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Environmental Causes of Lung Cancer By W. C. HUEPER, M.D. O BE SCIENTIFICALLY acceptable, known. However, an appreciable number of Tany theory on the etiology of lung cancer them have been identified, such as dusts and must reflect a critical, balanced, and competentfumes of nickel, chromium compounds, arseni- analysis of the entire epidemiological, medical, cals, asbestos, coal tar, soot, vapors or mists of and experimental evidence concerning the types and environmental distribution of and contacts with all known or suspected exogenous agents incriminated in respiratory carcinogenesis for environmental, occupational, or medical rea sons. It is only through such scrutiny that significant and worthwhile information may be obtained as to the relative role which the various individual respiratory carcinogens have played and are playing in the production of lung can ---------No. 36---------- cer. The following facts and observations form an important and integral part of such an assessment. A large amount of factual and circumstantial evidence of epidemiological, clinical, patho logical, and experimental types incriminates a The accompanying article discusses the principal findings presented in Public Health Monograph No. 36, published concurrently with this issue of Public Health Reports. The author is head of the Environmental Cancer Section of the National Cancer number of general environmental and specific Institute, National Institutes of Health, Public occupational air pollutants in the causation of cancer of the lung. Exposure to these agents exists for considerable parts of the population in general as well as for large groups of indus trial workers. Epidemiological observations on hand indicate that only a part of the environ mental agents which may cause lung cancer are Health Service. Readers wishing the data in full may purchase copies of the monograph from the Superintendent of Documents, Government Printing Office, Washington 25, D. C. A limited number of free copies are available on specific request to the Public Inquiries Branch of the Public Health Service. Copies will be found also in the libraries of profes sional schools and of the major universities Dr. Hueper is head of the Environmental Cancer Sec- and in selected public libraries. tion of the National Cancer Institute, Public Health Service, chairman of the Cancer Prevention Commit tee of the International Union Against Cancer? and a past president of the American Society for the Study of Arteriosclerosis. He is the author of more than 200 publications on environmental cancer and re lated subjects, including the book ccOccupational Tumors and Allied Diseases " published in 1942. Hueper, W. C.: A quest into the environ mental causes of cancer of the lung. Public Health Monograph No. 36 (Public Health Service Publication No. 452). 54 pages. Illustrated. U. S. Government Printing Office, Washington, D. C., 1955. Price 45 cents. 94 Public Health Reports isopropyl oil, certain cancer-producing petro leum derivatives, and radioactive ores and gases. Significant amounts of recognized cancer-pro ducing chemicals, moreover, have been demon strated in the exhaust of gasoline or diesel engines and in the atmospheric pollutants of English and American cities. They are con tained also in the dust of asphalted roads and in the carbon black constituting a considerable component of automobile tires. The number, variety, and amounts of cancer-producing con taminants of the general and occupational en vironment have grown during recent decades with the development of modern industry and the increased use of industry-related prod ucts. Numerous epidemiological observations strongly suggest that industry-related factors have played an important causal roll in the rise of lung cancers in the industrialized countries of the Western World observed during the last 50 years. Epidemiology The general epidemiological evidence sup porting this concept is as follows: While a real, definite, and progressive rise in lung-cancer fre quency has been noted since the turn of the cen tury, this development revealed marked varia tions in its time of onset, in its relative degree, and its progression rate in different countries and localities. In some countries, a rise in lung cancer death rates did not become apparent un til after 1930 (Denmark, Norway, Italy). In others, and particularly in highly industrialized countries (Germany, Switzerland, England), this change was demonstrable soon after 1900. English, German, Austrian, and American observations show consistently and significantly higher lung cancer death rates for inhabitants of urban-industrialized areas than those pre vailing for rural areas. Industrial life insurance male policyholders coming from low-income groups and engaged in manufacturing, mining, transportation, and other occupations with possible and often spe cific respiratory health hazards were found to have lung cancer rates which were 30 to 50 percent higher than those present for general policyholders, mainly composed of white-collar workers and the self-employed. There was not only a marked irregularity in the progression rates of lung cancer deaths and morbidity for 10 different metropolitan areas in the United States, according to surveys made in 1937 and 1947, but the annual lung cancer death progression rates in the United States were higher for 1914-30 than for 1931-44. Al lowing a 20-year latent period, one would ex pect that the progression of the death rate in recent years would be much higher than in the early period, if cigarette smoking would repre sent a major causal factor in the rise of lung cancer frequency. Considering the remarkable variations in the male-female sex ratio at different times, in dif ferent localities and different demographic groups ranging even during recent years from 1:1 to 50:1, it is most unlikely that such dis crepancies and changes are attributable to fluc tuations in the intensity of one single factor, such as cigarette smoking, but appear to be due to alterations in the type and extent of action of a broad spectrum of environmental carcino genic agents affecting the members of the two sexes to different degrees. Men are for occu pational and environmental reasons more in tensely and consistently exposed to a variety of known environmental cancer-producing atmos pheric pollutants than women. The various lung cancer-causing agents elicit lung cancers of various structural types. No special type of lung cancer is characteristic for any special carcinogenic factor. None of the main structural types was rare at any time or has any exclusive connection with cigarette smoking. There does not seem to exist any parallelism between the lung cancer death rate and the per capita consumption of cigarettes for different countries. In fact, the rise in lung cancer death rates parallels as closely, or even more closely, the rise in production and/or consumption rates of motor fuel, coal tar, petroleum products, and several carcinogenic metals and minerals, or the construction of asphalted roads, than that of cigarettes. Industry-Related Factors Occupational and epidemiological investiga tions present additional circumstantial evidence Vol. 71, No. 1, January 1956 367522--56----7 95 in support of industry-related factors as impor tant causal agents in the production of lung cancer. An analysis of lung cancer frequency among members of seven large industrial groups lists nonferrous metal workers with the highest rate, followed by transportation workers, while farm laborers have the lowest rate. Other investiga tions indicate that workers exposed to soot from coal- or oil-burning furnaces or powerplants, to metal fumes and dusts or arsenicals, have ex cessive lung cancer death rates. Included in these occupational groups are operating rail road workers, engineers, stokers, chimney sweeps, oilers, furnacemen, mechanics, welders, polishers, patent fuel workers, marine engineers, wipers, foundry workers, gashouse workers, tar workers, road workers and asphalters, sheetmetal workers, boilermakers, crane operators, smelter workers, molders, boiler scalers, lathe workers, iron ore miners, grain dockers. Since the total number of members of such occupa tional groups is considerable, it cannot be main tained that occupational cancer hazards account for only an insignificant portion of the total lung cancer deaths. It is, moreover, evident that abnormal occupational lung cancer hazards seem to exist only for certain groups of work ers and that for this reason they must be related to exposures to definite, specific, and identifiable substances. There is scarcely any likelihood that such occupational differences in lung cancer liability are attributable to fundamental dif ferences in cigarette smoking habits between members of the various occupational groups. Occupational Groups Occupational cancers of the respiratory or gans (lung, larynx, nasal cavity, and nasal si nuses) provide conclusive evidence of the exist ence of industry- and occupation-related respi ratory cancer hazards for members of well-de fined worker groups having contact with specific agents. Such respiratory cancer hazards have been demonstrated for retort workers of gas manu facturing plants and coke ovens, for workers employed in crude paraffin oil pressing opera tions, for isopropanol manufacturers, for nickel refinery workers, chromate manufacturers and chrome pigment handlers, for arsenical insecti cide producers and users, for asbestos workers, and radioactive ore miners. The lung cancer attack rates for members of these occupational groups are many times those found for the gen eral population of same age and sex. While the great majority of the victims of occupa tional respiratory cancer are males, because only males are employed in most of these haz ardous occupations, whenever females also were employed, such as in the asbestos industry, and have the same type and a similar degree of ex posure, there is a trend toward an equalization of the lung cancer attack rates for the two sexes. Exposures to occupational respiratory cancerproducing agents are sometimes characterized by a typical symptom complex involving not only the respiratory organs but also other tis sues and organ systems. The symptom com plex related to coal tar cancer provides a strik ing illustration of the value of this type of medical evidence in support of a specific etiology of a lung cancer. Medical evidence amply attests to the fact that contact of the skin with coal tar pitch, asphalt, soot, creosote, and tar oils has been responsible for several thousand cases of occu pational cancer of the skin, scrotum, and lip. There are, moreover, important cutaneous stig mata characteristic of occupational contacts with these products. These manifestations form a well-defined symptomatic coal tar can cer pattern consisting of chronic dermatitis, comedones, folliculitis, hyperpigmentations of the skin, leukoderma, cutaneous atrophies, warts, papillomas, cornified horns, and light hy persensitivity. Since respiratory exposure to coal tar fumes always entails also cutaneous contact with this material, pathological symp toms from both the cutaneous and respiratory systems combine in the composition of the symptom complex elicited by exposure to coal tar and related problems. In my opinion, the medical evidence sup porting a major role of cigarette smoking in the causation of lung cancer, on the other hand, is inadequate. It is surprising to note the ab sence of positive statistical associations between lung cancer aiid cigarette cough, although this latter symptom is clinically characteristic of chronic chain smokers. Despite the fact that 96 Public Health Reports the lips and oral mucosa are constantly bathed in the tarry liquor oozing from the tip of the cigarettes and despite the contact of these parts with the smoke coming from the cigarettes, there is no statistical association with cancer of these parts. The claim that no tarry material exudes from the cigarette tip cannot be taken seriously, con sidering the well-known fact that chronic cig arette smokers have notoriously dark-brownstained fingers. There is, on the other hand, not a single case of cancer of the fingers attributable to cigarette tar available, which would form the equivalent to the numerous cases of coal tar can cers of the hands placed on record. Such a lack of confirmatory medical evidence cannot conveniently be disposed of by assuming a spe cific "immunity of the skin of the first three fingers" to tobacco tar. The claimed absence of a positive association between lung cancer and the habit of inhaling cigarette smoke also is inconsistent with the rule that the incidence rate of occupational can cers increases with the intensity of exposure to a carcinogen. The medical considerations on cigarette-smoke cancer of the lung thus reveal a number of serious and fundamental defects and contradictions. Carcinogenicity of Industrial Agents Experimental investigations have furnished ample proof of the carcinogenicity of many of the agents involved in the production of hu man respiratory cancer of occupational ori gin. Such an experimental evidence is available for coal tar, pitch, soot, various mineral and petroleum oils, nickel, and radioactive sub stances. For the carcinogenic action of con stituents of coal tar there exists for instance, a large mass of experimental observations made on various species, such as mice, rats, rabbits, dogs, and chickens. Specific carcinogenic poly cyclic hydrocarbons, moreover, have been iso lated from coal tar and pitch, soot, mineral oils, and carbon black, and such findings have been confirmed by various investigators. The experimental evidence concerning a car cinogenic action of tobacco tar, on the other hand, is remarkably uncertain. There exists a considerable discrepancy in the observations made by various investigators as to its carcino genic action on mice and rabbits. While the majority either did not find any or a very mild carcinogenic effect when tobacco tar was applied to the skin of mice or rabbits, two groups of in vestigators reported remarkable results in this respect. It is rather disconcerting that the latest of these reports made only a year ago could not be confirmed by subsequent investi gators using a similar technique and time of application of the tobacco tar to the skin of mice. The best that can be said about the experi mental evidence on hand regarding carcino genic properties of tobacco tar is that it indi cates the presence of mildly carcinogenic agents in cigarette tar through the use of hyper-reac tive animals. There is no evidence that these observations of the skin of a strain of selectively inbred mice have any equivalent in man. Thus the practical importance of these observations as to cancer of the human lung is at present un certain. Conclusions 1. The total epidemiological, clinical, patho logical, and experimental evidence on hand clearly indicates that not a single one but sev eral if not numerous atmospheric pollutants are to a great part responsible for the causation of lung cancer. 2. The available data do not permit any defi nite statements as to the relative importance of the various recognized respiratory carcinogens in the production of cancers in the general popu lation. Additive, cumulative, and synergistic effects of several of such agents are a distinct possibility. 3. Observations on occupational respiratory cancers, on the other hand, indicate that in re stricted occupational groups exposed to welldefined and highly potent respiratory carcino gens all or most of the respiratory cancers found are attributable to one single carcinogenic air pollutant. 4. The widespread presence of industryrelated atmospheric pollutants of recognized carcinogenic properties suggests that the recent alarming rise in lung cancer frequency espe- Vol. 71, No. 1, January 1956 97 cially among males may in part be causally re lated to the local and general development of modern industry and the use of its products. 5. While it is possible that cigarette smoking has played a contributory role in this respect, the total evidence available if critically evalu ated does not favor the concept that cigarette smoking represents a major factor. 6. Since extensive and expensive efforts are required for obtaining an effective preventive control of the existing respiratory cancer haz ards, rigid measures should be taken to discour age the introduction of new atmospheric air pol lutants of carcinogenic type, especially if they are of the general environmental variety which are most difficult to control. important &L)ate Each month your health department and many hospitals, laboratories, schools, clinics, and homes receive a copy of PUBLIC HEALTH REPORTS, mailed to arrive on the 20th, or even earlier, depending upon geographic location of the subscriber. Its pages carry timely research reports, analyses of current trends, new methods, concepts, and ideas, and topical reviews for the busy scientist, teacher, or public health worker. Capsule coverage of im portant public health meetings, like those of the American Public Health Association, help the PHR reader. You can have your personal copy promptly. Use the subscription blank on the inside back cover. Let the 20th of each month be an important date for you, too. Seteduled for early publication APHA Conference Report Health Services in Civil Defense Clues To Suicide Encephalitis and Mosquitoes in Texas Refuse Handling in the United States 98 Public Health Reports