Document NGDpQX94EM1e82yX2k3nKv9Ow

FILE NAME Household Contact HC DATE 1949 DOC HC041 DOCUMENT DESCRIPTION Government Report - Environmental and Occupational Cancer . +. FEDERAL SECURITY AGENCY | Oscar R. Ewing Administrator ho ete cae PUBLIC HEALTH SERVICE General re Scheele Surgeon Leonard A. General . | -. Division of Public Health Methods ae . co G.St. J. Perrott Chief of Division ' = 7 ENVIRONMENTALENVIRONMENTALENVIRONMENTAL ENVIRONEMENNTVAENVIROLNMEINTALRONMENTAENLVIRONMENTEANLVEINROVIMERNOTANLMENTEALNVIRONMENTAL . - i from - The National Institutes of Health The NationalNational Cancer Institute Cancer Control Branch UNITED STATES GOVERNMENT PRINTING OFFICE WASHINGTON : 1949 . For sale by the Superintendent Superintendent ofDocuments U. Government Pri 20 c cene ts Government Printing Office Washingtoo 23 D. C. ae . " INTRODUCTION aaa eae ROLE OF ENVIRONMENTAL AGENTS IN HUMAN CANCER CAUSATION = Definition and types of environmental carcinogens -- Circumstantial evidence for environmental causes of cancer -_..-------- Conclusive evidence for of laeeeeen- cancer environmentalcauses watanneee Chemical environmental carcinogens products <= petroleum - ~ Tar and tar products and oil shale products _ - Aromatic amines - - neo Benzol ae Arsenic EEE woos . ad 7 7 + Chromium___ Nickel ----- woeer----- ne wee en eee carbonyl Berylliumee ere . _. ~ carcinogens Asbe ~~ es nvironment tal environmetal eno vironmes ntal + Potential chemical environmental ee Physical Physical environmental carcinogens aeeenen--e eeeee-ee Ultraviolet rays os------ wee nen eeee eeeeeeeeee weenee Roentgen rays and radioactive substances_ -:------ peeccecwecere-- = rrr ne eonnnnee a nen -- seernn nen en _ Dietary carcinogens eee e eee nnee = meeeccccacccceccacc= pharynx Cancer of the a eee anne aeee Liver cancer eeceneee- weceee Cancer of the environmtehnytraolid . .Indefinite ann-+ ee----- eneeeee oeeeee weenn---- ace carcinogens carcinogens nae ewnccocerce- Schistosomiasis cancer of the bladdesr eer Betel nut cancer of the mouth aocua-ee eee ce eeewencee a 23 23 24 26 27 27 28 28 28 29 Cancer of lip Khaini cancer of the lower pececeeceeneee the aenneee wewcenee eennnnee Thermic cancer nee en coer denne neces n nnn e none ee ere eeereren . Extrinsic co- pro- and carcinogenic factors ... weereeee - Causative mechanisms . pecan naceen-e aecenae weee-- OCCUPATIONAL FACTORS IN CANCER INCIDENCE GROWTH cece eee- eeeneee - Occupational carcinogenic agents meee Evidence supporting an occupational origin of cancer .~----------+---- Statistical evidence on ce cw ence cee we ene e ween neerceeereres Relation to medicinal and environmental cancers .------+-----+--- cececceccecceseaee Precancerous lesions cee 30 80 31 32 35 85 38 38 39 = '40 experimental Significance of cancers ewe c ewww nnn eee nee eeeeee -wenn 43 carcinogenesis Physicochemical investigations 44 . Summary of evidence of occupational ... ... eeecnnee e . ww, o Se an 6 - - lf. . ~ - ook ad an 7 7 7N ce cane Ter eee arena ~ oo 2 . . . Le occupational Occurrence and incidence of Cancer of the bladder cancers in the United States ---------2 ne ene nner enn nreeerrr Skin cancer ecceeee career eensewene-- Respiratory cancersLeeeeene- ec ee ne eee ee eae Leukemias_ - - PROBLEMS IN THE CONTROL OF OCCUPATIONAL CANCER Factors responsible for lack of interest ; management Industrial .. nee eden eee nnn tren nce nn Labor and labor organizations wa pee newer newman nnnees Industrial Legislative bodies ceControl Departments of Public Health Hygiene Cancer Control " Medical profession .. Weecan ccerceceeueeceneeennaennerene problems Public health and industrial Incidence and causation_ eb ewennccvewennseeenene carcinogens mechanisms_ Number of cee ceneaceercceseesene Variety of carcinogenic mechanisms_ peccnnden-eanee Defects in statistical determination pe cece nennewenenee-H Probability of increase in occupational cancer lee nes necrerr ; widespread Chance of exposure Need for study ene ence l eee ene n eee ee te ee eeu ewes Control of occupational cancers__ meee cree wee ne eee een nemeree= . Elimination or control of occupational carcinogens Medical examinations .----- ------- 2 enna ne cen ern errr Inspections _._.-n- en n- n nn- cer- n nn - e + r -- r - r - Labeling and packaging eee ennneces, Licensing of establishments . eee ron ree rere Notification 22 o-- ween een nee nr rere - Determination of minimal effective exposure ween sense ncn neroc nee Compensation laws Individual identification . ep ewecneccsecnecceceeeeece mene ner wanen smu eae TR eee water oo aamermngenre a te a a Environmental and Occupational oo, 0 Soe Ree Cancer e ec0 Ul. Ps wee agin awee _ . a heat a *! TF, ae ofa clinical and experimental efforts toward achieving achieving an effective -- - L Past cancer * - control of have dealt chiefly with attempts to improve diag- _ measures Without any doubt this nostic methods and therapeutic a has of TO work had a measurable amount succtehsast the reaching control - remember ' Bey However it may be well to 75 has depended - of infectious diseases achieved during the past years on the successful determination and identification . _ to a definite degree deal of extensive and of the causative organisms and on a great laborious epidemiological study Recent developments in the field _. make it seem likely that there exists a similar interde- of cancer of factors pertaining to etiology and control .. _ coe " pendence the causative agents responsible for over 99 percent of - As long as remain unknown as long as no determined and and human cancers made to fill in this serious gap in essential widespread efforts are in the control of - information there is little hope that rapid progress can be obtained by rational preventive prophylactic diag- cancer measures - The prospects of repeating in the nostic and therapeutic with the control of infectious field of cancer the results achieved therefore not too favorable unless some of the methods diseases are to cancer research and approaches used in the latter are applied Although there are many importaonft dainsedasaepspathreeinrtlsiymfiluanrdiatimeesnatlaslo * differences betweDeanttahaettpwroesgernotuapvsailable as to the number and types are numerous - of extrinsic carcinogenic factors suggest that the prospective spectrum and endogenous carcinogens may cover a range of agents of exogenous each other as widely as those composing the spectrum differing from The recently discovered species the pathogenic organisms is analogous to the species specific - specificity of carcinogenic agents infectious diseases The of the organisms causing pathogenicity organisms share with the organisms the marked carcinogens moreover ai Le od aaa bhah 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 reac- of the host tissues as happens with tuberculosis syphilis etc. tivity extrinsic carcinogens are likely to elicit various histologic responses so in the tissues such as hyperplasias hyperkeratoses warts nodular adenomatoid proliferations benign tumors papillomas and ade- cancers 0. experimental a evidence evidence shows that experimental Furthermore clinical as well as in both infectious diseases and cancer the sites of the anatomical ~ of responses are not only determined by the properties the particular pathogenic agent involved but awlhsiocbhydtehceitdeypteheordreovuetleopofmecnotntoafcttuwbietrh- it The conditions ofaenxdpoosfurtehe inhalation and ingestion culosis of the lungs fundamentally no different from those which are respectively of cancers of the skin bones lungs responsible for the development etc. after exposure to radioactive material by skin contact inhalation _ . ere is ingestion or parenteral introduction - Le An additional resemblance between cancer and the infectious dis- is the fact that the degree of pathogenicity or virulence of the eases causative agents only in part an extrinsic quality It depends to some extent also on the intensity and duratiwoonrkoefresxpionsduyree ptloatnthseims - Thus the incidence of bladder cancer among and those most massively exposed to aromatic amines hdiegchreeassteas maomnogng other operatives in proportion as their contaicntvwesittih- these highly potent carcinogens decreases Epidemiological have shown a similar crowding of tuberculous infections gations with active and open tuberculosis of the lung around persons In other words the epidemiological pattern of the spread of cancer qualitative and of infectious diseases from foci where causative agents are gen- 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 the development of modern industries and the continuous paralleling - of often unknown biological prop- creation of new industrial products factors which tend to result in the appearance of an increas- erties are carcinogenic foci Since the char- ing number and variety of extrinsic well as the type of exposure to it acter of a particular carcinogen as result determines the site of the ensuing cancer this development may in the course of time in a change of the quantitative and of the environmental carcinogenic spectrum and thereby in the aisnpceicdtesnce rate of cancer both as to total numbers and as to sites It is evident therefore that for an effective future control of cancer 21 ns ee nT ener Me . ee ae nh, nnn en a ne . we must abovetrends,will and . = oe metas al rs oo determine the and directiodnirsectioonsftthh e ne ew new trends trends = determine the causes institute institute their prevention repetition repetition repetition trends of of cancer procedures procedures different metropolitan areas the United ; first carried morbidity ten different ago and being undertaken again this - States States Cancer years year year the of the National Cancer assumes assumes significance Control Branch Branch considerations Institute A A second step toward significance adequate adequate epidemiological epidemiological analysis cancer was taken recently more adequate - ee of an Environmental Environmental Can- c= ancer Section within the Control creation Section cer cer epidemiological Control Branch This epidemiological investigations investigations into extrinsic '. plement es causative causative factors human cancer cancer investigtationhs ey related occupation , medicinal medicinal agents climate customs we and parasitic infections infections development in this field is launching by the New : . A A third development Committee the of launching launching New .~ York York Occupational Cancer histories several thousand project determine occupational histories thousand cancer patients patients in in detail Institute Institute Buffalo tories Roswell Roswell Memorial cancer These | asutstained sustained are to analyzed analyzed pa re, vious occupational - patients sustained order by concise and yet comprehensive pre- sentation sentation order make available available the environmental cancer pre- for sentation current knowledge knowledge but also by the medical problem for in general not public cancer specialists social welfare profession in and members health officials legislatures labor organizations the workers paper paper prepared management and of lectures given before following following national national Congress on It It baRseesdeaornch in St. Louis September Inter- -- and postgraduate postgraduate course of the Department of Occupational Medi- Medical cine cine University March 1948. I wish express express kindness my thanks theseorMgeandiizcaatlioSncshofoorl their in permitting me form revised to use substance substance of these lectures in this to use the substance ahube. 8 terven wereti ae 16 herds 3 de oC A g09261 - 49- - teeny Vtg . yuse, 2 tg nr ee i Preface |. at making occupationalEpidemiologically This study presents a comprehensive review of current knowledge of the environmental causes of human cancer Dr. W. C. Hueper interests have been in the fields of environmental and whose major has collected and analyzed the most im- occupational carcinogenesis both domestic and from abroad portant known facts on this problem 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 of The conclusion is inescapable that exogenous agents particularly industrial origin are important factors in the causation of certain of cancer It is true that neoplasms of known environmental ' teytpioelsogy comprise only a part of the total cancer incidence in the United States However the fact that there seems to be a constant increase in the appearance of these cancers in the though gradual carcinogenesis a general population is swiftly public health problem of very real importance reveal additional sub- for example much more needs to be done to , i. stances guilty of carcinogenic activities which admits of no simple solution as Dr. Hueper maIktesis calpearroblNeom one agency governmental or privaotfeteccahnniscoallveanidt Only a carefully coordinated and integrated program social controls supported by the cooperative efforts of government health organizations the medical profession management and private 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 wo | ~ aves =a / Role of Environmental Agents in 7 s2:-.Human Cancer Causation an u About the time when the microbial origin of infectious diseases was ~.. 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 ee TO. a several extrinsic agents The agents mentioned thus early were arsenic soot tar and crude paraffin oil 168 Unfortunately these basic ob- servations on the etiological significance of inanimate environmental factors in human cancer were not followed up with the same vigor . ee 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 fol- lowing decades on the list of causative agents belonging to the modern artificial industrial environment it was not until isolation of benzpy- rene from tar approximately 20 years ago that scientific thinking developed an appreciable interest in the causation of cancer by specific extrinsic factors . ee, . 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 uni- versal distribution the occurrence of demonstrable environmental can- cers 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 a . great number of highly diverse environmental conditions such as oc- 4 a gek Sk eset tg we tee ee aki > .- ~ 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 Sf environmental recent procedures of warfare - . causation of human The data supporting an extrinsic 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 occu- and with different climates and also are to be noted piantmioanraklegdrvoaurpisations 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 of the United States Gover found remarkable mixed population variations in different sections 130 The rates ranged in 1930 from - 127 100,000 for all cancers of both sexes in Rhode Island to 56 per in Arkansas Similar observations were reported from pdeifrfe1r0e0n,t00p0arts of Europe 58 62 where the lower incidence rates recorded from southern countries while the higher ones were generally of the continent The were usually found in the northern parts highest cancer mortality was observed in Denmark 58 Although some of these discrepancies are attributable to differences in quality and quantity of medical service and disease reporting in various parts of Europe and the United States it is not likely that this accounts for them in their entirety particularly since these factor associated with regional variations in total cancer mortality are of the various considerable variations in the distribution, of cancer , organs There was for instance not only a high rate of cutaneous cancer both sexes in the Southern States of the United States but also afomronalgl sites of cancer of the buccal cavity among females and for ht cancer of the pharynx and mouth among malensotiendcionmp1a93r5isaosnimwiiltahr al ie those found in the Northern States McDowell in different parts of the regional distribution of cutaneous cancer dahl i 5 i ian Sl at 7 vet! United States when he recorded an incidence rate of 157 for Atlanta ~ -129 for New Orleans 37 for Detroit 25 for Pittsburgh and 24 for of 17 Chicago 223 The incidence rate of cancer the stomach and of the total digestive tract on the other hand was found by Cramer to _. Pacific be higher in the northern sections and in the coast area than in the west south central and south regions 62 while cancer of the lung _ + '* 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 31 143 A similar environ- mental 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 _ 379,397,133,258 379,397,133,258 379,397,133,258 379,397,133,258 307 70 298 60 211,234 211,234 Additional evidence indicating that environmental factors appar- striking ently have a definite influence on the incidence rate of certain organ cancers was recently furnished by Lasch 200 He reported 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 1939 was considerably higher in the purely agrarian region of Mecklenburg than in the agricultural district of Anhalt the indus- trialized Saar or urban Vienna On the other hand gynecological cancers showed a higher frequency in the latter three areas than in the; agrarian district The practical absence of penile cancer in Hebrews its relative in Mohammedans its moderately high incidence in American Negroes 337 211 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 60,294 60,294 163 337 . 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 ere ne ee Ne mens wm me considerable discrepancies in the incidence of lung cancer in different parts of Europe in some regions of Germany England Switzerland and low in France and Italy They are probably caused by local variations in industrial activities habits diets and other environ- mental conditions 51 168 os It is generally recognized that racial differences in skin pigmentation 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 cancer patients against 1.7 percent of skin cancers among 724 colored cancer patients 387 Nevertheless the environmental origin of skin 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- tribute the excessive incidence of nasopharyngeal cancers in Chinese to a special racial susceptibility 858 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 extrinsic agents to a remarkable degree The incidence ratio for males and females for cancer of the skin is 1 293 for cancer of the lung 1 to 1 159 391 271 for cancer of the larynx 10 167 ; for cancer of the bladder 1 6 ; for cancer of the esophagus 10 Cancer of the stomach 385 and cancer of the liver 105 occur more often in males than in females ind It is also significant that the local distribution of cancers of the skin and of the intestinal tract as well follows a pattern which in- dicates that an extrinsic carcinogenic agent is most active at certain 4-. circumscribed areas favoring intense and prolonged contact such as Shes 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 e not only to known environmental carcinogenic agents such as soot tar mineral oil arsenic actinic energy and others of an occupational rimuler _ character but also to those of a more or less indefinite nature such as 7 diet general personal hygiene wearing apparelapparel living quarters 7 and is found habits found cancer increases It 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 in the lower economic classes for cancer of the scrotum and ;_ - - mortality 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 : additional im- least 175 to sooitn town dwellers was considered an -. Exposure portant etiologic factor cancer of the penis did not reveal a similar concluded that different causative economic distribution they _ factors are involved in the production of this neoplasm The statisti- Occupational showed that social grading is present with _ : cal evaluation moreover skin and of the larynx is very pronounced for cancers of cancer of the the remainder of the all sites above the pylorus but is not observed in LS ae alimentary tract =~ their studies of the incidence of skin cancer ex- Ryle and Russell in Scotland North Ireland clusive of scrotal cancer in England Wales found that there is no increase in incidence with lower- and Eire 327 while with males a distinct increase is ifnoguonfd socCilaalsscelsasseexspionsefdemtaolseusnlight soot and grime showed a high incidence For example among men exposed to soot such as furnace boiler firemen and rollers the rate was 225 against 70 in men stokers factors thus professional men and collar workers Clemmesen appeared to be more important than social class Indeed is concluded from his analysis of Danish death certificates that it not that the latency period for the development of cancer viamrpireosbaibnldeifferent occupational and social groups depending on the of the particular injurious agent and that this fact may ac- pcootuenntcfyor 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- and a high one in all industrial groups ity in all agricultural groups in the industrial group stood at 129 per- . The gwahsitrliecictawnacs eromnolryt5a7lipteyrcent in the collar class Other in- vceesnttigations show that cancers of the lung are excessively frequent in certain varied occupational groups such as engineers mechanics decorators metal grinders foundry workers etc. while they painters in clerks and typists 373 Although Ryle are relatively infrequent not related to ex- and Russell maintained that the melanomas are trinsic factors 327 Peller 288 noted that white American soldiers and sailors from the Southern States have melanomas less often than 4 those from the Northern States when the number of epitheliomas of this the skin are considered but that iis s when internal relation reversed cancers are analyzedcirumstanial circumstantial pointing Additional evidence to the action of extrinsic factorsin the development of cancers is foundin the exist- ence of differences in the local distribution of cancers in certain organ different systems such as the oral cavity 176 and skin 557 in 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 shiftsin sex distribution and differencesin age range 175 as well as variations in the absolute and relative frequencyusaloy f cancers of certain organs While fluctuations are usually ascribed to improvements in diagnosis and treatment and doubtlessly are due to these factors to some extent changes in the and qualitative composition of the envi- quantitative ronmental carcinogenic spectrum at different and localities play times evidently may also a major role The markedincrease 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 pronouncedin ~ males than in females and that the percentage of adenocarcinomas among the bronchiogenicbronchiogenic 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 responsible proof that a single extrinsic agent is wholly for this de- velopmentis not a valid reason against the conception since it is well Alger highly known that several agents with different physical and chemical States shy properties may cause pulmonary malignancies of occupational origin The definite rise in the incidence of leukemiain the United since 1900 and particularly since 1930-94.7 percent during the last represent 20 years -may another example of such an environ- mental change The rise is not accounted for by differencesin age dis- abe: tribution of the population and leukemia is twice as frequent in et whites as it is in Negroes and more often seen in males than in fe- Gf likely leukemiogenic males It more that some environmental agents ame benzol aromatic compounds tar actinic energy which appeared Omens some 40 to 50 years ago and have become increasingly common are for the rise responsible The various data of a circumstantial character which are advanced as favoring a frequent extrinsic causation of human cancers may not be ofimpressive value when taken separately However when seen as 9 t rae te ee ey Ferme nae ee ase mean a whole and integrated into a pattern they provide weighty evidence supporting such concept Their validity is greatly strengthened and the concept itself is made more concrete by the evidence supplied Circumstantial et _ by the various recognized environmental cancers ; fod be a 7 evidence for environmental cancer is outlined below = me _ both 1. Variations in total and organ incidence for ' sexes in different te regions ae Ley 2. Differences in incidence rate of certain cancers for males and females : .8 - Differences of incidence of all and certain organ cancers 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 - 7] 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 roentgen rays and . rays from radioactive matter A second large group of environmental tumors is elicited by exposure to defined mixtures of organic chemicals the carcinogenic components of which are incompletely known The members of this 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 A substance isolated from tar and crude shale 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 ee mee ee ! }} toy ern nairte .omerhe Joh masgeuw urmluns fero Samet kejnee a od ees agian webtedn and taplenbstc taed =! 208 wearin od 20 net ange Gate tebe weet ON Fae a Oe gore r gmt onpins ot tae TREC a hth pee Ye - ae mS Listed below the various groups of environmental carcinogens 1. Chemical carcinogens , ris O rganic chemicals Aromatic compounds tar pitch asphalt soot shale oil crude paraffin oil anthracene oil lubricating and fuel olls . greases creosote lamp black aromatic amines betanaphthylamine benzidine aniline benzoi Aliphatic compounds carbon tetrachloride B. Inorganic chemicals . Arsenicals chromates nickel carbonyl asbestos II Physical carcinogens . oe Ultraviolet rays corpuscular rays alpha and beta rays electronic rays gamma rays Roentgen rays IIL Dietary disturbances involving protein fat and vitamin metabolism and ~ affecting liver pharynx and thyroid . IV Undefined environmental carcinogens contained in betel quid khaini and Schistosoma hematobium - = The highly diverse physical and chemical properties of these agents make it improbable that they exert their specific pathogenic action through the same mechanism From an analysis of the available data and from theoretical considerations it appears that extrinsic carcino- genic factors may elicit malignant growths through one of the follow- . ing ways Some of the agents such as aromatic amines and the carcinogens contained in tar and related substances apparently act directly on the cellular substrate either in their original form or as metabolites or conjugates This action may be merely catalytic as only minute amounts of carcinogens of this type may bring about malignant cellu- lar transformations 285 62 343 or it may arise through interference with the normal cellular enzymatic activity or by combining with macromolecular proteins resulting in the formation of allergens A second group of extrinsic carcinogens apparently consists of agents which do not possess direct carcinogenic properties but which change some normal chemical constituent of the cells or tissue fluids in such a way that it becomes endowed with carcinogenic properties In view of the long latency period of actinic cancers it seems probable that such a mechanism may be active in their development A sim- ilar indirect and mechanism may also be responsible for the occupational cancers caused by exposure to certain metals 333 A third type of environmental carcinogens may cause quantitative or qualitative functional changes in some endocrine glands or the liver which respond with the generation of abnormal endogenous carcinogenic products Cancers of the dietary environmental type have this origin as may those produced by hepatoxic agents such may hydrocarbons It is as certain azo dyes and chlorinated aliphatic obvious that the demonstration of the actual existence of such a mech- 11 809261 ge re ee rn ee vbae ad - Rw - .- Mes . 2 pape . mR , se 7 : mee oes . 2: Sate . si 8 -.. _ -.. _ . ' . --; anism would not only establish a direct connection between extrinsic and intrinsic carcinogenesis but would widen at the same time the potential scope of extrinsic agents as producers of human cancer - ~ These considerations are of definite importance because of the recent _ isolation of cancerigenic substances from normal and neoplastic human .: tissues and the occurrence of congenital cancers and cancers in infants . ~ 186 154 357 408 329 392 138 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 = re i te , ~ - - -. $- =~ ...Chemical Environmental Carcinogens 7 | TarTar and Tar Products Petroleum and Oil Shale Products ; contacts with a 11 Human 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 cause the majority of environmental cancers in man The existence of 3,4 benzpyrene in tar 174 and shale oil 20 probably furnishes only a 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 direct 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 the numerous observations made previously on this subject and reviewed - in detail in my treatise on occupational cancers 169 English inves- tigators especially have furnished valuable data on the occupational aspects of these cancers and on the relationship between duration and intensity of exposure to the length of latent period and manifestation - age 175 154 147,37,19,235 147,37,19,235 147,37,19,235 147,37,19,235 These studies have again brought out the fact that environmental exposure to these substances is rather widespread and often not readily suspected Workers such as stevedores electric brush makers manufacturers of paper covered electric conduits slaters and bricklayers are subject to it Kingsbury re- ported the occurrence of a scrotal cancer in a Tamil engaged in antimalarial oiling of surfaces of water in India 179 No appreciable reduction in the incidence of tar and oil cancers seems to have taken place in England during the last decade In 1935 ex- 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 ff eT Pee of the skin among workers exposed to Scottish shale oil was obtained e haired by the use of a protective lanolin ointment and the exclusion of red- _ freckled and skinned workers from employment in opa erations entailing contact with shale oil 5,244 5,244 . 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- 109 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 Inas~-nuchas 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 940 Chase observed a typical scrotal cancer in a chimney sweep and Klauder . found an epithelioma in a paraffin presser 54 185 Although Jonas 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 the exposed skin 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 Pa) did not find any significant difference from that of the general popu- lation 121 In view of the carcinogenic action of some lubricating fuel and Diesel oils 371 192 cancerous reactions may result from the accidental injection of such products into the human tissues grease gun finger Diesel jet injuries 38,45,230,401 38,45,230,401 38,45,230,401 38,45,230,401 While the carcinogenicity of wood soot and wood tar present in | Wood foodstuffs smoked meat and medicinal and cosmetic agents oint- 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 bril- liantine containing petrolatum 334 noted a unique case of a bilateral carcinoma of the lung in a patient with lipoid pneumonia Ea ) by the inhalation of mist of mineral oil 406 caused The role which the inhalation of tar dust and fumes plays in the PR NOTIN, production of cancer of the lung in man is still unsettled 257 254 13 15 experimental soot gaso- 3 soot despite the evidence that obtained from , line motor exhaust products and from atmospheric dust causes cancer the lung after inhalation or sarcoma of the subcutaneous tissue after injection in mice and rats 290 47 343 Although the high incidence of lung cancer among stokers in a Japanese generator plant to the inhalation of hot tar fumes supports such a relation- exposed statistical studies of lung cancer mortality rates in ship 173 191 marked differences the population of various American cities havfiarngas a purely environ- in atmospheric seem to contradict it as st to soot is concerned The lung cancer rate among mentalexposure . males in Pittsburgh was found to be lower than that of any other large ts tarry 5 city surveyed with the exception of Denver - in A direct contact with tar and the inhalation of fumes .- 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 . . It is most likely that tarry combustion products play the major role in the development of cancer of the abdominal skin which accom- the use of certain heating devices such as the Kangri in Kash- panies the Kairo in Japan and possibly the Chang in China 264 131 mir ' for the chutta cancer of A similar mechanism is evidently responsible the mouth seen among the Northern Cicars of Vizagapatam province . i in India who develop cancer of the hard palate due to contact with tar 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 part 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 garment is not often removed and cleaned the accumulation of soot from the fireplace in addition to the decomposition products of unsaturated skin 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 52 227 362,55 New 2f1ew cases of bladder cancer in dye workers have been reported from sev- 14 ty eho, ae. mos Op +8 eral countries Switzerland Italy France England and the including Maguigan United States Both Slotkin and noted such tumors in plants 348 dye workers of Buffalo's chemical 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 phenyl- betanaphthylamine which is used for the prevention of aging in vu^<- canized rubber 57 92 It is significant in this respect that Rosenthal noted the occurrence of hemorrhagic cystitis among in employed homologues ot girls in a glue factory in which of aniline Koelsch Tall were usedin the preparation of the glue and that recorded woo similar symptoms in English ammunition workers handling aniline It MabnosPe m- and toluidine and xylidine 814,188 814,188 It is likely that the incidence of bladder cancer might rise if 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 Maguigan 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 89 experimental production of aniline cancers had been brought about by moatire Sahr in 1905 in dogs and rabbits The animals developed bladder neoplasms 3 months after ligation of the ureters and exposure to at) benzidine and betanaphthylamine fumes These results have been wtante confirmed by Slotkin 348 Experimental observations indicate that other aromatic chemicals me are capable of producing bladder tumors aminoazotoluene 407 sae 275 acetylaminofluorene 18 toluidine 259 and azotol- uene 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 _. 4 rceonmtaaiinneedd ininnorthmealuriinndiecating thereby thatthe carcinogenicagent is Benzol ae - oe an to " ~ Additional evidence of a leukemiogenic action of benzol has been recorded during recent years 216 142 382 164 301 289 272 236 widespread workmen The exposure of inin industry to benzolis evident . benzol from recent reports 402 75 165 356 341 196 115 is signifi- - Duvoir cantin this respect that 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 months respectively after cessation of exposure to this chemical observations suggest : that chronic exposure to benzol may be responsible for the development of polycythemia vera 247 142 Kirschbaum and Mixer did not succeedin 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 leukemiain a patient with subchronic naphthalin poisoning and that Rolland saw and the development of an acute leukemiain a workman handling naphthol :: 3 238 310 evidence indicates that tar several :: Experimental aromatic carcinogens are capable of eliciting leukemic re- synthetic sponisn e micse 184 118 119 193 212 239 149 170 100 204 Arsenic - - - os 7. - ; . inorganic chemicals Among the arsenic has enjoyed for years a doubtful role as a carcinogen although next to soot it is the oldest sub- stance related to the development of occupational cancer Paris 1825 Kennaway recently relegated this claim to realm of cancer mythol- seconded by the ogy and was Boyland 174,34 174,34 Schwartz asserted that contact of arsenicals with the skin does not cause cutaneous malig- nancies but that the ingestion of these substancesis 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 be 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 395 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 ca ae ce eR re re ee momar eo ! os nqrden d ly maried de Onhartle hat tes am eter re fide te th tinsel = s^'lavte hfere Ww OMY aoe, itee oe ptm Wy fe sis iba a Ve asnezit Lets [var rea wet. Sed Mae Wat a 864 Negishi recorded the occurrence of arsenic in lead- 260 poisoning workers , and Schaerrer reported cancers of the skinin arsenic silver miners 332 through Additional cases of occupational cancer contact arsen- ical spray or fumes from smelters have been recorded in America . 112 366 Japan 245 England 269 104 296 55 and Germany 287 146 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 low136 thereis no doubt that arsenical occupational dermatoses and hyperkeratoses 35,231,172,17,59 plants among various types of workers loaders andpackers of arsenicals cotton field workers vineyard workers workersin arsenic are not uncommon 335,231,172,117,59 335,231,172,117,59 335,231,172,117,59 evidence industrial arsenical Despite the controversial cancer of the skin its in in regard to on a medicinal basis appears to be occurrence firmly established 166 375384 300 286 15 325 281 337 248 308 view 326 9 106 316,147 316,147 In of the recent claim of Merewether 235 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 316 , who reported the oc- basis currence of a malignant melanoma on the leukomelanoderma of a medicinal arsenical . accumulated Strong evidence recently has according to Hunter indicating 164 that exposure to arsenicals may predispose to the development of cancer of 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 iin n bladder made regard to the causation of cancer In view of the rare development of hyperkeratoses and cancer in per- sons 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 303 163 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 unsatisfactory present in furred animalsis responsible for the mental results.. experi- . 17 d coed! ne mn we ve dada Chromium -. og Chromate cancer of the lung is another of the metal cancers which . deserves special attention because of its rather recent discovery and ~ the obscure nature of its causative mechanism 333 207 Although 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- the chromate workers at Griesheim 174 apparently re- cfeerrraimngontgo 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 . ; 1989 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 163 The incidence of lung cancer among the ~ rate 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 for the general adult population Recent observations indicate moreover that the occurrence of these cancers is not restricted to German operations as similar cases have been observed in American chromate plants 224a 4 Cancers developed mainly in workers employed in and around ; chromate and bichromate operations where exposure to chromate dust was present 7 186 187 Workers affected were employed in the grinding and mixing of ores in the oxidation of chromite to chromate and in the transformation of monochromate to bichromate Chromium pigment workers clerks glazers drivers and locksmiths working transitorily in and around such operations were also affected varied from 7 to 47 years and the age of work- The length of exposure from 29 to 69 years Kennaway's ers with manifest lung cancers recent statement 174 that the relatively advanced age of these work- mild cancerous stimulus despite the ers indicated a comparatively high incidence of lung cancer among those exposed is therefore open _ to Tquheesatcitounal extent of this cancer hazard cannot be properly evaluated at this time for lack of reliable data However it may be consider- able Chromium ores which are mined in South Africa Turkey 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- and nickel for the manufacture of speed tools exhaust dium turbine blades roller bearings and pump rods in stainless _ vstaelevlesprocessing for pigment making in inks paints glass and 18 ce ee ee nani = ee 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 .C , a 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 concept 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 because such reactions have not been seen among workers in organs 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 a 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 workers The attempt made by Campbell to produce lung rceafnicneerryin mice by the inhalation of nickel dust gave inconclusive . results 47 Beryllium ; The development of sarcoid granulomas in the lungs of workers to the inhalation of beryllium dust represents the most recent exposed and blastomatoid reactions to addition to the list of blastomatous metals in man 122 197 Lanza collected 20 to 25 such cases in a manufacturing fluorescent lamps Gardner mentioned a total plant reactions to beryllium Of these of about 100 cases with pulmonary 19 600261 169 00261 19 lie eS he considered about 60 as being genuine The relatively large num- ber of cases observed within a comparatively short time indicates the . industry posible extent of this industrial hazard 155 400 381 229 353 201 353 65 and reflects the wide use beryllium has foundin in recent The metalis used as an years iron copper aradio lloy nesium nickel and silver with aluminum mag- It is usedin fluorescent lamps as a phosphor Itis found in radio tubes incandescent lamps electric heating elementsin phosphorescent * compositions such as lumi- indicators Refractories nous 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 lungis unknown However thereis some indication that other fac tors besides beryllium are at work Experiments on dogs rabbits pulmonary guinea pigs white rats and white mice did not resultin ; proliferative responses when zinc beryllium oxide or other mixed phos- -4 phors such as strontium barium and cadmium were administered by inhalation or injection On the other hand rabbits injected intra- venously 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 cancers which may belong to the metal group is the cancer of the lung in 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 a total of 23 cases of asbestos cancer of the lung has been reported by Ameri- can English and German investigators 221 222 128 406 102 206 96 188 393 390 158 214 160 28 330 Wedler 990 noted that- there were 14 cases of lung cancer among a total of 92 autopsies on asbestosis patients Four of the cancers were present in females . the rest were in males They rangedin age from 35 to 75 years and years the exposure time from 3 to 27 Itis noteworthy that the mani- festation age of asbestos cancer is relatively young | The asbestos industryin the United States employed some 19,00019,000 workersin 1914 347 More than 10,000 of these were exposed ap- : preciably to asbestos dust 197 Despite this high percentage of * exposed individuals the incidence of asbestosis is low 347 This 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 The 20 incidence of this complication increased with the length of exposure Asbestosis was present in 5 percent of workers employed for less than 3 years 18 percent of those employed from 3 to 5 years 56 percent of working from 5 to 10 years and 79 percent of those exposed for over 10 years . Jo : inhalation ~ 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 nodular fibrosis of the lung The histological character of the or cell carcinoma instead of adenocarcinoma of the cancers squamous derivation of the tumors spontaneous type and the histogenetic : bronchial mucosa instead of alveolar epithelium of the spontaneous ei type support a specific causation of these reactions by inhaled asbestos eo dust . ore Potential Chemical Environmental Carcinogens v0 do evidence obtained during the last few years indicates PIB Experimental of the total number of existing environ- pp ta that perhaps only a small part and that entirely new types of agents mental carcinogens is known the work of American he be discovered This is foreshadowed by Outs may investigators who found that selenium diethylene glycol carbon tetra- - , ts chloride chloroform ethyl carbamate and ergot are capable of pro- sae tumors of the lung liver bladder or nervous tissue in mice ducing It interesting to note that several of these substances are gecoih or rats is which are not ordinarily credited with possessing b*ode aclairpchiantoigcecniocmpporuonpdersties However the possibility tehxaetrtasliupchhatain c on 2h chemicals or their cyclic condensation products may action in man is suggested by recent observations in the field of oc- cupational carcinogenesis The fact that environmental cancers can be produced by metals or aliphatic cotmhpaonunhdass sbeeeemnsgtiovceanllifnorthae gpraesatt deal more attention to these agents Se which has found extensive use in industry during recent a Beate Selenium of the called alkali disease among cattle in those ela years is the cause the soil contains excessive amounts ASS hie parts of the United States where were Tae EON of the substance Cirrhosis of the liver andMhaelpeartaotmsafsed 1 2 parnod- . AP na mre is gaelets duced in rats which were fed seldeenvieulmope2d6s2tones in the bladder after 4 percent of diethylene glycol in third of those as TMD 32 weeks and papillomatous bladder tumors apennnn 1 tested One of these tumors was carcinomatous 202 aun. action of chlorinated aliphatic hydrocarbons sm The hepatocarcinogenic and chloroform which are used as such as carbon tetrachloride Reminder anesthetics in medicine and as cleaning fluids and solvents in industry thins 21 ae earn ant ect ie 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 to livelivrer injuries 80 190 87 360,74,163 360,74,163 . ~ Of considerable significance is the discovery of the carcinogenic j 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 263 149 199 Propyl- butyl- 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 differ- ences 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 ^ 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 acetylaminofluorene a chemical developed as an insecticide 405 demonstrated . the possibility of an indirect contact of the brain with a cancer producing environmental agent 217 This action may 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 substances There are without doubt other environmental exposures which may 22 CT be involved 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 193 and of the alleged but still unproved similar effectin women the recent observationof swelling hyperplasia of the breasts due to a proliferative glandular in male workers engagedin 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 1 periods the a dose of diethylstilbestrol 1 mg daily for a total of 1,097 mg in prostate the treatment of cancer of 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 25 363,99 163,215 Since not only chronic solar or chemical dermatitis and cancer but also the called senile kera- toses are absent or very rare in colored persons it is probable that these environmental precursors of cutaneous cancer in the skin of white persons are at least in part the result of exposure to injurious influences 352 The actual causative mechanism of solar cancer has remained as ob- scure as that of other actinic cancers It is not likely however that these neoplastic reactions ensue from a sudden physically induced cel- lular mutation because of the long latent period usually observed Whether or not the photochemical production of endogenous car- cinogenic 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 859 153 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 - 2 } population of the 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 3 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 more prone to apply protective measures and also the fact that they undergo less exposure for _ reasonosf 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 4 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 90 378 377 111 169 389 261 254 255 399 88 404 270 35 251 812 303 39 3 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 roentgenologists : The others were general practitioners and specialists of other ; branches of medicine handling roentgen equipment and radium He | 3 believes that physicians in general are not sufficiently familiar with # an the techniques of using such devices and with the proper precautions Pn) to be observed The indiscriminate use of electronic energy during the First World r 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 entirely was not 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 4 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 radia- - tion injuries and cancer has been reported during recent years 295 ; 24 fit er dote be coset syinechcte gyeldimndian evencorter veel bene tse ta wii bel lr Ghatbe nouaereeicdy sat V 208 345 161 67 171 48 145 225 McMahon et al recorded what might be the first human case of sarcoma formation following a 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 cases having a median latent period . - mo, of 6 years 145 . - New evidence was advanced supporting the leukemiogenic action of small doses of electronic energy man similar to that seen previ- ously in mice 163 149 182 119 Ulrich found that the incidence of leukemia among American radiologists is eight times that of the average physician 876 A 3.9 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 376 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 those Japanese exposed to atom bomb radiation 389 among information has been recorded No fundamentally new or important during the last few years in regard to the causation of lung cancers the cobalt miners in Schneeberg and the uranium miners in among 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 pitchblende- containing 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 dust population puSrupcohseactivities entail exposure to the inhalation of radioactive and gases a hazard which may extend if proper precautions are not taken to the neighboring Similarly populations sur- atomic energy plants may be exposed to radioactive fumes raonudnwdaisntge waters In view of these facts it seems urgent that definite Schneeberg- information be obtained whether the lung cancers of the Joachimsthal miners are caused by radioactive energy 163 or by 25 3 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 re- .: ' - sults as to the development of lung cancers 47 Lorenz Heston Deringer and Eschenbrenner exposed mice to a continued ir- radiation 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 ex- posure 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 302 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 in Henshaw 149 and Henshaw and Riley 151 produced leukemic $ conditions addition to skin cancers in mice exposed to small } amounts of rays as well as 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 4j 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 ribo- flavin inositol choline biotine amino acids cystine avidin and | various oils on the susceptibility susceptibility or resistance of the liver in rats to the carcinogenic action of certain aromatic compounds 44 124 * 26 pee ere ee eevmemn corer er mm 157 272 187 342 205 212 43 ; the effect of cystine and lysine on the incidence of spontaneous cancers in the mouse 394 134 240 395 ; and the possible production of carcinogenic products through the development oxidated oils as the result of overheating animal and vegetable fats and lipoids 291 17 16 Lo, 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 reindeer meat and to salt fish Only during the short summer are green vegetables avail- ion able As result of this unbalanced deficient diet a symp- Sank tom complex appears mainly in women which is termed the Plummer- Vinson syndrome During the course of the deficiency state hyper- Diabet keratoses of the oral and nasopharyngeal mucosa develop which RiadaOIR ultimately lead to the appearance of cancer of the nofas1o2p3hwao rymnexn 4 wit2h 249 Ahlbom found this syndrome in 65 percent cancer of the mouth pharynx and esophagus 4 TAT Liver Cancer ye The second member of this group is the primary cancer of the liver wienme which occurs apparently on the basis of certain dietary deficiencies te African Negroes particularly Bantus employed as miners in wey among and also in the gold mines of Witwatersrand near Johannesburg Javanese and Chinese The excessive incidence of these cancers which uD are relatively rare among whites and also among colored people meg enjoying European living standards has been known for a Fe number of years 343 21 31 and has been attributed variously to ee some special racial susceptibility to endemic parasitic infection or to de nutritional deficiencies 174 21 317 yeatnab The dietary theory has found an increasing number of supporters na 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 60 80 26 follows certain dietary deficiencies and vitamin B complex and since it is known from human protein of observations that cirrhosis of the liver is a frequent precursor cancer of the liver a dietary origin for these cancers in the primary nourished colored people was suspected This concept recently received weighty support from the clinical pathological and experi- mental studies of a group of South African scientists 125 126 127 27 800261 ee ees ee re = =  ay ee Lada SEK it \ ah * aa t dated rcs wae sy nee t oe Pn 3 ve. ove om ~ ks roxy Seks WO fad Seay ad Deen ae a n succeeded producing the in who in cirrhosis of liver as well as primary- cancers of thatorgan in rats fed the deficient diet mealie pap and_ sour milk consumed by the Bantus Similar observations were re-=. ported by Copeland and Salmon 61 who elicited cirrhosis and carcinoma of the liverin rats fed a diet deficientin choline The ; ; primary animals developed not only tumors in the liver but also . cancers in other internal organs including the lungs It will be important to watch for the possible development of these i and other types of dietary cancers among the starving peoplein vari- - parts ous of the globe especially as the available dietis often deficient in proteins fats and vitamin B complex andin view of the fact that primary cancer of the liver is uncommon among white Europeans yield _ Another location which may additional confirmationis Trinidad in 85 where the laborers in the oil fields have a diet whichis grossly deficient in employed vitamins A and B Cancer of the Thyroid The excessiveincidence 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 380 These cancers usually originate from adenomatous nodular goiters and have their experimental counterparts to some extentin the thyroid hyperplasias and adenomas producedin 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 j 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 in- habitants 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 = 28 cue pe mms eee: wi eemeee e e Neeeme e ee t wang re tab od eve 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 bane of there were associated with schistosomiasis Twenty of his pa- pre tients were under 30 years of age 387 This is only one of many Saad environmental cancer observations incidentally which indicate that otek senile changes have very little connection with the causation of many = adn cancers : See Afifi has stated his doubts of the actual existence of causal relations hock LA between vesical schistosomiasis and bladder cancer 3 However FYE he also cited data from autopsy records obtained by Sorour in two tt e Egyptian hospitals which seem to support such relations Sorour cany found 85 cases of cancer of the bladder or 23.3 percent of the total aomat of 254 cases of cancer seen in 5,924 post mortem examinations This Ait 350 eb incidence rate is about 10 times the normal rate for bladder cancer . R While a schistosomiasis infection has repeatedly been connected DANN with development of primary cancer of the liver especially in the Chi- Bae 1S nese such a relation has not been observed in Egypt It seems to be losing ground increasingly in other parts of the world where schis- tosomiasis 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- 4 dence that the composition of the buyo quid is an important factor Le Eisen found for instance that this habit does not lead to mouth can- cers among the inhabitants of New Guinea and adjacent islands 97 a 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 habit 176 Khanolkar is inclined to agree with Somervell 349 who noted that the oral cancer inci- . dence is high in those parts of India in which the quid contains a strong variety of tobacco in addition to the usual ingredients Woel- fel Spies and Cline 405 suggested that the essential carcinogenic factors might be furnished from the betel leaves by certain allyl phe- nols and isomeric propenyl compounds which dimerize under the in- fluence of sunlight and form stilbenols 3 29 athh I t wos Har Y vemnon hi . 4 fas wets ' Lower Khaini Cancer of 9. oral of the lower lip Khaini cancer is the most common Cancer natives of Bihar in northwestern India It apparently among "_.... the irritation caused by the placing of a pinch of rubbed results from the front teeth and . tobacco mixed with lime in the groove between 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 lunga s of ca igar _ makane d sr orts ers 2 os Cancer of the Scalp ; . Carcinoma of the scalp is frequent among Mohammedans in North- _ India who shave their heads with blunt razors thereby causing ern abrasions and infections Similar observations have been re- frequent of North Africa ported among the Mohammedans Thermic Cancer The not infrequent development of cancers in accidental wounds and from burns is a recognized observation although the csacuasrastrievseumleticnhganism involved is obscure The carcinogenic action of thermic rays acting over a long period of time however is open to of cutaneous cancer on the shins of Eng- . qliusehstriaiolnroaTdheengoicnceuerrrsenaclelegedly caused by the heat from the firebox furnished the basis for such claims Warniek 388 recently revived . the development of a cancer of the face in this concept by reporting roller in a rolling mill a skinned haired man employed as a to excessive radiating heat Mattenci 232 where he was exposed : that basal cell 4 contended from an analysis of 93 cases of skin cancer cancers are elicited by infra rays while squamous cell cancers are due to ultraviolet rays noted the small number of . In commenting on his case Warniek of basal cell cancer in workers reports concerning the appearIannacsemuch as heat waves carry a rela- exposed to heat rays 388 would exert small amount of energy it is not likely that they tively the chemical structure of the various cellular com- profoundaenffdectthseorneby contribute to the causation of endogenous carthe fact ponents consideration moreover must be given to cinogens Proper heat are also usually in contact with that workers exposed to radiating the tarry combustion products of coaolr oil 30 cece ny Sd a Se Te etn cee nartin raenn ates Absurd une li^'s trin herad trinnherad pha pha pha me riflixt.Sharparak riflxt.Sharpkriflixt.Sharparak de has ok lang mo Bat a Bae ran iti, sera dd whine tee aeamin EF ~.- Extrinsic Co. Pro- and carcinogenic Factors A great deal of work has been done in recent years on the various cocarcinogenic procarcinogenic and anticarcinogenic factors of local and systemic 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 bas 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 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 69,115 203 274 304 311 319 367 The practical significance of the relation between trauma and cancer has again become of increased importance because of the present and future 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 bivalent properties in regard to the development and destruction of cancer has led several investigators to attempt the development of a biochemical or biophysical treatment of cancer by extending this principle to other carcinogens It was thought that the administra- tion either of small amounts of a known environmental or experi- mental 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 336 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 Some experts have suggested that one way 31 ' Miabee ROS more malignant : to prevent the 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 chemical - On the experimental side an antagonistic action between oe - .. carcinogens of high and low potency when applied to the skin of mice teow, ube 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 Boy- ae land concluded from similar experiments that a structural similarity Se, between potent carcinogenic and inhibitory compounds may be in- Fld. STE, volved in the antagonistic action 141 34 Additional experimental wee Ty _ evidence supporting such a correlation exists 354 33 , 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 observa- tions thus far made in this field are of sufficient promise to justify a.n extensive study of specific chemical anticarcinogens i. Ts Causative Mechanisms ' a re an oan vets sy as a oT _..-s _ a Among the considerable variety of carcinogenic agents already known or suspected the viruses and virus pathogens are con- spicuously absent Since the milk factor has been classified among the viruses by some observers it is not impossible that future studies demonstrate the presence of such ready for action carcino- may this direction is pre- gens in human cancers Suggestive evidence in the sented by the occasional development of cancer of the penis on 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 sys- tematization 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 future information on the causal genesis of cancer be adequately and with data on its formal genesis Due to the present supplemented state of knowledge of this aspect of the problem one can inadequate derived from the correlation of a number of oisnollyataeddvaonbsceerhvyaptoitohnessmesost of which are related to experimental and fish rep- cancers in animals spoIntthaanseobuesen found in recent years that not only cancers in tiles and birds but also a few papillomatous tumors in mammals such as the Shope cotton tail papilloma are caused by animated proteinic the called viruses 178 139 355 113 114 844 285 318,50 318,50 matter ta ab 32 + pee ae: eae wen ene wee we een ek im eee ~~ ye een,NE . ES a properties 224 A similar claim has possess antigenic These agents been made by Taylor 366 in regard to the agent responsible for and cancer of the mouse Specifically the milk ifsaocltatoerd ifnrvoolmvmedaminmaanrdyessential for the production of this tumor has wrens been identified as a virus of macromolecular proteinic nature 23 which acts as an antigen and produces antibodies when 10 383 42 to be established that it is nor- Paienrl injected into rabbits 132 It seems mother the offspring through the milk mally transmitted from the to the he and that this transmission is accomplished most readily during Le first 12 days of postfetal life This covers the period when the milk 208 consists of a mixture of actual milk and blood serum called colostrum De and when the intestinal mucosa of the young mice has an abnormal iad permeability which permits the penetration of macromolecular ma- secscant terial 246 It is thus possible that the milk factor is not actually a ere but merely a large pathogenic and antigenic protein molecule ctl vwihriucsh causes during the early part of postfetal life a chemical sensi- Fated tization that cannot become manifest until the shock organ the mam- mary gland has been transformed under the stimulus of estrogens tai into a reactive medium 76 77 ; of macromolecular carcinogen 94) The possible importance of cancerous growths is apparent complexes in the formal genesis of this nature from the work of Creech et al 63 64 with substances - prepared by the isocyanate method1of5c6ouepmlpihnagsairzoemdatthiec pcoasrsciibnleogseings- with proteins Osterhof of carci- nificance of such complexes as important links in the process out that amino groups of proteins couple nogenesis by pointing formed in the body from readily with quinones and that quinones are the aromatic amines and related substances 123 and thus become reactions Similarly the sulfhydryl group of the source of allergic for the combination of ptrhoetseeinmamcorloemcoulleecsulmeasy wpirtohviedxetriannsiacvecnaurceinogenic chemicals such as arsenic 123 108 The recent inability of Mayer 288 to prevent the proliferation of epithelial cells exposed to aromatic amines by the administration of pyribenzamine can scarcely be considered a valid for denying the absence of an allergic reaction in the develop- mreeanstonof such proliferative responses to spectihfeicdsetviemluolpimenTtimofofplreew- and Schewtschenko 970 also asserted that cancerous conditions in the lung is related to special allergens acting on the blood epithelium and mesenchyme and denaturing tissue proItteiisnisnteresting therefore that Miller and Miller 243 found in the livers of rats treated with the hepatocarcinogen dimethylamino- macromolecular cell constituent which was probably a pbreontzeeinne conajugated conjugated with the dye This dye could only be recovered 33 oe re rn pee Me EI TT cee ngeee rem we ngeee eeremmn sm ane  ed by protein the comples production macromolecular of and could not _; - by digestion digestion of fraction the complex and could not ae digestion the protein protein fraction complex complex present the the be extracted solvents solvents this dye complex 4ivelriver cells with had important the if tH in production Miller and lMiveir lclanecrertshaThtis conclusion received received place port from investigations port and Gillman pri- : > - cancer of investigations investigations investigations Gillman mary mary liver liver Bantu Bantu Negroes researchers ~: , macromolecular macromolecular - strated strated in the containing such individuals macromolecular - abnormally abnormally large carcinogenesis containing containing they ~. lated lated to carcinogenesis of the liver on tumor mentioned tumor immunity immunity When Spencer dissertation potential - 351 351 potential role substances substances substances cancer process process concludepdrocobnclludeedmthtaht emaposcsibriliotiems oposlsiebilcituiels aprossibilities immunologic immunologic ap- exhausted proach proach toresceaarchncdierrection which offers been exhausted cer research 34 . Sy + nemo & Occupational Factors in Growth of } Cancer Incidence Occupational Carcinogenic Agents occupa- t The great majority of cancers which can be traced to an tional origin in modern times have resulted from which carcinogens 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 par- ticularly 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 orand the same carcinogen may cause the development of tumors ginandifferent 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 fixed 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 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 cee capers weer re Te em er ee were mn ne erm mss ON RT MIRE AD IONE ON ABER 1 TONE AT AAT TI HATREDEAT AS ON EWEicRY AAE aTRE eSe EPT : en ~ at : wo ~ a . - carcinogenic agents and suspected occupational - Table Recognized suspected occupational Table Recognized and Lee a systems occupational ~ - - . , is i : : ' : TTT Respiratsoysrteym Asbestos soo Asbestos Eyelids 79777 Asphalt Respiratory <9 Benzol_ Benzidine derivatives Benzol Benzolderivatives 7777 Burns derivatives ? CChhlorrinoatmedaCtehslChloorr inaitedn0 ha ydt roe 0 cad rbohyn0 drsochaydrrocbarobonnss .-- ( 7" ...-- kidney Eye -e--e Bladder Bladder kidney kidney 777 ~ Blood forming organs kidney coe organs forming TTI Skin ... Respiratory system aeneneanat Li ft Lipp -- 7777777 Creosot <^'---------2777 woeren> ... Eve__do crude Respiratory system Mineral ofl, system Eve_ Bladder ureter kidney Nickel Respiratory kidney wore tract 0077777 shale Skin ... Paraffin 77 ... Oil Paraffin rs wecerererrre _... Pitch oil,crude-----. Lip_d. o .. MUUM Lip cere MUUM wececece=* i ueeees Piteh------ - " eceeee Bladder MUUM ..... . Radioactive Radioactive 9 ae coca| a Skin ---en ener Radioactive substBLluonogdsaffoorrmmin inngg H orc ganO s e noU oosM HOUM UMNON organs e wee ee cecuee nitrate Sodinutm Sodium nitrate Subepithelial forming Eye cece Subepithelial connective organs Subepithelial connective UMNON nr ... UMNON ..do .... UM nitrate, crude----- Bladder Spindle BladdeU r M Ski. n ... SpindlenS nt HUUUMU Tar oil.-----~ epee S kin Skin coeenr Respiratory M HUU UMU ene system HUUUMU HUUUMU forming system Bladder_ system HUUUMU Blood coceeeneceresren Eve Tar----- forming ... forming HUUUMU . MN MN woreree nen ecw errr 36 a Table 1. Classification of occupational carcinogens Established Doubtful Organ system Classifi Remarks Skin and its appendages Anthracene crude . Arsenic___Arsenic e_ ee _ eee_ -- Asphalt artificial ecneccen-| Burns thermic Mineral oil crude Oil shale.. eee eee Paraffin oil crude Pitch__ oe_ ee ee eee Radiant heat ? Radioactive substances Roentgen rays Sodium nitrate So ... . ot ee nen eee nn Spindle oil Tar one wee ee enn eee n eer ernn Ultraviolet rays AAAAAQARAHRAHABA AAAQARAHRAHABA A A AQARAHRAHABA AAAQARAHRAHABA A A AQARAHRAHABA AAAQARAHRAHABA A A AQARAHRAHABA A A AQARAHRAHABA A A AQARAHRAHABA AAAQARAHRAHABA A A AQARAHRAHABA A A AQARAHRAHABA AAAAAQARAHRAHABA AAAQARAHRAHABA A A AQARAHRAHABA A A AQARAHRAHABA Alimentary system Aromatic organic chemicals . | A A Arsenic . Dependent on ingredients Varies withwith gegoegoragprhaipchic oriorgiginin | Occurs in Chile only | Not recognized as occupational : | Hepatic tumors in laboratory ani- mals only Increased incidence of liver car- cinoma following cirrhosis Chlorinated aliphatic carbons ? bydro- | Creosote Mineral oil crude Pitch Tor .--onn eee ee nee Respiratory system Arsenic Asbestos- ee Asbesto es nc - e Chromates Mineral oil mists . Nickel carbonyl Radioactive substances A WAAW | WAAW WAAW WAAW Lip only Do. Do. Do. , AAHAAH AAHAAH AAHAAH AAHAAH | AAHAAH AAHAAH Lung cancer among miners , laboratory workers and Tar fumes Urogenous organs Benzidine Naphthylamine beta Pitc een h eee A AWA | Including some derivatives AWA AWA In agricultural workers in infested areas HAA eee ne Schistosoma HAA Soot_ Soot e_ nn HAA ere serene forming Blood forming organs AHWA forming Benzol__ oem ecececneeeenneee Radioactive substances- AHWA . AHWA Roentgen rays Tar cee Mesenchymatous nee nee emcee Mesenchymatous tissues Radioactive substances Roentgen rays AHWA AD Bone || AD Skin sarcomas bone Eye and its adnexae Arseneei e enc er ne Asphalt_ Asphalt_ eo ee Creosote. ernie Mineral oil crude Pitch___ PODDD | Lids only PODDD PODDD PODDD PODDD 37 UD, ae TD AT TEN, MPN SRA Ta REIL nthe eae el ce 4 Table 2. Classification of occupational carcinogens Continued Go eee ~ Eye and its A2A . : . rays : Roentgen A2A . = Tar A2A : | . Ultraviolet recorded rays Sot system Nervous None bes .... - eee eno ee eres * ---------------| _---| . glands Do. lee Endocrine ee woe _ ee : . - ok, , excretion of carcinogenic aromatic amines or their metabolic The of cancers of the bladder : derivatives responsible for the production 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 whio che the urine usually passes without delay The inhalation of carcinogenic fumes mists vapors gases or dusts which become precipitated or fixed in the linings of the respira- may the appearance of cancers tory conduits and sinuses accounts for . to radioactive of the bronchi and nasal sinuses in workers exposed dusts and gases chromate dusts nickel carbonyl vapors asbestos and arsenic dust and tar fumes . Pery . : - 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 from those of unknown etiology the proof that a particular agents or of cancer of industrial origin rests on evidence of case or type . casevarying 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 actiw viatsiesinhvaoslvoefdteinn bteheenptrhoe- first indication that an occupational agent duction of these neoplasms However this excessive appearance of of tumor is as a rule limited to groups of workers a particular type less intensive and prolonged contact with occupa- having more or and is therefore often not demonstrable tional carcinogenic agents reflected in the - for the entire worker population of a plant or even rate of this type of cancer among the population of a com- incidence that include indiscrim- munity or a region Statistical investigations of workers inately large and occupationally heterogeneous groups . 38 i eee eure ne Cee ee A NT oe eee Tre a mre or. Sr ' . population of them none at having widely differing degrees of exposure results render not only incorrect but misleading observed in up to 100 percent of the bladder has been contact with Thus cancer who had had severe and prolonged workers rate of those betanapthylamine and benzidine However when the incidence within the worker population of of bladder cancer was determined were observed the rate plants in which thetsheeisndaumsetraisalthnaetonpoltasemdsamong the patient popu- was approximately clinic Cancer of the lung occurs in about lation of a large urological of Schneeberg and in approximately 80 percent of the cobalt miners of Joachimsthal Joachimsthal yet there is no of the uranium miners the workers handling 50 percent of this cancer found among excessive frequency the manufacture of pigments or among the general | the cobalt ores in when the actual miners are excluded from of these regions consideration maintained that there is no evidence of an ex- It has recently been workers with asbestosis as the clini- of lung cancer in reveal a single case cessive incidence cal examination of 20,000 asbestos workers did not between diagnostic The fact is that the distinction of lung cancer lesions in members of this occupational group asbestosis and cancerous roentgenologic the examination must be difficult at times Actually in the general population would re- of such a number of individuals A total of 23 such cases cases of cancer of the lung veal one or more has been found by the much more reli- in association with asbestosis thus indicating the likeli- able method of post mortem examination be carcinogenic under certain circumstances hood that asbestos may and mule spinners the The scrotal cancer of the chimney sweeps of the and hands of the radiologistthse cancer cancer of the fingers the nickel refinery workers and the bron- nasal sinuses and lungs of other examples of oc- of the chromate workers are chiogenic cancer statistically significant incidence rates cupational cancers having prolonged Medicinal Medicinal and Environmental Cancers Relation to factors are known observations made of the Whenever the occupwahteionnatlhey form for other reasons a part with the same agents in deciding the question of a pos- human environment may be helpful of the skin for in- of cancer Arsenic cancer sible occupational cause number of individuals has been observed in an appreciable stance either in the form this chemical over periods who ingested of drinking water or wine Roentgen- of medicine or as a contaminant late complication of exces- of the skin is a not uncommon ray cancer growths have been ob- sive therapeutic irarfatdeirattihoenuseEpoiftvhaesleiloimnaetoorustar in cosmetics served repeatedly 39 | / Age eee me - TNT pee TE nee eee I sore 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 normal state of the tissues and the carcinomatous end result 2 3. Table 3. Description of precancerous occupational lesions - _ ew . 2 ~ Precancerous lesions Etiologic agent Alopecia ; - Atrophy . mee te Eczema Keratosis oe . . - Hyperkeratosis : Verruche Sporty loss of hair glistening Skin grossly thinned and glistening associated with keratotic : in patches rays substancesid | Pitch tar asphalt radioactive substances radiation including ultraviolet rays Dry seborrheic patches on akin Arsenic asphalt pitch scot tar Fist discrete scaly area on skin with raised pearly borders Usually on parts of skin ex- josed to carcinogen but may occur in uner- posed parts particularly with arsenic about sweat glands : Rough fissured keratotic plaques with small _ bard wart homs usually on bands and soles May become nodular and ulcerate Form of hyperkeratosis oo - Anthracene arsenic asphalt creosote crude mineral oil paraffin tar pitch sodium nitrate sutltarnacveisolertardiaayts ion including Ulceration Breakdown of keratotic lesions on . Leukoderma Absent pigmentation alone melanoderms Pateby increased and absent pigmentation of skin Most common in areas of highest pig mestation and may involve oral mucosa Anthracene arsenic asphalt cre- osote crude mineral oil paraffin pitch tar radioactive substances radiation includ- ing ultraviolet rays - Melanoderma Increased pigmentation alone Scleroderms skin | Dry scaly parchment with enlarged radioactive pores associated with leukomelanoderma Crude mineral oil paraffin oil substances radia tion NASAL PASSAGES Papillomas - Polyps | DeDvaetleosp in antrum ethmoid cells and turhi- Nickel carbonyl BLADDER Hemorrhage submucosal . Located Varying size with telangiectasis mainly in trigone and about ureteral orifices Aniline benziding betanabeptanaph-hthylamine and derivatives PapPapilomias lomas . Polypons of villous pedunculated or sessile often multiple about trigone and ureteral orifices EYES Papiliomas Pedu deven lop mc ainla y ont lidse occad sion-Armsienneiraclasopihlaltpictrcehosottare crarduidae- ally on eyeball rays including ultraviolet BONES AND BONE MARROW Blood Blood dyscrasias Hyperplastic hypoplastic splastic or hemoly enlarged Transitory anemia Thrombocytopenicpurpura with spleen not markedly leukoenismenocytosis derivatives BenBeznzooll andand derivatives rardadiio- o- active substances radiation LUNOS Pneumoconioses Chronic Pneumonia Bituminosis asbestosis lipoid chronic chemical arsenical | Bituminosis asbestosis lipoid pneumonia pneumonis dermatosis chromate ulcer of bands perforated nasal septum chromate arsenic Asbestos arsenic ter soot oil mist chrome salts chrome pigments nickel carbonyl Blood dyscrasias See bones and bone marrow above Radtiiooanctive substances - radin- 40 -. ee Ree mre ae poder Cae EAR ETT Sn eet ee, Toe an I poe pe et re These include hyperplasias hyperleucocytoses carcinomatoid and sarcomatoid 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 1slated substances and roentgen rays and radioactive substances - Hyperleucocytoses and leukemoid changes have been noted in indi- viduals exposed to benzol roentgen rays and radioactive energy Sar- comatoid lesions chronic radiation osteitis and chronic radium precursors periosteitis be the of the osteogenic sarcomas foundin seem to chronic poisoning . precancerous manifestations Although many of these 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 there- fore represents a warning signal that should not be disregardedlungs For this reason the occurrence of sarcoid granulomasin the lungs of beryllium workers should arouse suspicion as to their significance and ultimate development especially as Gardner has demonstrated car- cinogenic 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 hydrocar- degeneration man bons are known to produce liver - and cirrhosisin and have been shown to elicit hepatocarcinomas in mice ; Significance of Experimental Cancers ; The experimental reproduction of occupational cancers in animals j through their exposure to those agents apparently responsible for their d appearance in man is considered usually to be a conclusive link in the 4 chain of evidence On the other hand failure to repeat hunan experi- ence experimentally in animals has sometimes thrown more or less seri- ous doubts on the validity of the occupational evidence This situation years has been complicated further in late by the demonstration of . species specificity for certain carcinogenscarcinogens 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 ex- perimental reproduction of bladder cancer by the administration of 41 a mrt tren eee meee) ee gne - - 2ty. >) betanapthylamine was unsuccessful in mice gave controversial results 3 rae . .*' s+ in rabbits and was consistently accomplished in dogs The prolonge-d ; occupational _-? introduction of benzidine the second agent responsible -4 '. the development of bladder cancers in man into dogs did not result -.{ : go . 37 s+") in similar responses in their bladders while caused se . cancer of the liver in rats *. different the mr... Such divergent reactions of _ " it . species to and leukemia Fe 1 various occupa- | + Fo 3) ..* - tional carcinogens apparently have their basisin the existence of funda- - , Te mental differences in the metabolism of the various species These BY 7 oo po .. 7". Bo fel yooJere 0, * " : % - unique observations are by no means in biology They have their ~ - analogies in the often striking species specific differencesin the re- activity to numerous chemicalsand drugs as well as in the pathogenic- "+ ity of organisms Although the application of observations cancerology -" made in experimental " 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 . valid when derivedfroma suitable species informative and support experimental present The evidence at availablein car- 3 - 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 dis- ' : couraged any extensive experimental study of these tumors While adequate experimental evidence exists as to the production of cancers : -i- . mo of the skin by tar mineral oils and related substances ultraviolet rays roentgen rays and rays from radioactive matter the evidence is inadequate and controversial on experimental arsenic cancer of the skin jj 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 3 the bladder has been established by the experiments of several investi- , gators 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 J 4 - animals by the use of radioactive matter and roentgen rays while con- . troversial evidence only exists as to the leukemiogenic action of benzol : Conflicting results in animal experimentation are doubtlessly caused : i 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 5 42 ee ce eS ewe eek ewe ree cee Ee & : . species used 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 not 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 How- ever even these may acquire such properties if they are subjected to temperature and pressure distillation as aromatic com- pounds generated under these conditions from aliphatic ones Oils obtained by the distillation of shale have proved be carcino- genic 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 components Physicochemical Investigations Many attempts have been made to isolate the actual carcinogenic factors from the tumor tissue blood or excretions of individuals or animals with cancers elicited by occupational agents and thus to provide the most convincing evidence of their etiology However most efforts in this direction have failed It has been possiblteo recover chromium from the tumor tissue of chromate workers radioactive matter from the lung cancers of the Schneeberg miners and from the sarcomas of dial workers and arsenic from the neoplastic osteogenic this chemical However the tissue of the skin of persons exposed to metabolite of betanaphthylamine naphthol appearing in the urine is not definitely carcinogenic and extracts from cancers caused by roentgen rays were noncarcinogenic Whether or not this course of events will be changed by the recent _ of Ekman and Stroembeck 98 remains to be seen These discovery derivatives of investigators isolated toluidines or substituted 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 seem to be of special importance as to the causation of obblsaedrdvearttiounmsors in men since they succeeded in obtaining considerable amounts of primary aromatic amines some of which might be present in oxidized form from the urine of patients with nonoccupational bladder cancer 43 ee eR Te eet 2 cen peewene ere ree moe ano A  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 onlyin 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 evidenceis of < 7 definite sufficient weight to justify the _ acceptance of the occupational a * origin of most of the cancers listed occupational This scientific recognition of the etiology of certain ~ cancers does not automatically iin n 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 resultingfrom radioactive material and chromates for cancers of amines 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 compensable included among the . occupational diseases even in Europe At present they enjoy a sort of probationary status in that they are recognizedin some countries while not others Since occupational carcinogens probably will continue to be used by industry and to cause occupational cancers thereis little doubt that most of the cancers of this doubtful group will reach compensable status as and when the number of cases increases and the importance of oc- cy cupational cancers is more generally appreciated a an - and Incidence of Occupational Cancersin the Occurrence 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 responsible in varying degrees for this what condition The information available represents not actually exists but what has been recorded or is conceded ne ens . Cancer of the Bladder 61 11 Cancer of the bladder in dye workers has been part of the American i industrial scene since 1932thatis some 15 years after the start of sited a 44 Sednat Saliva we ae large production of aromatic amines for the manufacture of dyes A No Approximately 100 cases of this occupational cancer were recorded to 1938 from one American chemical concern additional in- up 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 company in 1947 . a L, . 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 close derivatives of the many other chemical manufacturing plants or by plants using those chemicals or their including the rubber and . pharmaceutical industries However assuming that the actual number of bladder cancers with this causation were five times the recorded figure or 1,000 cases only a very small fraction of the total would be represented since about 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 Skin Cancer Occupational cancers of the skin resulting from contact with solar 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 com- mented on the comparatively high frequency of cancer of the skin 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- occurring grease in pit workers of service stations recently men- . arms tioned by Stewart 358 Since pressure temperature fractionation and cracking of oil by hydrogenation is being used to increasing degree in the modern petroleum industry and inasmuch an toward the formation of cyclic compounds of poten- taisaltlhyectaerncidneongceynic properties is thereby enhanctehdetchoemmiengnyteiarosneAld- . _ possibility deserves serious attention during of oil shale and bitumen for the production though the industrial use of minor importance in - of oil gas and related products is at present situation may undergo a fundamental change in this country the result of the rapid exhaustion of our natural oil the near future as a ~ not then taken to prevent the If reserves proper precautions are and use of carcinogenic shale oils occupational cancers moafntuhfeascktiunrmeay 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 and nasal sinuses in workers exposed to the inhalation of of the lung arsenicals nickel car- and fumes containing radioactive matter gases and tar However Lynch and Smith reported in 1935 the first bonyl of the lungs associated with American case of primary carcinoma ~ 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 granuloma- tous lesions seen in beryllium workers it may be mentioansebdestthoastisthaenrde is on record a single case of existent pulmonary ' to sarcoidosis 347 too ; early for pulmonary malignancies to occur in It is definitely dusts and gases during workers who have had contact with radioactive of of radioactive ores for the production the mining and processing in which this type of radium and atomic energy since operations have taken place have been carried on in this country for exposure may of time to cover the usual latent period of these an insufficient length of factories tumors As for arsenic the reports of the chief inspector have mentioned repeatedly during the last few years the in England of of the lung in workers exposed the inhalation appearance cancers There is consequently need for of arsenical dusts and fumes 36,55 36,55 detailed study of this field in the United States because of the exten- to arsenic to which large parts of the industrially em- sive exposure well as the general population in certain regions of the ployed as country are liable These investigations might throw some light on which the remarkable increase in the mortality rate for lung cancer more than doubled between 1933 and from 4 to about 9 percent 46 OO: ot eden lplitep et whan we dR re Cd i met aaa rap cnx 4. mim s am sik Ria A san; wret awe wooo ere ae ae ' of all cancer deaths which shows marked variations in various regions of the country workers which so far has been of the lung in chromate - in the United Cancer from Germany only has definitely appeared reported in this cancer on the part of those con- States 224a The interest considerable during recent cerned with chromate production has been absence - No definite information is available on the presence or yoefacrasncer of the nasal sinuses and of the lungsailnthwoourgkherasninapApmreerciiacbalne Wales nickel refineries using the carbonyl procesfsrom South radioactive number of such cancers shaarscboemeanirnedpioarltpeadinters applying radioactive ( Industrial osteogenic the only occupational neoplasm observed ex- material represents this country No new cases have been placed on record 15 years ago 229 clusively some since their first epidemic appearance to benzol or radioactive persons exposed Leukemic reactions in six cases of have been observed in this country There are | energy benzol leukemia occurring in painters workers in can occupational artificial factories and factories manufacteustraiblnigshpmleanntsts Other workers employed in the hyperleuco- rotogrfaavcutroeripersinatnidngalso exposed to benzol have shown made same cytoses or leukemoid reactions Similar observations have with radioactive energy in whom in individuals coming in contact well as leukemia have preleukemic leucocytotic and conditions as of occupational radiation been observed The first American case an Since then two leukemia was reported in 1929 by Stewart 358 studies on have been recorded and several statistical additional cases of leukemia among radiologists have provided the excessive incidence radiation leukemia Thus for the concept of an occupational support all exposed to radiation leukemic hazard exists for persons industrial or scien- a potential with atomic energy for military while working radioactive matter in the radio and tific purposes and handling eliminators textile and other industries using radioactive static ee cw ee ae eae eee BS TSN NE 47 PAR aeSart a \ q ' 1 t q ! ^' 3 1 A : Problems in the Control of | ss Occupational Cancer profession 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 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 Industrial The limited publicity which occupational cancers and their causa- * tive agents have been given has left considerable portions of industrial of the existence of such sequelae mtoanceargteaminenintduisntrcioamlpalcettieviitginesoraFnucerthermore the general uncertainty prevailing in regard to the etiocloognyceorfnicnagnctehres miencgheanneirsalm toefndtshetior create a reaction of scepticism of some members of indus- actual occurrence Thus the reluctance claims as to the presence of occupa- ttriioanlalmacanracgienomgeennticthoaazcacredpstianntyheir plants and operations is a natural reaction of persons not adequately informed on the biological peculiari- ties of occupational cancers especially their long latent period 4 Furthermore the not infrequent absence of reliable and convincing statistical data on the occurrence and incidence of occupational can- well as the existence of improperly prepared and therefore cmeirssleaasding 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 that an unrestricted public recording and scientific dis management 48 rr. ar i nd a : Fa . a tt a oh. Lo a. supervision i. Be makes such of opment opment the industrial neoplasms neoplasms neoplasms and such workers - * opment opment essential some the the industrial industrial neoplasms makes supervision supervision discovered an an often disease which and workers workers only teo only forego medical examinations examinations , . 3B from from _ from prevent prevent ap- pearance pearance reliable adequate cancer the 6 9D: ThT e he absence absence adequate information information signifi- cance cance and scope scope arppreciatieon tlhie aocbcuplatieonal occupational cancer hazard hazard aosn wseiglnlifia - n et appreciation hazard the extent of insufficient part officials officials officials organizations seems be responsible responsible fact organizations __, that, that that far thesperoblem and generally have evinceedffoo nlrytoccasionimparess l Co interest interest interest problem management with exerted little _ workers workers management ( te " Legislative Legislative protection workers against occu - Tt pational pational obvious that adequate and protection of protection workers against occu- occu- hazards hazards general population population against against vironmental vironmental industrial carcinogens depends covering large extent the laws facets existence and special enforcementoef nforcement cpormoppleerx problem facets and Occupational conditions conditions of modern the products industrial- relatively essentially Consequently industrial- have izationrelatively recent phenomena and Consequently not yet most subject subject established even intelligent legislative not procedures procedures laws countries Furthermore those countries countries occupational which have with cancers not always always made sure that they adequate Most of them are more less defective defective in insuring reasonably reasonably safe working conditions factories workshops workshops laboratories using handling handling carcinogens for producing occupational Compensation Compensation lawos nly carcinogenic to defined for . example apply contact with some of the agents they defined do operations which long these agents exist exposure operations proper account account latent period following _ thus Criminal Criminal eliminate great number number cognizance justified claims willful C codes should should cognizance the fact that the willful occupational and undue exposure exposure individual individual carcinogenic and agent gain by another is for practical purposes practical equivalent equivalent personal attack with deadly weapon weapon all delayed delayed action action mechanism mechanism with @ weapon weapon to an attack Departments Departments Control Control dearth dearth Health, Industrial Cancer manifest occu- occur pational cancers nature existing laws applying these these lack defective apropriations appropriations for study study, neoplasms and various governmental sufficient with study + have prevaenntdedthe governmental governmental governmental coagnecnceiresnw edith this this governmental 50 various have prevented Ld eg we industrial hazard from becoming sufficiently active Official statis_ ng tics on the problem are therefore highly incomplete in most countries a The situation is somewhat better however in countries which have made occupational cancers notifiable diseases and in which govern- mental inspection of factories and workshops has been instituted gone ae Medical ProfessionProfession The medical profession in general has been slow in the past to . appreciate properly the causative role which the prolonged and un- obtrusive 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 begun 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 or a chemical worker at the time 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 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 deduc- tions from them on the relation of the data obtained to the existing cancer can be made only by persons possessing a genuine knowledge of industrial conditions industrial carcinogenic hazards and occupa- tional cancers At present this type of specialized information is relatively possessed only by a cal profession small number of members of the medi- Public Health and Industrial Problems Incidence and Causation To date some 8,000 cases of occupational cancer caused by a large number of definitely recognized or strongly suspected carcinogens of physical chemical or parasitic character have been observed in workers engaged 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 . tee ST ~ _ and the reactivity of the organism The fact is thus established that . extrinsic agents connected with the occupational activity of man are - physiologic pathologic senile irrespective capable of eliciting cancerous growths in human tissues &f any or changes or in- hereditary - - F 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 haz- ardous operations have increased at a rate paralleling the degree of expansion and diversification of industrial "las activities during thesame period -: ah oe - Variety of Carcinogenic Mechanisms ; The marked discrepanciesin 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 can- | cerization 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 inter- nal organs such as the liver or endocrine glands which then generate endogenous carcinogenic substances It is evident therefore that can- cers 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 incidence 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 in their incidence rate and manifestation age from their prototypes of 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 | . ee ee se vd ESTM INT TTT des RU pcetbad eynaeren ey twe me ara HE Chae ee ee se a a 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 se Probability of Increase in Occupational Cancers . The abnormal character of some of the industrial activities of recent years makes it probable that there will be a rise in the number and 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- hazards inherent in many of their operations It is possible gtehnaitcsuch 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 made until some 10 to 20 years have elapsed and a detailed and thor- ough study of cancer incidence among the large number of former employees of these plants has been made The elaborate precautionary measures taken in these operations on the other hand do furnish a striking illustration of the seriousness of the occupational cancer bazard as applied to a fairly limited industrial activity and to an \ agent which can be traced with comparative ease 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 fraonmdtfhoelhluorwriinegdWdoervledloWpamerntI of large chemical industries during may be repeated 53 - ates - -- . -- woe OO aioe EE BS aan NTRS . LR ED LTA :EE CENT NE E CIA TERI, FON PT Oe En Tne = re eme or en en HAVURTH le Te HAVURTH -- a ExpoofsExuporsuere 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 realized These agents may affect workers in basic industries producing using and handling raw materials and i 4 2 . g semifinished goods possessing carcinogenic properties in consuming _ industries workshops trades and professions using the output of -- -.3 vd |. w.0Fe6 the basic industries and in transport and merchandising organiza- LB ewrne ' tions engaged in packing loading shipping and selling industrial Ef 6 goods with carcinogenic properties They also may have an adverse arbel effect on that part of the general public which consumes such goods or tab which comes in contact with carcinogenic.industrial wastes discharged 06019 Gime into the air water or soil The chain of events whereby an occupa- tees tional carcinogen may be transformed into a medicinal or environ- mental one is readily demonstrable with substances such as tar or arHe saubdran senic The general existence of these various interrelations is shown AUER by the appearance of the various occupatiionndaulstcrainecserpsroidnucdiinffgertehnet , c<l>e countries following the establishment of 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 in the human being the local and systemic reactions elicited investigate and manifestation periods of by such agents during the preparatory - 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 ee Tin YP YY & 2 bipalredsb cuterst i eta AewheGs nnd! b phe se aoe b dbe eh Prager: tid -_ Elimination or Control of Occupational Carcinogens in industry should be eliminated wherever Exposure to carcinogens the technically feasible minimum possible or at least reduced to This can be achieved by designing buildings and machinery to prevent the of dus fumes mists and vapors the closed system of escape the institution of efficient exhaust ventilation by ; pmariondtuacitniinogn abyhigh level of good housekeeping by disposing of A2fl wastes with suitable precautions and when necessary F carcinogenic from the rest of the plant . be by the isolation of sahcaorucilndogefnuircniospheerdatwiiotnh suitable protective cloth- a1 t Exposed workers devices The degree of un- H ing gloves masks and similar safety bey avoidable contact should be further reduced by the installation and 0 . enforced use of proper sanitary measures such as special eating washing and bathing facilities and separate lockers for qsturaerettercslothes and work attire Workers should be familiarized through lectures repeated at regular intervals with the type of car- cinogenic hazard present so 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 is likely to occur and the repair and cleaning of machinery and agent specially trained and protected pipelines should be performed by 7 teams teams Mensures designed to reduce contact with occupational carcinogens are of great value as observations made in connection with several cancers and with experimental cancers of animals have occupational decrease in the degree of exposure results in a lengthen- . shown that a the manifestation of a ing of the latent period thus possibly delaying cancer even beyond the average span of human life Medical Examinations Since the practical importance and general appreciation of occu- hazards is bound to grow during the coming years pational cancer in preplacement examinations employers would be wise to determine the applicant's complete occupational history for ascertaining any sustained exposure to occupational carcinogenic agents pIrnevviioeuwsloyf the usually long latent period of occupational cancers this procedure represents an expedient safeguard against subsequent com- claims for such disorders originating from exposures sus- pensation before entering the employment of the party tained by the claimant it is not sued Applicants for clerical jobs should be included as uncommon that persons formerly employed in production and labora- tory work may later change to white collar jobs should be Medical supervision and periodic medical examinations 55 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 back- ground 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 ; oa operation of such clinics - - re ( 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 medical examinations should be increased with the age of the periodic and with the length of his employment in the hazard- _ eoxupsoospeedreamtpiloonyeTehe type of medical examination should be properly carcinogenic hazard adapted to the special kind of 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 infre- quently symptomatically silent especially as to the presence of hema- turia until they have reached an advanced stage cystoscopic exami- nations afford the only efficient diagnostic means for the discovery of bladder cancers in dye workers while they are still in a precancerous Whether or not the frequent cytologic study or early cancerous stage method may be of addi- of urinary sediment with the Papanicolaou tional help in this respect remains to be determined In periodic studies of the blood of workers exposed to actinic energy attention should be paid to the presence of hyper- and benzol special increases of monocytes Roent- leukocytotic reactions and to excessive intervals for all films of the chest should be made at year gen to the inhalation of radioactive substances tar fumes workers exposed nickel carbonyl vapors mists arsenical dust chromate dust and fumes compounds oils asbestos dust and beryllium Similar in sotfudmiienseroaflthe nasal sinuses are indicated for workers employed contact with nickel carbonyl These toepsetrsatmiiognhstewnetlalilbiengsuinphpalleamteonrtyed by periodic cytologic examinations 56 er eee emp TR TI OR 9 meM e Te mene me pr ae terre eta tees names ee Bs TEST ET of the sputum and of the nasal discharge particularly where chronic ree inflammatory conditions of the respective air conduits exist ~ Inspections a teae The adoption of a system regular inspection of all plants using Cr handling or producing industrial carcinogens by government in- spectors is desirable Such a system has been used successfully for a number of years in England in connection with occupational cancer MULE control Factory inspectors would be charged with checking on the OMDB, presence of carcinogenic agents in plants and workshops with enforc- 2 TD ing regulations covering the handling storing and use of such agents T CNOA with supervising the protection of workers exposed to them and with approving methods of disposal of carcinogenic wastes While the last- BH mentioned aspect has recently received some prominence in connection 4S with the disposal of radioactive waste products an indiscriminate OR discharge of carcinogenic chemical wastes represents a distinct poten- EP tial hazard to the health of the factory and general populations and MONE Ot thus deserves serious attention Labeling and Packaging 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 elimi- nate 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 ' All precancerous and cancerous lesions produced by recognized or . suspected occupational carcinogens as well as all cancers observed among workers employed or once employed in operations with carcinogenic hazards should be made notifiable with departments of labor or health Both the managers of such operations and the attending physicians should be held liable and violations of such a law might be considered criminal offenses Regulations of this nature are in force in several states and countries and form an essential basis for an effective control of occupational cancers through governmental cooperation " with industry Determination of Minimal Effective Exposure - Definite efforts should be made to determine the maximal permissible degree of exposure to the various carcinogenic agents and to the different types of contact with them This task is obviously a very difficult and tedious one as it entails the qualitative and quantitative determination of the various carcinogenic agents not only in different industrial products but also in biological media such as blood urine bile tissue juices and tissues Long and detailed observations on men and animals exposed to these agents are essential for the establishment of biologic standards vali ' Compensation Laws Te, - and Tt tere The institution and enforcement of adequate and uniform com- pensation laws designed to cover the special aspects of occupational @ cancer worded in sufficiently general terms to include any future de- 8 velopments in this field are an urgent need in many States 152 In ean view of the complex character of the occupational cancer problem it may be desirable to staff compensation courts judging cases of occu- pational cancer with medical and technical experts ni _ Individual Identification ta=hnt Gaia The names and other essential data of identification such as social security number of all workers exposed for a sufficiently long period to any known or suspected occupational carcinogen should be recorded the with the departments of labor public health or industrial hygiene ries for future reference Only thus can factual evidence be obtained of aad the total number of workers exposed to such hazards the types of beek o carcinogens contacts and operations involved ; the length of the latent he 1 period; incidence rates types and sites of cancer observed; sex race ee and contributory factors playing a part ; and other data of importance i bh With the increasing industrial activity of women it is essential that A ar at 58 otead o grtser. enca n cote rooms such 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 under- taking of research on these disorders may be accomplished best if the two would coordinate their efforts and establish an active exchange of the experiences of their respective investigators Only thus can the reaching ramifications of this complex problem be explored effec- tively and economically Lo. Such cooperative efforts are particularly important in the study of the epidemiology of occupational cancers in the discovery and identification 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 por wee ww we eee ones eee ee ae -. ., .References 1 Abramson W. and Warshawsky H J. Urol 59 76 1948 2 Adair Fr. .: Bull New York Acad Med 23 383 1947 Comp Med 1 17 1946 3 AfiLf . .i: CanRcese7r 537 1947 4 AhlHb . .o ; Bm ritMed 23 2 21 31 1936 5 Aitken R. Edinburg Med J. 51 339 1944 6 7 AAlllweemnasnnW.RBaSnckheweiE.z m E.edanWdchJnosncehsrW 76 1A0r0c9h1f94Ge6werbepath 7 69 1936 _ 8 9 10 11 12 oy 1942 and 19 14 15 16 17 18 19 e 20 Amer A. .: Ber d 8. 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