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FILE NAME Kent KNT DATE 1956 July DOC KNT145 DOCUMENT DESCRIPTION Journal Article - Etiological Problems in Human Lung Cancer - Cancer August 1956 VOLUME 9 NUMBER 1 LIPPINCOTT COMPANY PHILADELPHIA ETIOLOGICAL ETIOLOGICAL PROBLEM HUMAN LUNG CANCER PAUL E. STEINER M.D N 1950 18.313 18.313 deaths were attributed to now exposur 4 lung cancer in the United explained by any recognized States among or other factors and they are designate -an 11 bont all causes in a population of spontaneous obvious obvious absurdity in phy $ | 160,000,000 people A survey in 1917 sical universo Mauy recent lines of investiga investiga band 19918 by the National Cancer Institute in tion have opened the possibility of accounting en American cities reported crude pulmo- for this ggrroouu pp However the numerous leads 4 Bax anortality rates per 100,000 white have increased the apparent complexity complexity of the population of 15anortality in Birmingham 15.5 in problem The current situation resembles that Pittsburgh 15.9 in Dallas 18.3 in Detroit 18.6 in Chicago 21.8 in Philadelphia and 22.5 in New New Oricans in three cities in which the ligures for whites and nonwhites were com- Lined the rates were 8,9 in Atlanta 14.8 in Denver and 20.8 in San Francisco It is not known to what extent these are real but in any event sizeable large differences the mortality is The risk can be expressed in another simple Jarm Of every 100 babies born in this country nearly two will ultimately develop lung can- cer mostly between 50 and 80 years of age Brany disease having such small attack rate and only after so long a time recognition of the etiological factors is extremely difficult especially if they are multiple if only inter- ittently present and if the long interval Tom birth to disease represents the induction time from cumulative effects The problem is quite different from that acute disease such as measles in which fl persons are attacked nearly 100 per cent usually within the first ten years of life shortly after exposure exposure to the etiological agent and by an agent that has multiplied and that is present when the clisease is manifest The problem of the etiology of lung cancer is greatly complicated by the probability that there are multiple factors The occasional tumors that occur in childhood see reference 16 for references are hardly attributable to the same agents are those found in uranium and cobalt miners or in asbestos chromate mickel- tur- and other special worker groups The great majority of individual cases are From the Department of Pathology The University oi Chicago Chicago Illinois The basic work was supported in part by a grant bram the American Cancer Society Society Juc on recommen dation of the Committee on Growth of the National ) of pneumonia in about the year when i its numerous etiological agents were just be ginning to be separated out and identified by oa the bacterial colony technique the use of Koch's postulates and epidemiologici PPuurr however methods Refiable methods for proving importance importance of suspected agents are the not available in lung cancer The recent identification of 3,4 benzpviene park benzpviene benzpviene park park a potent carcinogenic agent and other aroma polycyclic ! tie polycyclic hydrocarbons in soots and car ! bon 7 blacks assumes importance in view of - j the global pigmentation of human brings by SEP anthracatic materials and the demonstratic demonstratic demonstratic of this compound in atmospheric dustst2 and in human lung Likewise the dis the Jang Jang covery of these carcinogens in other commion ,, atmospheric contaminants such as the fume . of combustion engines 21 asphalts and rubber tires and other products products provides H ver toxtox kov kov additional possible sources for etiological agents having a wide distribution The sta kov Sell fl - fl tistical association between the use of tobacco and lung cancer l4 8 ete presents another pos proh sibility which is greatly strengthened now prop that a carcinogen benzpyrene has beef I; identified the tar of cigarette smoke shot shot In view of the plecfiora of possible shot agents in one concept of the current etiological situations we in the United States may be outlined about as follows Table ) THROW fi From this annual total of approximately approximately three quaters of a billion years of ex nigh The posure to possible sources of agent only about The 20,000 lung cancels occur each year It not known whether these few persons develop the disease because their pulmonary cells have the highest susceptibility to neoplastic transforma tion because they have had the greatest ex posure to causative agents or because these Research Commit Jactors are combined Neither is it known Received for publication September 22 1955 whether the effects of these and other hypo C 66-1 Ra al a TmnErle TmnErle itusp ... Do nth tea! AE Chalten MC ETIOLOGICAL PROBETXE PROBETXE IN HUMAN LUNG CANCER Menter fl- TABLE1 HUMAN HUMAN PULMONARY PULMONARY EXPOSURE EXPOSUERXPOSEURE TO ESTABLISHED ESTABLISHED AND HYPOTIHLURGAL HYPOTIHLURGAL HYPOTIHLURGAL CARCINOGENS dexposure = designated ma phy savestiga savestiga muntingmunting Gratis leads ax the aidiles that when JN be CARCINOGENS CARCINOGENS ApproximateApproximate mumber of persons beingbeing exposed annually tal 3,4 benzpyrene and other carcinogens in 50015 3,4 benzpyrene benzpyrene and other hydrocar- bons in engine exhaust fines benzpurene 3,4 3,4 in and other hydrocar- asphalts etc. benzpri^nebenzpri^ne and other carcinogens in rubber products such tires etc. possible carcinogens carcinogens in tobacco prod- 31015 asbestos chromates chromates turkel Luther unevognized unevognized agents 164,0 0 1641,000,000 1641,000,000 160,0160,0000,0000 ,1060,0000,0000 160,000,000 160,000,000 160,000,000 100,000,000 100,000,000 $ 5,000,000 5,000,000 ^' : 3 hed by the use Testualanmurai Testualnmurai Testualanmurai van of exposureexposure exposure approx fatal annuallulng ung cancers about 725,000.009 725,0007.25,000.09 0725,090.0 9 20.GED mological ing the f. : wever wever pene: aleanca- and car view of riptical chemical agents sae in whole or in part additive mutually inhibitory synergis- synergis- unmentioned tc simmatable to other unmentioned and perhaps nonspecific factors or whether they operate in still other ways The difficulties in pointing the respon- sible agent or factors in individual human angs by ustration ustration tase oh the dis Common Tunes ophatis9 provides ologicaololgical Fise Subxacto mer pos ra HOW apps been lung cancers are great If for example a serial number beginning with number and going through to 20,000 were assigned to each of the hung carcinomas as they show up on January Lead Lead therealier of any year the etiological problem would be that of determining in case number the relative importance of each fac- the in the list given and of others as yet Anown Thesame problem would present it self in case number 2 and in each succeeding subject to number 20,000 In no two cases probably would the responsible agents their proportions and their sources be exactly the wie, agents agents Situation alwout as asinately asinately ts oral ey. ats aboms at is now oa bp the have the . ustoa taa It possible that further investigation will show that cue or several agents predominate some or even in a majority of cases The demonstration of this fact would be easier if apore of the agents were chemically unique Benzpyrene found in lung with cancer might have come from one or several sources the identification of which would be difficult or impossible The chemically chemically unique carcinogens Table 1 were consequently the first ja be recognized Extracts of human lungs ested for carcinogenic activity with no at- ATOSE OY. + these known 3 ten livpo # tempt at hactionation of the components have yielded evidence of activity activity of the degree emphasized by Kennaway as of importance importance importance in human cancer TIME im caawe Fm 1. six gouve gouve devesee ltoepxetd Comparyiou of an experiment experiment in 11 De which 1100 per cent timer in two years with human carcinogene carcinogene of animals lung cancer In experimental ble by varying the species species species and stain carcinogenesis it is possi- carcinogen its dosage the of aminual the tissue ex posed and other factors to 100 per centy of low vields in a few months to ashieve high cup cup 25 pr Ey utiliziutilizi Despite ability ability rigidly to control the experimental conditions the interpretation interpretation interpretation of the results is sometimes difficult Having exerted its effects the can cinogen may be absent in that chemical form when the tumor appears Furthermore the presence of an agent known to be carcinogenic does not necessarily prove that it will induce or has induced a tumo } even that is biologically active The inactivation benzpyrene 3.4 ticles may by adsorption adsorption to carbon par explain explain why the inhalation of approximately 200 gper year of this chem ical does not result in greater number of human lung catiers The effects of 150 pg aus 8.1 per year of 8.1 benzpyrene benzpyrene in cigarette aus may also be mitigated by this phenomenon ol biologicalbiological living in inactivation I 160,001,000 propie an environmenenvtironment arcinogenic arcinogenic agents develop only 20,000 lung cancers each year important important protective protective factors must be in operation The human etiological problem is difficult not only biologically and chemically but also epidemiologically This is illustrated by Fig which Curve A represents an experiment in 100 per cent ofthe animals injected injected with a carcinogen developed developed tumor within two years Interpretation of the results of this magnitude may have several be extremely extremely difficut it several agents been combined In conllast conllast the CHINC for lung cancer in human population fol lowed for eighty years would be represented at the level cent point so urar the base line that it cannot even be demonstrated by the scale used in Fig 1. Nevertheless as was recently pointed out by Kennaway this is the order of magnitude in which it is necessary necessary to think in fuman cancer etiology dilhcult level of causative factors It that the the statistician and epidemiologist epidemiologist the geneticist geneticist and the chemist must work with , separate and in identify in bung cancer Of course the epidemi- ' , Bech CANCER July Turgust 1956 Yep alogist uses other techniques by which he hopes to sumplily the analysis Having come this far may be permissible and desirable to speculate a bit further further about the problem in the eventual eventual control of sung Gencer lay arevention Her Here Here there an 1 comacogmagingiconmagging analogy in principle provided by experimental experimental carcinogenesis carcinogenesis This is to the ellect that it is not necessary to withhold a acinogenic acinogenic acinogenic agent completely to prevent a REFERENCES Ason Careitingens in digueries Ab PUP 33 4161934 4161934 Editorial | Brit 2. Cooper 14 Lixissty Lixissty A. and Waltte R. Ofie Ofie presencepresence of Benzpviene in cigarette spoke enter to the Editor Cheer badust 1964 1118 tr } 3. Craik S. and LovELAND LovELAND B. The risk of developing lung cancer and his relationship to smoking Nat Came Tosk 15 201 211 1954 Dost R. and Hui A. .: The mortality of aloe-aloe- ants in relatives to their sibaking babits a prelinduar repeat But M. J. HS1-1 1954 3. PARK 11.1 and Siriser P. 12 of aromallaeromal e polvivelic litiliocarlan's Game Research : 30 19662 The identification in carbon blacks PAK H. Siriser P. . Goras Goras .; skoa and Elykis Elykis .: Carcinoge Carcinoge air hydrocarbous hydrocarbous hydrocarbous hydrocarbous related compounds in processed rubber Cancer search 11 318 321 1961 and Res 7. Gorimox Fa and Fareer Fareer M. Experiments in identilation of 3 benzpsacare ^fin domestic sout by mesans at the fluorescence spretimim Brit J. Caneca 3 187-193 1989 8. HaxMosi E. and berween berween human smoking Hoss Habis Habis D. The relationship and dent dent ratest a be fleas up study 187.766 187.766 men 1. A. M. f 1316 1998 1954 3. Hiveir W. ( Occupational Occupational Lumets and Allied Diseases Springfield Illinois Catales ( Thomas 112 112 10. Huren Huren W. Enviennental Enviennental Enviennental Enviennental Taulust Med 2 Sing 21 150622 150622 1915 lung cancer 11. RENNAWAY U2 The The statistical statistical statistical significance significance of Deadoginal DeadogginDeaadolg inal datar Beir M. F. 12 468 1954 12. KOTIN FAIR H. 1. M Moematic hyrhovanimons APADOR P. and ThowAS ThowAS I. Presence Presence Los cancer but onix to reduce the exposure belos certain threshold level If the small risk that man has to lung cancer represents the com bination of highest susceptibility plus greatest greatest dosage the problem of prevention becomes one of a further slight reduction in exposte by withholding a part of the presently acting agent or agents his would become a logical consequence of successful efforts identifying and assigning correct roles to each agent REFERENCES Angeles atmospliete and pheric extracts ... 1951 the carcinogenicity of ativos ativos beh Didust Hygg 9 15344621534462 ] Kand indr Vey have Jeka 13. Konx P. Park H. and Thoxrxs M Ap mati hydrocarbons hydrocarbons I. Presence in the periculat periculat phase of gasoline engine exhausts and the ~ arcinogenic's ity exhaust extracts A. M. J. Arch Indust Th 1666-177 1666-177 1958 13. Pertu Hi the Service DEPARTMENT DEPARTMENT Dia Auth EDUCATION EDUCATION AND WELFARE WELFARE Vital Statistics of the Uniteiz States 1950 Valiane 111 Mortality Data Washington DC Government Government Printing Othee 1953 a 15. Pewne Hixter SERVICE FEDERAL FEDERAL FEDERAL SECURITY SECURITY AGEN ex Cancer Morbidity Series 10 Public Health Sep ior Puid No. 13 67 112 126 152. 178 216 217 218 Washington DC Government Printing Office 1950 Vitec Mass Nou Wie? Bray han 1931 wal STEINER 6. Etiological implications geographical geographical distribution of bing cuicer deles infernal confre cancer 9 150-175 1958 at tha Unisa 17. Shiver P. .: mental carcinogenesis carcinogenesis 211 211 , 19169363 Haman significance of experi experi 27 M. f Arch Path 55 18 18 SILINER P. E. The conditional biological activit activit of the carcinogens in carbon blacks and its elimina tion Cancer Research 14 103-110 103-110 1964 19. Straxer F. and Earg IL Summation and inhibition inhibition effects of weak and strong carcinogenic in drocarbons benzanthracene duysenie 1 Henzanthracene and methylchol^nthmetheylcholn^nthenee Cance Research Research 11 56 63 1941 20. SILINER P. Ba STANGER D. W. and Bor YARD N. A search for carcinogenit carcinogenit substances substances in carcino 5 matous human lungs bich Path 43 590-831 1917 21. Waitar R. E. The benzpyrene coment of town air Brit J. Cancer 6 821 821 1952 cdin divi aad Was CT that mi~ d MMe a? and bin class class tra