Document 6RYk6ypxgBZmjdX2EaVzV57ME

FILE NAME: Oil Industry and American Petroleum Institute (API) DATE: 1952 & 1953 DOC#: API154 DOCUMENT DESCRIPTION: Journal Article - Environmental Cancers-A Review with Cover Letter > Copy from D. V. Stroop for Information of Members and A ssociates of the Medical Advisory Committee ________________________________________________ 1-19-53 ESSO LABORATORIES Standard O il Development Company Medical Research D iv isio n ' p. o. Box 51 Linden, N. J. January 15, 1953 Mr. D. V. Stroop American Petroleum I n s titu te 50 West 50th S tr e e t Nev York 20, Rev York Dear Mr. Stroop: I am attaching a r ep rin t of an a r t ic le rec en tly w ritten by Dr. Hueper. I think th a t th is a r t ic le should be brought to the a tte n tio n of a l l of the members and a sso c ia tes of the Medical Advisory Committee of the API. Very tru ly yours, / s / R. E. Eckardt R. E. ECKARDT, M. D. REE:i l k Enel. - Environmental Cancers: A Reviev by Dr. W. C. Hueper Reprinted from CANCER RESEARCH Vol. 12, No. 10, pp. 691-97, October 1952. API 05554 ) Reprinted for private circulation from cancer research Vol. 12, No. 10, p p . 691-97, O ctober 1952 C o p y rig h t 1952 by Cancer Research, Inc. nuxrtc U4 .5.A. Environmental Cancers: A Review W . C. H ueper (Sation&l Cancer In*titute, United State* Public Health Service, Federal Security Agency, Betheeda, Md.) although the knowledge of an environmental causation of human cancer is much older than that of the exogenous origin of infectious diseases, there exists a striking, if not alarming, contrast between the extent to which this information has been put to scientific and practical use in the study and control of these two important groups of diseases. In the attack on the infectious diseases the main efforts were expended on the discovery of the specif ic causative agents and on their subsequent elimi nation from the erternal and internal human environment by appropriate preventive, prophy lactic, and therapeutic measures. Interest in the endogenous properties of the host, as represented by heredity, constitution, aging processes, race, and sex, in determining the development and course of infectious diseases did not, as a rule, assume a dominating character. These factors were recognized as having mainly a modifying, but not a causal role, by exerting a certain influence on individual susceptibility to the pathogenic micro organisms and on the course of the disease. The investigation of the anatomic and biologic proper ties on the various reaction products, particularly those of chronic granulomatous nature, remained usually a less important side issue in devising effective control measures. The investigations directed against human cancer, on the other hand, paid relatively little attention to the factual evidence of its established environmental causation, but concentrated first on the various morphological aspects of cancer and cancer cells and, more recently, on the biochemical and biophysical properties of cancer tissue. Can cer was, and still is, considered by many investiga tor a distinct disease entity and is not regarded aa an atomic reaction product to a large number of Received for public!ion June M, I9J, diverse chemical and physical agents. It has been for the same reason that the rather diffuse etiologic concepts of physiologic aging and heredity have enjoyed a much greater and much more lasting appeal than the much more definite and reliable observations on the diverse exogenous causes of a considerable variety of human cancers. HxamrTT Since, in a recent discussion of the age aspects of environmental and occupational cancers (15) the fundamental fallacy of this concept as to the majority of human cancers was discussed in detail, it remains to point out that a similar situation seems to prevail as to the validity of the heredity theory. Conclusions drawn from selectively inbred strains of mice, a notorious biologic artifact with out parallel in nature, have been instrumental in giving to hereditary factors an exaggerated and distorted significance as immediate causes of human cancer. While it may be conceded that there exist a few rare cancers which display hereditary tendencies, at least one of them (cancer of the skin in xeroderma pigmentosum) depends in its causation on the primary action of an exoge nous agent. Although xeroderma pigmentosum is due to an inherited hypersensitivity to solar radia tion prevalent among some inbred family groups, this fact would scarcely justify the conclusion that the ordinary type of solar cancer of the skin is pri marily an inherited manifestation of the host organism which is activated by an exposure to solar rays. Such an inversion or perversion of normal reasoning would have to disregard the fundamental fact that without solar radiation there is no cancer, irrespective of the constitution of the individual. The allegation that hereditary factors baseci on 691 692 Cancer Research prolonged inbreeding play an important causal role in the production of the lung cancers among miners of radioactive ore in Schneeberg and Joachimsthal (Vesin [39]; Macklin [27]; Lorenz [26]) represents another example of the rather loose speculations which have been advanced to bolster the cause of the heredity theory. Apart from the fact that none of the various proponents has offered any concrete evidence in support of such a claim, any significant degree of inbreeding in a community of about 10,000 inhabitants (Schneeberg) having a railroad station for many years would indeed represent a most remarkable biologic and sociologic feat. This speculation ad vanced by investigators remote from these opera tions has no basis in fact according to German in vestigators.1 The occasional occurrence of lung cancers in several members of the same family working in these mines certainly cannot be regarded as proof of a hereditary liability. Similar observations of a familial appearance of skin (scrotal) cancers were reported from England during the past century in families of chimney sweeps. Such familial cancers were obviously caused by an occupational or en vironmental exposure to soot by several members of such families without necessitating the assump tion of a common hereditary susceptibility. The high rates of attack of several environmen tal cancers rather clearly indicate that heredity evidently plays a relatively insignificant role in their production (cancer of the lung in 75 per cent of miners employed in radioactive mines--Baader [8]; Hueper [16]; cancer of the bladder in almost 100 per cent of dye workers following highly exces sive and prolonged exposure to certain aromatic amines--Goldblatt [11]; Mueller [32]; Gross [12]; Hueper [17]; cancer of the skin in 100 per cent of workers with contact with pitch for more than 40 years--Sladden [35]). It is likely, however, that such an almost com plete obliteration of individual inherited or ac quired constitutional differences in susceptibility to exogenous carcinogens occurs only in the pres ence of an overwhelming, high intensity exposure. Whenever groups of individuals become exposed to carcinogens of low potency or sustain exposures of low intensity and duration, there appears evidence indicating variations in the speed and character of the individual responses to the environmental carcinogen. A constitutional influence evidently 1None of the numerous German worker* mentioned in their paper* the occurrence of inbreeding in the mining population of the Erzgebirge and Limbach in answer to a recent inquiry stated that nothing is known among German scientists in this respect. controls the susceptibility of different races solar cancer of the skin, to which light-pigment individuals are much more liable than dar pigmented individuals. The effect of this racia difference in reactivity to t.ne carcinogenic actioi of the ultraviolet radiation from solar sources L reflected not only in a lower incidence of ski: cancer in Negroes than in whites, but also in i different topographical distribution of the ski; cancers observe in the twc racial groups. Whil skin cancers in whites are mainly located in th skin of the exposed parts of the head, neck, am upper extremities, those observed in Negroes an predominantly situated in the usually cove; parts of the body and the lower extremities (31)| Since arsenical cancers not infrequently involvi the unexposed parts of the skin, it is reasonable conclude from the above evidence that the vari tions in the topographical distribution of s cancers in whites and Negroes are, in part, due differences in causal agents active in the produ tion of these cancers. It is unwise, however, to generalize or overei phasize the role of racial factors in the causation environmental cancers. Although primary hepati cancer incidence is high among West Afri Negroes, their American descendants do not play any such tendency (Berman [5]), indicati: thereby that not racial or hereditary factors b environmental factors are underlying the Afri experience. Likewise, it can be considered established that the absence of penile can among Jews and the high liability of Chinese this type of malignant tumor do not depend u race-conditioned constitutional differences, but mainly the result of differences in personal h. giene, especially the circumcision practiced at early age by the Jews. There thus exist not o; "environmental familial cancers," but also "ei vironmental racial cancers." which have no re! tion to heredity. S ix Differences in the sex distribution of cancers fecting several organs (lip, mouth, larynx, broncl skin, and bladder) have given rise to the conce' of a sex-conditioned susceptibility to certa; cancers. Observations on environmental cance; lend no substantial support to such a theo Cancer of the lung of unknown origin has a mat female sex ratio of from 4:1 to 24:1, according t various investigators (18). Asbestosis cancer of th lung, on the other hand, displays a male-female s ratio of 2.4:1, indicating that with an equalization of exposure to a carcinogenic agent there occur also an equalization of the incidence rates of lum API 05556 H e p e r -- Environmental Cancers: A Review 69S 'ial ction es , I skiQ ' 'n a skin 'Vhile n the t 3-Hr] ;s ar? * vered (31), , ivolve tble to varia i skin due to iroduc- >`erem. tion of lepatic African iOt dis.eating >rs but .African d as ,ancer nese to id upon but are nal hyd at an lot only iso "en no rela ncers afbronchi, concept certain 1 cancers i theory s a male ording to cer of the emale sex ualization re occurs es of Iud? ^ " 7 the tw0 sexes (Merewether [30]). Like- csocev fr ^ improbable that the male-female wisei '^ lS . j . j for Mexican men and women X ratio 0 ^ dmondson [37]) living in Los 7 Steiner, seX-related factors. It is note- Ange'es. , ;s reipect that the entrance of female worthy 'n ^ .n t^e English textile plants was fol- mUl7 Plfter a suitable latent period by the appearlon-ed a cers 0f the vulva in some of these anCe s which fact thereby demonstrates that o^^e^ulespinners acquire the anatomic equiva- fe -o , the scrotal cancer of their male counter- ^eflt s (13) While ora* cancer ' s rare *n white Parls .his tumor is rather frequent in Indian *men chewing betel quids (Bashford [4]). This hvo cancer of the oral cavity represents 12 per bu\ of all cancers among Filipino women. For this Tiison, the sex ratio of oral cancer among Fili^ os is inverse to that found among white people P Habiting the temperate zones, where the malefemale sex ratio is 3:1 (Maxwell [29]; Vedder [38]). These and other similar observations indicate that the differences in the sex ratio of certain cancers of unknown origin are apparently not due? in the main, to hormonal factors but rather reflect variations in the types and intensity of exposure to environmental carcinogens affecting members of the two sexes to a different degree for reasons of occupations, habits, customs, clothing, hobbies, and general living conditions. Erconooi/oaic Pattern The type of the epidemiologic pattern of en vironmental cancers depends less on certain con stitutional factors of the population studied (heredity, race, sex, age) than on the composition, as well as the type, intensity, and duration of action of the agents constituting the environmen tal carcinogenic spectrum to which they have been exposed. The physical and chemical carcinogens exert their disease-producing effect, just like the pathogenic micro-organism, whenever and wher ever they operate under proper conditions of ex posure and irrespective of the special type of con tact (occupational, medicinal, dietary, habitual, environmental, etc.) present. The general soundness of this concept is at tested by the following observations. The appear ance of occupational cancers in the various indus trialized countries has closely followed the spread of certain industries. This sequence of events is well illustrated by the chronologic and geographic appearance of bladder cancer among dye workers in different countries following the establishment of aniline dye industries (Table 1). Additional support for the concept proposed is derived from the demonstration of a centrifugal spread and scatter pattern of occupational cancer hazards from the focus of original production of carcinogens in basic industries through processing and consumer industries to the ultimate handler and general consumer of the finished products. This pattern becomes apparent in the occurrence of skin and lung cancer among the producers of tar and pitch in gas plants and coke ovens, the appearance of similar cancers among tar refinery workers, roofers, road construction workers, cork brick manufacturers, and other members of sec ondary industries and trades handling and using tar and pitch. An identical chain of environmental cancers among successively exposed population groups exists in regard to arsenicals, which have TABLE 1 Chronologic and Geographic Appearance op Bladder Cancer among Dye Workers in Different Countries (17) Country Germany Fiftt year reported 1805 Switaerland Great Britain Russia Austria United States Italy Japan France 1005 1018 102 1032 1034 1038 1040 1048 Author Rehn Sch edler Rosa Rosenbaum and Gottlieb Schueller Ferguson et ai. di Maio Nagayo and Kinosita Billiard-Duchesne Total oo. recorded op to lflJl Approxi mately 350 190 300 71 (*; fc5C 9C * (7) 41 elicited cancers among miners of arsenic-contain ing ores, smelter workers, manufacturers of ar senical insecticides, users and consumers of food stuffs and drinking water contaminated with such arsenicals, as well as individuals receiving arseni cals for medicinal reasons (Hueper [16]; Neubauer [33]; Arhelger and Kremen [2]; Butzengeiger [8]; Hill and Faning [14]; Arguello, Tello, Macola, and Manzano [1]). Occupational cancer hazards also display a cancer distribution pattern which shows the highest attack rates among the population groups employed within the immediate vicinity of the carcinogenic industrial foci and gradually decreas ing attack rates among population groups increas ingly remote from it and thus less intensely and frequently in contact with carcinogenic agents. A good illustration of this concentric distribution pattern of occupational cancers is offered by the aromatic amine bladder cancers. The bladder can cer incidence rate, according to past experience, was highest among intermittently but intenselyexposed maintenance and repair men who were followed in decreasing order by operators regularly 694 Cancer Research employed in the manufacture of beta-naphthylamine and benzidine, these by truck drivers, yard men, chemists, engineers, and supervisors who have irregular and mitigated exposures. Whether or not "neighborhood cases" of aromatic amine cancers actually occurred among the population residing or working within the fume and waste dis posal zone of aromatic amine operations is still doubtful and controversial (Mueller [32], Hueper [17], and Gross [12]). Since, according to Gehr mann, Foulger, and Fleming (10), workers em ployed in a building formerly used for the produc tion of beta-naphthylamine have an occupational bladder cancer hazard from contact with the minute amounts of the chemical volatilized from impregnated building material, neighborhood cases of this occupational cancer may conceivably occur among persons living near aniline dye plants with defective loading, shipping, and waste dis posal arrangements for beta-naphthylamine and benzidine. Another major factor determining the char acter of the epidemiologic pattern of occupational cancers is represented by their latent period, which in turn depends upon the relative potency of a particular carcinogen, its physicochemical proper ties (solubility, dispersion, chemical reactivity TABLE 4 OrjM Skin Lung Bladder La t e n t Perio ds of E n v ir o n m e n t At a n d Occupational Canc ebs Aftnt Arsenic: medicinal occupation*! Tar Creosote oil Mineral oil Crude paraffin oil Solar radiation X-radiation Asbestos Chromates Nidcel Tar fumes Ionising radiation Aromatic amines At, Uteat period (year) 18 45 40-44 45 50-54 15-18 40-80 7 18 15 44 16 15-55 11-15 RjLUfC of to. tost period lyeor.) 8-40 4-46 1-50 15-40 4-75 5-85 15-40 1-14 15-41 5-47 6-50 -45 7-50 4-40 and affinity, etc.), the physicochemical and co carcinogenic or anticarcinogenic properties of its vehicle or its associated agents, the route of con tact, the intensity of the individual exposures, their rhythm, and the total duration of exposure. These factors, which have a distinct influence upon the incidence rate of cancers among exposed popula tion groups, also exert a definite influence upon the length of the latent period. With decreasing in tensity of exposure there occurs a reduction in the incidence of cancers and a lengthening of their latent period. Apart from individual differences i susceptibility, these irregularities in the intensit of exposure to environmental carcinogens main! account for the wide range of latent periods r corded for environmental cancers (Table 2). The target organ of environmental carcinoge depends on various factors. Special tissue affinit of benzene to the fat tissue contained in Lemato poietic organs thus seems to account for its exclu sive leukemogenic actioD. The intensity of er TABLE S Sit e of Cancer a n d Route of E xposure Typ* o! COUtact Carciaortoic Site of cancer Cutan*- A m n ic Coil tar, pitch, soot,, asphalt Creosoti oil, anthracene oU Petroleum asphalt, coke, Ur Petroleum oils (high boiling) Shale oil, crude paraffin oil Lignite oil and para/fin oil Ultraviolet radiation X-radiation, radioactive chemicals Benzene Skin Hematopoietic' sues Respirtory Arsenic dust Chromium compound dust and fumes Nickel dust and vapors Asbestos dust Beta-naphthylamine, bene- dine oust and vapors Coal tar fumes Petroleum oil mist Isopropyl oil vapors* Radioactive dust and gases Lung Lung Lung, nasal eavi and sinuses Lung Bladder Lung Lung Nasal sinuses, ynx, and lung Lung Inges tion Arsenic Radium, mesotborium Skin Bone Iopropyl oil io the crude liquor from wbich opropanol i ob by d iftillatioo (40). posure to some environmental carcinogens a seems to determine the distributory mechanism the resulting cancers. The relatively high f quency of heterotopi: multiple primary can' observed among dye workers with cancers of urogenous tract as well as other organs (lu stomach, intestine, prostate--Mueller [32]; H per [16]) seems to be due to an unusual hemat enous spread of the carcinogenic hydrocarbo ordinarily mainly excreted through the uri (Bonser [7]). The principal reason for the appe ance of cancers in various organs, however, represented by the route of exposure (Table S) Epidemiologic and demographic studies card out during the past two decades have demo strated the existence of marked and signific variations in the total incidence of cancer as well in the organ, sex, age, and race distribution cancers in different countries, regions and popuU API 05558 j jm r lifferences in the intensity ogens mainly it periods re. able 2). il carcinogens tissue affinity ?d in hemato; for its excluensity of ex- XPOSUKE Site of cincer kin hematopoietic tis sues -ting -ting l.ung, nasal cavity, and sinuses ung Bladder Lung un g ,asal sinuses, lar ynx, and lung Lung akin Bone opropfcool ii obtiioed rcinogens also mechanism of vely high fre-imary cancers cancers of the organs (lung, Her [32]; Hueusual hematog- hydrocarbons ugh the urine for the appearis, however, is re (Table 3). studies carried * have demonand significant ?ancer as well as distribution of ms and popula- H ueper-- Environmental Cancers: A Review 695 tion ci roups- While a part of such variations is due differences in the age distribution of the various ulation groups surveyed as well as in the qual- Pf f medical care and of medical recording of Ir'eascS' there remains for many of these discrep'cies in rates of regional cancer incidence no other &Uusible explanation than the differences in ex posure to environmental carcinogenic factors (Table 4). _ , The striking differences in the lung cancer orbidity rates in metropolitan centers located in the same part of the country militate against the concept that such local discrepancies can justly be attributed to variations in medical care and re cording, or to differences in the biologic composi tion and hereditary properties of the populations concerned, or to the predominant action of a single etioloeic environmental factor, especially cigarette smoking (Wynder and Graham [41]). The local variations as well as the consistent increase of lung cancer morbidity rates must be ascribed to a combination of exogenous factors affecting, to differing degrees, the various population groups as well as the two sexes surveyed. Since the known environmental lung cancers have a latent period ranging usually from 10 to 25 years, it may be concluded that the rising trend of lung cancers is attributable to changes in the environmental carcinogenic spectrum which started around the tum of the century and the effects of which are be coming increasingly evident (Hueper [18]). Sup porting this concept is the fact that the majority of environmental and occupational cancers dis covered during the last 25 years involve cancers of the respiratory tract (cancers produced by chro mium compounds, nickel, arsenicals, asbestos, coal tar, petroleum oils, isopropyl oil, radioactive sub stances) (21, 28). In the conduct of epidemiologic studies on en vironmental cancers certain important precautions have to be observed, if misleading, incorrect, or in conclusive results are to be avoided (Hueper [17]; Downing [9]). It is essential to survey as far as practicable the total effectively erposed popula tion, and to exclude from membership in the actually exposed population group all those indi viduals who have merely an "administrative" ad herence to it. In a survey of environmental can cers among oil refinery workers, for instance, it is scientifically not permissible to include office per sonnel, sales people, and other white-collar work ers, unless they sustain real contact within the refinery area to suspected or recognized carcino genic agents for occupational reasons. Similarly, whenever, within an industrial population to be surveyed, only a restricted group is shown to have a carcinogenic hazard, figures on incidence must be calculated for this group only, and not for the total plant population, since the latter procedure results in an undue dilution of positive evidence and thereby in distorted epidemiology informa tion. The limited occurrence of bladder cancer to relatively small and restricted groups of dye work ers (10), the excessive liability to scrotal cancer limited to workers employed in paraffir. pressing operations in oil refineries (34), and the increased liability to lung cancer among persons with asbestosis--and not among all persons employed in asbestos operations--provide pertinent illustra tions of this point. TABLE 4 Lung Cancer M o bbidity Rate, 1937 and 1947, fob R e s id e n t s of E ight M etropolitan Centers per 100,000 Population* ClTT Atlanta New Orleans Dallas Birmingham Denver San Francisco Chicago Pittsburgh Ma u i 1097 1047 3.0 13.4 13.1 39.1 5 9 29.0 4.5 18.9 9 1 ill.9 13 6 34.3 13.3 29.5 9.7 26.1 Fxmalx* 1097 1047 1.0 5.0 2.8 4.2 0.5 6.4 2.1 3.9 4.2 8.1 3.9 8. 1 4.3 7.0 4.9 3.5 Total 1057 1047 2 9 8.9 7.6 20.8 3.1 17.2 3.3 11.0 6 6 14 8 9.8 20.8 8.8 18.0 7.3 15.6 * Supplied by Biometrics Sectioo, N itio o il Cm cer Institute. An analysis of the population "at risk" should include not only workers presently employed for a sufficiently long period, so as to cover the minimal latent period of the average occupational cancer (5 years), but also all formerly employ<"d workers dead or alive who left the industry, plant, opera tion, or trade group fulfilling this concition. The inclusion of large groups of short-term employees with insufficient exposure and latent period into the surveyed group also introduces a serious dilution factor which causes misleading or inconclusive re sults (23, 36). Since the occurrence of environmental cancers rarely has the character of an epidemic, but as a rule appears as an endemic, it is necessary to con duct epidemiologic studies as long-term investiga tions, which means the analysis of data covering periods of at least 5 years. Negative results ob tained from short-term investigations comprising periods of 1 or 2 years give, at best, inconclusive results if not incorrect ones (6). In view of the long latent period of environmen tal cancers it is necessary to restrict occupational cancer surveys to plants which have been in operation for at least 10 years, unless a large por tion of the workers in their employ has previously been employed in similar operations eisewhere. The absence of published reports on the occur- API 05559 a. -1 696 Cancer Research rence of occupational cancers in an industry hav ing known or suspected cancer hazards is no assur ance that a serious occupational cancer problem in these establishments is nonexistent. Perhaps the most notorious example that can be cited as an illustration of such occurrences is represented by the long delayed discovery of the lung cancers among uranium miners of Joachimsthal. Although the existence of a high lung cancer incidence among the Schneeberg miners was established in 1876, despite repeated inquiries made by German investigators with the various governmental au thorities under whose jurisdiction the uranium mines in Joachimsthal located nearby on the southern slope of the Erzgebirge were operated, it was not until some 50 years later that the high frequency of lung cancers among this group of similarly exposed workers was recognized. Until that time (1926), the century-old practice of mis taking lung cancers of the Joachimsthal miners for pulmonary silicosis or tuberculosis was continued. Likewise, associated pathologic conditions some times may operate in obscuring the co-existence of an occupational cancer. This danger exists, for instance, for absestosis cancer of the lung, unless a thorough necropsy study is made. CABcmoaEKisis An analysis of the action mechanism of the vari ous recognized, suspected, or potential human carcinogens supports the viewpoint that the ma jority of cancers develop at sites where, for some reason, the most intense or most prolonged ex posure to the carcinogen takes place. The follow ing types of mechanisms determining the distribu tion of environmental cancers may be distin guished. a) Cancers developing at sites of primary contact. --To this group belong the cancers of the skin re sulting from cutaneous exposures to substances such as coal tar, petroleum oils, creosote oil, soot, and similar combustion and high temperature dis tillation products of carbonaceous matter, as well as to ultraviolet and ionizing radiations; moreover, the cancers of the nasal cavity, nasal sinuses, larynx, and lung elicited by the inhalation of arsenicals, chromium, and nickel compounds, (beryllium?), asbestos, isopropyl oil, tarry matter, and radioactive gases and dusts. The cancers of the connective, bony, and hematopoietic tissues following exposure to penetrating ionizing radia tion may be included in this group of primary contact cancers. b) Cancers developing at sites of selective deposi tion.--Arsenical cancers of the skin, osteogenic sarcomas following ingestion of radium and/or mesothorium, leukemia following contact wi benzene, (thyroid carcinoma following radioactiv iodine medication, leukemia subsequent to radii active phosphorus medication, osteogenic sarco: following inhalation of beryllium compounds?) may be included in this group. 1 c) Cancers developing in organs with specialfunc tional or toxic affinityfor carcinogens.--Represen tives of this group are almost exclusively caused b; carcinogens of potential importance as far as hu mans are concerned and thus have been observ mainly in experimental animals. Cancers of thi type are the tumors of the liver developing follow ing exposure to various azo dyes, aminofluoren- compounds, chlorinated hydrocarbons and lenium, the cancers of the breast and uterus su sequent to an excessive exposure to estrogens, am cancers of the thyroid following the prolonged ad ministration of thiouraeil derivatives. d) Cancers developing in organs of excretion oj carcinogens.--Cancers of the bladder, ureter, and! kidney observed in individuals and experimen animals having cutaneous, ingestive, and respi: tory contact with certain aromatic amines and a: compounds due to the presence of carcinogens material in the urine belong to this group. e) Cancers developing on the basis of fu n d i abnormalities due to cer'ain dietary deficiencies a representing a type of indirect or secondary envin mental carcinogenesis.--Cancers of the h pharynx and of the liver noted among populatio: groups subjected to a diet deficient in vitamin complex and protein as well as cancer of the liv in rats kept on a choline-deficient diet are membe: of this group. f) Cancers of the young resulting from a tra placental penetration of carcinogens.--There exi. so far only experimental evidence in support such an exposure route in the demonstration of tb development of pulmonary tumors in the off. spring of pregnant mice given urethan near te: (Larsen [25]; Klein [24|). Whether or not a si mechanism may be active in the production congenital cancers or cancers developing during in fancy and early childhood appears to be a worth while subject of investigation in view of th- findings. While it is not likely that exogenous agents ai the only factors responsible for human cancel the increasing number and widening variety environmental carcinogenic agents suggest they seem to be operative in a much la proportion of cancers than is recognized realized at present, It appears from the eviden available that the study of environmental cam hazards and cancers offers not only the mo: API 05560 act w ith dioactive to radio. sarcoma, pounds?) dal June. presenta. raused by i ar as hu- I I observed I rs of this lg follow, lofluorene and seerus sub gens, and jnged ad- cretion of eter, and erimental d respiras and azo -cinogenic ip. functional encics and y environhe hypo>opulation itamin B f the liver members a a translere exists upport of tion of the l i the offnear term t a similar luction of during in e a worth of these agents are i n cancers, variety of ;gest that ich larger gnized or e evidence ital cancer the most H c e p e r -- Ennronmenlal Cancers: A Review 697 nromising approach to the determination of the P sation of human cancers, but is also the princicft"route through which the primary prevention of mav be achieved. r efer en c es , roceuuo. R- A.; T ello, E. .; Macla, B, A.: and NIaNIano, L. Loa cancers cutneos en el arsenicismo irnico regional endmico en la provincia de Crdoba, D Rv. Fac. cien. md. L'niv. Crdoba, 8:409-3, 1950. i irbeloeb, S. W,, and Kremen, A. J. Arsenical Epiheliomas o Medicinal Origin. Surgery, 30:977-86, 1951. J BcaOEH, E. W. Der Lungenkrebs als gewerbemedizi3 nisches Prohlem. Verhandl. Deutsch. Gesellsch. inn. Med., 57:322-32,1951. RiBaroRD, E. F. An Address on Cancer in Man and Animals. Lancet. 2:691-701, 1909. , rjrju.v, C. Primary Carcinoma ai the Liver, pp. 1-18. London: H. K. Lewis It Co., 1951. . RtpjxRCT P. L. Carcinoma o the Lung in Chromate Workers. Brit. J. Ind. Med., 8:302-5, 1951. 7 Bonsee, G. M.; Clatson, D. B.; and J ull, J. W. An Erperimental Inquiry into the Cause o Industrial Blad der Cancer. Lancet, 159:286-B8, 1951. 8 Butzengeiger, K. H. Die chronische Arsenvergitung der Winzer. rxtl. Wchnschr., 4:365--69, 1949. g Downeno, J. G. Cancer of Skin and Occupational Trauma. 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