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FILE NAME Oil Industry and American Petroleum Institute API DATE 1948 DOC API148 DOCUMENT DESCRIPTION Book Excerpt - Environmental and Occupational Cancer . Pubs itement 209 @ Public Health Reports 1948 wood tte Glan . Environmental an and ecupational Cancer . . By W. C. HuepeMr. D. pp 20-21 20-21 se Dag FEDERAL SECURITY AGENCY BERVICE PUBLIC HEALTH SERVICE | P.005 NO.0344 TX 11:55 04/14/00 = --- = - + * tes Ement 209 - MAC MAC Public Reports @ 1948 Environmental and ee Mert By W. C. M. D. Hueper, Co FEDERAL SECURITY AGENCY PUBLIC HEALTH SERVICE P.5 78 P.5 99 14104482368 99 barry TO 08:38 02-18-94 6401 362 410 API 07872 FROM ement 209 ' Public Health Reports 1948 wld eeB ght ee gle >.Environmental and eS By W. C. Hueper D. ay aS 7 FEDERAL SECURITY AGENCY pa PUBLIC HEALTH SERVICE API 07872 | FEDERAL SECURITY AGENCY Oscar R. Eucing Administrator PUBLIC HEALTH SERVICE Leonard A. Scheele Surgeon General Division of Public Health Methods G. St. J. Perrott Chief of Division from The National Institutes of Health The National Cancer Institute Cancer Control Branch UNITED STATES . COVERNMENT PRINTING OFFICE WASHINGTON : 1948 For sale by the Superintendent Superintendent of Dom ents U. Pri 20 c coe nt Printing Oka W acn iamg, tes T ) API 07873 Preface This study presents a comprehensive review of current knowledge of the environmental causes of human cancer Dr. W. C. Hueper whose major interests have been in the fields of environmental and occupational carcinogenesis has collected and analyzed the most important known facts on this problem both domestic and from abroad His summation of the data and his evaluation of their significance reported in compact and usable form should be of very real value to everyone concerned with the Nation's health The conclusion is inescapable that exogenous agents particularly of Findustrial origin are important factors in the causation of certain types of cancer It is true that neoplasms of known environmental etiology comprise only a part of the total cancer incidence in the United States However the fact that there seems to be a constant though gradual increase in the appearance of these cancers in the general population is swiftly making occupational carcinogenesis a public health problem of very real importance Epidemiologically for example much more needs to be done to reveal additional substances guilty of carcinogenic activities It is a problem which admits of no simple solution as Dr. Hueper makes clear No one agency governmental or private can solve it Only a carefully coordinated and integrated program of technical and social controls supported by the cooperative efforts of government private health organizations the medical profession management and labor can begin to cope successfully with this growing occupational hazard Such a program deserves the most careful consideration and awareness of everyone concerned with the health of the American people API 07874 Contents : INTRODUCTION ...22 022-222 ene nnn ne nn wwe ene en ee eee eee Page 1 ROLE OF ENVIRONMENTAL AGENTS IN HUMAN CANCER CAUSATION eee eet eee tee baw ee teen neees 4 Definition and types of environmental 4 Circumstantial evidence for environmental causes of cancer . b Conclusive evidence for environmental causes of cancer 10 Chemical environmental carcinogens ~~~. - ---- ee eee 12 Tar and tar products petroleum and oil shale products 12 Aromatic amines 2- 2-0 Benzol - 2-22 ee ee eee ce ene ne eee ee eee ee ee ee eee renew neces 14 16 Arsenic___ Arsenic___ ene ee eee ee ee ee ee ee eee eneeeee 18 Chromium_ 2-222 ee ee ee ce ee meee 18 Nickel carbonyl . 22-2 ee ee ene ee eee 19 Beryllium 220.22 ------ eee nee een ee en ae ee enews 19 Asbe ---s -----t 2 o ees e; nee een eee nce ee ees 20 Potential chemical environmental carcinogens 21 Physical environmental carcinog2e 2.n 2 slee ee eee Ultraviolet raya . 2 we wee eee ee eee ee eee nee eee ec ceee 23 23 Roentgen rays and radioactive substances . 24 Dietary carcinogens . 2-0 en ee eee ene eee 26 _. Cancer of the pharynx Liver cancer 2 2-2-0 ee ee ee enn ee ee eee eee 27 27 Cancer of the thyroid 0-2 eee eee eee 28 Indefinite environmental carcinogens . 2. ee ee eee 28 Schistosomiasis cancer of the bladder e evens 28 nee Betel nut cancer of the mouth eee ee ee 29 Khaini cancer of the lower lip 1... - 222 30 Cancer of the scalp 2-0 ee ee eee eee 30 Thermic can e c eee ee er ee ee eee 30 Extrinsic co- pro- and carcinogenic factore 31 Causative mechanisms ee eee 32 OCCUPATIONAL FACTORS IN CANCER INCIDENCE GROWTH 35 Occupational carcinogenic agents 0-2 ee ee eee 35 Evidence supporting an occupational origin of cancer . 38 Statistical evidence 2... ee ee eee 38 Relation to medicinal and environmental cancers 39 Precancerous lesions 2-022... -- 2 ee ee eee eee 40 Significance of experimental cancers 41 Physicochemical investigations ec eee ee ween eee a 43 Summary of evidence of occupational carcinogenesis . 44 Vv API 07875 ag Ae Occurrence and incidence of occupational cancers in the United States Cancer of the bladder 22-2000 2-02 - ee eee eee. Skin cancer .-- -- n-ne eee eee ee eee eee ee eee Respiratory cancers .. 22 - . Leukemias 22... eee ee ee een ne eee ee ee ee eee nee, ee ee eee ee ee eee, PROBLEMS IN THE CONTROL OF OCCUPATIONAL CANCER Factors responsible for lack of interees ee eet e eee Industrial management 222. 2 ne ne ee ee eee ee eee, Labor and labor organizations . we e eee ee ne Legislative boHed althi Health Inde ustrial Ins dustrial ee enews Departments of Public Health Industrial Hygiene Cancer Control Medical profession .... 222-20 2 eee eee ee ee eee ee eee Public health and industrial prob 2.l .. 2-0e -2 eem eee ens e eee Incidence and causation 2.2 ee eee ee ee nee cence cee Number of carcinogens 2.22.2 - eee ce en ne ce eee ee eens Variety of carcinogenic mechanisms eee cece nae Defects in statistical determination Probability of increase in occupational cancer Chance of exposure widespread 2-2 ee e eee Need for study 2-2-0 ee ee eee eee Control of occupational cancers 2.2. ee eee ee eee eee Elimination or control of occupational carcinogens Medical examinations 2-0-2 0-2 ee ee ween Determination of minimal effective expo2s 2...u .0.. r -- ee e eee Compensation laws 2.22. 2 ne ee eee wee nee Individual identification --- ee eee eee _ API 07876 Environmental and Occupational Cancer . By W. C. HUEPER M. D. Past clinical and experimental efforts toward achieving an effective . control of cancer have dealt chiefly with attempts to improve diagnostic methods and therapeutic measures Without any doubt this work has had a measurable amount of succ^'es However it may be well to remember that the reaching control of infectious diseases achieved during the past 75 years has depended to definite degree on the successful determination and identification of the causative organisms and on a great deal of extensive and aborious epidemiological study Recent developments in the field of cancer make it seem likely that there exists a similar interdependence of factors pertaining to etiology and control As long as the causative agents responsible for over 99 percent of Shuman cancers remain unknown and as long as no determined and widespread efforts are made to fill in this serious gap in essential information there is little hope that rapid progress in the control of ancer can be obtained by rational preventive prophylactic diagJostic and therapeutic measures The prospects of repeating in the held of cancer the results achieved with the control of infectious diseases are therefore not too favorable unless some of methods and approaches used in the latter are applied to cancer research - Although there are many important and apparently fundamental differences between the two groups of diseases their similarities also are numerous Data at present available as to the number and types suggest of extrinsic carcinogenic factors that the prospective spectrum of exogenous and endogenous carcinogens may cover a range of agents spectrum differing from each other as widely as those composing the the pathogenic The recently discovered species organisms pecificity of carcinogenic is analogous to the species specific agents pathogenicity of the organisms infectious diseases The causing arcinogens moreover share with the organisms the marked API 07877 differences in pathogenic potency which characterize the various infec- tious disease agents Just as with several of the infectious diseases the causative infecting agent brings about a sequence of different histological reaction products reflecting changes in the state of reactivity of the host tissues as happens with tuberculosis syphilis etc. so extrinsic carcinogens are likely to elicit various histologic responsen in the tissues such as hyperplasias byperkeratoses warts nodular adenomatoid proliferations benign tumors papillomas and ade- nomas and cancers Furthermore clinical as well as experimental evidence shows that in both infectious diseases and cancer the sites of the anatomical responses are not only determined by the properties of the particulari pathogenic agent involved but also by the type or route of contact with it The conditions of exposure which decide the development of tuberculosis of the lungs and of the inhalation and ingestion respectively fundamentally no different from those which are responsible for the development of cancers of the skin bones lungs etc. after exposure to radioactive material by skin contact inhalation ingestion or parenteral introduction An additional resemblance between cancer and the infectious dis eases is the fact that the degree of pathogenicity or virulence of the causative agents is only in part an extrinsic quality It depends taj some extent also on the intensity and duration of exposure to them Thus the incidence of bladder cancer among workers in dye plants it highest among those most massively exposed to aromatic amines and decreases among other operatives in proportion as their contact with gations have shown a similar crowding of tuberculous infection around persons with active and open tuberculosis of the lung In other words the epidemiological pattern of the spread of cancer and of infectious diseases from foci where causative agents are gent erated is essentially identical For the future control of cancer this fact is of special importance for several reasons The progressive march of occupational cancers through all industrialized countries paralleling the development of modern industries and the continuou creation of new industrial products of often unknown biological prop erties are factors which tend to result in the appearance of an increas ing number and variety of extrinsic carcinogenic foci Since the char it acter of a particular carcinogen as well as the type of exposure to determines the site of the ensuing cancer this development may result in the course of time in a change of the quantitative and qualitative aspects of the environmental carcinogenic spectrum and thereby in the incidence rate of cancer both as to total numbers and as to sites It is evident therefore that for an effective future control of cancer API 07878 we must determine the causes and directions of the new trends and institute procedures for their prevention The repetition of a survey of cancer morbidity in ten different metropolitan areas of the United States first carried out 10 years ago and being undertaken again this year by the Cancer Control Branch of the National Cancer Institute assumes special significance in the light of the above considerations A second step toward more adequate epidemiological analysis of cancer was taken recently with the creation of an Environmental Can- cer Section within the Cancer Control Branch This Section will sup- plement epidemiological studies with investigations into the extrinsic causative factors of human cancer as they are related to occupation medicinal agents diet climate customs habits geological conditions and parasitic infections A third recent development in this field is the launching by the New York State Occupational Cancer Committee of a project to determine in detail the occupational histories of several thousand cancer patients at the Roswell Park Memorial Institute at Buffalo Y. These histories are to be analyzed for previous occupational cancer hazards ustained by the patients - In order to make available a concise and yet comprehensive presentation of current knowledge on the environmental cancer problem for use not only by cancer specialists but also by the medical profession in general public health officials legislatures social welfare workers and members of management and of labor organizations the following per was prepared It is based on lectures given before the Intersational Congress on Cancer Research in St. Louis September 1947 and the postgraduate course of the Department of Occupational Medie Yale University Medical School March 1948. I wish to express by thanks to these organizations for their kindness in permitting me to use the substance of these lectures in this revised form 809261 3 API 07879 Role of Environmental Agents in Human Cancer Causation About the time when the microbial origin of infectious diseases wa established by Pasteur and Koch some 75 years ago the first important data were also made available on the causation of cancer in man by several extrinsic The agents mentioned thus early were arsenic soot tar and crude paraffin oil 163 Unfortunately these basic ob servations on the etiological significance of inanimate environmental factors in human cancer were not followed up with the same vigor vision and persistence as were those relating to the pathogenic ani mate members of our natural environment Although a few addi- tional physical and chemical carcinogens were placed during the following decades on the list of causative agents belonging to the modern artificial industrial environment it was not until isolation of benzpyrene from tar approximately 20 years ago that scientific thinking developed an appreciable interest in the causation of cancer by specific extrinsic factors } Since then a vast amount of experimental cancer research on ani- mals using numerous newly synthesized carcinogenic chemicals has been performed However this scientifically valuable information has added relatively little to our knowledge of the causation of human can- cer 83 Definition and Types of Environmental Carcinogens Any physical chemical or parasitic agent forming a part of our natural or artificial environment that on proper exposure directly or indirectly elicits cancerous growths in one several or all types of human tissues represents an environmental carcinogen Although some of these agents like solar rays soot and arsenic have a practically universal distribution the occurrence of demonstrable environmental cancers is restricted as a rule to regions or to groups of individuals having a particularly intense prolonged or otherwise positive contact with these carcinogenic agents Exposure to these factors is related to great number of highly diverse environmental conditions such as oc- 4 API 07880 . cupational activities diets medicines and medicinal devices cosmetics wearing apparel building materials habits and customs climate fauna contaminants in drinking water atmospheric air foodstuffs and recent procedures of warfare The data supporting an extrinsic environmental causation of human cancers are of two types Some of the evidence is of circumstantial character derived from statistical observations showing definite dif- ferences in the incidence rates of cancers These differences appear in different regions among different races sexes and social and occupational groups and with different climates and also are to be noted in marked variations in the relative distribution of cancers upon the different organs in different countries and population groups The second type of evidence is of a more definite nature and applies to the environmental tumors proper Circumstantial Evidence for Environmental Causes of Cancer From the large amount of circumstantial evidence indicating the action of extrinsic factors in the production of human cancer only a few typical and more recent examples will be cited Analyzing the recorded cancer mortality among the racially highly mixed population of the United States Gover found remarkable variations in different sections 130 The rates ranged in 1930 from 127 per 100,000 for all cancers of both sexes in Rhode Island to 56 per 100,000 in Arkansas Similar observations were reported from Different parts of Europe 58 62 where the lower incidence rates generally recorded from southern countries while the higher ones usually found in the northern parts of the continent The highest cancer mortality was observed in Denmark 58 Although some of these discrepancies are attributable to differences the quality and quantity of medical service and disease reporting in arious parts of Europe and the United States it is not likely that this actor accounts for them in their entirety particularly since these gional variations in total cancer mortality are associated with onsiderable variations in the distribution of cancer of the various gans There was for instance not only a high rate of cutaneous cancer mong both sexes in the Southern States of the United States but also or all sites of cancer of the buccal cavity among females and for acer of the pharynx and mouth among males in comparison with found in the Northern States McDowell noted in 1938 a similar gional distribution of cutaneous cancer in different parts of the 5 API 07881 eeu United States when he recorded an incidence rate of 15 for Atlanta 129 for New Orleans 37 for Detroit 25 for Pittsburgh and 24 for Chicago 233 The incidence rate of cancer of the stomach and of the total digestive tract on the other hand was found by Cramer to be higher in the northern sections and in the Pacific coast area than in lung the west south central and south regions 62 while cancer of the was relatively high in the northeast and Pacific sections Cramer also noted that gastric cancer is most frequent among mem bers of the Caucasian race in Europe and America but there are wide variations of frequency even within that racial group In England and Wales gastric cancer accounts for 22.2 percent of the total cancer mortality in the United States for 42.8 percent of the total cancer mortality in Holland for 55.5 percent in Sweden for 60.5 percent and in Czechoslovakia for 66.0 percent While gastric cancer is rare among the Javanese it is as frequent as in European whites among Chinese with European living habits $ 143 A similar environmental influence is found in connection with primary liver cancer which is very frequent among Negroes in Africa and among Javanese and Chinese in Java while its incidence rate among American Negroes does not differ from that found among American whites 379 397 133 258 307 70 298 60 211 234 Additional evidence indicating that environmental factors appar ently have a definite influence on the incidence rate of certain organ cancers was recently furnished by Lasch 200 He reported striking differences in gastric cancer morbidity rates in various parts of Ger many where for several years an obligatory system of notification was in force Lasch noted that the incidence rate from 1937 to 1989 was considerably higher in the purely agrarian region of Mecklenburg than in the agricultural district of Anhalt the industrialized Saar or urban Vienna On the other hand gynecological cancers showed a higher frequency in the latter three areas than in the The practical absence of penile cancer in Hebrews its relative rarity in Mohammedans its moderately high incidence in American Negroes 357 211 and its very high frequency in Ceylonese Javanese and Chinese do not reflect racial susceptibilities On the contrary these differences are attributable to hygienic environmental conditions related to frequency of and age at circumcision the occurrence of phimosis and similar factors favoring the action of decomposing smegma 60 29 163 357 The marked variations in the localization of cancer in different parts of the oral cavity which have been observed in various parts of India have been attributed to local differences in habits and hygiene 176 It is also doubtful that racial or constitutional factors account for the 6 eC ~? ! t S API 07882 OLE | ABPELI PV onsiderable discrepancies in the incidence of lung cancer in different parts of Europe in some regions of Germany England SwitzerHand and low in France and Italy They are probably caused by local variations in industrial activities habits diets and other environ- mental conditions 61 163 It is generally recognized that racial differences in skin pigmenta- tion are responsible for the higher susceptibility of the skin of fair blond and eyed persons to cutaneous cancer Schrek reports that there were 18.4 percent of cutaneous cancers among 10,857 white Leancer patients against 1.7 percent of skin cancers among 724 colored cancer patients 357 Nevertheless the environmental origin of akin malignancies is clearly indicated by the sex distribution as these neoplasms are much more frequent in male whites than in female whites contrasting sharply with the equal sex distribution observed in colored individuals There exists no valid reason however to at- stribute the excessive incidence of nasopharyngeal cancers in Chinese to a special racial susceptibility 368 It is much more likely that environmental factors of a possibly dietary nature are responsible for | } . ' this phenomenon While conditioned endogenous carcinogenic factors may be be- hind some of the remarkable differences in the cancer incidence of the two sexes there can be little doubt that environmental agents also = ! exert a decided influence A high incidence in males is found for cancers of several organs which have direct or indirect exposure to axtrinsic agents to a remarkable degree The incidence ratio for males and females for cancer of the skin is 4 293 for cancer of the lung 4 to 7 169 391 271 for cancer of the larynx 10 167 ; for cancer of the bladder 5 6 ; for cancer of the esophagus S 10 Cancer of the stomach 385 and cancer of the liver 105 occur more often in males than in females ; , also significant that the local distribution of cancers of the skin andof the intestinal tract as well follows a pattern which in- | fidicates that an extrinsic carcinogenic agent is most active at certain circumscribed areas favoring intense and prolonged contact such as : the face the neck and the hands for cancer of the skin and the physio- logical narrows and curvatures as well as the presphincter regions of the alimentary tract Additional support for these conclusions is derived from studies on the distribution of cancer social cancer among the members of certain economic groups 62 175 327 Such a classification divides the population into groups having varying degrees of exposure not only to known environmental carcinogenic agents such as soot tar mineral oil arsenic actinic energy and others of an occupational character but also to those of a more or less indefinite nature such as j 7 API 07883 diet general personal hygiene wearing apparel living quarters and habits It is found that cancer mortality increases progressively in each lower economic class for all types of cancers except that of the breast Kennaway and Kennaway established the principle of higher cancer mortality in the lower economic classes for cancer of the scrotum and concluded that this type of malignancy is most prevalent in men be longing to a class doing the heaviest type of labor and usually washing least 175 Exposure to soot in town dwellers was considered an additional im portant etiologic factor cancer of the penis did not reveal a similar economic distribution they concluded that different causative factors are involved in the production of this neoplasm The statistical evaluation moreover showed that social grading is present with cancer of the skin and of the larynx is very pronounced for cancers of all sites above the pylorus but is not observed in the remainder of the alimentary tract Ryle and Russell in their studies of the incidence of skin cancer exclusive of scrotal cancer in England Wales Scotland North Ireland and Eire 527 found that there is no increase in incidence with lower ing of social classes in females while with males a distinct increase is found Classes exposed to sunlight soot and grime showed a high incidence For example among men exposed to soot such as furnace men stokers boiler firemen and rollers the rate was 225 against 70 in professional men and collar workers Occupational factors thus appeared to be more important than social class Indeed Clemmesen concluded from his analysis of Danish death certificates that it is not improbable that the latency period for the development of cancer varies in different occupational and social groups depending on the potency of the particular injurious agent and that this fact may sc- count for the differences in local distribution of cancer in different localities and population groups 58 In the Danish material for example there was a low cancer mortal- ity in all agricultural groups and a high one in all industrial groupe The gastric cancer mortality in the industrial group stood at 129 per cent while it was only 57 percent in the collar class Other in vestigations show that cancers of the lung are excessively frequent ini certain varied occupational groups such as engineers mechanics painters decorators metal grinders foundry workers etc. while ther are relatively infrequent in clerks and typists 573 Although Ryle and Russell maintained that the melanomas are not related to ex- trinsic factors 327 Peller 288 noted that white American soldierwi and sailors from the Southern States have melanomas less often API 07884 ose from the Northern States when the number of epitheliomas of the skin are considered but that this relation is reversed when internal cancers are analyzed Additional circumstantial evidence pointing to the action of extrinsic factors in the development of cancers is found in the exist- ence of differences in the local distribution of cancers in certain organ Fystems such as the oral cavity 176 and skin 357 in different regions or racial or occupational groups Similarly significant are the variations in the incidence of simultaneous or successive multi- plicity of cancers during different periods shifts in sex distribution and differences in age range 175 as well as variations in the absolute and relative frequency of cancers of certain organs While such fluctuations are usually ascribed to improvements in diagnosis and treatment and doubtlessly are due to these factors to some extent changes in the quantitative and qualitative composition of the environmental carcinogenic spectrum at different times and localities evidently may also play a major role The marked increase in the number of lung cancers recorded during the last 40 years from many parts of the globe apparently represents a typical example of the results of such an environmental alteration 78 271 333 159 163 391 An extrinsic origin of this phenomenon is suggested by the fact that the increase has been more pronounced in males than in females and that the percentage of adenocarcinomas among the bronchiogenic cancers has been much higher in females 51.7 percent than in males 14.7 percent among whom the squa- mous cell type of cancer predominated 159 The present lack of roof that a single extrinsic agent is wholly responsible for this derelopment is not a valid reason against the conception since it is well known that several agents with highly different physical and chemical properties may cause pulmonary malignancies of occupational origin The definite rise in the incidence of leukemia in the United States since 1900 and particularly since 1930-94.7 percent during the last 20 years -may represent another example of such an environmental change The rise is not accounted for by differences in age distribution of the population and leukemia is twice as frequent in whites as it is in Negroes and more often seen in males than in fe males It is more likely that some environmental leukemiogenic agents benzol aromatic compounds tar actinic energy which appeared some 40 to 50 years ago and have become increasingly common are responsible for the rise The various data of a circumstantial character which are advanced ts favoring a frequent extrinsic causation of human cancers may not be of impressive value when taken separately However when seen as 9 | | | API 07885 a whole and integrated into a pattern they provide weighty evidence supporting such a concept Their validity is greatly strengthened and the concept itself is made more concrete by the evidence supplied by the various recognized environmental cancers Circumstantial evidence for environmental cancer is outlined below 1. Variations in total and organ incidence for both sexes in different regions 2. Differences in incidence rate of certain cancers for males and females 8. Differences of incidence of all and certain organ caucers among vari ous occupational and economical groups and among populations of agricultural industrial and urban regions 4. Differences in the local distribution of cancers in certain organs or organ systems in different regions or population groups 5. Shifts in organ incidence sex distribution frequency of multiplicity age range during different time periods Conclusive Evidence for Environmental Causes of Cancer The environmental carcinogenic spectrum is composed of agents which vary remarkably in their physical and chemical properties In only relatively few instances can the origin of environmental can- cers be traced to contact with defined chemical or physical agents possessing established or suspected carcinogenic qualities such as arsenic benzol aromatic amines ultraviolet rays roentgan rays and rays from radioactive matter A second large group of environmental tumors is elicited by ex posure to defined mixtures of organic chemicals the carcinogenic this components of which are incompletely known The members of second group are tar pitch asphalt soot carbon black crude mineral oils paraffin oils shale oils anthracene oil lubricating and fuel oils creosote and bitumen substance isolated from tar and crude shalo oil benzpyrene is carcinogenic to mice 174 19 and is suspected also to be carcinogenic to man Still a third group of environmental cancers seem to result from contact with inorganic substances particularly certain minerals such as chromates nickel carbonyl asbestos and perhaps beryllium Several dietary deficiencies involving the protein fat vitamin and iodine metabolism are thought to be responsible for a fourth group of environmental cancers while a fifth group is composed of neoplasms arising after contact with chemical irritants of unknown nature such as those contained in betel nut quids or generated by or associated with Schistosoma hematobium 10 API 07886 Listed below are the various groups of environmental carcinogens: 1. Chemical carcinogens Organic chemicals Aromatic compounds tar pitch asphalt soot shale oil crude paramin oll anthracene oil lubricating and fuel oils greases creosote lamp black aromatic amines betanaphthylamine benzidine aniline benzol Aliphatic compounds carbon tetrachloride B. Inorganic chemicals Arsenicals chromates nickei carbonyl asbestos II Physical carcinogens Ultraviolet rays corpusenlar rays alpha and beta rays electronic rays gamma rays Roentgen rays II Dietary disturbances involving protein fat and vitamin metabolism and ee affecting liver pharynx and thyroid ww e IV Undefined environmental carcinogens contained in bete quid khaini and , Schistosoma hematobium The highly diverse physical and chemical properties of these agents hake it improbable that they exert their specific pathogenic action hrough the same mechanism From an analysis of the available data nd from theoretical considerations it appears that extrinsic carcino- enic factors may elicit malignant growths through one of the follow- ways Some of the agents such as aromatic amines and the carcinogens I Contained in tar and related substances apparently act directly on be cellular substrate either in their original form or as metabolites conjugates This action may be merely catalytic as only minute mounts of carcinogens of this type may bring about malignant cellu- transformations 285 62 343 or it may arise through interference with the normal cellular enzymatic activity or by combining with pacromolecular proteins resulting in the formation of allergens A second group of extrinsic carcinogens apparently consists of gents which do not possess direct carcinogenic properties but which bange some normal chemical constituent of the cells or tissue fluids such a way that it becomes endowed with carcinogenic properties In view of the long latency period of actinic cancers it seems probable hat such a mechanism may be active in their development A sim- indirect and secondary mechanism may also be responsible for he occupational cancers caused by exposure to certain metals 393 A third type of environmental carcinogens may cause quantitative or qualitative functional changes in some endocrine glands or the iver which respond with the generation of abnormal endogenous arcinogenic products Cancers of the dietary environmental type may have this origin as may those produced by hepatoxic agents such As certain azo dyes and chlorinated aliphatic hydrocarbons It is obvious that the demonstration of the actual existence of such a mech- 809261 _ 11 API 07887 anism would not only establish a direct connection between extrinsia and intrinsic carcinogenesis but would widen at the same time the potential scope of extrinsic agents as producers of human cancer recent These considerations are of definite importance because of the isolation of cancerigenic substances from normal and neoplastic human infanta tissues and the occurrence of congenital cancers and cancers in 186 154. 357 408. 329,392 329,392 188 These latter may be related to the action of extrinsic carcinogenic agents entering the maternal organism | during pregnancy and acting on the rapidly proliferating fetal tissues after placental penetration Chemical Environmental Carcinogens Tar and Tar Products Petroleum and Oil Shale Products Human contacts with tar soot carbon black pitch asphalt crude petroleum shale oil creosote paraffin oil lubricating and fuel oils greases anthracene oil and other distillation and fractionation products of coal shale lignite petroleum and wood apparently caus the majority of environmental cancers in man The existence of 3,4 benzpyrene in tar 174 and shale oil 20 probably furnishes only partial explanation for the carcinogenic action of these and related substances although Miescher Almasy and Zehender recently claimed that the carcinogenic effect of tar on mice shows a simple and direc . relationship to its content of benzpyrene 241 Reports from various countries during recent years have supplied a great deal of additional evidence confirming and extending thi numerous observations made previously on this subject and reviewa in detail in my treatise on occupational cancers 168 English inves tigators especially have furnished valuable data on the occupationa aspects of these cancers and on the relationship between duration and intensity of exposure to the length of latent period and manifestation age 176 154 147 37 19 235 These studies have again brought on the fact that environmental exposure to these substances is widespread and often not readily suspected Workers such as steTO dores electric brush makers manufacturers of paper covered electric conduits alaters and bricklayers are subject to it Kingsbury rey ported the occurrence of a scrotal cancer in a Tamil engaged in anti malarial oiling of surfaces of water in India 179 : No appreciable reduction in the incidence of tar and oil cancers segma to have taken place in England during the last decade In 1935 posure to tar pitch mineral oil and creosote caused 171 epitheliomas in 1936 the figure was 142 120 ; and in 1943 it was back at 160 235 Some measure of success in reducing the excessive incidence of cancer 12 API 07888 - of the skin among workers exposed to Scottish shale oil was obtained by the use of a protective lanolin ointment and the exclusion of redhaired freckled and skinned workers from employment in op- erations entailing contact with shale oil 5 44 Reports from France Belgium and the United States on the occur- rence of tar and oil cancers are rather meager but there are good rea- sons to assume that the number of cases reported represents only a fraction of the cases which actually were observed 18 268 Firquet and Malter found two cases of skin cancer among 126 Bel- gian workers exposed to tar and pitch containing on spectrographic analysis 1 to 8 percent of 1.2 benzanthracene and traces to as high as 0.4 percent of benzpyrene 109 Inasmuch as the incidence of : skin cancer in this occupational group did not differ from that seen in the general population these investigators concluded that the two chemicals mentioned were apparently not carcinogenic to man a con- clusion evidently not warranted by the evidence on hand In the United States Schwartz and Tulipan mentioned the occurrence of epitheliomas in 5 out of 100 workers employed in a manufacture of electric conduits covered with pitch impregnated paper 340 Chase . observed a typical scrotal cancer in a chimney sweep and Klauder . . found an epithelioma in a paraffin presser 185 Although Jonas j , L as well as Schwartz reported the occurrence of numerous cases of creosote burns in workers creosoting wooden blocks and in construc- tion workers handling creosoted lumber no case of creosote cancer - of the skin was placed on record in the United States 168 339 Although Stewart recently mentioned the occurrence of cancer of exposed skin the in especially the hands and forearms of grease pit -workers in service stations 358 Gafafer and Sitgreaves analyzing the incidence rate of cancer among the employees of an oil refinery :. f did not find any significant difference from that of the general popyR lation 121 In view of the carcinogenic action of some lubricating R~ fuel and Diesel oils 571 192 cancerous reactions may result from the accidental injection of such products into the human tissues grease g P gun finger Diesel jet injuries 38,45,230,401 38,45,230,401 38,45,230,401 38,45,230,401 f While the carcinogenicity of wood soot and wood tar present in F foodstuffs smoked meat and medicinal and cosmetic agents oint- f ments hair lotions eyebrow pencils etc. is not certain 280 Schock reported from Germany a observation on the development of numerous warts of the scalp following the prolonged use of a brilliantine containing petrolatum 384 Wood noted a unique case of a bilateral carcinoma of the lungin a patient with lipoid pneumonia caused by the inhalation of mist of mineral oil 406 The role which the inhalation of tar dust and fumes plays in the production of cancer of the lung in man is still unsettled 257 254 13 API 07889 ee = ( 315 despite the experimental evidence that soot obtained from gaso line motor exhaust products and from atmospheric dust causes cancer of the lung after inhalation or sarcoma of the subcutaneous tissue after injection in mice and rats 290 47 345 Although the high incidence of lung cancer among stokers in a Japanese generator plant exposed to the inhalation of hot tar fumes supports such a relation ship 173. 191 statistical studies of lung cancer mortality rates in the population of various American cities having marked differences in atmospheric soot seem to contradict it as far as purely environ mental exposure to soot is concerned The lung cancer rate among males in Pittsburgh was found to be lower than that of any other large city surveyed with the exception of Denver A direct contact with tnr and the inhalation of tarry fumes in connection with tobacco smoking has been related on the basis of some doubtful evidence to the occurrence of cancer of the lip oral cavity tongue and larynx 167,237 167,237 It is most likely that tarry combustion products play the major role in the development of cancer of the abdominal skin which accom panies the use of certain heating devices such as the Kangri in Kashmir the Kairo in Japan and possibly the Chang in China 264 131 A similar mechanism is evidently responsible for the chutta cancer of the mouth seen among the Northern Cicars of Vizagapatam province in India who develop cancer of the hard palate due to contact with tari fumes and to burns caused by smoking cigars with the lighted end inside the mouth 180 181 This practice is followed by men and women alike and is responsible for the fact that cancer of this parti of the oral cavity is six times more frequent among the Northern Cicars than it is among the inhabitants of the Bombay region An other example of a habitual cancer in which contact with soot and grime seems to play the major part is offered by the dhoti cancer which develops in the region of the loin and the groin as the result of friction and chemical irritation produced by the continued wearing of a loin cloth covering the nether parts of the body As this garmenti is not often removed and cleaned the accumulation of soot from the fireplace in addition to the decomposition products of unsaturated akin fats 177 play the causative role as it seems also to do in the production of scrotal cancer among the poorer classes in England 175 235 Aromatic Amines The possible production of cancer of the urogenic organs by exposure to aromatic amines and aniline dyes has attracted continued attention during the past few years 68 305 313 265 6 52 227 862 55 New am cases of bladder cancer in dye workers have been reported from sev . 14 i i API 07890 al countries including Switzerland Italy France England and the United States Both Slotkin and Maguigan noted such tumors in dye workers of Buffalo's chemical plants 348 227 Recent clinical observations finally seem to have established the carcinogenic prop- erties of benzidine about which there existed some doubt While betanaphthylamine is generally recognized as a potent carcinogen alphanaphthylamine seems to be noncarcinogenic and aniline has remained in the controversial column A great deal of uncertainty also exists in regard to related aromatic amines such as phenylbetanaphthylamine which is used for the prevention of aging in vul canized rubber 57 92 It is significant in this respect that Rosenthal noted the occurrence of hemorrhagic cystitis among girls employed in a glue factory in which homologues of aniline were used in the preparation of the glue and that Koelsch recorded similar symptoms in English ammunition workers handling aniline o- m- and toluidine and xylidine 314 188 It is likely that the incidence of bladder cancer might rise if a therapeutic practice originally advocated by Henschen in 1937 and recently endorsed by Allemann should find general acceptance Henschen advised the treatment of bladder cancers by oral medication with betanaphthylamine which he and Allemann believe to be a form of biological chemotherapy for cancers of this organ 6 148 On the experimental side the work of Bonser and of Maguigan and Dobriner has confirmed the previous investigation of Hueper and workers by producing cancer of the bladder in dogs by ingestion of commercial as well as pure betanaphthylamine 32 227 163 Laguigan and Dobriner 227 however failed to cause such tumors in dogs by the administration of benzidine though it evoked hepatomas and leukemias in rats Slotkin announced that the first successful . experimental production of aniline cancers had been brought about by Sahr in 1905 in dogs and rabbits The animals developed bladder neoplasms 3 months after ligation of the ureters and exposure to benzidine and betanaphthylamine fumes These results have been confirmed by Slotkin 348 Experimental observations indicate that other aromatic chemicals are capable of producing bladder tumors aminoazotoluene 407 275 acetylaminofluorene 19 toluidine 252 and azotoluene 361 Stroembeck's experiments on rats incidentally seem to settle a controversy of long standing as to whether the carcinogenic substances elicit neoplastic responses by direct contact with the vesical mucosa as urinary constituents or reach this tissue by the hematogenous route 361 Stroembeck implanted a segment of the bladder of rats into the liver and then administered azotoluene While tumors developed in the bladder stump the transplants in the liver 15 API 07891 ae Ve remained normal indicating thereby that the carcinogenic agent is contained in the urine Bensol Additional evidence of a leukemiogenic action of benzol has been recorded during recent years 91 216 142. 382. 164 301 289 272 236 The widespread exposure of workmen in industry to benzol is evident from recent reports 402 75 165 356 341 196 116.9 It is significant in this respect that Duvoir Fabre Fabre and Derobert 84 were able to demonstrate benzol in the bone marrow of two men who died from chronic benzol poisoning 14 and 20 months respectively after cessation of exposure to this chemical Other observations suggest that chronic exposure to benzol may be responsible for the development of polycythemia vera 247 148 Kirschbaum and Mixer did not succeed in verifying the previous claims of deLignac that mice exposed over several months to benzol develop leukemia 184 Finally it may be noted that Meyer observed the occurrence of acute leukemia in a patient with subchronic naphthalin poisoning and that Rolland saw the development of an acute leukemia in a workman handling naphthol 238 310 Experimental evidence indicates that tar and several synthetic aromatic carcinogens are capable of eliciting leukemic re- sponses in mice 184 118 119 193 212 239 149 170 100 204 Arsenic - Among the inorganic chemicals arsenic has enjoyed for years a doubtful role as a carcinogen although next to soot it is the oldest substance related to the development of occupational cancer Paris 1825 Kennaway recently relegated this claim to the realm of cancer mythology and was seconded by Boyland 174 Schwartz asserted that contact of arsenicals with the skin does not cause cutaneous malignancies but that the ingestion of these substances is essential 339 While Henry was uncertain whether or not to accept as of arsenic origin a scrotal cancer in a sheepdip worker handling sodium arsenite , he conceded that such an etiology might exist for 3 cases with medicinal . | i e oral exposure to this chemical and mentioned 13 additional cases which he suspected might have the same causation 147 It is interesting to recall in this connection that Richerand reported the presence of scrotal cancer in arsenic workers as early as 1815 and that Bayle noted them in 1833 in lead workers according to White 396 Although White did not consider these reports reliable it may be worth noting that Tamponi recently mentioned the develop- ment of ulcers of the scrotal skin in certain Sardinian workers who used a spray containing sodium arsenite for combatting ' grasshoppers 16 API 07892 om =e 364 Negishi recorded the occurrence of arsenic poisoning in lead- workers 260 and Schaerrer reported arsenic of cancers the skinin , silver miners 352 Additional cases of occupational cancer through contact with arsen- Lical spray or fumes from smelters have been recorded in America 112 366 Japan 245 England 269 104 296 55 and Germany 287 146 29 While none of these cases showed scrotal lesions this fact scarcely represents a valid reason for denying such a localization especially if the conditions of exposure and of personal hygiene should favor a cancerous development at that site Although Gross con- sidered the incidence of industrial arsenic cancer as low 136 there is no doubt that arsenical occupational dermatoses and hyperkeratoses among various types of workers loaders and packers of arsenicals cotton field workers vineyard workers workers in arsenic plants are not uncommon 335 231 172 117,53 117,53 Despite the controversial evidencein regard to industrial arsenical cancer of the skin its occurrence on medicinal basis appears to be In firmly established 166 375 384 300 286 16 325 281 357 248 308 1-326 9 106 316 147 129 view of the recent claim of Merewether 35 that nobody could relate the development of a melanomatous malignancy to an exposure to an extrinsic agent mention may be made of an observation of Rothman and Felsher 16 who reported the oc- -currence of a malignant melanoma on the basis of a medicinal arsenical leukomelanoderma Strong evidence recently has accumulated according to Hunter 164 indicating that exposure to arsenicals may predispose to the development of cancer of the lung In support to this claim he revived the theory of the arsenical origin of the lung cancers in the miners of * Schneeberg and Joachimsthal The occurrence of cancer of the lung in persons with cutaneous evidence of chronic arsenic poisoning in con- nection with industrial or medicinal exposure was reported for nine . cases 36 235 147 248 287 129 Similar claims have been made in regard to the causation of bladder cancer In view of the rare development of hyperkeratoses and cancer in persons exposed to arsenicals among 12.321 orchardists known to be in contact with lead arsenate 259 and none among the arsenic eat- ing mountaineers of Tyrol and Styria -Wile considered other predisposing factors to be essential 398 The experimental evidence of the carcinogenicity of arsenicals is meager and is merely suggestive 309 163 It is possible that the relatively short lifespan of the mice used prevented the arsenicals from taking proper effect or that the more rapid and effective excretion of arsenicals through the hair in furred animals is responsible for the present unsatisfactory experi- mental results 17 API 07893 Chromium which Chromate cancer of the lung is another of the metal cancers deserves special attention because of its rather recent discovery Although the obscure nature of its causative mechanism 338 207 Stewart recently asserted that the statistical evidence supporting the claim of an occupational origin of these tumors was filamentous 358 this contention is not borne out by the actual data available Kennaway commented on the extremely high incidence of lung can cer among the chromate workers at Griesheim 174 apparently ra ferring to a previous statement of Gross 136 who had placed the incidence rate of lung cancer as high as 40 percent for the worker popu lation of some plants From the official information available there were in Germany up to 1939 a total of 39 cases of lung cancer among approximately 1,000 chromate workers employed in several plants for a sufficiently long time to be affected 165 The incidence of lung cancer among the chromate workers living and dead was thus 4 percent according to noncorrected figures and was in all probability higher This is at least four times the normal rate for the general adult population Recent observations indicate moreover that the occurrence of them cancers is not restricted to German operations as similar cases have been observed in American chromate plants 224a Cancers developed mainly in workers employed in and aroun chromate and bichromate operations where exposure to chromat i dust was present 7 136 137 Workers affected were employed the grinding and mixing of ores in the oxidation of chromite t chromate and in the transformation of monochromate to bichromati Chromium pigment workers clerks glazers drivers and locksmith working transitorily in and around such operations were also affected The length of exposure varied from 7 to 47 years and the age of work ers with manifest lung cancers from 29 to 69 years Kennaway recent statement 174 that the relatively advanced age of these work thi ers indicated a comparatively mild cancerous stimulus despite high incidence of lung cancer among those exposed is therefore oper 2 to question The actual extent of this cancer hazard cannot be properly evaluated at this time for lack of reliable data However it may be considen able Chromium ores which are mined in South Africa Turker Greece and the Philippines are extensively used for the production of armor plate projectiles gun carriages axles springs cutlery and other steel goods as an alloy of manganese cobalt tungsten vana dium and nickel for the manufacture of speed tools exhaum valves turbine blades roller bearings and pump rods in stainles steel processing for pigment making in inks paints glass 18 - a wets, API 07894 pg 1 - 1 enamels as oxidizers in aniline dye production as mordants and tanning agents for bleaching fats and oils and for the plating of metal parts 380 The only experimental evidence available is that offered by Schinz who implanted metallic chromium in the thighs of rabbits and ob- served in some which survived for more than 4 years a few sarcomas at the site of implantation and some lung carcinomas 333 Nickel Carbonyl The occurrence of cancer of the nasal sinuses and of the lung in copper refinery workers in South Wales may represent another example of metal cancer with nickel or nickel carbonyl as the active agents The South Wales refineries use nickel ores mined at Sudbury * Canada and subject them to the Mond process which uses nickel carbonyl in the separation of copper from the nickel 24 This con- * cept is disputed by Amor 8 who claims that none of the workers who come in contact with nickel carbonyl suffer from any diseases > of the respiratory tract He believes that arsenic is the carcinogen responsible for these cancerous manifestations in the respiratory , organs because such reactions have not been seen among workers in y Canadian refineries using the same ores and the same procedures , except that sulfuric acid is not employed for the extraction of copper It is not possible at this time to comment on these claims without knowing the length of time that the Canadian plants have been in #> operation As the average latent period of these cancers is 22 years . the apparent absence of nasal and pulmonary cancers among the Canadian workers may simply be due to time factor " Up to 1939 there were 34 cancers of the nasal cavity and sinuses _ , mainly the turbinates and ethmoids and 24 cancers of the lung 55 An analysis of the death certificates issued in South Wales showed that 36 or 34.2 percent of the 105 cancers of the respiratory organs * which occurred between 1907 and 1934 among the population of the - district in which the nickel refineries are located were in copper refinery workers The attempt made by Campbell to produce lung cancer in mice by the inhalation of nickel dust gave inconclusive results 47 Beryllium The development of sarcoid granulomas in the lungs of workers exposed to the inhalation of beryllium dust represents the most recent addition to the list of blastomatous and blastomatoid reactions to metals in man 122 197 Lanza collected 20 to 25 such cases in a plant manufacturing fluorescent Gardner mentioned a total of about 100 cases with pulmonary reactions to beryllium Of these 809261 * 19 API 07895 he considered about 60 as being genuine The relatively large num ber of cases observed within a comparatively short time indicates the possible extent of this industrial hazard 155. 400 381. 229 353. 201 65 and reflects the wide use beryllium has found in industry in recent years The metal is used as an alloy with copper aluminum magnesium nickel iron and silver It is used in fluorescent lamps as a phosphor It is found in radio tubes incandescent lamps electric heating elements and in phosphorescent compositions such as lumi nous indicators Refractories particularly certain types of crucibles contain it as do vitreous enamels gas mantles and certain textiles It may also be a part of the process of producing atomic energy The actual causation of these pulmonary reactions in the human lung is unknown However there is some indication that other factors besides beryllium are at work Experiments on dogs rabbits guinea pigs white rats and white mice did not result in pulmonary proliferative responses when zinc beryllium oxide or other mixed phos phors such as strontium barium and cadmium were administered by inhalation or injection On the other hand rabbits injected intravenously with zinc beryllium silicate and insoluble beryllium oxide almost invariably developed highly malignant sarcomas of the bones within 5 to 7 months 122 These tumors closely resembled those caused in the bones of luminous dial painters by radioactive matter Asbestos Another one of the more recently discovered occupational cancer in which may belong to the metal group is the cancer of the lung asbestos workers Asbestos consists of polymerized silicon oxide mole cules which form long chains laterally interconnected by weak metal ion links iron magnesium aluminum caesium Since 1935 of 23 cases of asbestos cancer of the lung has been reported by American English and German investigators 221 222 128 406 162 96 188 393 390 158 214 160 28 330 Wedler 390 noted that on there were 14 cases of lung cancer a among total of 92 autopsies asbestosis patients Four of the cancers were present in females the rest were in males They ranged in age from 35 to 75 yearasnd the exposure time from 3 to 27 years It is noteworthy that the manifestation age of asbestos cancer is relatively young The asbestos industry in the United States employed some 19,000 workers in 1944 347 More than 10,000 of these were exposed ap preciably to asbestos dust 197 Despite this high percentage This exposed individuals the incidence of asbestosis is low 347 information contrasts strongly with that available from Germany where Boehme studying 132 out of 500 workers in an asbestos factory found radiological evidence of asbestosis in 29 percent 27 7 Te ee ~ ee me re me a: API 07896 d ncidence of this complication increased with the length of exposure Asbestosis was present in 5 percent of workers employed for less than 8 years 18 percent of those employed from 3 to 5 years 56 percent of those working from 5 to 10 years and 79 percent of those exposed for over 10 years Nordmann and Sorge 267 exposed mice to inhalation of asbestos dust for from 6 to 9 weeks Of the surviving animals 20 percent developed squamous cell carcinoma originating from the bronchial mucosa Other epithelial growths in various stages of development - were present in 42 to 57 percent of the animals in addition to diffuse or nodular fibrosis of the lung The histological character of the cancers squamous cell carcinoma instead of adenocarcinoma of the spontaneous type and the histogenetic derivation of the tumors bronchial mucosa instead of alveolar epithelium of the spontaneous type support a specific causation of these reactions by inhaled asbestos dust - Potential Chemical Environmental Carcinogens Experimental evidence obtained during the last few years indicates . that perhaps only a small part of the total number of existing environmental carcinogens is known and that entirely new types of agents * may be discovered This is foreshadowed by the work of American investigators who found that selenium diethylene glycol carbon tetrachloride chloroform ethyl carbamate and ergot are capable of producing tumors of the lung liver bladder or nervous tissue in mice rats It is interesting to note that several of these substances are _ aliphatic compounds which are not ordinarily credited with possessing carcinogenic properties However the possibility that aliphatic p chemicals or their cyclic condensation products may exert such an i action in man is suggested by recent observations in the field of oc- B cupational carcinogenesis The fact that environmental cancers can , be produced by metals or aliphatic compounds seems to call for a great * deal more attention to these agents than has been given in the past Selenium which has found extensive use in industry during recent years is the cause of the called alkali disease among cattle in those parts of the United States where the soil contains excessive amounts of the substance Cirrhosis of the liver and hepatomas were produced in rats which were fed selenium 262 Male rats fed 1. and 4 percent of diethylene glycol developed stones in the bladder after 32 weeks and papillomatous bladder tumors in third of those tested One of these tumors was carcinomatous 262 The hepatocarcinogenic action of chlorinated aliphatic hydrocarbons such as carbon tetrachloride and chloroform which are used as anesthetics in medicine and as cleaning fluids and solvents in industry 21 API 07897 offers another example of the incompletely explored spectrum of environmental carcinogens 95. 93 102 94 101 While there is no information as yet on hepatic malignancies in man resulting from cirrhosis of the liver caused by an exposure to these substances ample evidence is available to show that these chlorinated hydrocarbons rep resent a considerable industrial hazard and have occasionally given rise to liver injuries 80.190.87,360.74 80.190.87,360.74 80.190.87,360.74 80.190.87,360.74 80.190.87,360.74 163 Of considerable significance is the discovery of the carcinogenic action of urethane ethyl carbamate on the lungs of mice When urethane was administered with the drinking water or by subcutaneous or intraperitoneal injection once a week for not more than 4 weeks the incidence of lung cancers rose from a normal level of 5 percent to 80 percent within 4 months of observation 263 149 150 199 Propylbutyl and carbamates were relatively ineffective in this respect Inasmuch as mice and other small laboratory animals are much more sensitive to the pharmaco actions of urethane than are dogs and men it is possible that there may be similar specific differences in its carcinogenic effect It is significant however that ethyl carbamate exhibits an ambivalence concerning cancer which is similar to that shown by other carcinogens such as roentgen rays radioactive | substances arsenic and benzol Like these it is not only capable of eliciting cancerous growths but also of inhibiting them Urethane when given repeatedly over a period of several months to patients with myeloid or lymphoid leukemia produces a transitory reduction in the number of leucocytes and in the size of the spleen and lymph- node resembling that caused by the administration of roentgen rays or benzol 284 Another hint at the carcinogenic potentialities of our modern envi- ronment is offered by the fact that rats treated over a period of several : months with ergot developed neurofibromas in the ear 262 This observation is of special interest since no direct evidence of any envi- ronmental causation of tumors of the nervous system has as yet been put on record That such a causative mechanism is possible is indicated by the fact that animal tissues react with the development of gliomas and gliosarcomas when synthetic aromatic hydrocarbons are implanted Nervous tissue is thus shown to be susceptible to these agents More over the appearance of a glioma in the brain of a rat fed acetylamino- | 4 fluorene a chemical developed as an insecticide 405 demonstrated the possibility of an indirect contact of the brain with a cancer produo- ing environmental agent 217 This action perhaps depend on certain chemical affinities of the nervous tissue similar to those pos- sessed by bone marrow for benzol and of bony tissue for radioactive g substances There are without doubt other environmental exposures which may 22 API 07898 ey x 3 ^' 5 < dad nvolved in the causation of cancer in man In view of the role which estrogens play as cocarcinogens in the production of mammary cancer in mice including those of the male sex 195 and of the alleged . but still unproved similar effect in women the recent observation of swelling of the breasts due to a proliferative glandular hyperplasia ee ayn in male workers engaged in the production of stilbestrol is of distinct interest 331 110 The subsequent appearance of mammary cancers in such workers would provide positive proof of the existence of such relations since cancers of the breast are rarely met with in human males The ratio of male to female mammary cancer is 1 to 88 281 Suggestive evidence supporting such interrelations was provided recently by Abramson and Warshawsky who observed the development of a mammary cancer in a man who received over prolonged periods a dose of diethylstilbestrol 1 mg daily for a total of 1,097 mg in the treatment of cancer of the prostate 1 Physical Environmental Carcinogens Ultraviolet Rays - The concept of the causation of cancer of the exposed parts of the human skin and lower lip by the ultraviolet portion of the solar spectrum has during recent years received additional support from epidemiological occupational sexual racial and experimental ob- servations 293 25 363 216 Since not only chronic solar for chemical dermatitis and cancer but also the called senile kera- ses are absent or very rare in colored persons it is probable that these ecursors of cutaneous cancer in the skin of white persons are at least part the result of exposure to injurious environmental influences 352 The actual causative mechanism of solar cancer has remained as obscure as that of other actinic cancers Itis not likely however that these neoplastic reactions ensue from a sudden physically induced cellular mutation because of the long latent period usually observed Whether or not the photochemical production of endogenous carcinogenic chemicals through a direct action of ultraviolet rays upon certain cellular components sterols aromatic protein complexes pyrimidines might be responsible for these cancers is still uncertain as attempts to isolate a chemical carcinogen from irradiated tissue have been unsuccessful 359 153 Discussing the practical importance of solar cancer for members of the white race Blum 25 noted that even if a carcinogenic action of solar rays on the human skin is granted there is no cause for alarm Under most severe conditions of exposure only tenths of 1 percent 23 API 07899 of the population develop skin cancers It is not thought that the solar cancer hazard would necessitate the exclusion of the skinned members of the white race from colonizing the tropics since adequate protective measures are available and since the existing hazard is small This conclusion receives some support from the considerably lower incidence of solar cancer among the female part of a population in sunny dry regions Probably this is due to the fact that women : take better care of their skin and are more prone to apply protective measures and also to the fact that they undergo less exposure for reasons of sport and occupation Roentgen Rays and Radioactive Substances The danger of cancer formation through exposure to corpuscular energy alpha and beta rays and electronic energy gamma rays and roentgen rays which was previously restricted to relatively small groups of individuals has reached considerable proportions through the scientific military and civilian use of atomic energy with its numerous radioactive fission products 193 206 79 49 90 378 877 111. 169 389 261 254 255 399. 88. 404 270 35 251 312 303. 39 Uhlmann pointed out in 1942 that despite the improvements in roentgen apparatus and technique many injuries are still caused by actinic burns 374 He saw 70 such cases in 3 years in the Tumor Clinic of Michael Reese Hospital Chicago While about half of these injuries were present in physicians only five were found in roentgenol ogists The others were general practitioners and specialists of other branches of medicine handling roentgen equipment and radium He believes that physicians in general are not sufficiently familiar with the techniques of using such devices and with the proper precautions to be observed The indiscriminate use of electronic energy during the First World War resulted in many burns with their frequent carcinomatous sequelae which are said to follow in 25 percent of all chronic radiodermatitis cases Evidence is accumulating that the industrial and medical use of roentgen rays and radium during World War II was not entirely free from similar complications despite the increase in knowledge of protective measures essential to their use Drinker recently noted 80 that the misuse of ray equipment in the hospital of one Maritime Commission shipyard forms an unwholesome chapter in our war history and that in other shipyards where roentgen rays and radium were employed for the inspection of weldings and castings proper precautions were observed only after some struggle with the physicists in charge and the managements Additional evidence on occupational medicinal and cosmetic radiation injuries and cancer has been reported during recent years 295 24 AFI 07900 * 208 345 161 67 171 48 145 225 McMahon et al recorded what might be the first human case of sarcoma formation following diagnostic intravenous injection of thorotrast 12 years previously 225 Hatcher reported the occurrence of bone sarcomas following the irradiation of tuberculous joints with large doses of roentgen rays and radium and collected 24 such eases having a median latent period of 6 years 145 New evidence was advanced supporting the leukemiogenic action of small doses of electronic energy in man similar to that seen previously in mice 163 149 182 119 Ulrich found that the incidence , of leukemia among American radiologists is eight times that of the average physician 576 A 8.9 percent mortality from leukemia was reported among 205 radiologists who died between 1935 and 1944 against 0.44 percent among 34,626 physicians dying during the same . period Using similar statistical materials March 576 noted similar relations over a period of 15 years 8 cases of leukemia in American radiologists with 23 additional cases recorded in the world literature Correlations of the incidence of leukemia among American physicians with that of the white male population in general revealed that leukemia is 1.7 times more frequent among the former 150 Similar evi- dence was found in the Decennial Supplement part IIa Occupational Mortality Report of the Registrar of England and Wales 1931. It is interesting to note that Warren observed one case of monocytic leukemia following a preliminary leukopenia and anemia among those Japanese exposed to atom bomb radiation 389 No fundamentally new or important information has been recorded during the last few years in regard to the causation of lung cancers among the cobalt miners in Schneeberg and the uranium miners in , Joachimsthal although the significance of this problem has greatly increased If reports from these regions are correct these mines as well as those previously abandoned in adjacent territory are being worked with high intensity for radioactive ores Other pitchblendecontaining mines in Canada and the Congo have been mined for atomic fission materials at a greatly increased rate since the end of the war Search for similar ores is carried on in many lands for the same purpose Such activities entail exposure to the inhalation of radioactive dust and gases a hazard which may extend if proper precautions are not taken to the neighboring population Similarly populations surrounding atomic energy plants may be exposed to radioactive fumes and waste waters In view of these facts it seems urgent that definite information be obtained whether the lung cancers of the Schneeberg Joachimsthal miners are caused by radioactive energy 163 or by 25 API 07901 other substances present in the ores such as arsenic 8 nickel 333 chromium 136 or at least in part by concomitant silicosis 218 Campbell's experiments on mice inhaling a pitchblende dust con- taining no arsenic and practically no radium gave inconclusive results as to the development of lung cancers 47 Lorenz Heston Deringer and Eschenbrenner exposed mice to a continued irradiation with gamma rays 8.8 r gamma per 8 definitely higher than that to which the Schneeberg miners are subjected and found that lung tumors increased over 50 percent above the normal level 219 In view of the marked differences in exposure these investigators concluded that the Schneeberg cancers are apparently not of radioactive origin However inasmuch as the degree of exposure to radioactive materials varies greatly at different times and in different mines at Schneeburg this conclusion cannot be accepted without distinct reservations On the other hand experiments of a similar nature performed on mice by Rajewski Schraub and Kahlau 502 resulted in a larger increase in the incidence of lung tumors but they cannot be regarded as reliable because of improper experi- mental conditions as to age and selection of animals Henshaw 149 and Henshaw and Riley 151 produced leukemic conditions in addition to skin cancers in mice exposed to small amounts of rays as well to pile radiation Furth 119 observed not only leukemic conditions but also ovarian cancers in female mice after a generalized radiation Osteogenic sarcomas were produced in animals by the intradermal injection and oral feeding of 25 to 100 gamma of radium 82 103 and by the insertion of mesothorium into the bone marrow of rabbits 338 Brues 40 obtained bone tumors in animals exposed to various uranium fission products from a chronic reacting pile The length of the latent period of these tumors was a function of the dose Petrov and Krotkina 292 furnished proof of their observations reported several years ago on the development of carcinoma of the gall bladder in guinea pigs following the implanta- tion of radium Dietary Carcinogens A great deal of experimental evidence relates dietary conditions to | the development of cancer in animals 46 253 297 321 such as the effect of caloric restriction on the incidence of cancer 365 323 324 198 322 ; the influence of members of the vitamin B complex riboflavin inositol choline biotine amino acids cystine avidin and various oils on the susceptibility or resistance of the liver in rats to the carcinogenic action of certain aromatic compounds 44 124 26 ares C9 DC API 07902 FOT LESIPEV 57 272 187 342 205 212 45 ; the effect of cystine and lysine on the ncidence of spontaneous cancers in the mouse 394 134 240 395 ; and the possible production of carcinogenic products through the development of oxidated oils as the result of overheating animal and vegetable fats and lipoids 291 17 16 | - While these experimental observations have no counterpart as yet in the production of human cancers by environmental agents there are several environmental cancers in man in which dietary factors apparently play a definite while indirect role Cancer of the Pharynx In those parts of Sweden and Finland located within the Arctic Circle the main diet throughout the year consists of reindear meat and salt fish Only during the short summer are green vegetables available As a result of this unbalanced deficient diet a symptom complex appears mainly in women which is termed the PlummerVinson syndrome During the course of the deficiency state hyperkeratoses of the oral and nasopharyngeal mucosa develop which ultimately lead to the appearance of cancer of the nasopharynx 4 2 249 Ahlbom found this syndrome in 65 percent of 123 women with cancer of the mouth pharynx and esophagus 4 - Liver Cancer The second member of this group is the primary cancer of the liver which occurs apparently on the basis of certain dietary deficiencies among African Negroes particularly Bantus employed as miners in the gold mines of Witwatersrand near Johannesburg and also in Javanese and Chinese The excessive incidence of these cancers which | are relatively rare among whites and also among colored people . joying European living standards has been known for a number of years 343 21 31 and has been attributed variously to some special racial susceptibility to endemic parasitic infection or to nutritional deficiencies 174 21 317 The dietary theory has found an increasing number of supporters in recent years as these cancers developed on the basis of a cirrhosis Since it had been shown that cirrhosis of the liver in experimental animals 30 140 66 86 26 follows certain dietary deficiencies protein and vitamin B complex and since it is known from human observations that cirrhosis of the liver is a frequent precursor of primary cancer of the liver a dietary origin for these cancers in the nourished colored people was suspected This concept recently received weighty support from the clinical pathological and experimental studies of a group of South African scientists 125 126 127 809261 27 API 07903 who succeeded in producing cirrhosis of the liver as well as primary cancers of that organ in rats fed the deficient diet mealie pap and sour milk consumed by the Bantus Similar observations were reported by Copeland and Salmon 61 who elicited cirrhosis and carcinoma of the liver in rats fed a diet deficient in choline The animals developed not only tumors in the liver but also primary cancers in other internal organs including the lungs It will be important to watch for the possible development of these and other types of dietary cancers among the starving people in vari ous parts of the globe especially as the available diet is often deficient in proteins fats and vitamin B complex and in view of the fact that primary cancer of the liver is uncommon among white Europeans Another location which may yield additional confirmation is Trinidad where the laborers employed in the oil fields have a diet which is grossly deficient in vitamins A and B 85 Cancer of the Thyroid The excessive incidence of carcinoma of the thyroid in regions with endemic goiter due to iodine deficiency in the soil drinking water and foodstuffs represents the third example of an environmental cancer in man on the basis of dietary imbalances 386 These cancers usually originate from adenomatous nodular goiters and have their experimental counterparts to some extent in the thyroid hyperplasias and adenomas produced in rats when given a diet of rapeseed or one containing thiourea 299 135 In 2 of 30 rats given thiourea the resulting thyroid tumors were metastasizing carcinomas This malig nant transformation of thiourea thyroids can be enhanced by the simultaneous administration of aminofluorene 22 The possible implications of these observations in rats as to the potential | hazards connected with a prolonged thiouracil treatment of toxic goiter in man are obvious Indefinite Environmental Carcinogens The last group of cancers to be listed has a established relation to environmental agents which are of defined character Schistosomiasis Cancer of the Bladder Although the excessive incidence of bladder cancer among the inhabitants of Egypt and the causal relation of this neoplasm to an in- fection with Schistosoma hematobium has been known for many years in fact it is the oldest recognized environmental cancer it still | { API 07904 | seems to be rather common among the fellahs of the Nile Valley Ward recently observed 130 cases of bladder cancer in a Cairo hospital most of them were associated with schistosomiasis Twenty of his pa tients were under 30 years of age 387 This is only one of many environmental cancer observations incidentally which indicate that senile changes have very little connection with the causation of many cancers Afifi has stated his doubts of the actual existence of causal relations between vesical schistosomiasis and bladder cancer 3 However he also cited data from autopsy records obtained by Sorour in two Egyptian hospitals which seem to support such relations Sorour found 85 cases of cancer of the bladder or 23.3 percent of the total of 254 cases of cancer seen in 5,924 post mortem examinations This incidence rate is about 10 times the normal rate for bladder cancer 350 While a schistosomiasis infection has repeatedly been connected with development of primary cancer of the liver especially in the Chinese such a relation has not been observed in Egypt It seems to be losing ground increasingly in other parts of the world where schistosomiasis occurs 143 226 The repeated occurrence of schistosomiasis in veterans of World War II who acquired the infection while serving abroad in areas where the disease is endemic 368 291,250 291,250 possibly may result in the development of bladder cancer in some of these former soldiers in years to come Betelnut Cancer of the Mouth While in general the habit of betel chewing is undoubtedly the cause of the excessive incidence of cancers of the oral cavity observed in certain parts of India and the Philippine Islands there is evi dence that the composition of the buyo quid is an important factor Eisen found for instance that this habit does not lead to mouth cancers among the inhabitants of New Guinea and adjacent islands 97 Khanolkar also reported that there were considerable variations in the incidence of oral cancer in different parts of India despite widespread adherence to the betel nut chewing babit 176 Khanolkar is inclined to agree with Somervell 349 who noted that the oral cancer incidence is high in those parts of India in which the quid contains a strong variety of tobacco in addition to the usual ingredients Woelfel Spies and Cline 405 suggested that the essential carcinogenic factors might be furnished from the betel leaves by certain allyl phehols and isomeric propenyl compounds which dimerize under the influence of sunlight and form stilbenols 29 API 07905 Khaini Cancer of the Lower Lip Cancer of the lower lip Khaini cancer is the most common oral cancer among natives of Bihar in northwestern India It apparently results from the irritation caused by the placing of a pinch of rubbed tobacco mixed with lime in the groove between the front teeth and the lower lip 177 The composition of this mixture resembles that of the buyo quid inasmuch as it also contains tobacco and lime These observations receive some support from a report of Friedell and Rosen- thal 277 on the etiologic role of chewing tobacco in cancer of the mouth and from claims made by German investigators 278. 279 in regard to the carcinogenic effect of tobacco dust on the lungs of cigar makers and sorters Cancer of the Scalp Carcinoma of the scalp is frequent among Mohammedans in North- ern India who shave their heads with blunt razors thereby causing frequent abrasions and infections Similar observations have been reported among the Mohammedans of North Africa Thermic Cancer The not infrequent development of cancers in accidental wounds and scars resulting from burns is a recognized observation although the causative mechanism involved is still obscure The carcinogenic action of thermic rays acting over a long period of time however is open to question The occurrence of cutaneous cancer on the shins of English railroad engineers allegedly caused by the heat from the firebox furnished the basis for such claims Warniek 388 recently revived this concept by reporting the development of a cancer of the face in a skinned haired man employed as a roller in a rolling mill where he was exposed to excessive radiating heat Mattenci 232 contended from an analysis of 93 cases of skin cancer that basal cell cancers are elicited by infra rays while squamous cell cancers are due to ultraviolet rays In commenting on his case Warniek noted the small number of reports concerning the appearance of basal cell cancer in workers exposed to heat rays 388 Inasmuch as heat waves carry a relatively small amount of energy it is not likely that they would exert profound effects on the chemical structure of the various cellular components and thereby contribute to the causation of endogenous carcinogens Proper consideration moreover must be given to the fact that workers exposed to radiating heat are also usually in contact with the tarry combustion products of coal or oil 30 e l 7 eal oe Extrinsic Co- Pro- and carcinogenic Factors A great deal of work has been done in recent yearosn the various Docarcinogenic procarcinogenic and anticarcinogenic factors of local - and systemio nature active in and influencing experimental carcinogenesis 321 285 19 210 However there is very little definite information in this connection on environmental cancers even though such data are of considerable importance in regard to the conditions ; influencing local incidence individual susceptibility epidemiology and development of effective preventive and prophylactic measures 346 The postulated causative role which physical or chemical trauma is _ , supposed to play in the production of accidental cancer has for many years been of special scientific and medicolegal interest The problem has been the subject of a great deal of experimental work particularly in recent times and contradictory results have been obtained Many investigators obtained negative answers as to the positive effect of trauma of various kinds on different types of carcinogenesis 41,71,73 41,71,73 41,71,73 . 72 220 283 320 Others found that physical or chemical traumas * seemed to favor the development of cancer in prepared soil 195 372 306 19 163 62 213 56 115 203 274 304 311 319 367 The f practical significance of the relation between trauma and cancer has * again become of increased importance because of the present and future F medicolegal adjudication of claims derived from war injuries 189 89 209 59 81 107 249 - The knowledge that several environmental carcinogens such as roentgen rays radioactive substances benzol and arsenic possess hivalent properties in regard to the development and destruction of ncer has led several investigators to attempt the development of a oiochemical or biophysical treatment of cancer by extending this principle to other carcinogens It was thought that the administration either of small amounts of a known environmental or experimental carcinogen or of a carcinogen of low potency or of a chemical noncarcinogen possessing a structure closely resembling that of a carcinogen might counteract the development or further growth of a } cancer of known or unknown etiology 886 This type of reasoning bas during recent years received important support from the successful application of structural blockage to the chemotherapy and immunotherapy of infectious diseases as well as to the action mechanism of various vitamins Thus Henschen and Allemann proposed the treatment of bladder cancer by the intravesical or intravenous administration of betanaphthylamine 6 148 It may be possible that the antagonistic action of estrogens on the growth activities of prostate cancer depends on such a mechanism 141 Some experts have suggested that one way 31 API 07907 to prevent the more malignant cancers of the internal organs would be to elicit skin cancers biologically less malignant and more easily cured by physical or chemical means 11.12.288 11.12.288 11.12.288 On the experimental side an antagonistic action between chemical carcinogens of high and low potency when applied to the skin of mice has been reported 194 Hashida has recorded the anticarcinogenic properties of certain aniline dyes in the production of liver cancer by aminoazotoluene 144 Haddow Harris and Kon as well as Borland concluded from similar experiments that a structural similarity between potent carcinogenic and inhibitory compounds may be involved in the antagonistic action 141.34 141.34 Additional experimental evidence supporting such a correlation exists 354,93 354,93 Although the practical therapeutic application of the principle of ambivalence has given permanent curative results only in connection with roentgen rays and radioactive substances the various observations thus far made in this field are of sufficient promise to justify an extensive study of specific chemical anticarcinogens Causative Mechanisms Among the considerable variety of carcinogenic agents already known or suspected the viruses and virus pathogens are conspicuously absent Since the milk factor has been classified among the viruses by some observers it is not impossible that future studies may demonstrate the presence of such ready for action carcino gens in human cancers Suggestive evidence in this direction is presented by the occasional development of cancer of the penis on the basis of condylomata acuminata which have an established virus causation It can be anticipated that with the increasing identifica- tion and characterization of extrinsic carcinogens an intelligent systematization of such agents will be developed which will equal that now existing for the microbial human pathogens But before this information can become fully useful it is essential that the present and future information on the causal genesis of cancer be adequately supplemented with data on its formal genesis Due to the present inadequate state of knowledge of this aspect of the problem one can only advance hypotheses derived from the correlation of a number of isolated observations most of which are related to experimental and spontaneous cancers in animals It has been found in recent years that not only cancers in fish reptiles and birds but also a few papillomatous tumors in mammals such as the Shope cotton tail papilloma are caused by animated proteinic matter the called viruses 178 139 355 113 114 344 285 318 50 32 AOS Ses er API 07908 These agents possess antigenic properties 224 A similar claim has been made by Taylor 366 in regard to the agent responsible for and isolated from mammary cancer of the mouse Specifically the milk factor involved in and essential for the production of this tumor has been identified as a virus of macromolecular proteinic nature 23 10. 389 42 which acts as an antigen and produces antibodies when injected into rabbits 152 It seems to be established that it is normally transmitted from the mother to the offspring through the milk and that this transmission is accomplished most readily during the first 12 days of postfetal life This covers the period when the milk consists of a mixture of actual milk and blood serum called colostrum and when the intestinal mucosa of the young mice has an abnormal permeability which permits the penetration of macromolecular material 246 It is thus possible that the milk factor is not actually a virus but merely a large pathogenic and antigenic protein molecule which causes during the early part of postfetal life a chemical sensi- tization that cannot become manifest until the shock organ the mam- mary gland has been transformed under the stimulus of estrogens into a reactive medium 76,77 The possible importance of macromolecular carcinogen complexes in the formal genesis of cancerous growths is apparent from the work of Creech et al 63 64 with substances of this nature prepared by the isocyanate method of coupling aromatic carcinogens with proteins Osterhof 156 emphasized the possible significance of such complexes as important links in the process of carcinogenesis by pointing out that amino groups of proteins couple readily with quinones and that quinones are formed in the body from aromatic amines and related substances 123 and thus become the source of allergic reactions Similarly the sulfhydryl group of the protein molecules may provide an avenue for the combination of these macromolecules with extrinsic carcinogenic chemicals such as arsenic 123 108 The recent inability of Mayer 233 to prevent the proliferation of epithelial cells exposed to aromatic amines by the administration of pyribenzamine can scarcely be considered a valid reason for denying the absence of an allergic reaction in the development of such proliferative responses to specific stimuli Timofiew and Schewtschenko 370 also asserted that the development of precancerous conditions in the lung is related to special allergens acting on the blood epithelium and mesenchyme and denaturing tissue proteins It is interesting therefore that Miller and Miller 245 found in the livers of rats treated with the hepatocarcinogen dimethylaminobenzene a macromolecular cell constituent which was probably a protein conjugated with the dye This dye could only be recovered 33 API 07909 by the digestion of the protein fraction of the complex and could not be extracted with solvents As this dye complex was present in the liver cells only Miller and Miller felt that it had an important place in the production of the liver cancers This conclusion received support from the investigations of Gillman and Gillman 126 on pri mary cancer of the liver in Bantu Negroes These researchers denion- strated in the liver and blood of such individuals a macromolecular abnormally large containing protein whose presence they related to the carcinogenesis of the liver When Spencer mentioned in his dissertation on tumor immunity 351 the potential role of macromolecular substances in the cancer process and concluded that the possibilities of an immunologic approach to the cancer problem had not been exhausted he pointed cancer research in a direction which offers hope and promise API 07910 Occupational Factors in Growth of Cancer Incidence Occupational Carcinogenic Agents The great majority of cancers which can be traced to an occupational origin in modern times have resulted from carcinogens which entered industrial processes during the past 50 years or less Table 1 presents all the known or commonly suspected chemical physical and parasitic carcinogens of occupational importance The recent experimental production of cancers in animals by other agents of industrial significance such as chlorinated aliphatic hydrocarbons urethane selenium and beryllium has demonstrated their potential carcinogenic properties Consequently it may be assumed that a more intensive study of the effects of industrial environmental factors will reveal some or many additional occupational carcinogens The physicochemical properties of the agent the type of contact of the worker with it and the reaction of the organism to it i e particularly its metabolization excretion and fixation in certain organs determine the site of the resulting neoplasm It is for these reasons that different occupational carcinogens elicit cancers in the same organ and the same carcinogen may cause the development of tumors in different organs Table 2 briefly summarizes the existing known conditions and interrelations As a general rule occupational cancers arise at those sites where the particular carcinogen has the most prolonged and intense contact with the tissues Thus ultraviolet rays roentgen rays and radio- active substances acting externally upon the skin cause the development of cancers at the exposed parts i e face neck and hands Arsenicals on the other hand which are fixed by the sulfhydryl groups of the epidermis and hair follicles may develop cancers also in unexposed parts of the body Ingested radioactive matter that is fixed in the bones causes sarcoma of the bones and leukemias starting from the bone marrow The leukemiogenic action of benzol which may be ingested or inhaled is due to the fixation of the chemical in the fat tissues of the bone marrow 35 API 07911 Table 2. Recognized and suspected occupational carcinogenic showing organ systems affected Classification Established Doubtful agents Substance ' Organ of sysEM Class Aniline and derivatives - Bladder ureter kidney AWQMQAWA kidney eee eee eee Anthracene crude .. j Skin ----- 22-22-22 AWQMQAWA Aromatic organic chemicals ...-- fe Liver AWQMQAWA ee Arsenic Liver .. earns j} 2-2-2 eee sore Respiratory system eee eee -- AWQMQAWA Evelids AWQMQAWA Asbestos ..2. ee eee eee Respiratory system AWQMQAWA eee eee. Asphalt SkEvien . e ee e eee ee ee nee ee ..... WHAHAHAH WHAHAHAH Benzidine and derivatives Benzol . eee eee eee Benzol derivatives . Burns thermic Chlorinated aliphatic hydrocarbons | Chromates Bladder ureter kidney WHAHAHAH Blood forming organs WHAHAHAH Blood forming organs WHAHAHAH Skin Liver WHAHAHAH : WHAHAHAH Respiratory system WHAHAHAH Skin eee WWH eee e ee 22 Creosote Lip oe eee eee wee eee WWH Eve WWH . Mineral oil SRkeisnpiratory WOOW Mineral oil system crude crude.....--------eee- ) .. WOOW Ey system .. ne e eee eee WOOW Naphthylamine beta Bladder ureter kidney WOWW Nickel carbonyl . Respiratory tract WOWW Oil shale .. eee eee eee Skin . tra. ct ee eee ee WOWW Paraffin crude do WOWW Pitc..h . Lip acccrceenrnc WAAW enw ceccccctceuceccees _ do___ do___ Lip eee en veccon eee ee eee eee Bladder WAAW 2222.22. 22222 Eye WAAW Radiant beat .. Skin . 2-22. e eee eee eee A --- do ce ee eee eee RHHAWWWWA substances . Radioactive j . cece ee Lungs organs RHHAWWWWA Blood forming organs . RHHAWWWWA Bone RHHAWWWWA Roentgenrays Bloodforming tissues RHAW WA ccccc eccccveeece Blood orang. forming organs Subepithelial connective tissues RHHAWWWWA Eve...---..------------e-e--e RHHAWWWWA Skin WAWQ HD Sodium nitrate crude won .. do_ eee eer eee ee ee eee eee eee eee Soot__ Soot__ Soot__ 222 WAWWWQQQHDD ence Bladder eeee ee eeeeee Spindle oil Skin .. 72-222 WAW WQ QHD .. 2.00 eee enee- Lip_ 22 eee eee eee eee ee WAW WQ QHD Tar . ep eecucceacccecencccuns Skin .. WAWWQQHD Respiratory system WAWWWQQQHDD Bladder WAWWWQQQHDD Blood forming organs WAWWWQQQHDD Eye WAW WQ QHD 0.02 eee eee eee Ultraviolet rayB . Eye stot WAWQ HD 36 _ . oe ! i ; API 07912 Se. fe ee A ee ee ee ee Table 1. Classification of occupational carcinogens Established Doubtful Organ system Skin and its appendages Anthracene crude Asphalt artificial Burns thermic_ ween n ne ee eee Mineral oil crude Remarks Dependent on ingredients Varies with geographic origin Roentgen rays nitrate Sodium Ultraviolet rays Alimentary system Aromatic organic chemicals ... carbons ? Arsenic 2. ee ee ee eee Nickel carbonyl Radioactive substances Tar fumes .. Erogenous Erogenous organs Benzidine Naphthylamine beta Pitch ee een Tar forming organs Benzol Radioactive substances . Roentgen rays weve nnene Mesenchymatous tissues Radioactive substances Roentgen rays ! Eye and its adnexae Asphalt . Creosot eee eee Mineral oil crude Pi oet ee ec ee enh n eee Occurs in Chile only Not recognised as occupational Hepatic tumors in laboratory mals only Increased incidence of liver cinoma following cirrhosis anicar- Lip only Do. Do. Do. . Lung cancer among laboratory workers miners and Including some derivatives In agricultural workers in infested areas Bone Skin sarcomas bone Lids only a _ API 07913 Table 2. Classification of occupational carcinogens Organ system Chassit cation | Remarks i Eye and its Continued Roentgen rays Tar 2. -.-- ee eee eee ee eee eee Ultraviolet rays . Nervous system 2. -....--------- Endocrine glands | E } | | | E nee | eee ; leneeee. None recorded Do. The excretion of carcinogenic aromatic amines or their metabolic derivatives is responsible for the production of cancers of the bladder where the carcinogenic urine may act over prolonged periods on the vesical mucosa This accounts for the fact that only rarely do such cancers develop in the renal pelvis or the ureter through which the urine usually passes without delay The inhalation of carcinogenic fumes mists vapors gases or dusts which may become precipitated or fixed in the linings of the respiratory conduits and sinuses accounts for the appearance of cancers of the bronchi and nasal sinuses in workers exposed to radioactive dusts and gases chromate dusts nickel carbonyl vapors asbestos and arsenic dust and tar fumes Evidence Supporting an Occupational Origin of Cancer Inasmuch as occupational cancers do not differ fundamentally from those elicited by similar or different medicinal or environmental agents or from those of unknown etiology the proof that a particular case or type of cancer is of industrial origin rests on evidence of varying types and significance Statistical Evidence An excessive incidence of a certain type of cancer among a group of workers engaged in a definite operation or exposed to some physical or chemical agent during their normal activities has often been the first indication that an occupational agent was involved in the production of these neoplasms However this excessive appearance of a particular type of tumor is as a rule limited to groups of workers having more or less intensive and prolonged contact with occupational carcinogenic agents and is therefore often not demonstrable for the entire worker population of a plant or even reflected in the incidence rate of this type of cancer among the population of a community or region Statistical investigations that include indiscrim- inately large and occupationally heterogeneous groups of workers } API 07914 1 having widely differing degrees of exposure of them none at render not only incorrect but misleading results Thus cancer of the bladder has been observed in up to 100 percent of those workers who had had severe and prolonged contact with betanapthylamine and benzidine However when the incidence rate of bladder cancer was determined within the worker population of plants in which these industrial neoplasms were observed the rate was approximately the same as that noted among the patient population of a large urological clinic Cancer of the lung occurs in about 80 percent of the cobalt miners of Schneeberg and in approximately 50 percent of the uranium miners of Joachimsthal yet there is no excessive frequency of this cancer found among the workers handling the cobalt ores in the manufacture of pigments or among the general population of these regions when the actual miners are excluded from consideration It has recently been maintained that there is no evidence of an excessive incidence of lung cancer in workers with asbestosis as the clinical examination of 20,000 asbestos workers did not reveal a single case of lung cancer The fact is that the diagnostic distinction between asbestosis and cancerous lesions in members of this occupational group must be difficult at times Actually the roentgenologic examination of such a number of individuals in the general population would reveal one or more cases of cancer of the lung A total of 23 such cases in association with asbestosis has been found by the much more reliable method of post mortem examination thus indicating the likelihood that asbestos may under certain circumstances be carcinogenic The scrotal cancer of the chimney sweeps and mule spinners the cancer of the fingers and hands of the radiologists the cancer of the nasal sinuses and lungs of the nickel refinery workers and the bronchiogenic cancer of the chromate workers are other examples of oc- cupational cancers having statistically significant incidence rates Relation to Medicinal and Environmental Cancers Whenever the occupational factors are known observations made with the same agents when they form for other reasons a part of the human environment may be helpful in deciding the question of a possible occupational cause of cancer Arsenic cancer of the skin for instance has been observed in an appreciable number of individuals who ingested this chemical over prolonged periods either in the form of medicine or as a contaminant of drinking water or wine Roentgenray cancer of the skin is a not uncommon late complication of excessive therapeutic irradiation Epitheliomatous growths have been observed repeatedly after the use of vaseline or tar in cosmetics 39 API 07915 Precancerous Lesions Several industrial carcinogenic agents elicit precancerous reactions which are characteristic to a certain extent of the causative agent and which represent various transitional stages between the original nor mal state of the tissues and the carcinomatous end result Table 3. Description of precancerous occupational lesions Precancerous lesions Etiologic agent SKIN Alopecia Atrophy Ecsema Keratosis Hyperkeratosis Verrucas Ulceration Leukoderma melanoderma Spotty loss of bair Arsenic radioactive substauons rays substauons and | Bkin grossly thinned glistening in patches amociated with keratotic preas Pitch tar asphalt radioactive substances radiation includ- . ing ultraviolet rays Dry seborrheic patches on skin Arsenic asphalt pitch soot tar Flat discrete scaly area on skin with raised borders to pearly particularalboyut parta posed with arsenic Usually on parts of skin ex- glands occur particularly sweat . Rough Basured kerstotic plaques with small hard wart horns usually on bands and soles May become nodular and ulcerate crude mineral | Anibracene creosote arsenic asphalt oil | paramn pitch sodium nitrate | stances tarradioactiinvcliuncedluidinngg ultraviolet rys Form of hyperkeratosis Breakdown of keratotic lesions Absent pigmentation alone Anthracene arsenic asphalt cre- -. osote Crude mineral oil par- | : Patchy increased and absent pigmentation of akin Most common in areas of highest pig- affo pitch tar radioactive substances radiation inchad mentation and may involve oral mucosa ing ultraviolet rays Melanoderms Increased pigmentation alone Seleroderma radioactive | Dry scaly parchment skin with enlarged pores associated with melanoderma Crude mineral of parafin oil mbstances radia tion NASAL PASSAGES Papillomas Papillomas Polype Develoipn antrum ethmoid cella and turbi- | Nickel carbonyl nates BLADDER Hemorrhage submucosal Papiliomas Varying site with telangiectasis Located mainly orifices in trigone and about ureteral Polypous or villous pedunculated or sexslie ofteAcnes multiple about trigone and ureteral ori- Aniline benzidine betanaphthylamine and derivatives EYES Papillomas Pedunculated develop ally on eyeball Arsenic asphalt creosote redus mainly on lids occasion- mineral including ultra redus rays BONE BONES : MARROW Hyperplastic Thrombocytopenic Transitory | Blood dynuras^ AS Hyperplastic , bypoplasticbypoplasticbypoplastic, splspalasstticic or hemhoelmyoly Hyperplastic anemia Thrombocytopenic with the purpurs spleen not markedly leukopenis monocytosia Benrol and derivatives radio radio active substances radiation LUNOS Pneumoconioses Chronic Pneumonia | Bituminosis abertosis lipoid pneumonia chronie ebemical pneumonia arsenical derma- Asbestos arsenic tar soot of mist chrome mits chrome tosis chromate ulcer of bands perforated pigments nickel carbonyl natal septum chromats arsenic Blood dyscrasia See boneansd bone marrow above Radioactive substances radia- txon 40 API 07916 ; ~~. These include hyperplasias hyperleucocytoses carcinomatoid and arcomatoid atypical proliferative responses and leukemoid reactions Hyperkeratoses warts and epithelial cornified horns are seen in chronic dermatoses caused by exposure to arsenic tar mineral oil and related substances and roentgen rays and radioactive substances Hyperleucocytoses and leukemoid changes have been noted in individuals exposed to benzol roentgen rays and radioactive energy Sarcomatoid lesions chronic radiation osteitis and periosteitis seem to be the precursors of the osteogenic sarcomas found in chronic radium poisoning Although many of these precancerous manifestations regress spon- taneously if the exposure to the causative occupational agent ceases some of them are followed by or transformed into malignant growths The appearance of such reactions in workers exposed to an agent which has been shown to be carcinogenic in some species of animals therefore represents a warning signal that should not be disregarded For this reason the occurrence of sarcoid granulomas in the lungs of beryllium workers should arouse suspicion as to their significance and ultimate development especially as Gardner has demonstrated carcinogenic properties for several beryllium compounds in experiments with rabbits 122 Similar considerations should cause the various chlorinated aliphatic hydrocarbons such as chloroform and carbon tetrachloride to be viewed as possible carcinogens These hydrocarbons are known to produce liver degeneration and cirrhosis in man and have been shown to elicit hepatocarcinomas in mice Significance of Experimental Cancers The experimental reproduction of occupational cancers in animals through their exposure to those agents apparently responsible for their appearance in man is considered usually to be a conclusive link in the chain of evidence On the other hand failure to repeat human experience experimentally in animals has sometimes thrown more or less seri- ous doubts on the validity of the occupational evidence This situation has been complicated further in late years by the demonstration of species specificity for certain carcinogens in relation to experimental animals Cancer of the skin for instance can be consistently produced with carcinogenic tar in mice and rabbits with distinct difficulty in rats and dogs and not at all in monkeys Ultraviolet ray cancer of the skin is elicited readily in mice and rats but all efforts to produce it in rabbits have failed Although the occurrence of arsenic cancer of the skin in men is generally accepted its reproduction in mice rats rabbits dogs or fowls has not yet been accomplished unequivocally The experimental reproduction of bladder cancer by the administration of 41 API 07917 betanapthylamine was unsuccessful in mice gave controversial results in rabbits and was consistently accomplished in dogs The prolonged introduction of benzidine the second occupational agent responsible for the development of bladder cancers in man into dogs did not result in similar responses in their bladders while it caused leukemia and cancer of the liver in rats Such divergent reactions of different species to the various occupational carcinogens apparently have their basis in the existence of fundamental differences in the metabolism of the various species These observations are by no means unique in biology They have their analogies in the often striking species specific differences in the reactivity to numerous chemicals and drugs as well as in the pathogenicity of organisms Although the application of observations made in experimental cancerology to man is subject to limitations similar to those obtained in experimental pharmacology and micro- biology there can be no doubt that they are equally informative and valid when derived from a suitable species The experimental evidence at present availablein support of a car- cinogenic action on the part of many of the suspected occupational agents is often inadequate controversial or completely lacking The prevailing preference for mice in this type of work is in part respon- sible for this situation The secretiveness and the restrictions with which occupational cancers are often surrounded has moreover discouraged any extensive experimental study of these tumors While adequate experimental evidence exists as to the production of cancers of the skin by tar mineral oils and related substances ultraviolet rays roentgen rays and rays from radioactive matter the evidence is inade- quate and controversial on experimental arsenic cancer of the skin Reliable experimental observations indicate the carcinogenic action on the respiratory tract of tar and quite recently of radioactive gases The evidence for such respiratory cancers is defective however as to chromates and asbestos and is entirely lacking for arsenicals and | nickel carbonyl The carcinogenic action of betanaphthylamine on the bladder has been established by the experiments of several investigators while experimental evidence as to benzidine and several other suspected agents in this organ such as tar dyes and arsenic is missing - Osteogenic sarcoma and leukemia have been reproduced reliably in animals by the use of radioactive matter and roentgen rays while controversial evidence only exists as to the leukemiogenic action of benzol Conflicting results in animal experimentation are doubtlessly caused in part by the use of different strains or species and by variations in experimental conditions diet solvent of agent intensity and duration | of exposure particle size of agent inhaled anatomical peculiarities of 42 eciesused They may also be due to the administration of sus; pected materials of different composition and therefore of varying carcinogenic properties For example tar produced in high tem- perature retorts from coal is usually carcinogenic while tar coming from low temperature retorts possesses such qualities to a lower degree or not at all Wood tar frequently employed for medicinal purposes is usually noncarcinogenic Some crude mineral oils containing originally aromatic substances are carcinogenic while mineral oils coming = from other fields and having a different composition are not Howr^,vereven these may acquire such properties if they are subjected to temperature and pressure distillation as aromatic compounds are generated under these conditions from aliphatic ones Oils obtained by the distillation of shale have proved to be carcinoganic in Scotland and Germany unless they are subjected subsequently to special processing Asbestos likewise not only differs in physical respects but also chemically particularly in regard to its metallic fi Many attempts have been made to isolate the actual carcinogenic factors from the tumor tissue blood or excretions of individuals or nimals with cancers elicited by occupational agents and thus to proride the most convincing evidence of their etiology However most Horts in this direction have failed It has been possible to recover chromium from the tumor tissue of chromate workers radioactive atter from the lung cancers of the Schneeberg miners and from the osteogenic sarcomas of dial workers and arsenic from the neoplastic tissue of the skin of persons exposed to this chemical However the metabolite of betanaphthylamine naphthol appearing in the urine is not definitely carcinogenic and extracts from cancers used by roentgen rays were noncarcinogenic 2 Whether or not this course of events will be changed by the recent discovery of Ekman and Stroembeck 98 remains to be seen These vestigators isolated toluidines or substituted derivatives of toluidine from the urine of rats with bladder tumors resulting from the administration of aromatic compounds and produced bladder papillomas in other rats given the isolated substances Their observations seem to be of special importance as to the causation of bladder tumors in men since they succeededin obtaining considerable amounts of primary aromatic amines some of which might be present m oxidized form from the urine of patients with nonoccupational bladder cancer API 07919 Summary of Evidence of Occupational Carcinogenesis It is apparent that much of the evidence by which cancerigenesis is connected with occupational activities is circumstantial and that only in a relatively few types of occupational cancers is definite and specific evidence available Despite these shortcomings in kind the sum total of the statistical clinical and experimental evidence is of sufficient weight to justify the definite acceptance of the occupational origin of most of the cancers listed This scientific recognition of the occupational etiology of certain cancers does not automatically in most instances imply a medicolegal acceptance of such interrelations with all their important economic and social implications However the resistance usually encountered on the medicolegal front has been partially overcome at least abroad for cancers of the skin caused by tar pitch oils and their derivatives arsenic roentgen rays and radioactive substances for cancers of the lung resulting from radioactive material and chromates for cancers of the bladder caused by aromatic amines and for osteogenic sarcomas elicited by radioactive substances The other industrial cancers previously mentioned have not yet been generally included among the compensable occupational diseases even in Europe At present they enjoy a sort of probationary status in that they are recognized in some countries while not in others Since occupational carcinogens probably will continue to be used by industry and to cause occupational cancers there is little doubt that most of compensable the cancers of this doubtful group will reach status as and when the number of cases increases and the importance of oc- cupational cancers is more generally appreciated Occurrence and Incidence of Occupational Cancers in the United States It is not possible to give any definite information on the types of occupational cancers occurring in the United States nor are there any even approximately accurate and reliable data on the actual number of occupational neoplasms to be found in this country Industrial management labor legislative bodies public health organizations and the medical profession are all responsiblein varying degrees for this condition The information available represents not what actually exists but what has been recorded or is conceded Cancer of the Bladder Cancer of the bladder in dye workers has been part of the American off industrial scene since 1932 is some 15 years after the start 44 if T API 07920 ee ete _ large production of aromatic amines for the manufacture of dyes Approximately 100 cases of this occupational cancer were recorded up to 1938 from one American chemical concern No additional in- formation on this subject has been made a matter of public informa- tion since that time except for a brief communication regarding the . occurrence of such cancers among the workers of another chemical i company in 1947 2 From information available it appears that a total of about 200 cases of occupational cancer of the bladder have been observed during . the last 20 years among the workers in three chemical organizations including both producers and consumers of betanaphthylamine and benzidine No information has been published on this problem by any : of the many other chemical manufacturing plants or by plants using those chemicals or their close derivatives including the rubber and pharmaceutical industries - However assuming that the actual number of bladder cancers with E this causation were five times the recorded figure or 1,000 cases only s very small fraction of the total would be represented since about e 100,000 bladder cancers were reported in the year period surveyed = 1928-47 Thus only 1 out of every 100 cases could be attributed ; to occupational contact with the aromatic amines on the basis of the above assumption Doubtlessly additional and important exogenous : and endogenous factors are involved in the causation of bladder cancer p Skin Cancer Occupational cancers of the skin resulting from contact with solar P rays roentgen rays rays from radioactive material tar pitch mineral ; oil lubricants soot and arsenicals have been reported in this country ; since 1900 when the first cases of roentgen cancer were placed on record This was followed in 1910 by the description of five cases of tar epitheliomas and in 1932 by a report of two cases of industrial arsenic cancer However as long ago as 1906 Hyde 276 had commented the comparatively high frequency of cancer of the skin F among outdoor workers in the dry and sunny regions of the Middle * West With the exception of the skin cancers of suspected solar origin which many investigators consider to be the most prevalent type of this malignancy an astonishingly small number of occupational cancers of the skin has been placed on record in the United States There are 71 tar and pitch cancers 62 grease and oil cancers 45 roentgen cancers and 18 arsenic cancers Needless to say the majority of the tar and oil cancers have not been reported while the long latent period of arsenic cancer may account in part for the small number of reported cases with arsenical causation No incidence figures are available on cancer of the hands and fore- 45 API 07921 arms occurring in grease pit workers of service stations recently mentioned by Stewart 358 Since pressure temperature fractionation and cracking of oil by hydrogenation is being used to an increasing degree in the modern petroleum industry and inasmuch as the tendency toward the formation of cyclic compounds of potentially carcinogenic properties is thereby enhanced the mentioned possibility deserves serious attention during the coming years Although the industrial use of oil shale and bitumen for the production of oil gas and related products is at present of minor importance in this country the situation may undergo a fundamental change in the near future as a result of the rapid exhaustion of our natural oil reserves If proper precautions are not then taken to prevent the manufacture and use of carcinogenic shale oils occupational cancers of the skin may appear at a rate similar to that found among the shale oil workers and mule spinners in England and Scotland Respiratory Cancers No official records exist in this country as to the occurrence of cancers of the lung and nasal sinuses in workers exposed to the inhalation of gases and fumes containing radioactive matter arsenicals nickel carbonyl and tar However Lynch and Smith reported in 1935 the first American case of primary carcinoma of the lungs associated with asbestosis 222 Since then 8 additional cases have been reported from this country out of a total of 23 cases from England Germany and the United States In view of the sarcoid nature of the granulomatous lesions seen in beryllium workers it may be mentioned that there is on record a single case of existent pulmonary asbestosis and sarcoidosis 347 It is definitely too early for pulmonary malignancies to occur in workers who have had contact with radioactive dusts and gases during { the mining and processing of radioactive ores for the production of radium and atomic energy since operations in which this type of exposure may have taken place have been carried on in this country for | an insufficient length of time to cover the usual latent period of these tumors As for arsenic the reports of the chief inspector of factories in England have mentioned repeatedly during the last few years the appearance of cancers of the lung in workers exposed to the inhalation of arsenical dusts and fumes 55 There is consequently need for detailed study of this field in the United States because of the extensive exposure to arsenic to which large parts of the industrially employed as well as the general population in certain regions of the country are liable These investigations might throw some light on the remarkable increase in the mortality rate for lung cancer which more than doubled between 1933 and from 4 to about 9 percent 46 API 07922 of all cancer deaths which shows marked variations in various regions of the country Cancer of the lung in chromate workers which so far has been reported from Germany only has definitely appeared in the United States 224a The interest in this cancer on the part of those con- cerned with chromate production has been considerable during recent years No definite information is available on the presence or absence of cancer of the nasal sinuses and of the lungs in workers in American nickel refineries using the carbonyl process although an appreciable number of such cancers has been reported from South Wales Industrial osteogenic sarcoma in dial painters applying radioactive material represents the only occupational neoplasm observed ex. clusively in this country No new cases have been placed on record since their first epidemic appearance some 15 years ago 229 | Leukemias Leukemic reactions in persons exposed to benzol or radioactive energy have been observed in this country There are six cases of occupational benzol leukemia occurring in painters workers in can factories manufacturing plants artificial factories and rotogravure printing establishments Other workers employed in the y same factories and also exposed to benzol have shown hyperleuco- cytoses or leukemoid reactions Similar observations have been made in individuals coming in contact with radioactive energy in whom . leucocytotic and preleukemic conditions as well as leukemia have been observed The first American case of an occupational radiation leukemia was reported in 1929 by Stewart 358 Since then two additional cases have been recorded and several statistical studies on the excessive incidence of leukemia among radiologists have provided support for the concept of an occupational radiation leukemia Thus A potential leukemic hazard exists for all persons exposed to radiation while working with atomic energy for military industrial or scientific purposes and handling radioactive matter in the radio and textile and other industries using radioactive static eliminators 47 API 07923 Problems in the Control of Occupational Cancer It is obvious from the foregoing that occupational cancer presents an increasingly serious health problem in the United States 282 as it does wherever industrial processes proliferate and men and women are brought into intensive and prolonged contact with occupational carcinogens Nevertheless the subject has attracted relatively little attention from industry labor public health bodies or the medical profession Sufficient data have been accumulated it is believed to indicate the extent of the problem and to call for aggressive control procedures on the part of the various sectors of our society mentioned Factors Responsible for Lack of Interest Industrial Management The limited publicity which occupational cancers and their causative agents have been given has left considerable portions of industrial management in complete ignorance of the existence of such sequelae to certain industrial activities Furthermore the general uncertainty prevailing in regard to the etiology of cancers in general tends to create a reaction of scepticism concerning the mechanism of their actual occurrence Thus the reluctance of some members of industrial management to accept any claims as to the presence of occupa- tional carcinogenic hazards in their plants and operations is a natural reaction of persons not adequately informed on the biological peculiarities of occupational cancers especially their long latent period Furthermore the not infrequent absence of reliable and convincing statistical data on the occurrence and incidence of occupational cancers as well as the existence of improperly prepared and therefore misleading statistical evidence favor the development of a negative reaction among members of industrial management A second factor which tends to interfere with a wider knowledge of the incidence of occupational cancers is the apprehension of industrial management that an unrestricted public recording and scientific dis 48 ade, API 07924 b- OC. ahs Soe . nnd, Mars ussion of these neoplasms might result in undesirable publicity to the organizations involved in such hazards and might thus impair the sale of their products It is feared moreover that such publicity might cause the institution of expensive and sometimes unwarranted compensation suits that it might necessitate the costly rebuilding of existing plants and that it might require the introduction of extensive and complicated technical sanitary and medical precautionary measures which might possibly hinder production alarm workers and cause considerable outlay over prolonged periods Although the financial burden connected with such measures would not represent a serious obstacle to their adoption by management as the cost can be passed on to the consuming public an uneven application of such regulations in different States would result in unbalancing the competitive field and thus would be objectionable There is also the possibility in management's mind that a greater degree of publicity on occupational cancers might result in the passage of laws and and regulations requiring a closer and more stringent governmental supervision of plant operations and of treatment of workers _ Labor and Labor Organisations Although neither labor nor management is always aware of the carcinogenic hazards connected with certain occupational activities it cannot be said that labor always adopts readily the preventive and prophylactic measures prescribed by management for labor's protection against hazards already recognized Such an attitude toward " precautionary measures is dictated in part by the common human negligence toward everyday injurious agents not causing readily apparent disease manifestations and in part by the fact that such measures may cause some physical inconvenience to the workers or may , interfere with their productivity and thereby their income For instance periodic cystoscopic examinations for workers in certain dye plants cause them a definite degree of discomfort For this reason their importance as a prophylactic measure may not always be properly appreciated by the workers concerned The relatively high incidence of precancerous chronic roentgen dermatitis observed among radiol ogists indicates that this indifference to a known carcinogenic hazard is not limited to workers without a proper education in biology and medicine Another example of the same attitude is often shown by workers who leave occupations in which they sustained dangerous exposure to carcinogenic agents and who neglect later on to remain under medical supervision even when regularly urged to do so by their former employers The excessively long latent period involved in the devel- 49 API 07925 opment of some of the industrial neoplasms makes such supervision an essential if the disease is to be discovered in time and yet workers only too often forego medical examinations which could save them from the worst manifestations of cancer or even prevent its ap- pearance The absence of reliable and adequate information on the signifi cance and scope of the occupational cancer hazard as well as an insufficient appreciation of the extent of that hazard on the part of officials of labor organizations seems to be responsible for the fact that so far these leaders generally have evinced only an occasional interest in the problem and have exerted little effort to impress either . workers or management with its urgency Legislative Bodies It is obvious that the adequate protection of workers against occupational cancer hazards and of the general population against environmental industrial carcinogens depends to a large extent on the existence and enforcement of proper laws covering the many facets and special conditions of this complex problem Occupational cancers essentially the products of modern industrial ization are relatively recent phenomena Consequently they have j not yet become the subject of established and intelligent legislative procedures in most countries Furthermore even those countries which have laws dealing with occupational cancers have not always made sure that they are adequate Most of them are more or less defective in insuring reasonably safe working conditions in factories workshops and laboratories producing using or handling carcinogens Compensation laws covering carcinogenic occupational hazards for - example often apply only to some of the agents or to defined: operations in which contact with these agents exist Often they do not take proper account of the long latent period following exposure and thus eliminate a great number of justified claims Criminal codes should take cognizance of the fact that the willful and undue exposure of an individual to a carcinogenic occupational agent for personal gain by another party is for all practical purposes equivalent to an attack with a deadly weapon with a delayed action mechanism % Departments of Public Health Industrial Hygiene Cancer Control and Labor The manifest dearth of reliable and adequate information on occupational cancers the defective nature of existing laws applying to these neoplasms and the lack of sufficient appropriations for their study 4 have prevented various governmental agencies concerned with this L dustrial hazard from becoming sufficiently active Official statis- Ics on the problem are therefore highly incomplete in most countries The situation is somewhat better however in countries which have made occupational cancers notifiable diseases and in which governmental inspection of factories and workshops has been instituted Medical Profession The medical profession in general has been slow in the past to appreciate properly the causative role which the prolonged and unobtrusive action of extrinsic physical and chemical agents may play in the production of many chronic and often etiologically still obscure degenerative diseases such as arteriosclerosis arthritis and cancer It is therefore not surprising that most physicians have scarcely bagun to learn about the carcinogenic properties of occupational agents Occupational data in the histories of cancer patients are consequently either completely lacking or of little scientific value It is not enough to record for instance that a patient was a mechanic a chemical worker at the time a cancer became manifest On the contrary it is essential to ascertain his complete occupational history in relatively great detail for as much as some 20 years before the discovery The appropriate occupational risks must be looked for in the earlier work experience of men afflicted with cancer of possibly industrial origin Such tedious inquiries however are not being made today even in hospitals predominantly handling cancer patients It is obvious moreover that any such inquiries and any intelligent deductions from them on the relation of the data obtained to the existing incer can be made only by persons possessing a genuine knowledge of industrial conditions industrial carcinogenic hazards and occupational cancers At present this type of specialized information is posesed only by a relatively small number of members of the medical profession Public Health and Industrial Problems lacidence and Causation . To date some 8.000 cases of occupational cancer caused by a large Dumber of definitely recognized or strongly suspected carcinogens of physical chemical or parasitic character have been observed in workengaged in a great variety of occupational activities These can- cers have affected many organs and tissues Their localization in dif- ferent parts of the body has depended in part on the type of contact with a particular agent in part upon its physicochemical qualities 51 API 07927 and the reactivity of the organism The fact is thus established that extrinsic agents connected with the occupational activity of man are capable of eliciting cancerous growths in human tissues irrespective of any physiologic or pathologic senile changes or hereditary in- fluences Number of Carcinogens The number and variety of occupational carcinogenic agents have been increasing steadily and rapidly during the past 60 years table 1 and at the same time the number and types of carcinogenically hazardous operations have increased at a rate paralleling the degree of expansion and diversification of industrial activities during the same period Variety of Carcinogenic Mechanisms The marked discrepancies in the physicochemical properties of the different recognized and suspected occupational agents indicate that they exert their specific carcinogenic effect on the tissues by different mechanisms Some seem to possess properties of direct cellular cancerization others elicit such reactions in an indirect way either by causing endogenous carcinogenic substances in the tissues with which they come into contact or by eliciting metabolic disturbances in internal organs such as the liver or endocrine glands which then generate endogenous carcinogenic substances It is evident therefore that cancers of apparently endogenous origin may actually have a primary extrinsic causation Defects in Statistical Determination The demonstration of an occupational origin of cancers depends mainly on statistical evidence which often shows an excessive in cidence of a certain type or types of cancers in a restricted group of workers Inasmuch as recent analyses of the incidence rate and manifestation age of occupational cancers have shown that these factors depend on the potency of the carcinogen the intensity and duration of exposure to it and the age of onset it is obvious that statistical methods will miss all those occupational cancers which do not differ of in their incidence rate and manifestation age from their prototypes unknown etiology in the general population The existing evidence therefore suggests that at present only the most potent and obvious occupational cancers and carcinogens have been discovered while those of low incidence rate caused by carcinogens of low potency have not yet been recognized 52 This conclusion is supported by the fact that so far occupational cancers have not been demonstrated in either the intestinal tract or the nervous system The cells of the alimentary tract obviously come in direct contact with a host of extrinsic factors those of the nervous system react readily to a great number of them following their resorption into the organism On general grounds therefore it is highly improbable that two entire organ systems should be totally immune to extrinsic carcinogens including those of occupational origin These considerations add to the evidence indicating that the number of occupational cancers is appreciably higher and their variety as to sites and types definitely greater than is suggested by recorded figures Probability of Increase in Occupational Cancers The abnormal character of some of the industrial activities of recent years makes it probabtlhaet there will be a rise in the numbeanrd types of occupational cancers during the next decades as happened - under similar conditions after the First World War Evidence again is accumulating that under war pressure plants were built and manned by men inadequately familiar with the occupational carcino- genic hazards inherent in many of their operations It is possible that such hazards were in the main avoided in the construction and operation of American plants and laboratories handling radioactive * substances However the final evaluation of this problem cannot be P made until some 10 to 20 years have elapsed and a detailed and thor- 'o^,,ghstudy of cancer incidence among the large number of former - employees of these plants has been made The elaborate precaution- . ary measures taken in these operations on the other hand do furnish striking illustration of the seriousness of the occupational cancer hazard as applied to a fairly limited industrial activity and to an ' agent which can be traced with comparative ease va e A second factor growing out of World War II which may bring . about an increase in the incidence of occupational cancers during the coming years is the dislocation of many industries particularly ~ abroad This is due partly to the destruction or dismantling of many factories and partly to the construction of plants in certain countries which formerly had different types or little industrial production - and thus were not experienced in the control of operations using car- cinogenic occupational agents This means that the bad record car- - cinogenically speaking which resulted from the hurried development of large chemical industries during and following World War I may be repeated 53 API 07929 Chance of Exposure Widespread The scope of the occupational cancer problem is made even more apparent when the types and numbers of persons potentially exposed to occupational carcinogens is realized These agents may affect workers in basic industries producing using and handling raw materials and semifinished goods possessing carcinogenic properties in consuming industries workshops trades and professions using the output of the basic industries and in transport and merchandising organizations engaged in packing loading shipping and selling industrial goods with carcinogenic properties They also may have an adverse effect on that part of the general public which consumes such goods or which comes in contact with carcinogenic.industrial wastes discharged into the air water or soil The chain of events whereby an occupa- tional carcinogen may be transformed into a medicinal or environmental one is readily demonstrable with substances such as tar or arsenic The general existence of these various interrelations is shown by the appearance of the various occupational cancers in different countries following the establishment of industries producing the carcinogens Need for Study The scientific study of occupational cancers precancerous condi- tions and causative agents offers a unique opportunity for ascertaining the nature of extrinsic agents which are carcinogenic to man and to investigate in the human being the local and systemic reactions elicited by such agents during the preparatory and manifestation periods of the cancerization process The study of occupational cancers also permits the determination of the role which associated environmental hereditary and constitutional factors play in the susceptibility to occupational carcinogens in man In addition it makes possible the development of specific or nonspecific preventive prophylactic and therapeutic measures many of which might be applicable to human cancer in general Control of Occupational Cancers An effective rational control of occupational cancers depends on accurate knowledge of the causative agents and on the institution and strict enforcement of adequate preventive and prophylactic measures This goal may be approached through the following methods and procedures 54 API 07930 ' Elimination or Control of Occupational Carcinogens to carcinogens in industry should be eliminated wherever possible or at least reduced to the technically feasible minimum This can be achieved by designing buildings and machinery to prevent the escape of dust fumes mists and vapors the closed system of production ; by the institution of efficient exhaust ventilation by maintaining a high level of good housekeeping by disposing of carcinogenic wastes with suitable precautions and when necessary by the isolation of a carcinogenic operation from the rest of the plant Exposed workers should be furnished with suitable protective cloth^nggloves masks similar safety devices The degree of un- avoidable contact should be further reduced by the installation and Inforced use of proper sanitary measures such as special eating quarters washing and bathing facilities and separate lockers for treet clothes and work attire Workers should be familiarized Through lectures repeated at regular intervals with the type of car nogenic hazard presensto as to obtain their willing cooperation in The enforcement of the various precautionary measures Repairs After accidents during which an increased exposure to the carcinogenic Agent is likely to occur and the repair and cleaning of machinery and ipelines should be performed by specially trained and protected fi Measures designed to reduce contact with occupational carcinogens are of great value as observations made in connection with several Excupational cancers and with experimental cancers of animals have hown that a decrease in the degree of exposure results in a lengthenng of the latent period thus possibly delaying the manifestation of a canoer even beyond the average span of human life pational Since the practical importance and general appreciation of occupational cancer hazards is bound to grow during the coming years employers be wise to determine in preplacement examinations B^'he applicant's complete occupational history for ascertaining any previously sustained exposure to occupational carcinogenic agents In view of the usually long latent period of occupational cancers this procedure represents an expedient safeguard against subsequent compensation claims for such disorders originating from exposures sustained by the claimant before entering the employment of the party med Applicants for clerical jobs should be included as it is not uncommon that persons formerly employed in production and labora- tory work may later change to white collar jobs }* Medical supervision and periodic medical examinations should be 55 API 07931 ~_ ~ maintained not only during the time of employment in a hazardous | operation but for some 15 to 20 years beyond the end of employment thus providing medical observation of the exposed workers for the entire latent period of occupational cancers It may be advisable to establish for this purpose a number of industrial cancer detection clinics staffed by physicians experienced in the occupational background of precancerous and cancerous manifestations and provided with technical assistants trained to cover the various medical aspects of occupational cancer which would be required for the efficient operation of such clinics Periodic medical examinations should be made not only of those workers who are regularly employed in operations with carcinogenic hazards but also of those who may enter such operations at irregular intervals such as repairmen guards truckers shippers supervisors and chemists and physicists of control departments and laboratories as well as of those who are working within an effective range of such operations fume zone such as yard workers The frequency of periodic medical examinations should be increased with the age of the exposed employee and with the length of his employment in the hazard ous operation The type of medical examination should be properly adapted to the special kind of carcinogenic hazard existing Frequent spectrographic examinations of the urine of workers in contact with aromatic amines for the presence of these substances and of their metabolic derivatives should be practiced in plants producing or handling such products Annual or annual cystoscopic ex- { aminations are highly desirable wherever workers can be persuaded to submit to these procedures Inasmuch as bladder cancers are not infrequently symptomatically silent especially as to the presence of hematuria until they have reached an advanced stage cystoscopic examinations afford the only efficient diagnostic means for the discovery of bladder cancers in dye workers while they are still in a precancerous or early cancerous stage Whether or not the frequent cytologic study of urinary sediment with the Papanicolaou method may be of additional help in this respect remains to be determined In periodic studies of the blood of workers exposed to actinic energy and benzol special attention should be paid to the presence of hyperleukocytotic reactions and to excessive increases of monocytes Roent- all gen films of the chest should be made at year intervals for workers exposed to the inhalation of radioactive substances tar fumes arsenical dust chromate dust and fumes nickel carbonyl vapors mistai of mineral oils asbestos dust and beryllium compounds Similar in studies of the nasal sinuses are indicated for workers employed operations entailing inhalatory contact with nickel carbonyl Thes tests might well be supplemented by periodic cytologic examinations 56 of the sputum and of the nasal discharge particularly where chronic inflammatory conditions of the respective air conduits exist Inspections The adoption of a system of regular inspection of all plants using handling or producing industrial carcinogens by government inspectors is desirable Such a system has been used successfully for a number of years in England in connection with occupational cancer control Factory inspectors would be charged with checking on the presence of carcinogenic agents in plants and workshops with enforcing regulations covering the handling storing and use of such agents with supervising the protection of workers exposed to them and with approving methods of disposal of carcinogenic wastes While the last. mentioned aspect has recently received some prominence in connection with the disposal of radioactive waste products an indiscriminate discharge of carcinogenic chemical wastes represents a distinct poten- ; tial hazard to the health of the factory and general populations and ' thus deserves serious attention Mechanical devices capable of producing carcinogenic actinic energy should carry proper warning labels and should be furnished with explicit instructions as to suitable protective measures Carcinogenic ; chemicals should be packed in strong leakproof containers to eliminate any danger to loaders shippers and other persons handling them during transport storage merchandising or use The containers should be constructed in such a way that they can be emptied without | hazard to the workers performing the task and to those employed nearby Such requirements are particularly applicable to highly potent occupational carcinogens such as betanaphthylamine and radioactive substances Carcinogenic material containers should carry prominent labels with appropriate warnings Licensing of Establishments Factories workshops laboratories and other establishments produc ing handling or using carcinogenic materials should be obliged to register with departments of labor and public health and to obtain special operating licenses This would aid in establishing the supervision of plants by factory inspectors and would act as an educational measure by familiarizing the managers of such operations with the potential carcinogenic properties of the substances and devices used in their establishments 57 API 07933 Luch a compilation of information should include all presently and formerly employed female workers The availability of such data is an important prerequisite to the determination of the scope of the | occupational cancer problem and for the preparation of effective controls Education All available means of education and information should be used to spread knowledge and understanding of the occupational cancer problem among the various parties directly or indirectly concerned with it One of the aims of such education should be to create among the various groups a spirit of cooperation essential for combatting successfully the occupational cancers that form an important part of . the general cancer problem Research Inasmuch as occupational cancers are of direct concern both to industry and to government the financial support and actual under- taking of research on these disorders may be accomplished best if the = two would coordinate their efforts and establish an active exchange of t the experiences of their respective investigators Only thus can the : reaching ramifications of this complex problem be explored effec- F tively and economically | Such cooperative efforts are particularly important in the study of e the epidemiology of occupational cancers in the discovery and identi- fication of new carcinogenic agents and of the types of exposure in- volved and in the development of applicable control measures The - fruits of investigations thus jointly carried out will not only reward management and labor but will also aid in the ultimate conquest of the problem of cancer in general 59 API 07934 References 1 Abramson W. and Warshawsky H J. 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