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Environmental Causes of Cancer in Man
Environmental Causes of Cancer in Man ERNEST L. WYNDER, M.D. THE cause of cancer has puzzled man for generations. To our present knowledge there is no single cause. This does not deny the fact, however, that a large number of factors, both of extrinsic and intrinsic origin, may induce or promote cancer in man and the experimental animal. Cancer causes may be compared to a chain of links. The chain can be more readily joined if all the links are present, though it may be completed also in the absence of certain links. The stronger a given link, the more . necessary that link is for the completion of the chain. Similarly, many factors may be required for human cancer to develop. No presently known factor can be regarded as "the" cause of cancer, but only as "a" cause. It is the purpose of this communication to summarize these causes of cancer in man, bearing in mind the limitations of "cause" as just delineated, a subject recently well analyzed by Hammond. 1
History
It is of some interest that cancer research has received its initial impetus through observations based upon environmental factors that seemed to influence the development of cancer in man. It was in 1775 that Percival Pott observed a high incidence of scrotal cancer among chimney sweeps. Not until 100 years later were further observations made relating human cancer to the exposure to certain industrial agents. The outstanding examples are bladder cancer among aniline dye workers and skin cancer among fanners, sailors and coal tar workers. Later observations continued to be made in the field of industrial medicine, a subject well summarized by Hueper.2 Only relatively recently with the introduction of the lung cancer problem have environmental causes of cancer been studied from a broader point of view. Studies are now being conducted not only to detennine the incidence rates among certain groups or to discover isolated factors but to detennine the entire spectrum of the environmental pattern to which man is exposed. It was realized that only by such a complete program could it be detennined whether a given factor is of primary, secondary or no significance in the development of human cancer. From the Department of Preventive Medicine, Memorial Hospital; and the Section of Epidemiology, DiIliBion of Preventive Medicine, Sloan-K:ettering In.titute.
629
680
Ernesl L. W ynder CARCINOGENIC STIMULI
According to our elinical, statistical and experimental experience certain cell types, especially epithelial cells, rarely undergo malignant transformation in the absence of carcinogenic stimuli. These stimuli may be defined as substances, conditions or physical forces which have the ability to transform normal cells into neoplastic cells. These carcinogens or carcinogenic conditions may be extrinsic or intrinsic. Of these two the former are more clearly understood, a subject which has been reviewed by several writers recently.3-6 Along these lines, co-carcinogens are of course also of considerable importance. These include substances which, though they cannot initiate cancer, can promote cancer after a carcinogen has been applied to the tissue initially. Such co-carcinogens, although rather well documented experimentally, are not well established for man, although they most probably are significant in humans, too. Industrial Factors
Data relating industrial factors to human cancer are based essentially on statistics indicating a higher rate of certain cancers in given industrial groups. We have listed in Table 1 the major factors together with the site most commonly affected. 7 - 10 In most instances these factors contribute to only a relatively small number of cancer deaths. It cannot be said whether all of these factors are to be regarded as carcinogens per se or whether they function as co-carcinogens. For example, it may be argued that metal workers may have a higher rate of cancer of the lung because metal dust acts as a co-carcinogen to tobacco smoke. Before one can incriminate an agent as a carcinogen in man, other extrinsic factors must be ruled out in each particular case. Often the data linking industrial carcinogens to cancer in man are based upon but few cases, and other possible environmental factors have not been considered. This, however, is not to deny the importance of introducing preventive measures against these suspected industrial agents, because as long as they increase the risk of causing a given cancer it is of only academic importance whether they are carcinogenic or co-carcinogenic, since with their removal or reduction a decrease in a given cancer rate can be expected. The success of preventive medicine has been particularly well demonstrated in some dye factories where control of exposure to betanaphthylamine reduced the incidence of bladder cancer.ll The study of industrial factors is important not only for suggesting and promoting preventive measures but also for academic research in that it pinpoints substances that produce cancer in man and may thus elucidate cancer causation in man. Tobacco
Tobacco and its various products have long been suspected as a cause of cancer in man. The most extensive studies on this subject involve
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681
Table 1 BIOLOGIC 1;'ACTOHS AND
l'RJ<;VlcNTIVg MEASURJ<;S IN CANCER
SITE OF
SUSPgCTf;D 1,NVIRONMl;;NTAL
CANCER
CARCINom;NIC Am;NTS
Lung
Larynx, Hypopharynx Penis Cervix Bladder
Tobacco, * chromate, * radioactive dust, * arsenic, t lubricating oils, t isopropyl oils, t metal dust and fumes, t paint, t wood dust, t nickel, t asbestost Tobacco,* alcohol,* metal dusts and fumest Smegma or other agents under the foreskin * Smegma or other agents under the foreskin of the penis, * therapeutic estrogenst Beta-naphthylamine, * bilharziasis, * benzidinet
Oral cavity
Tobacco, * syphilis (tongue), * dietary deficiencies, * alcohol, t poor teeth,t oral sepsist
Esophagus
Tobacco, t alcohol, t dietary deficiencies, t thermal factors,t spices,t poor dental and oral hygienet
Stomach
Thermal factors,t spices,t alcohol,t tobaceo,t poor dental and oral hygiene,t dietary factorst Dietary deficiency, * alcohol,t bilharziasist
Liver Skin and lip
Ultraviolet light, * arsenic, * tars, * oils (mineral, shale and paraffin), * roentgen rays, * tobacco (pipe-lip) * anthracene, * asphalt, * pitch, * heatt
PREVENTIVE MEASURES
Moderation of smoking habits Research into possible carcinogenic agents in tobacco tars with the aim of reducing or removing them Industrial hygienic measures§ Moderation of smoking habits Avoidance of cxcessive alcohol consumption Circumcision in infancy Good genital hygiene Male circumcision and good penile hygiene Industrial hygienic measures§ Improvement of waterways and supplies Moderation of tobacco habits Early treatment of syphilis Improved diets (especially in vitamin B complexes, also iron for females) Moderation of tobacco habits Moderation in use of certain alcoholic beverages Improved diets as for oral cavity Present evidcnce too inconclusive to suggest definite prcventive measures Improved diets (especially in vitamin B complex and proteins) Limited exposure to sunlight, especially of susceptible persons Use of effective preventive ointments Industrial hygienic measurcs§ Cautious use of x-ray Moderation in pipe smoking
* Evidence is good. t Evidence is fair. t Factors suggested, but without particular evidence.
§ Industrial hygienic measures include instruction in hygiene, good washing facilities, protective clothing, daily change of work clothing, rotation of personnel, closed production systems, good ventilation and periodic medical examinations.
682
Ernest L. W ynder Table 1 (Continued) SITE OF CANCER
SUSPECTED ENVIRONMENTAL CARCINOGENIC AGENTS
Leukemia
Radiation, * benzol*
Thyroid gland
Dietary factors, * radiation, * positive goitrogenic agents, t radioactive iodinet
Breast
Milk factor,t therapeutic estrogenst
Endometrium
Therapeutic estrogens,t radiationt
PREVENTIVE MEASURES
Cautious use of and protection from x-rays Industrial hygienic measures§ Adequate supplements of iodine to diets, if insufficient Irradiation of thymus gland in the young (to be carried out with caution) Radioactive iodine (to be avoided under the age of 45) Present evidence too inconclusive to suggest definite preventive measures Cautious use of estrogens and of pelvic irradiation
*Evidence is good. tEvidence is fair. tFactors suggested, but without particular evidence. §Industrial hygienic measures include instruction in hygiene, good washing facilities, protective clothing, daily change of work clothing, rotation of personnel, closed production systems, good ventilation and periodic medical examinations.
cancer of the lung and are based on both prospective and retrospective epidemiologic studies. 12-16 Both types of studies clearly show the risk of smokers to be considerably greater than that of nonsmokers and demonstrate that this risk is increased with the amount of tobacco consumed. In Figure 85 we indicate this finding as shown from data collected at Memorial Center.16 Recent data by Hammond and Horn, based upon the prospective study approach, are shown in Figure 86. 17 The data obtained by these authors also indicate that the effect of smoking is largely independent of possible influences of air pollution (Fig. 87). Tobacco smoking is now regarded to be of causative significance in lung cancer for the following reasons: 1. Lung cancer has increased sharply throughout those countries where there has been a great increase in tobacco consumption, particularly in the form of cigarettes. Notably low rates, such as in Iceland, where there is a low consumption of tobacco, re-emphasize this point. 2. The predominant male ratio of lung cancer is compatible with the long-term smoking habits of the two sexes. 3. The gradual increase in smoking by women beginning some 20 years ago is compatible with a slight increase in the incidence of lung cancer among females.
Environmental Causes of Cancer in Man
688
4. The higher rate of lung cancer among urban as compared to the rural population is compatible with the greater cigarette consumption among city dwellers. 5. The characteristic peak of lung cancer among males in their late fifties and early sixties is, as pointed out by Clemmesen and Levin, compatible with the introduction of carcinogen some 30 to 35 years ago. This falls into the time period of the first major upswing in cigarette consumption.
2.0 If) ~ If)
a:
-• •
~
,g a:
1.0
.5
Smoking no. pe' day 1-15
35+
Fig. 85. Estimated relative risks of lung cancer patients compared to control groups for different smoking categories. (Wynder, E., Day, E. and Bross, 1.2 8)
6. Considering the latent period of cancer, the increase of lung cancer is compatible with the increase in the sale of cigarettes. While this factor by itself may mean little, in addition to the other factors listed it is important; in the absence of an increase in cigarette consumption, tobacco could not be regarded as a major factor in the development of lung cancer. 7. Epidermoid cancer, either in animals or in man, is but rarely found in areas not exposed to specific forms of extrinsic irritation. Recently, precancerous changes have been demonstrated in sectioned bronchi of heavy smokers by Auerbach. 18 8. The statistical tobacco data have been regarded as most significant by many of the clinicians who have seen many lung cancer patients and who have taken detailed histories. A history of smoking in lung cancer patients has served as a valuable aid in the differential diagnosis of lung conditions. 9. Condensed cigarette smoke has induced epidermoid Cancer of the skin in several strains of mice. 19 • 20 10. We can visualize no other plausible explanation for the statistical association found than that tobacco is also a causative factor in lung cancer.
Ernest L. W ynder CARCINOMA OF LUNG WELL ESTABLISHED DIAGNOSIS (Excluding Adenocorcinoma)
CURRENT CIGARETTE SMOKING AT TIME OF QUESTIONING
119.0
Ex-regular Cigarette Smokers
--
67.3 31.6
4.5
Never <.1 2 Smoked None Occasional Pock Regularly
t-I Pock
1-2 Pocks
2+ Pocks
Fig. 86. Age standardized male lung cancer death rates per 100,000 (age standardized to 1953 V.S. white male popUlation) based upon well established lung cancer deaths occurring from November 1, 1952 through October 31, 1954 by current amount of cigarette smoking at time of questioning. (Hammond, E. C. and Horn, D.l7)
CARCINOMA OF LUNG WELL ESTABLISHED DIAGNOSIS (Excluding Adenocarcinoma)
UA!Never Smoked Regularly •
5.6
~ City of 50,000+
City of 10,000-50,000
Cigarette
4.3
ruJJ
Suburb or Town
o Rural
Fig. 87. Age standardized male lung cancer death rates per 100,000 (age standardized to 1953 U.S. white male population) based upon well established lung cancer deaths occurring from November 1, 1952 through October 31, 1954 by smoking habits and by place of residence at time of questioning. (Hammond, E. C. and Horn, DY)
Environmental Causes of Cancer in M an
635
Tobacco has also been shown to be related to cancer of the entire oral cavity with the possible exception of cancer of the pharynx (Tables 1 and 2). These data also show smoking to be related to cancer of the esophagus. For cancer of the lip, pipe smoking seems to be a predominant factorY Tobacco chewing has been shown to be related to cancer of the oral cavity by Moore and others.22. 23 Wynder and Jacobsson have demonstrated a relation of snuff chewing to cancer of the buccal cavity and gingiva in Sweden. 24 These latter observations are of interest in that they Suggest a carcinogen in tobacco that does not require combustion in order to be active to man. Unlike the tobacco chewed in this country, the snuff Table 2 TOTAL PATIENTS DrSTRIBUT],D BY CLASS OF ILLNESS AND TYPE OF SMOKING (From Sadowsky, D. A., et al.)
Total patients Per cent who smoked Per cent who smoked cigarettest
LIP
TONGUE
OTHER ORAL CAVITY*
PHARYNX
ESOPHAGUS
ILLNESS OTHER THAN CANCER
571 91.9
132 94.7
348 92.8
85 89.4
104 96.2
615 86.8
65.5
62.9
54.0
76.5
77.9
72.5
* Comprises cancer of the floor and roof of mouth, gum, buccal mucosa, palate and tonsil. t Those who smoked cigarettes only, or cigarettes together with cigars and/or pipes.
chewed in Sweden does not include anything except tobacco. Swedish data show a close association between the location where the snuff is held and the occurrence of the cancer. A recent study showed smoking to be as closely related to laryngeal cancer as to cancer of the lung. 16 The exception was that cigar and pipe smoking are more closely associated with laryngeal cancer, particularly of the extrinsic type (hypopharynx), than to cancer of the lung. On the basis of statistical evidence indicating the greater risk of smokers developing cancer than nonsmokers, added to the present sex ratio of lung cancer and the increasing incidence as well as the geographic distribution of lung cancer, it may be said that between 80 and 90 per cent of all squamous and anaplastic lung cancer occurring in man today would not occur in the absence of smoking. In view of the fact that lung cancer represents the most common cause of cancer deaths among males in many western countries, the preventive measures required are of foremost importance.
Alcohol Heavy alcohol intake has been thought to be related to cancer of the tongue, esophagus and extrinsic larynx on the basis of observations of
Ernest L. Wynder
636
many clinicians and a few statistical data in which, however, control cases were not usually considered. 3 Only recently a retrospective study that was adequately controlled demonstrated a relationship of cancer of the larynx, particularly of the extrinsic type, to heavy whiskey consutnption 16 (Fig. 88). It is of interest to note that below 7 units of alcohol a day the relative risk of laryngeal cancer does not seem to be greater thEm for lighter drinking. (A unit of alcohol is defined as an ounce of whiskey, 4 ounces of wine or 8 ounces of beer.) Thus the risk from ESTIMATES OF RELATIVE RISKS OF LARYNX CANCER TO CONTROL GROUPS AMONG THOSE SMOKING FROM 16 TO 34 CIGARETTES /DAY
3.0 co .oc
.!!
a:
-• •
~
~
a:
1.0
Drinking per day
*Iftcludes those consuming varied types of alcohol. Fig. 88. The baseline group (risk at equal to one) is the other than 7 plus per day whiskey drinkers. (A unit of alcohol is defined as 1 ounce of whiskey, 4 ounces of wine, or 8 ounces of beer.) (Wynder, E., Day, E. and Bross, VS)
alcohol is different from that of tobacco where a proportionate risk of lung as well as laryngeal cancer has been noted for the lower amounts of tobacco consumed. The question as to whether alcohol acts as a promoter of cancer of the larynx or whether it can initiate it could best be answered if one could find heavy drinkers who did not smoke, a combination rarely encountered. At the present time we feel that heavy alcohol consumption functions primarily as a promoting rather than an initiating factor. Nutrition
Nutritional deficiencies have long been thought to play a role in the development of cancer of the liver. Since liver cancer is rather uncommon in the western world, its epidemiology has never been investigated with the same care as some of the more prominent cancer types. Recently, we completed a survey on cancer of the oral cavity and hypopharynx in Swedish women and found a close association of these cancer sites,
Environmental Causes of Cancer in Man
637
particularly that of the lower hypopharynx, to Plummer-Vinson's syndrome, a condition which we like to term nutritional dysphagia. 24 This disease, which represents a marked deficiency in iron and also possibly of vitamin C and vitamin B, can lead to an atrophy of the mucous membranes of the upper alimentary tract which predisposes to cancer in these areas. Patients with this type of dysphagia, mostly women, generally neither smoke nor drink. If treated early in life, the condition usually responds to adequate iron therapy. There is a suggestion that with an improvement in the dietary regimen, the nutritional dysphagia as well as the subsequent cancers are decreasing in incidence. Further laboratory studies are required to pinpoint possible nutritional factors other than iron in these patients. Diets deficient in iodine and those excessive in vegetables of the cabbage family, particularly those involving rutabaga, and to a lesser extent turnips, which contain an active antithyroid principle, appear to be related to goiter formation.26 In this connection it is of particular interest to note the Swiss data which suggest a decline of goiter as well as of thyroid cancer in the population groups after the introduction of iodized salt. 26 Smegma
It is well established that cancer of the penis is a rarity in circumcised males. Only two penile cancers have been reported in males circumcised at birth. 3 The factor suspected is a material collecting under the foreskin of unclean, uncircumcised males, consisting largely of smegma and its decomposition products. Whatever the suspected factor, it has been amply demonstrated that even if males have been circumcised in early youth rather than at birth, provided this occurs prior to the age of 14, penile cancer is not likely to occurY More recently, studies have demonstrated that circumcision and thus in all probability a factor relating to smegma may also reduce the incidence of cancer of the cervix. 28 Cancer of the cervix is significantly less common among groups that practice circumcision and good penile hygiene. With all other variables standardized, circumcision as such was shown to affect independently the rate of cervical cancer (Fig. 89). As stated, one can only suppose that the actual cause is a factor such as smegma which accumulates under the foreskin of uncircumcised unclean males.
Sunlight
As early as 1894 Unna recognized that exposure to sunlight was related to cancer of the skin. This observation was based upon the fact that this cancer occurred most commonly in persons much exposed to the sun and particularly in areas exposed to solar radiation. Later work, especially that by Blum, has extended the original and correct observation of
Ernest L. Wynder
638
Unna. 29 It has been well demonstrated that the rate of skin cancer rises in direct proportion to the amount of sunlight present in given geographic areas. Radiation
Radiation is one of the well established carcinogenic agents in man. This subject has been discussed more fully in this volume by Nickson. Carcinoma types that seem to be particularly prone to develop following radiation include leukemia, osteogenic sarcomas and cancer of the skin. 100
_
Cervical cancer
~ Control
group
c
.2 ; :I
..g.::: .!!!
o
cQ) ~
Q)
0.
Non-Jewish,White
Negro
Jewish
Circumcised Partner On Iy Fig. 89. Percentage of cervix cancer and control groups at American hospitals exposed to only a circumcised sexual partner. (Wynder, E., Cornfield, J., Shroff, P. D. and Doraiswami, K. R.28)
Miscellaneous Factors
Trauma. Much has been written about repeated injury as a possible cause of cancer. In particular, injury has been thought to play a role in the development of cancer of the breast. 3o Considering, however, that a patient with breast cancer is more likely to recall an injury to that breast than a patient without a breast lesion, we do not think, in agreement with Stewart, that satisfactory evidence exists that injury may initiate cancer of the breast or for that matter any other cancer in man. 3! Definite evidence is equally lacking that repeated trauma, such as the possible irritation from ill-fitting dentures, can initiate human cancer. Air Pollution. Because of the higher rate of lung cancer in urban areas, air pollution has been considered to be a factor in the development of lung cancer. Studies by Doll and Hill as well as by Hammond and
Environmental Causes of Cancer in Man
639
Horn have suggested, however, that the major part, if not all, of the excess of lung cancer found in cities can be explained by the fact that city populations are heavier consumers of cigarettesP· 24 Recently Stocks and Campbell have found that in Liverpool, England, the rate of lung cancer is higher in nonsmokers and in different groups of smokers than in corresponding groups in rural areas. 33 They suggested that, in the rural areas studied, nearly all of the lung cancer cases were due to smoking whereas in Liverpool half were due to smoking and threefourths of the other half were due to some other factor which they suggested might be benzpyrene in the city air. This study, however, did not give results on occupations which, rather than city air, might have accounted for the higher rate of lung cancer in Liverpool. These authors will present further data subsequently, and we must await these findings before final evaluation of the result. Similar studies should also be done in other cities because Liverpool may have certain peculiarities of air pollution not found elsewhere. Stocks and Camp bell suggest from their preliminary review that the benzpyrene in the air added to the benzpyrene obtained from cigarette smoke is responsible for the higher rate of lung cancer in Liverpool as compared with that of rural areas. Syphilis. Studies on cancer of the tongue show that in lesions affecting the anterior two-thirds of the tongue a history of syphilis is encountered more frequently than in the general population. Martin found histories of syphilis in 33 per cent of his tongue cancer group as compared with 14 per cent among controls.34 It remains to be determined, however, whether syphilitic glossitis acts as a co-factor to a carcinogen such as tobacco or whether this glossitis can initiate cancer itself. Pregnancy. Pregnancy has been long suspected to be a factor in the development of cancer of the cervix. This belief was based upon the fact that patients with cancer of the cervix have a higher pregnancy rate than control groups studied. This assumption is based upon a statistical fallacy. Though it is true that patients with cancer of the cervix have more children than the general population, this fact is a consequence only of the earlier marriage and economic status of the patients with cancer of the cervix. 28 Matching patients with cancer of the cervix and control groups in reepect to economic status and age of first marriage, indicates that there is no difference in the pregnancy rate at all (Fig. 90). This point emphasizes how important it is to make careful statistical evaluations of environmental cancer data before attributing causative significance to any given factor. Along these same lines, it is possible that the apparent lower pregnancy rate of patients with cancer of the breast is a result of later marriage among these patients rather than the lesser degree of fertility found among these patients. Bacteria and Parasites. In the older literature various types of bacteria,
Ernest L. Wynder particularly the tuberculosis bacillus, as well as parasites were considered capable of initiating cancer in man. However, there appears to be little confirmation for these data today with the possible exception of the relationship of schistosomiasis to cancer of the bladder. Most workers in this field from Egypt believe that this parasite accounts for the high rate of bladder cancer in their country, although this is doubted by Afifi. 35 . 36 Properly controlled environmental studies in this respect are still Jacking. Schistosomiasis has also been considered to be a cause of cancer of the liver.37
L\1 CERVIX CANCER GROUP • CONTROL GROUP
3333 (/)
w
(/)
~ ~ 20 ~
o
o
I to 2
3 to 4
5 to 6
7 to 8
9+
NUM8ER OF PREGNANCIES Fig. 90. Pregnancy rate of cervix cancer and control groups for white non-Jewish women standardized to age of first marriage. (Wynder, E., Cornfield, J., Shroff, P. D. ap.d Doraiswami, K. R.28)
Human Milk. For the sake of completeness, reference must be made to the milk factor which, because of its established significance in the development of cancer of the breast in mice, had been considered as of possible importance in the development of breast cancer in man. However, two studies on this question did not show that breast cancer patient~ we:('e. fed by their mothers to any greater extent than were members of control groupS.3S. 39 Hormones. The excessive use of hormones, particularly of estrogens, has been suspected of initiating or promoting cancers that arise in organs affected by hormones, such as the breast, the uterine fundus and the prostate.40-42 Though there are a number of reports in the literature suggesting that a few cancer cases involving these sites may have been initiated or promoted by an excessive use of hormones, it is the current belief of cancer researchers that the use of hormones is not likely to initiate can~r in these sites, though it may well promote it. Betel Nut Chewing. Data from India clearly associate cancer of the oral cavity and hypopharynx with the habit of betel nut chewing. 43
Environmental Causes of Cancer in Man
641
The betel nut quid consists of betel nuts and leaves, shell lime, catechu, and in most cases also tobacco. It remains to be established whether tobacco is a necessary ingredient of the quid in order for this quid to be carcinogenic to man. Heat. Though heat has been suspected to be a carcinogenic element to man, there is no satisfactory evidence to prove this. It appears true that members of a certain group in India that carry heated coals in contact with their abdomens apparently have a higher than expected rate of cancer of the skin in this area. 44 However, it cannot be determined whether it is the heat or the material combusted from the coals themselves that initiate these skin cancers. It is also possible that scars resulting from burning may promote skin cancers in these cases. 45 Anhnal Experimentation
So far in this report we have not referred to animal data. The reason for this is that we believe that no animal data can be used to establish a causative role in cancer in man. Such proof can come only from hunian epidemiologic data. If animal experimentation confirms a carcinogen previously suspected also to be carcinogenic to man, confirmative evidence is then at hand; but animal evidence by itself can never establish a human carcinogen nor can it ever disprove it. Animal experimentation has its greatest importance in this field in that it may elucidate the mechanism through which a carcinogen works in man and it may permit us to identify the specific carcinogens out of a group of suspected substances to which man has been exposed. For example, if we suspect tobacco as a carcinogen to man, animal experimentation can determine the specific parts of tobacco which are carcinogenic to animals. Once identified, we can only assume that these specific carcinogens are the same to which man also responds and introduce preventive measures accordingly. Epidemiologic Research
Preventive measures have long been the desired goal of medical research. These have been well established for infectious diseases. It is our belief that they are of similar value for cancer. Through epidemiologic techniques, using the retrospective as well as the prospective approach, it has been repeatedly shown that the greater the exposure to certain specific environmental factors, the greater the risk of developing certain types of cancer. Though these factors may not be the only ones responsible for the induction of these cancers, in their absence the cancer incidence is greatly reduced. As stated, a variety of factors may initiate cancer and as such are regarded as carcinogens. It may be desirable to define postulates which must be met by a given agent to be regarded as carcinogenic to man. Four such postulates are presented in Table 3. As an example we shall
Ernest L. Wynder measure the consistency of the factors of smoking and lung cancer as based on these postulates. Postulate 1. The data on relative risk for lung cancer show a proportionate increase with increasing amounts of tobacco smoked. Thus cigarette smoking complies with Postulate 1 (Figs. 85, 86). Postulate 2. The tobacco data are compatible with the sex ratio of lung cancer because of the longer duration and heavier consumption found in the smoking habits of men. They are consistent with the fact that. lung cancer occurs more commonly among men living in cities than in rural areas since men in cities are heavier cigarette smokers than those living in rural areas. The data are compatible with the fact that in those countries where tobacco consumption is low, lung cancer is uncommon. The data thus are consistent with Postulate 2. Table 3 POSTULATES FOR HUMAN CARCINOGENS
1. The relative risk must rise in proportion to the degree of exposure. 2. Rates among specific population groups must be consistent with the distribution of the agent. 3. Withdrawal, reduction or modification of the agent in a population group must be followed by a decrease in incidence of a given cancer after a suitable latent period. 4. The agent should be shown to be carcinogenic to some animal species (not obligatory).
Postulate 3. The effect of a withdrawal, reduction or modification of an agent in the environment of a population group must, of course, await such action before this postulate can be evaluated. However preliminary data published by Hammond and Horn on ex-smokers seem to suggest that in them the risk of lung cancer is less than in those men who continue to smoke (Fig. 86). Postulate 4. Condensed cigarette smoke has induced cancer of the skin in at least three different strains of mice. The postulate referring to experimental data is not obligatory. Though it has been demonstrated that tobacco is carcinogenic to mice, the ultimate proof as to whether a given agent can induce cancer in man can, as prevously stated, rest only on epidemiologic data. If epidemiologic data are derived under carefully controlled conditions by an experienced team of clinicians, statisticians and interviewers, such data are just as scientific as any laboratory study and represent the only way in which to establish cause and effect relationships between an agent and human cancer. If found statistically significant, the variables must also meet the first two postulates outlined in order to be also of causative significance. It may be argued that the final proof lies in the fulfillment of the third postulate. Unfortunately, the third postulate can-
Environmental Causes of Cancer in M an not be evaluated until after action is taken. Such aetion seems mandatory on the basis of the first two postulates. Summation
In the preceding paragraphs, we have listed environmental factors which are believed to play a role in the development of cancer in man (Table 1). In previous years most of the suspected environmental factors were of an industrial nature. Though affecting a considerable number of workers, they did not arouse the interest of the general public who were not directly associated with these substances. However, since more recent epidemiologic surveys have indicated that such general materials as tobacco could affect the rate of cancer in man, epidemiologic research and preventive measures that are derived therefrom have gained much attention from public and researchers alike. Were we to consider the tobacco type cancers alone, that is those involving the lung, the oral cavity, the larynx and the esophagus, we would recognize at once that at least as far as males are concerned we arc confronted with a large proportion of cancer deaths. If we add to this number the types of cancers that seem to be related to smegma, to nutritional deficiencies, to radiation, and to various industrial agents, we are dealing with a large proportion of all cancers occurring in man. Further research may show other environmental causes that we as yet do not suspect. Studies in environmental cancer research have proved most valuable and will continue to do so. These investigations may not only help to uncover the mechanism by means of which cancers develop in man, but they will present us with tools that may enable us to curtail, if not to prevent, some of the cancers that are today fatal to man. It is our belief that the application of the principles of preventive medicine will do for the field of cancer what they have so successfully done in the past for other branches of medicine. CONCLUSIONS
1. Environmental factors play a significant role in the production of many types of human cancer. 2. Only by studying all possible environmental factors for a given cancer can it be determined which factors are of primary, secondary or no etiologic significance. 3. If clinical, statistical relationships established for a factor and a given cancer are consistent with the geographic and incidence pattern of this cancer, a cause and effect relationship of these two factors may be regarded as proved. 4. Proof of such a cause and effect relationship depends upon epidemiologic data rather than upon animal experimentation. 5. Epidemiologic research has added and will continue to contribute
644
Ernest L. Wynder
to our understanding of the causation of cancer in man. At the same time it will propose preventive measures which if followed may lead to the curtailment of many types of human cancer. Along these lines lies the primary goal of epidemiologic research in the field of cancer. REFERENCES 1. Hammond, E. C.: Cause and Effect. Chapter 7 in Wynder, E. L. (ed.): Biologic Effects of Tobacco. Boston, Little, Brown & Co., 1955.
2. Hueper, W. C.: Occupational Tumors and Allied Diseases, 896 pp. Springfield, Ill., Charles C Thomas, 1942. 3. Wynder, E. L.: Some Practical Aspects of Cancer Prevention. New England J. Med. 246: 492-503 (March 27); 538-546 (April 3); 573-582 (April 10) 1952. 4. Hueper, W. C.: Environmental and Occupational Cancer. Pub. Health Rep., Supp. 209, 1948. 5. Lombard, H. L.: Statistical Studies in Cancer. In Homburger, F., and Fishman, W. H.: The Physiopathology of Cancer. New York, Paul B. Hoeber, Inc., 1953, pp. 778-812. 6. Druckrey, H.: Aetiologie und Prophylaxe des Krebses. Strahlentherapie 93: 165180,1954. 7. Lynch, K. M. and Smith, W. A.: Pulmonary Asbestosis: Carcinoma of Lung in Asbestos-Silicosis. Am. J. Cancer 24: 56-64, 1935. 8. Sikl, H.: Present Status of Knowledge about Jachymov Disease. Acta Uoio Internat. contra Cancrum 6: 1366-1375, 1950. 9. Machle, W. and Gregorius, F.: Cancer of Respiratory System in United States Chromate-Producing Industry. Pub. Health Rcp. 63: 1114-1127, 1948. 10. Neubauer, 0.: Arsenical Cancer: Review. Brit. J. Cancer 1: 192-251, 1947. 11. Maguigan, W. H.: Occupational Bladder Tumors. Acta Unio Internat. contra Cancrum 6: 1359-1367, 1950. 12. Wynder, E. L. and Graham, E. A.: Tobacco Smoking as Possible Etiologic Factor in Bronchiogenic Carcinoma: A Study of Six Hundred and Eightyfour Proved Cases. J.A.M.A. 143: 329-336 (May 27) 1950. 13. Doll, R. and Hill, A. B.: A Study of the Etiology of Carcinoma of the Lung. Brit. M. J. 2: 1271-1286 (Dec. 13) 1952. 14. Hammond, E. C. and Horn, D.: Relationship Between Human Smoking Habits and Death Rate. J.A.M.A. 155: 1316-1328 (Aug. 7) 1954. 15. Doll, R. and Hill, A. B.: Mortality of Doctors in Relation to Their Smoking Habits. Brit. M. J. 1: 1451-1455 (June 26) 1954. 16. Wynder, E. L., Bross, I. J. and Day, E.: A Study of Environmental Factors in Cancer of the Larynx. Cancer 9: 86-110, 1956. 17. Hammond, E. C. and Horn, D.: Bronchiogenic Carcinoma, Death Rates in Relation to Smoking Habits. J.A.M.A. (in press). 18. Auerbach, O. and others: Anatomic Approach to Study of Smoking and Bronchiogenic Carcinoma. A Preliminary Report of 41 Cases. Cancer 9: 76-83, 1956. 19. Wynder, E. L., Graham, E. A. and Croninger, A. B.: Experimental Production of Carcinoma with Cigarette Tar. Cancer Research 13: 855-864 (Dec.) 1953. 20. Wynder, E. L., Graham, E. A. and Croninger, A. B.: Experimental Production of Carcinoma with Cigarette Tal'. n. Tests with Different Mouse Strains. Cancer Research 15: 445-448 (Aug.) 1955. 21. Levin, M. L., Goldstein, H. and Gerhardt, P. R.: Cancer and Tobacco Smoking: A Preliminary Report. J.A.M.A. 143: 336-338 (May 27) 1950. 22. Moore, G. E., Bissinger, L. L. and Proehl, E. C.: Intraoral Cancer and Use of Chewing Tobacco. J. Am. Geriat. Soc. 1: 497-506, 1953. 23. Friedell, H. L. and Rosenthal, L. M.: Etiologic Role of Chewing Tobacco in Cancer of Mouth. J.A.M.A. 116: 2130-2135, 1941. 24. Wynder, E. L. and Jacobsson, F.: Unpublished data. 25. Greer, M. A.: Nutrition and Goiter. Physiol. Rev. 30: 513-548, 1950.
Environmental Causes of Cancer in Man
645
26. Wespi, H. J. and Eggenberger, H. U.: Personal communication. 27. Kennaway, E. J.: Cancer of Penis and Circumcision in Relation to Incubation Period of Cancer. Brit. J. Cancer 1: 335-344, 1947. 28. Wynder, E. L., Cornfield, J., Shroff, P. D. and Doraiswami, K. R.: A Study of Environmental Factors in Carcinoma of Cervix. Am. J. Obst. & Gynec. 68: 1016-1052, 1954. 29. Blum, H. F.: Sunlight as Causal Factor in Cancer of Skin of Man. J. N at. Cancer Inst. 9: 247-258, 1948. 30. Lane-Claypon, J. E.: A Further Report on Cancer of Breast with Special Reference to Its Associated Antecedent Conditions. Ministry of Health, Reports on Public Health and Medical Subjects 32. London, His Majesty's Stationery Office, 1926. 31. Stewart, F. W.: Occupational and Post-traumatic Cancer. Bull. New York Acad. Med. 23: 145-162 (March) 1947. 32. Doll, R.: Mortality from Lung Cancer Among Non-smokers. Brit. J. Cancer 7: 303-312 (Sept.) 1953. 33. Stocks, P. and Campbell, J. M.: Lung Cancer Death Rates among Non-smokers and Pipe and Cigarette Smokers. Brit. M. J. 2: 923-929 (Oct. 15) 1955. 34. Martin, H. E., Munster, H. and Sugarbaker, E. D.: Cancer of Tongue. Arch. Surg. 41:888-936,1940. 35. Dolbey, R. V. and Mooro, A. W.: Incidence of Cancer in Egypt. Lancet 1: 587590,1924. 36. Afifi, M. A.: Cancer Mortality in Egypt. Cancer Research 7: 537-546, 1947. 37. Katata, B.: Geographical Statistics of Malignant Tumors in Yamanashi Prefecture and Relation between Cancer and Schistosomiasis Japonica. Verhand!. d. Japanischen Path. Gesellsch. 16: 271-278, 1926. 38. Adair, F. E.: Surgical Problems Involved in Breast Cancer. Ann. Roy. Co!. Surg. 4: 360-380, 1949. 39. Horne, H. W. Jr.: "Milk Factor" in Carcinoma of Human Breast; Analysis of 88 Cases. New England J. Med. 243: 373-375, 1950. 40. Auchincloss, H. and HaagenseD, C. D.: Cancer of Breast Possibly Induced by Estrogenic Substance. J.A.M.A. 114: 1517-1523, 1940. 41. Fremont-Smith, M., Meigs, J. V., Graham, R. M. and Gilbert, H. H.: Cancer of Endometrium and Prolonged Estrogen Therapy. J.A.M.A. 131: 805-808, 1946. 42. Abramson, W. and Warshawsky, H.: Cancer of Breast in Male, Secondary to Estrogenic Administration: Report of Case. J. Uro!. 59: 76-82, 1948. 43. Sanghvi, L. D., Rao, K. C. M. and Khanolkar, V. R.: Smoking and Chewing of Tobacco in Relation to Cancer of Upper Alimentary Tract. Brit. M. J. 1: 1111 (May) 1955. 44. Smith, W. E., Sunderland, D. A. and Sugiura, K.: Experimental Analysis of Carcinogenic Activity of Certain Petroleum Products. Arch. Indust. Hyg. & Occup. Med. 4: 299-314, 1951. 45. Schrek, R.: Cutaneous Carcinoma: Statistical Analysis with Respect to Site, Sex and Pre-existing Scars. Arch. Path. 31: 434-448, 1941.
History
It is of some interest that cancer research has received its initial impetus through observations based upon environmental factors that seemed to influence the development of cancer in man. It was in 1775 that Percival Pott observed a high incidence of scrotal cancer among chimney sweeps. Not until 100 years later were further observations made relating human cancer to the exposure to certain industrial agents. The outstanding examples are bladder cancer among aniline dye workers and skin cancer among fanners, sailors and coal tar workers. Later observations continued to be made in the field of industrial medicine, a subject well summarized by Hueper.2 Only relatively recently with the introduction of the lung cancer problem have environmental causes of cancer been studied from a broader point of view. Studies are now being conducted not only to detennine the incidence rates among certain groups or to discover isolated factors but to detennine the entire spectrum of the environmental pattern to which man is exposed. It was realized that only by such a complete program could it be detennined whether a given factor is of primary, secondary or no significance in the development of human cancer. From the Department of Preventive Medicine, Memorial Hospital; and the Section of Epidemiology, DiIliBion of Preventive Medicine, Sloan-K:ettering In.titute.
629
680
Ernesl L. W ynder CARCINOGENIC STIMULI
According to our elinical, statistical and experimental experience certain cell types, especially epithelial cells, rarely undergo malignant transformation in the absence of carcinogenic stimuli. These stimuli may be defined as substances, conditions or physical forces which have the ability to transform normal cells into neoplastic cells. These carcinogens or carcinogenic conditions may be extrinsic or intrinsic. Of these two the former are more clearly understood, a subject which has been reviewed by several writers recently.3-6 Along these lines, co-carcinogens are of course also of considerable importance. These include substances which, though they cannot initiate cancer, can promote cancer after a carcinogen has been applied to the tissue initially. Such co-carcinogens, although rather well documented experimentally, are not well established for man, although they most probably are significant in humans, too. Industrial Factors
Data relating industrial factors to human cancer are based essentially on statistics indicating a higher rate of certain cancers in given industrial groups. We have listed in Table 1 the major factors together with the site most commonly affected. 7 - 10 In most instances these factors contribute to only a relatively small number of cancer deaths. It cannot be said whether all of these factors are to be regarded as carcinogens per se or whether they function as co-carcinogens. For example, it may be argued that metal workers may have a higher rate of cancer of the lung because metal dust acts as a co-carcinogen to tobacco smoke. Before one can incriminate an agent as a carcinogen in man, other extrinsic factors must be ruled out in each particular case. Often the data linking industrial carcinogens to cancer in man are based upon but few cases, and other possible environmental factors have not been considered. This, however, is not to deny the importance of introducing preventive measures against these suspected industrial agents, because as long as they increase the risk of causing a given cancer it is of only academic importance whether they are carcinogenic or co-carcinogenic, since with their removal or reduction a decrease in a given cancer rate can be expected. The success of preventive medicine has been particularly well demonstrated in some dye factories where control of exposure to betanaphthylamine reduced the incidence of bladder cancer.ll The study of industrial factors is important not only for suggesting and promoting preventive measures but also for academic research in that it pinpoints substances that produce cancer in man and may thus elucidate cancer causation in man. Tobacco
Tobacco and its various products have long been suspected as a cause of cancer in man. The most extensive studies on this subject involve
Environmental Causes of Cancer £n 1J1an
681
Table 1 BIOLOGIC 1;'ACTOHS AND
l'RJ<;VlcNTIVg MEASURJ<;S IN CANCER
SITE OF
SUSPgCTf;D 1,NVIRONMl;;NTAL
CANCER
CARCINom;NIC Am;NTS
Lung
Larynx, Hypopharynx Penis Cervix Bladder
Tobacco, * chromate, * radioactive dust, * arsenic, t lubricating oils, t isopropyl oils, t metal dust and fumes, t paint, t wood dust, t nickel, t asbestost Tobacco,* alcohol,* metal dusts and fumest Smegma or other agents under the foreskin * Smegma or other agents under the foreskin of the penis, * therapeutic estrogenst Beta-naphthylamine, * bilharziasis, * benzidinet
Oral cavity
Tobacco, * syphilis (tongue), * dietary deficiencies, * alcohol, t poor teeth,t oral sepsist
Esophagus
Tobacco, t alcohol, t dietary deficiencies, t thermal factors,t spices,t poor dental and oral hygienet
Stomach
Thermal factors,t spices,t alcohol,t tobaceo,t poor dental and oral hygiene,t dietary factorst Dietary deficiency, * alcohol,t bilharziasist
Liver Skin and lip
Ultraviolet light, * arsenic, * tars, * oils (mineral, shale and paraffin), * roentgen rays, * tobacco (pipe-lip) * anthracene, * asphalt, * pitch, * heatt
PREVENTIVE MEASURES
Moderation of smoking habits Research into possible carcinogenic agents in tobacco tars with the aim of reducing or removing them Industrial hygienic measures§ Moderation of smoking habits Avoidance of cxcessive alcohol consumption Circumcision in infancy Good genital hygiene Male circumcision and good penile hygiene Industrial hygienic measures§ Improvement of waterways and supplies Moderation of tobacco habits Early treatment of syphilis Improved diets (especially in vitamin B complexes, also iron for females) Moderation of tobacco habits Moderation in use of certain alcoholic beverages Improved diets as for oral cavity Present evidcnce too inconclusive to suggest definite prcventive measures Improved diets (especially in vitamin B complex and proteins) Limited exposure to sunlight, especially of susceptible persons Use of effective preventive ointments Industrial hygienic measurcs§ Cautious use of x-ray Moderation in pipe smoking
* Evidence is good. t Evidence is fair. t Factors suggested, but without particular evidence.
§ Industrial hygienic measures include instruction in hygiene, good washing facilities, protective clothing, daily change of work clothing, rotation of personnel, closed production systems, good ventilation and periodic medical examinations.
682
Ernest L. W ynder Table 1 (Continued) SITE OF CANCER
SUSPECTED ENVIRONMENTAL CARCINOGENIC AGENTS
Leukemia
Radiation, * benzol*
Thyroid gland
Dietary factors, * radiation, * positive goitrogenic agents, t radioactive iodinet
Breast
Milk factor,t therapeutic estrogenst
Endometrium
Therapeutic estrogens,t radiationt
PREVENTIVE MEASURES
Cautious use of and protection from x-rays Industrial hygienic measures§ Adequate supplements of iodine to diets, if insufficient Irradiation of thymus gland in the young (to be carried out with caution) Radioactive iodine (to be avoided under the age of 45) Present evidence too inconclusive to suggest definite preventive measures Cautious use of estrogens and of pelvic irradiation
*Evidence is good. tEvidence is fair. tFactors suggested, but without particular evidence. §Industrial hygienic measures include instruction in hygiene, good washing facilities, protective clothing, daily change of work clothing, rotation of personnel, closed production systems, good ventilation and periodic medical examinations.
cancer of the lung and are based on both prospective and retrospective epidemiologic studies. 12-16 Both types of studies clearly show the risk of smokers to be considerably greater than that of nonsmokers and demonstrate that this risk is increased with the amount of tobacco consumed. In Figure 85 we indicate this finding as shown from data collected at Memorial Center.16 Recent data by Hammond and Horn, based upon the prospective study approach, are shown in Figure 86. 17 The data obtained by these authors also indicate that the effect of smoking is largely independent of possible influences of air pollution (Fig. 87). Tobacco smoking is now regarded to be of causative significance in lung cancer for the following reasons: 1. Lung cancer has increased sharply throughout those countries where there has been a great increase in tobacco consumption, particularly in the form of cigarettes. Notably low rates, such as in Iceland, where there is a low consumption of tobacco, re-emphasize this point. 2. The predominant male ratio of lung cancer is compatible with the long-term smoking habits of the two sexes. 3. The gradual increase in smoking by women beginning some 20 years ago is compatible with a slight increase in the incidence of lung cancer among females.
Environmental Causes of Cancer in Man
688
4. The higher rate of lung cancer among urban as compared to the rural population is compatible with the greater cigarette consumption among city dwellers. 5. The characteristic peak of lung cancer among males in their late fifties and early sixties is, as pointed out by Clemmesen and Levin, compatible with the introduction of carcinogen some 30 to 35 years ago. This falls into the time period of the first major upswing in cigarette consumption.
2.0 If) ~ If)
a:
-• •
~
,g a:
1.0
.5
Smoking no. pe' day 1-15
35+
Fig. 85. Estimated relative risks of lung cancer patients compared to control groups for different smoking categories. (Wynder, E., Day, E. and Bross, 1.2 8)
6. Considering the latent period of cancer, the increase of lung cancer is compatible with the increase in the sale of cigarettes. While this factor by itself may mean little, in addition to the other factors listed it is important; in the absence of an increase in cigarette consumption, tobacco could not be regarded as a major factor in the development of lung cancer. 7. Epidermoid cancer, either in animals or in man, is but rarely found in areas not exposed to specific forms of extrinsic irritation. Recently, precancerous changes have been demonstrated in sectioned bronchi of heavy smokers by Auerbach. 18 8. The statistical tobacco data have been regarded as most significant by many of the clinicians who have seen many lung cancer patients and who have taken detailed histories. A history of smoking in lung cancer patients has served as a valuable aid in the differential diagnosis of lung conditions. 9. Condensed cigarette smoke has induced epidermoid Cancer of the skin in several strains of mice. 19 • 20 10. We can visualize no other plausible explanation for the statistical association found than that tobacco is also a causative factor in lung cancer.
Ernest L. W ynder CARCINOMA OF LUNG WELL ESTABLISHED DIAGNOSIS (Excluding Adenocorcinoma)
CURRENT CIGARETTE SMOKING AT TIME OF QUESTIONING
119.0
Ex-regular Cigarette Smokers
--
67.3 31.6
4.5
Never <.1 2 Smoked None Occasional Pock Regularly
t-I Pock
1-2 Pocks
2+ Pocks
Fig. 86. Age standardized male lung cancer death rates per 100,000 (age standardized to 1953 V.S. white male popUlation) based upon well established lung cancer deaths occurring from November 1, 1952 through October 31, 1954 by current amount of cigarette smoking at time of questioning. (Hammond, E. C. and Horn, D.l7)
CARCINOMA OF LUNG WELL ESTABLISHED DIAGNOSIS (Excluding Adenocarcinoma)
UA!Never Smoked Regularly •
5.6
~ City of 50,000+
City of 10,000-50,000
Cigarette
4.3
ruJJ
Suburb or Town
o Rural
Fig. 87. Age standardized male lung cancer death rates per 100,000 (age standardized to 1953 U.S. white male population) based upon well established lung cancer deaths occurring from November 1, 1952 through October 31, 1954 by smoking habits and by place of residence at time of questioning. (Hammond, E. C. and Horn, DY)
Environmental Causes of Cancer in M an
635
Tobacco has also been shown to be related to cancer of the entire oral cavity with the possible exception of cancer of the pharynx (Tables 1 and 2). These data also show smoking to be related to cancer of the esophagus. For cancer of the lip, pipe smoking seems to be a predominant factorY Tobacco chewing has been shown to be related to cancer of the oral cavity by Moore and others.22. 23 Wynder and Jacobsson have demonstrated a relation of snuff chewing to cancer of the buccal cavity and gingiva in Sweden. 24 These latter observations are of interest in that they Suggest a carcinogen in tobacco that does not require combustion in order to be active to man. Unlike the tobacco chewed in this country, the snuff Table 2 TOTAL PATIENTS DrSTRIBUT],D BY CLASS OF ILLNESS AND TYPE OF SMOKING (From Sadowsky, D. A., et al.)
Total patients Per cent who smoked Per cent who smoked cigarettest
LIP
TONGUE
OTHER ORAL CAVITY*
PHARYNX
ESOPHAGUS
ILLNESS OTHER THAN CANCER
571 91.9
132 94.7
348 92.8
85 89.4
104 96.2
615 86.8
65.5
62.9
54.0
76.5
77.9
72.5
* Comprises cancer of the floor and roof of mouth, gum, buccal mucosa, palate and tonsil. t Those who smoked cigarettes only, or cigarettes together with cigars and/or pipes.
chewed in Sweden does not include anything except tobacco. Swedish data show a close association between the location where the snuff is held and the occurrence of the cancer. A recent study showed smoking to be as closely related to laryngeal cancer as to cancer of the lung. 16 The exception was that cigar and pipe smoking are more closely associated with laryngeal cancer, particularly of the extrinsic type (hypopharynx), than to cancer of the lung. On the basis of statistical evidence indicating the greater risk of smokers developing cancer than nonsmokers, added to the present sex ratio of lung cancer and the increasing incidence as well as the geographic distribution of lung cancer, it may be said that between 80 and 90 per cent of all squamous and anaplastic lung cancer occurring in man today would not occur in the absence of smoking. In view of the fact that lung cancer represents the most common cause of cancer deaths among males in many western countries, the preventive measures required are of foremost importance.
Alcohol Heavy alcohol intake has been thought to be related to cancer of the tongue, esophagus and extrinsic larynx on the basis of observations of
Ernest L. Wynder
636
many clinicians and a few statistical data in which, however, control cases were not usually considered. 3 Only recently a retrospective study that was adequately controlled demonstrated a relationship of cancer of the larynx, particularly of the extrinsic type, to heavy whiskey consutnption 16 (Fig. 88). It is of interest to note that below 7 units of alcohol a day the relative risk of laryngeal cancer does not seem to be greater thEm for lighter drinking. (A unit of alcohol is defined as an ounce of whiskey, 4 ounces of wine or 8 ounces of beer.) Thus the risk from ESTIMATES OF RELATIVE RISKS OF LARYNX CANCER TO CONTROL GROUPS AMONG THOSE SMOKING FROM 16 TO 34 CIGARETTES /DAY
3.0 co .oc
.!!
a:
-• •
~
~
a:
1.0
Drinking per day
*Iftcludes those consuming varied types of alcohol. Fig. 88. The baseline group (risk at equal to one) is the other than 7 plus per day whiskey drinkers. (A unit of alcohol is defined as 1 ounce of whiskey, 4 ounces of wine, or 8 ounces of beer.) (Wynder, E., Day, E. and Bross, VS)
alcohol is different from that of tobacco where a proportionate risk of lung as well as laryngeal cancer has been noted for the lower amounts of tobacco consumed. The question as to whether alcohol acts as a promoter of cancer of the larynx or whether it can initiate it could best be answered if one could find heavy drinkers who did not smoke, a combination rarely encountered. At the present time we feel that heavy alcohol consumption functions primarily as a promoting rather than an initiating factor. Nutrition
Nutritional deficiencies have long been thought to play a role in the development of cancer of the liver. Since liver cancer is rather uncommon in the western world, its epidemiology has never been investigated with the same care as some of the more prominent cancer types. Recently, we completed a survey on cancer of the oral cavity and hypopharynx in Swedish women and found a close association of these cancer sites,
Environmental Causes of Cancer in Man
637
particularly that of the lower hypopharynx, to Plummer-Vinson's syndrome, a condition which we like to term nutritional dysphagia. 24 This disease, which represents a marked deficiency in iron and also possibly of vitamin C and vitamin B, can lead to an atrophy of the mucous membranes of the upper alimentary tract which predisposes to cancer in these areas. Patients with this type of dysphagia, mostly women, generally neither smoke nor drink. If treated early in life, the condition usually responds to adequate iron therapy. There is a suggestion that with an improvement in the dietary regimen, the nutritional dysphagia as well as the subsequent cancers are decreasing in incidence. Further laboratory studies are required to pinpoint possible nutritional factors other than iron in these patients. Diets deficient in iodine and those excessive in vegetables of the cabbage family, particularly those involving rutabaga, and to a lesser extent turnips, which contain an active antithyroid principle, appear to be related to goiter formation.26 In this connection it is of particular interest to note the Swiss data which suggest a decline of goiter as well as of thyroid cancer in the population groups after the introduction of iodized salt. 26 Smegma
It is well established that cancer of the penis is a rarity in circumcised males. Only two penile cancers have been reported in males circumcised at birth. 3 The factor suspected is a material collecting under the foreskin of unclean, uncircumcised males, consisting largely of smegma and its decomposition products. Whatever the suspected factor, it has been amply demonstrated that even if males have been circumcised in early youth rather than at birth, provided this occurs prior to the age of 14, penile cancer is not likely to occurY More recently, studies have demonstrated that circumcision and thus in all probability a factor relating to smegma may also reduce the incidence of cancer of the cervix. 28 Cancer of the cervix is significantly less common among groups that practice circumcision and good penile hygiene. With all other variables standardized, circumcision as such was shown to affect independently the rate of cervical cancer (Fig. 89). As stated, one can only suppose that the actual cause is a factor such as smegma which accumulates under the foreskin of uncircumcised unclean males.
Sunlight
As early as 1894 Unna recognized that exposure to sunlight was related to cancer of the skin. This observation was based upon the fact that this cancer occurred most commonly in persons much exposed to the sun and particularly in areas exposed to solar radiation. Later work, especially that by Blum, has extended the original and correct observation of
Ernest L. Wynder
638
Unna. 29 It has been well demonstrated that the rate of skin cancer rises in direct proportion to the amount of sunlight present in given geographic areas. Radiation
Radiation is one of the well established carcinogenic agents in man. This subject has been discussed more fully in this volume by Nickson. Carcinoma types that seem to be particularly prone to develop following radiation include leukemia, osteogenic sarcomas and cancer of the skin. 100
_
Cervical cancer
~ Control
group
c
.2 ; :I
..g.::: .!!!
o
cQ) ~
Q)
0.
Non-Jewish,White
Negro
Jewish
Circumcised Partner On Iy Fig. 89. Percentage of cervix cancer and control groups at American hospitals exposed to only a circumcised sexual partner. (Wynder, E., Cornfield, J., Shroff, P. D. and Doraiswami, K. R.28)
Miscellaneous Factors
Trauma. Much has been written about repeated injury as a possible cause of cancer. In particular, injury has been thought to play a role in the development of cancer of the breast. 3o Considering, however, that a patient with breast cancer is more likely to recall an injury to that breast than a patient without a breast lesion, we do not think, in agreement with Stewart, that satisfactory evidence exists that injury may initiate cancer of the breast or for that matter any other cancer in man. 3! Definite evidence is equally lacking that repeated trauma, such as the possible irritation from ill-fitting dentures, can initiate human cancer. Air Pollution. Because of the higher rate of lung cancer in urban areas, air pollution has been considered to be a factor in the development of lung cancer. Studies by Doll and Hill as well as by Hammond and
Environmental Causes of Cancer in Man
639
Horn have suggested, however, that the major part, if not all, of the excess of lung cancer found in cities can be explained by the fact that city populations are heavier consumers of cigarettesP· 24 Recently Stocks and Campbell have found that in Liverpool, England, the rate of lung cancer is higher in nonsmokers and in different groups of smokers than in corresponding groups in rural areas. 33 They suggested that, in the rural areas studied, nearly all of the lung cancer cases were due to smoking whereas in Liverpool half were due to smoking and threefourths of the other half were due to some other factor which they suggested might be benzpyrene in the city air. This study, however, did not give results on occupations which, rather than city air, might have accounted for the higher rate of lung cancer in Liverpool. These authors will present further data subsequently, and we must await these findings before final evaluation of the result. Similar studies should also be done in other cities because Liverpool may have certain peculiarities of air pollution not found elsewhere. Stocks and Camp bell suggest from their preliminary review that the benzpyrene in the air added to the benzpyrene obtained from cigarette smoke is responsible for the higher rate of lung cancer in Liverpool as compared with that of rural areas. Syphilis. Studies on cancer of the tongue show that in lesions affecting the anterior two-thirds of the tongue a history of syphilis is encountered more frequently than in the general population. Martin found histories of syphilis in 33 per cent of his tongue cancer group as compared with 14 per cent among controls.34 It remains to be determined, however, whether syphilitic glossitis acts as a co-factor to a carcinogen such as tobacco or whether this glossitis can initiate cancer itself. Pregnancy. Pregnancy has been long suspected to be a factor in the development of cancer of the cervix. This belief was based upon the fact that patients with cancer of the cervix have a higher pregnancy rate than control groups studied. This assumption is based upon a statistical fallacy. Though it is true that patients with cancer of the cervix have more children than the general population, this fact is a consequence only of the earlier marriage and economic status of the patients with cancer of the cervix. 28 Matching patients with cancer of the cervix and control groups in reepect to economic status and age of first marriage, indicates that there is no difference in the pregnancy rate at all (Fig. 90). This point emphasizes how important it is to make careful statistical evaluations of environmental cancer data before attributing causative significance to any given factor. Along these same lines, it is possible that the apparent lower pregnancy rate of patients with cancer of the breast is a result of later marriage among these patients rather than the lesser degree of fertility found among these patients. Bacteria and Parasites. In the older literature various types of bacteria,
Ernest L. Wynder particularly the tuberculosis bacillus, as well as parasites were considered capable of initiating cancer in man. However, there appears to be little confirmation for these data today with the possible exception of the relationship of schistosomiasis to cancer of the bladder. Most workers in this field from Egypt believe that this parasite accounts for the high rate of bladder cancer in their country, although this is doubted by Afifi. 35 . 36 Properly controlled environmental studies in this respect are still Jacking. Schistosomiasis has also been considered to be a cause of cancer of the liver.37
L\1 CERVIX CANCER GROUP • CONTROL GROUP
3333 (/)
w
(/)
~ ~ 20 ~
o
o
I to 2
3 to 4
5 to 6
7 to 8
9+
NUM8ER OF PREGNANCIES Fig. 90. Pregnancy rate of cervix cancer and control groups for white non-Jewish women standardized to age of first marriage. (Wynder, E., Cornfield, J., Shroff, P. D. ap.d Doraiswami, K. R.28)
Human Milk. For the sake of completeness, reference must be made to the milk factor which, because of its established significance in the development of cancer of the breast in mice, had been considered as of possible importance in the development of breast cancer in man. However, two studies on this question did not show that breast cancer patient~ we:('e. fed by their mothers to any greater extent than were members of control groupS.3S. 39 Hormones. The excessive use of hormones, particularly of estrogens, has been suspected of initiating or promoting cancers that arise in organs affected by hormones, such as the breast, the uterine fundus and the prostate.40-42 Though there are a number of reports in the literature suggesting that a few cancer cases involving these sites may have been initiated or promoted by an excessive use of hormones, it is the current belief of cancer researchers that the use of hormones is not likely to initiate can~r in these sites, though it may well promote it. Betel Nut Chewing. Data from India clearly associate cancer of the oral cavity and hypopharynx with the habit of betel nut chewing. 43
Environmental Causes of Cancer in Man
641
The betel nut quid consists of betel nuts and leaves, shell lime, catechu, and in most cases also tobacco. It remains to be established whether tobacco is a necessary ingredient of the quid in order for this quid to be carcinogenic to man. Heat. Though heat has been suspected to be a carcinogenic element to man, there is no satisfactory evidence to prove this. It appears true that members of a certain group in India that carry heated coals in contact with their abdomens apparently have a higher than expected rate of cancer of the skin in this area. 44 However, it cannot be determined whether it is the heat or the material combusted from the coals themselves that initiate these skin cancers. It is also possible that scars resulting from burning may promote skin cancers in these cases. 45 Anhnal Experimentation
So far in this report we have not referred to animal data. The reason for this is that we believe that no animal data can be used to establish a causative role in cancer in man. Such proof can come only from hunian epidemiologic data. If animal experimentation confirms a carcinogen previously suspected also to be carcinogenic to man, confirmative evidence is then at hand; but animal evidence by itself can never establish a human carcinogen nor can it ever disprove it. Animal experimentation has its greatest importance in this field in that it may elucidate the mechanism through which a carcinogen works in man and it may permit us to identify the specific carcinogens out of a group of suspected substances to which man has been exposed. For example, if we suspect tobacco as a carcinogen to man, animal experimentation can determine the specific parts of tobacco which are carcinogenic to animals. Once identified, we can only assume that these specific carcinogens are the same to which man also responds and introduce preventive measures accordingly. Epidemiologic Research
Preventive measures have long been the desired goal of medical research. These have been well established for infectious diseases. It is our belief that they are of similar value for cancer. Through epidemiologic techniques, using the retrospective as well as the prospective approach, it has been repeatedly shown that the greater the exposure to certain specific environmental factors, the greater the risk of developing certain types of cancer. Though these factors may not be the only ones responsible for the induction of these cancers, in their absence the cancer incidence is greatly reduced. As stated, a variety of factors may initiate cancer and as such are regarded as carcinogens. It may be desirable to define postulates which must be met by a given agent to be regarded as carcinogenic to man. Four such postulates are presented in Table 3. As an example we shall
Ernest L. Wynder measure the consistency of the factors of smoking and lung cancer as based on these postulates. Postulate 1. The data on relative risk for lung cancer show a proportionate increase with increasing amounts of tobacco smoked. Thus cigarette smoking complies with Postulate 1 (Figs. 85, 86). Postulate 2. The tobacco data are compatible with the sex ratio of lung cancer because of the longer duration and heavier consumption found in the smoking habits of men. They are consistent with the fact that. lung cancer occurs more commonly among men living in cities than in rural areas since men in cities are heavier cigarette smokers than those living in rural areas. The data are compatible with the fact that in those countries where tobacco consumption is low, lung cancer is uncommon. The data thus are consistent with Postulate 2. Table 3 POSTULATES FOR HUMAN CARCINOGENS
1. The relative risk must rise in proportion to the degree of exposure. 2. Rates among specific population groups must be consistent with the distribution of the agent. 3. Withdrawal, reduction or modification of the agent in a population group must be followed by a decrease in incidence of a given cancer after a suitable latent period. 4. The agent should be shown to be carcinogenic to some animal species (not obligatory).
Postulate 3. The effect of a withdrawal, reduction or modification of an agent in the environment of a population group must, of course, await such action before this postulate can be evaluated. However preliminary data published by Hammond and Horn on ex-smokers seem to suggest that in them the risk of lung cancer is less than in those men who continue to smoke (Fig. 86). Postulate 4. Condensed cigarette smoke has induced cancer of the skin in at least three different strains of mice. The postulate referring to experimental data is not obligatory. Though it has been demonstrated that tobacco is carcinogenic to mice, the ultimate proof as to whether a given agent can induce cancer in man can, as prevously stated, rest only on epidemiologic data. If epidemiologic data are derived under carefully controlled conditions by an experienced team of clinicians, statisticians and interviewers, such data are just as scientific as any laboratory study and represent the only way in which to establish cause and effect relationships between an agent and human cancer. If found statistically significant, the variables must also meet the first two postulates outlined in order to be also of causative significance. It may be argued that the final proof lies in the fulfillment of the third postulate. Unfortunately, the third postulate can-
Environmental Causes of Cancer in M an not be evaluated until after action is taken. Such aetion seems mandatory on the basis of the first two postulates. Summation
In the preceding paragraphs, we have listed environmental factors which are believed to play a role in the development of cancer in man (Table 1). In previous years most of the suspected environmental factors were of an industrial nature. Though affecting a considerable number of workers, they did not arouse the interest of the general public who were not directly associated with these substances. However, since more recent epidemiologic surveys have indicated that such general materials as tobacco could affect the rate of cancer in man, epidemiologic research and preventive measures that are derived therefrom have gained much attention from public and researchers alike. Were we to consider the tobacco type cancers alone, that is those involving the lung, the oral cavity, the larynx and the esophagus, we would recognize at once that at least as far as males are concerned we arc confronted with a large proportion of cancer deaths. If we add to this number the types of cancers that seem to be related to smegma, to nutritional deficiencies, to radiation, and to various industrial agents, we are dealing with a large proportion of all cancers occurring in man. Further research may show other environmental causes that we as yet do not suspect. Studies in environmental cancer research have proved most valuable and will continue to do so. These investigations may not only help to uncover the mechanism by means of which cancers develop in man, but they will present us with tools that may enable us to curtail, if not to prevent, some of the cancers that are today fatal to man. It is our belief that the application of the principles of preventive medicine will do for the field of cancer what they have so successfully done in the past for other branches of medicine. CONCLUSIONS
1. Environmental factors play a significant role in the production of many types of human cancer. 2. Only by studying all possible environmental factors for a given cancer can it be determined which factors are of primary, secondary or no etiologic significance. 3. If clinical, statistical relationships established for a factor and a given cancer are consistent with the geographic and incidence pattern of this cancer, a cause and effect relationship of these two factors may be regarded as proved. 4. Proof of such a cause and effect relationship depends upon epidemiologic data rather than upon animal experimentation. 5. Epidemiologic research has added and will continue to contribute
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to our understanding of the causation of cancer in man. At the same time it will propose preventive measures which if followed may lead to the curtailment of many types of human cancer. Along these lines lies the primary goal of epidemiologic research in the field of cancer. REFERENCES 1. Hammond, E. C.: Cause and Effect. Chapter 7 in Wynder, E. L. (ed.): Biologic Effects of Tobacco. Boston, Little, Brown & Co., 1955.
2. Hueper, W. C.: Occupational Tumors and Allied Diseases, 896 pp. Springfield, Ill., Charles C Thomas, 1942. 3. Wynder, E. L.: Some Practical Aspects of Cancer Prevention. New England J. Med. 246: 492-503 (March 27); 538-546 (April 3); 573-582 (April 10) 1952. 4. Hueper, W. C.: Environmental and Occupational Cancer. Pub. Health Rep., Supp. 209, 1948. 5. Lombard, H. L.: Statistical Studies in Cancer. In Homburger, F., and Fishman, W. H.: The Physiopathology of Cancer. New York, Paul B. Hoeber, Inc., 1953, pp. 778-812. 6. Druckrey, H.: Aetiologie und Prophylaxe des Krebses. Strahlentherapie 93: 165180,1954. 7. Lynch, K. M. and Smith, W. A.: Pulmonary Asbestosis: Carcinoma of Lung in Asbestos-Silicosis. Am. J. Cancer 24: 56-64, 1935. 8. Sikl, H.: Present Status of Knowledge about Jachymov Disease. Acta Uoio Internat. contra Cancrum 6: 1366-1375, 1950. 9. Machle, W. and Gregorius, F.: Cancer of Respiratory System in United States Chromate-Producing Industry. Pub. Health Rcp. 63: 1114-1127, 1948. 10. Neubauer, 0.: Arsenical Cancer: Review. Brit. J. Cancer 1: 192-251, 1947. 11. Maguigan, W. H.: Occupational Bladder Tumors. Acta Unio Internat. contra Cancrum 6: 1359-1367, 1950. 12. Wynder, E. L. and Graham, E. A.: Tobacco Smoking as Possible Etiologic Factor in Bronchiogenic Carcinoma: A Study of Six Hundred and Eightyfour Proved Cases. J.A.M.A. 143: 329-336 (May 27) 1950. 13. Doll, R. and Hill, A. B.: A Study of the Etiology of Carcinoma of the Lung. Brit. M. J. 2: 1271-1286 (Dec. 13) 1952. 14. Hammond, E. C. and Horn, D.: Relationship Between Human Smoking Habits and Death Rate. J.A.M.A. 155: 1316-1328 (Aug. 7) 1954. 15. Doll, R. and Hill, A. B.: Mortality of Doctors in Relation to Their Smoking Habits. Brit. M. J. 1: 1451-1455 (June 26) 1954. 16. Wynder, E. L., Bross, I. J. and Day, E.: A Study of Environmental Factors in Cancer of the Larynx. Cancer 9: 86-110, 1956. 17. Hammond, E. C. and Horn, D.: Bronchiogenic Carcinoma, Death Rates in Relation to Smoking Habits. J.A.M.A. (in press). 18. Auerbach, O. and others: Anatomic Approach to Study of Smoking and Bronchiogenic Carcinoma. A Preliminary Report of 41 Cases. Cancer 9: 76-83, 1956. 19. Wynder, E. L., Graham, E. A. and Croninger, A. B.: Experimental Production of Carcinoma with Cigarette Tar. Cancer Research 13: 855-864 (Dec.) 1953. 20. Wynder, E. L., Graham, E. A. and Croninger, A. B.: Experimental Production of Carcinoma with Cigarette Tal'. n. Tests with Different Mouse Strains. Cancer Research 15: 445-448 (Aug.) 1955. 21. Levin, M. L., Goldstein, H. and Gerhardt, P. R.: Cancer and Tobacco Smoking: A Preliminary Report. J.A.M.A. 143: 336-338 (May 27) 1950. 22. Moore, G. E., Bissinger, L. L. and Proehl, E. C.: Intraoral Cancer and Use of Chewing Tobacco. J. Am. Geriat. Soc. 1: 497-506, 1953. 23. Friedell, H. L. and Rosenthal, L. M.: Etiologic Role of Chewing Tobacco in Cancer of Mouth. J.A.M.A. 116: 2130-2135, 1941. 24. Wynder, E. L. and Jacobsson, F.: Unpublished data. 25. Greer, M. A.: Nutrition and Goiter. Physiol. Rev. 30: 513-548, 1950.
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26. Wespi, H. J. and Eggenberger, H. U.: Personal communication. 27. Kennaway, E. J.: Cancer of Penis and Circumcision in Relation to Incubation Period of Cancer. Brit. J. Cancer 1: 335-344, 1947. 28. Wynder, E. L., Cornfield, J., Shroff, P. D. and Doraiswami, K. R.: A Study of Environmental Factors in Carcinoma of Cervix. Am. J. Obst. & Gynec. 68: 1016-1052, 1954. 29. Blum, H. F.: Sunlight as Causal Factor in Cancer of Skin of Man. J. N at. Cancer Inst. 9: 247-258, 1948. 30. Lane-Claypon, J. E.: A Further Report on Cancer of Breast with Special Reference to Its Associated Antecedent Conditions. Ministry of Health, Reports on Public Health and Medical Subjects 32. London, His Majesty's Stationery Office, 1926. 31. Stewart, F. W.: Occupational and Post-traumatic Cancer. Bull. New York Acad. Med. 23: 145-162 (March) 1947. 32. Doll, R.: Mortality from Lung Cancer Among Non-smokers. Brit. J. Cancer 7: 303-312 (Sept.) 1953. 33. Stocks, P. and Campbell, J. M.: Lung Cancer Death Rates among Non-smokers and Pipe and Cigarette Smokers. Brit. M. J. 2: 923-929 (Oct. 15) 1955. 34. Martin, H. E., Munster, H. and Sugarbaker, E. D.: Cancer of Tongue. Arch. Surg. 41:888-936,1940. 35. Dolbey, R. V. and Mooro, A. W.: Incidence of Cancer in Egypt. Lancet 1: 587590,1924. 36. Afifi, M. A.: Cancer Mortality in Egypt. Cancer Research 7: 537-546, 1947. 37. Katata, B.: Geographical Statistics of Malignant Tumors in Yamanashi Prefecture and Relation between Cancer and Schistosomiasis Japonica. Verhand!. d. Japanischen Path. Gesellsch. 16: 271-278, 1926. 38. Adair, F. E.: Surgical Problems Involved in Breast Cancer. Ann. Roy. Co!. Surg. 4: 360-380, 1949. 39. Horne, H. W. Jr.: "Milk Factor" in Carcinoma of Human Breast; Analysis of 88 Cases. New England J. Med. 243: 373-375, 1950. 40. Auchincloss, H. and HaagenseD, C. D.: Cancer of Breast Possibly Induced by Estrogenic Substance. J.A.M.A. 114: 1517-1523, 1940. 41. Fremont-Smith, M., Meigs, J. V., Graham, R. M. and Gilbert, H. H.: Cancer of Endometrium and Prolonged Estrogen Therapy. J.A.M.A. 131: 805-808, 1946. 42. Abramson, W. and Warshawsky, H.: Cancer of Breast in Male, Secondary to Estrogenic Administration: Report of Case. J. Uro!. 59: 76-82, 1948. 43. Sanghvi, L. D., Rao, K. C. M. and Khanolkar, V. R.: Smoking and Chewing of Tobacco in Relation to Cancer of Upper Alimentary Tract. Brit. M. J. 1: 1111 (May) 1955. 44. Smith, W. E., Sunderland, D. A. and Sugiura, K.: Experimental Analysis of Carcinogenic Activity of Certain Petroleum Products. Arch. Indust. Hyg. & Occup. Med. 4: 299-314, 1951. 45. Schrek, R.: Cutaneous Carcinoma: Statistical Analysis with Respect to Site, Sex and Pre-existing Scars. Arch. Path. 31: 434-448, 1941.