosahn, P.D. (1940). Arch. Path., 29,649. 24. Smith, W. F. (1949). Oancer Rea., 9, 712. 25. Snegigeff, H. and Lombard, O. (1951). Arch. i~duat~. Hyg. ooculm Med., 4, 199. 26. Vorwald, A. J. and Karr, J . W. (1938). Ara. J . Path., 14, 49. 27. Woodruff, C. E. and Nahas, H. C. (1951). Am. Rev. Tuberc., 64, 620. 28. Woodruff, C. E., Sen-Gupta, N. C. e~ aL (1952). lb/d., 66, 151. 29. Wynder, E. L. and Graham, E. A. (1950). J . A . M . A . , 143, 329.

A c ~ . I wish to acknowledge the interest and advice of I~rofessor C. V. Harrison and Dr.

B. E. Heard. I also wish to thank Dr. T, S. McDonald for his help in the preparation of this paper.