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FILE NAME Kent KNT DATE 1955 DOC KNT102 DOCUMENT DESCRIPTION US Dept of Health Environmental Causes of Cancer of the Lung A Quest Into the e Peatte bdr vi aiit Necsus viu No. 36 re e Se ye A Quest Into epe The Environmental Causes e tr Of Cancer i Of the Lung S. DEPARTMENTDEPARTMENT of HEALTH EDUCATION AND WELFARE | Contents Page 1 Introduction tieneral epidemiological considerations considerations Occupational evidence and respiratory carcinogens carcinogens carcinogens Epidemiological data large industrial groups Ocupational OccupatiOoccunpataionlal respiratory respiratory respiratory carers carers and carcinogens of environmental lung cancer hazards Scope Pattern and types of respiratory respiratory respiratory cancer hazards Occupational respiratory cancers Physicochemical state of atmospheric carcinogens and ical distribution of cancers in the respiratory Trart topograph- Specifie gens Inorganic chemicals Nickel Chromium Arsenic brou I 15 15 IN 18 am 22 201 23 23 24 27 20 30 Berylliumi Organic chemicals Combustion and distillation eee Doo . products of coal Potrolento shale oil and natural gas Carbon and silicon polymers polymers Asbestos : propyl oil Mustard gas Radioactive chemicals dments and conclusions megaphy 31 31 33 35 35 88 a 88 39 . 43 . 46 t 1 : Introduction we scientifically acceptable any theory tiology of ling entrer must reflect a balanced and competent analysis of sire epidemiological medical and ex- stal evidence concerning the types anil mental distribution of and contacts known or susperted exogenous agents cated in respiratory carcinogenesis for environmental occupational or medical reasons only through such serutiny that significant and worthwhile information may be obtained as to the relative role which the various indi- vidual respiratory carcinogens have played and are playing in the production of lung cancer The following following fiets and observations observations form an inportant and integral part of such an assessment General Epidemiological Considerations ConsideratiConosidenratisons Considerations Considerations definite and progressive increase in eney of lung cancer started in most sized countries around the turn of the tables 1-3 that is at time when smoking was still a habit of minor sigProbst Berblinger Grosze Kahlau Lacking This rise was first clearly by pathologists of Central Europe early 1920's through a study of stata collected during the first two the 20th century and was subse- walirmed and elaborated upon by investigations from America and ach mainly used cancer mortality eee records indicate that this develop caled marked variations in the time bag cancer in its relative degree of m its progression rate for different countries In Germany for in- serease in the incidence of lung best vi noted in Saxony and Central As late as 1931. Fischer re- deg cancer represented 113 pervers Saxoy against 6,6 percent Opermanay In Denmark necordset a rise in lung cancer fre8 doubtful during the first three 20th century and only beenme definite after 19:10 Similar observations as to late appearance of this increase were made in Italy There still exist striking differences in the lung cancer mortality rates of different countries and different regions of the samne country flig 2 In England for instance 25 percent of all caneers in males involve the ling the corresponding figure for Norway is less than 6 percent Similar discrepancies exist for lung cameer morbidity rates for different metropolitan areas in the United States as well as for their relative progression rates iable 41. Another example of the existence of striking regional variations in lung cancer frequency is presented by the remarkable differences in lung cancer mortality rates between industrialized areas and rural districts This has been demonstrated for England and Wales and for the United States where lung cancer death rates were found to be consistently higher in urban areas than in rural areas tables 5-7 figs 3 and 4 Such observations have been made in Ohio New York and Connecticut Mancuso McFar- land and Porterfield Levin Kraus Goldberg and Gerhardt and were reported from England and Wales by Stocks Kennaway and Kennaway Fulton Philipps Stocks reported the comparative mortality ratios for males in ** > fl Heatte Heatte Monograph No. 36 1955  2 #1 t E Table 1. Frequency rates of lung cancers in autopsy material Probst Author Lung cancers 4 Period Number of Total o: Absolute | autopsies - ! carcinomas No. + . i ' + ! : ! Percent of all cases 1852-1900 venues Reinhard 2 | |. ll. | Fr . 1852-76 8,716 8,716 bool. Fuchs cn eee eee eee eee. Wolf ee Passler ee ee ee Wolf_ . Perutz weeny et Marchesani 2.02. 2 22 1... ...| 1854-85 1877 | 12,307' 22 Le 84 4,172 (2222. 1881-94 1881-94 9 246 | 870 1885-94 1885-97 1887-96 7,228 7,228 [eee ene j eee ELL cu 1 1 946 1 Kikuth ooo... Feilchenfeld 2 SS * 0 oe. wee Riechelmann 2 2 02. ole Sehrt ... e wee ewe ! Marchesani Done eee J cee ew oe, 1889-18989-9991891895-1900: 1895-1901 1899-1903 1886-1906 | 5. 022 7,790 7,790 , 741 3.337 Vole \ lee | 511 | 711 | 159 (022 lee 5 one 8 j--------2- 9 16 1.83 1.83 31Ee eee 9 1.27 1.27 4 loll 10 |. 22 27 eee eee 4.3 3. 3 G6 {eee 1.88 1.88 ll ! 1900-1925 ; ; T . Redlich 2... Seyfahrt 2.000 Karrenstein concen eee eens e ee 2. 20. wee ee ce e e le ee KikStu achelinte h_e. eee Stachelin 00. 20) Le! 1900-05 1900-06 1900-07 1900-11 1900-11 | 2,002 2,002 496 | 2 Jee 10 272 | 934 | eee fo ' lee 566 | 31 elle 2828 2828 12 Bejach ee Probst02 2 10. eee. 2.202 Seyfahrt oo -) Briese Bejach ee. Bejach a | aan Bejach oe Marchesani 0 Marchesani ' 202.. le . e Rau 2... Lawes eee eee ee ee et Berblinger 22.200... 2. eee Materna ol. eeeecee eee 1904-08 ; 715 | 20 1906-10 1907-13 2,739 ; 265 3 1828 - 1898-1916 12,971 1,287 1,287 1828 6.808 1908-13 6.808 | 692 1828 1909-12 5.801 5.801 | 586 29 1906-16 i 4,754 oll 6 1909-14 4,816 4,816 552 15 1910-14 2,347 2,347 363 | 8 1912-14 | 866 | 48 | 1 2 Stachelin 0022 Probst 22200002. 0022. Seyfal~-rt 2202020200 Assmann 200 eee Materna Breckwoldt 00 20 ' ot 0.0022.2---. 12.2. Rau Berblinger Berblinger tee eee eee Probst 22 ll. wees lee eee eee eee 1912 14448 218 ! Il 1911-15 1914-18 : 3 448 | 389 13 in SL anes 1912-22 bo, | a ne 1915-17 | 1,667 1,667 70 5 1914-19 ! 6. 083 | 554 21 1915-19 5,518 5,518 | 580 | 27 1915-19 3 280 337 5 10 1916-20 4,989 4,989 | 392 | 24 Materna ....-...--.. ote 1918-20 1,609 1,609 ; 94 |: 5 Kikuth ee 5 Marchesani2. 200 0. lst Stachelin2 Lubarsch_ 22. 8. eee cence 2... . ., Seyfahrt 2.20 2. Berblinger ee Hin 00022222 . Materna 0... Breckwoldt - eee Probst 2 ee eee Stachelin 002.0020 eee 1912-23 Foe Lee. | 1916-22 3,336 jo. 1915-23 Pool lll 1920-21 jf... 0.0L. 1919-23 2,429 1920-24 2,429 2,429 8 ( 755 301 287 1921-23 | 1,049 1,049 75 1920-25 6 359 892 1921-25 3,697 3,697 502 1924 749 [ool 146 10 J... 38 458 24 6 26 36 5 7.14 3. 4.8 2. 6. 12 31 5.8 Ue. 4. 5. 8.75 8.75 8. 8. 2.7 7.17 4. Environmental Causes of Cancer of the a etcece Set ee S Cr. ALEVANSA ALEVANSA ALEVANSA ALEVANSA ALEVANSAsama AGEAFANGENISAMLINGE AGEAFANGENISAMLINGE with deviations from the 1m9o4rt6a-l4i9ty raterate set at 100 as follows average Groups of adjacent towns with over 200,000 occupied dwellings London East Hain West West Ham Croydon Birmingham Smethwick Walsall West West Bromwich eee Manchester Salford Stockport see. Liverpool Bootle Birkenhead WallaseWy allasey Leeds Bradford Halifax 220020 156 156 159 162 132 mortality ratios for lung cancer mortality of selected sites among white males 25-64 years of age urban and rural counties were Metropolitan counties 8 .0.000.0.2000-0---- Urban counties 7 . 000. Rural 73 Ruracl ounticeosunties 02... we nee cee eee ee ee eee eee eee ee 122.9 81. 6688.. The standard mortality ratio is Observed deaths ^ ^ EExpexctepd ecteddedaeatthhss 100 . L Sofield with 124,000 occupied dwellings SSofieeldwcastle : and Gateshead with 87,000 occupied cs Fellings . 50,000 50,00 to 85,000 tungate towns each each with with 50,000 505,00,00000 ttoo85,00085,000 dwellings towns dwellings wee tee eee 3 recupied with P surregate of towns each 10,000 to 50.000 . . secupied dwellings 2.2 oo. F gregate of 12 towns each with 30,000 16 . 40,000 occupied dwellings L oca eee kagregate of 13 towns each with 20,000 20,000 to 20,000 occupied dwellings .. weeeee eee | kengate of 29 towns each with less than 30 occupied dwellings 2202220000022... 135 114 113113 107 104 100 89 In Ohio for the years 1947-51 Mancuso MeFarlane and Porterfield the standardized The type of county is defined according to degree of urbanization as follows Metropoli- tan countcounty y containing contaicning ities with 1950 popula- tions of 100,000 or more 91 percent urban containing populations urban containing containing cities wiwitth h 1199550 0 populations urban cities ; of 100,000 66.2 percent urban rural- containing communities with 1950 populations below 50,000 41.4 percent urban Curwen Kennaway and Kennaway only recently recorded recently recorded recorded fresh fresh eevviiddeennccee supportsupiponrtigng earlier observations The new evidence indi- cated the existence of positive correlations between population density in England and Wales and mortality from cancer of the lungs Table2. Frequency rates of lung cancers in autopsy material of German pathological institutes 1906 51906 2521 1 i Author : City Period Percentage of lung i, cancers all among caneers | Sex . Male Female | Wasels . .: Frankfurt _ ; Paes...) Goettingen. and Sehoe- Jena .. . _- ee eee oe a eee Lone fairer - Seer. } Berlin Soars. _.t Ce eee ; 22] Met * wo. Dusseldorf Zwickau wee? 1 Dneee . Lene ek bee aad Dresden . . eee ee le _.. -2 ne . . es Mee] Germany So . . 7 vee. w. Goettingen . .. . - Berlin Lee oe . . . eee vee Zwickau 0... ee und Duesseldorf und Knoll Frankfurt 0 and Schoe- + Jena |. . coe ce eee |. eee Lo. . _. eee a ce wee . 1906 oe. 1906-12 1910-14 | : 1913-17 | 1920 23| 1924-27 1924-31 1923-33 = 1927-31 1927-31 1928-31 1931-40 1931-40 1932 1932-39 a 1. 0.97 0.97 2.59 Ic aae 2.2 ee : ee jones 1. tee - 61 ll 12.9 ee ee eee awe 19.79 er 13.0 83 Vo. ee ene Clee . aee 15.4 ee 13. wee eatin ee ween 12.28 13. | 12. | 0 Lee beeen wie el eee cee ee een ean ene 0 Wasels sees _-+: Frankfurt Duesseldorf 00) 2000) 0 eee 1938 1942 45 21.86 12. 000.2 2. 38 ee Leipzig -.: a wee eee 2 1945 + 48 13. 4.8 atte > Bavaria 20 Ll cee nt 1945-48 21. 4.8 joc 2 .. Jena_ eee 2 wee) 1946-48 | 13. nn ce ee Duesseldorf 2 eee eee, 1948 35. 53 on Frankfurt re 1 eee ie. German0y 28. i 2.20... a 1952 23. 5. 1952 : Ce nemeeeee nin ee 7 vee en f i i 5 j m ae iy Pac a4 Figure 1 Comparative trends in respiratory rancer mortality 1921 50 ENGLAND & WALES MALES U.S.A. MALES NORWAY MALES j a Poe ct State ; walt! BalB~al~--ke ke ; Ir P NORWAY FEMALES | | = | au To ae \ ee , { i | SWITZERLAND SWITZERLAND MALES eo / a }) d : & ENGLAND WALES FEMALES |- ane ~G 0 : Ch Lee aio ~ U.S.AU.S.A pen FEMALES wan o7 - - wort oor i 1928 | 1932 T 1936 | 1940 FEMALES | 1944 | 1948 1950 Environmental Causes of Cancer of the Lung P a ALEG . .LES .LES AY AY ES zales and females and cancer of the larynx statud at 755 persons per square miles and 1 males but not of femades This relation is Po apparent when comparing relative ; ver death death rraates tes in the United States States lung and and and with the relative poppoulation ulation density and career death per 2300 inhabitants It has recently been observed that the lung cancer death rate for white males living in the downtown area of Pittsburgh is excessively living twice high twice the rate for males living elsewhere jtese cocuntorieus ntries jtese in Whereas in the United poulation in city the city me rtain is It is somewhat meertain whether joes with a population of 45 persons per this observation carries the same implication as ge mile 1 long cancer death necites per the observations made in Ohio and in England inhabitants England these ligatres inhabitns in England ligatres and Wales Such interinterppation retation is suggested suggested 3. Lung cancer rates in necropsy material of various German institutes of pathology 1893 1925 for the period Period PPeeriord iod Period Total TotaTotal l ccanaeers neecranseers Laung capers Percent of Julig Julig eatheers eathers eatheers eathers eatheers among all caneerscane rs RaRange nge Range AAvevreagreage Average 903 903 aa, ne. 8014 8014 276 10. 276 1751 1831 1.9 5.0 81 6.2 1.9 6.2 81 y 2.1 5.0 i 3.2 -7 ) 2. adjusted death rates for respiratory cancer per 100,000 schite males in the United States 1930 Lew [_J Under 17 17-20 Off 21-24 GE 25 & Over ND .ES se ese _ 1950 the Line love Healthu Monograph No. 36 1955 5 istun 3 a Table 1 ^ ncidenceof respiratory cancer morbidity rates per 100,000 by sex 1937 and 1917 population for 9 metropolitan re Priars sale and eats Brouchits and bing Mbrota New Orlea Dallas Birmingharu Denver San Frameiso Chicago Pittsburgh Delrot Larynxi Arlauda New Orleans Dallas Dallas Birminghain Deuver San Francisco Chiengo Pittsburgh Detroit Mades 1947 1947 Percent Percent iberease Murbadity rates Pondles 1937 1937 1917 1917 11 993377 Total 1917 1917 P ine 5. 13. 3.9 1.5 9.1 15.6 hs 10.7 12.6 12.6 1. 11.3 3.2 1 ( 4.5 ary 1. or) 1. 11.9 ws io | NON 70 Nou an | His 198 392 320 ttt 120 ne 169 131 ESG 32 66 186 lt Mi | so N3 . 2. 2 3. 1. ! 2.3 3 a4 1.5 u u Z | t ft 5.0 1. 6. 3. . S. 7.0 oe 3.7 0. 1. .4| 13 ( JN aay LS 3 100 " 1. 180 SG 93 108 63 12 Lis 150 73 300 50 LOVE 24 9 7. li 3. 3. ui 9. 5. 7.3 7. DORIST DORIST DORIST DORIST 9 Niisdei 3 ar) Niisdei ci 8. 20. 17.2 11. 11. 20. 1.8.0 15.6 15.6 19,0 2 7. > 27 16 2. di 3. 1 3. by fact that the white male inhabitants also had an abnormally high skin cancer death rate Patno This is in agreement with the general experience demonstrating the dual role played by many occupational carcinogens such as arsenicals coal tar petroleum derivatives and radioactive substances in the production of both eutaneous and respiratory caneers An additional expression of this urban pattern of lung cancer rates is contained its the recent report of Lew who found that these rates were 20 to 50 percent higher among induss trial policy holders of the Metropolitan Life Insurance Company than among males holding general policies Lew fomuld the other hand that such differences did not exist for female holders of the two types of policies He pointed out that industrial policyholders represent for the most part urban wage earners and their families in the income brackets and include a high proportion of men engaged in manufacturing mechanical industries mining transportation and personal service In cot- trast the general policyholders are drawn mostly from middle- and income groups groups engaged in nonhazardous occupations 6 The apparent causal significance of th epidemiological findings has been demoustra by several investigators investigators Appreciable amou of benzpyrene have been demonstrated Waller and Cooper R. L. among the air poll ants of English cities by Kotin and associa in the particulate phase of these atmosph constituents in Los Angeles and in the exha fumes of gasoline and diesel engines table and 91. has been estimated from the figures by Blacklock Kennaway Lewis Urquhart that about 16 mg of benzpyri Table 3. Cancer of lung and larynx England Wades 1916 a 1K9 ennaway and Kennaway Type of community Lung can- cer ratio 1 Larynx ca cer ratio Males F males Fe Males mal Greater Lontudon County borough . Other urban districts Rural districts sees 100 129 160 233 100 137 156 155 Number of persons producing 1 death 100 125 148 | 170I Environmental Causes of Cancer of the Lur iit vag Table 6. United 100.109 100.109 100.109 Lung cancer death rates in States 1916 and 1948 erude 24 States of death rates the per - : * State 1916 is Trehustnalized States > sortient sortient .. Maryland .. Massachusetts Mibigan Mibigan Son Hampshire Na Jersey sea York - os . asvivania asvivania Je Islamit >> >> === === t === === === 10.2 == 0 == / States with regional industrializindustriaalizationtindiustroializnation 1916 1915 Figure 3. Cancer of the lung in males aged 25 years and over England 1921 30 Reproduced by per- mission of the British Empire Career Campaign a {\ 5 a. Counties including County Boroughs ! ' nan u - : Os a 75 Hho a 7A Noo "4 SN su dlls Agricultural States Actual mortality cent of that expected from the distribution of population by age and clasosf district 130-145UD i Veger 70 70 - 85-100 85-100 85-100 115 - 130-145UD 130-145UD eel ~ i 1946 1948 eames } t toy . Malisas Mexico Mexico Carolina Poole Dakota Mgt. a Carolina Svetanglon Yo mang : - 100 3. 100 100 = = = 31 0 3. 3. 1. 1. 1. wT 1. ou death rates for the year 1916 were taken from American Cancer Society In 1949 Cativer vot, Rates for each State in the United States fe (oe those for the year BHS were produced by the joc sal Office of Vital Statisties > Figure 1. Observed and expected lung cancer deaths in urban and rural Ohio 1917 1917 331 1 F. Manenso Manenso a wo | . ~ en eas. Oo taReeY Re a \ ; CUTAHOGA C. VEGANO owe RADY 1 6O ' cn ... 3f 3 ; f Table 1. draths Lung cancer mortality rates per by sex in Austria 1954 Herhich Nembold 1,000 and . Comunitnsity Comunitnsity Comunitnsity i Comunitnsity t Total Total Males FF i i males " os D^ O -1,400,000 -1,40,0 -1,400,000 7 20,000 -1,400,000 . atzier Austria 32.7 18. 2 IN A 59.0 31.6 31.6 32.3 32.3 17.3 . : nn HAMIL LONG CINCINTA Lang cancer deaths S conuutjes Remainder of Ohio Ohserved 1. 550 728 Expertel Expertel 1,261 1,261 1.017 . > Fabhe Health Monograph No. 36 1955 rt 4 is: 3 4 ik ry a 8 fas ri if te 3 ty oy sag hk Irak Oot a Hy f By HEE ae Hh Doe AI pean : Nie PORN TESTS Table 8. carbuns Estimated amount sil in minute samples of aromatic hydro- hydro- gasoline gasoline exhaust with varying engine revolution speeds Katin RevReovodadtioan-tion- ReRv evoo dad tioan-tioRevodan tion- per teint Ppo restprestie ie Catupooninel pooninel pooninel Benz- BenzPete Benze Auth- zu li- zuuli- Femme 500 1.000 1,500 2,000 2.500 3,000 3,500 hy 439 . 507 371 316 121 iN 120 235 GT 177 33 HD 10 a4 aoa 70 ist SA : Mm ie 153 102 36 27 31 VI 15 Chiruttilies Chiruttilies are expiressed expiressed in ^,gneat 0 kogud may be inhaled and retained in the lungs from these sources during a lifetime and that this quantity represents approximately 40,000 times the dose 10.4 microgramso capable of producing cancer in mice upon subentaneous introduction It should be emphasized in this connection that benzpyrene is only one of the several caur- cinogenic chemicals isolated from atmospheric therefore pollutants and that therefore the actual total amount of atmospheric carcinogens reaching reaching the lung is considerably higher Falk and Steiner Kotin and associates The benzpy- rene content of the air was increased fourfold during smog days Waller It is difficult if not impossible obvious the obvious causal significance significance of of to reconcile this this factual factual evidence with the claim that such regional and especial y differences in especially urban differences in lung cancer differ frequency are totally accounted for by totally frequency by cigaret e enees the cigarette smoking smoking habhabiits ts of the Two population groups or merely reflect local discrepancies in the diagnostic urbar physicians diagnostic in acumen of and rural physicians and in availability availability the availability of diagnostic medical facilities explanations Such tenable view of increase in the fact become even less that the annual adjusted increase increase in frefquenrcy equefrneqcueyncy ooff cancer lung cancer ddeeaatthhss was higher in 1914-30 than in 1931--44 table 10 , whereas whereas whereas the markedly markedly increased cigarette cigarette con- sumption during previous years should have boosted the annual progression rate above that seen during the earlier period It has been sug gested Lickint Hammond that this parado cal beliavior of progression rates is attributable to the fact that many cigarette smokers di, cancer not live long enough to develop a lung because of their precocious death from coronary sclerosis which also is assumed to be elicited in Table 10 Annual adjusted increase quency of lung cancer mortality of | free Sex Tete Males Fernales Percent increase Tre sc e ene ct 1914 301 1931-401 ee nema at acer amon ae 10.5 8. 0 8. 2. 1 Dorn * Potter Table 9. Estimated amount ' of aromatic hydrocarbon in minute samples of diesel exhaust with varying loud and engine revolution speed and with injection inefficiency Kotin Revolus Revolus per viens per initiate LLooad ad ComCeofmietfiiotn ion J. QRHE 1 200 1. 100 : 0 Compression release do sy tn on wt hee fr an Myo do Tp yy 100 do 0 . do oo o oP do 4 Lethe, \ tte Quantities are expressed in gmmin Pyrene Pyrene 137 267 1. 800 2 500 208 257 148 888 1.912 188 177 220 734 822 Compound X 22 76 640 639 0 0) 278 188 614 ( 56 76 337 346 Benzpyrene 146 465 Benz- perylene perylene ; Anthan- .4 threne 22 42 1. 320 876 9 47 437 432 3.706 3.706 80 78 1. 372 982 1.687 1.687 610 1.265 1.265 79 10 171 930 976 9 0 368 1.071 1.071 944 Environmental Causes of Cancer of the Lung observationot oesses Dy eigsrethe smoking _ majority cording to statistical evidence explanaboa convemently convemently disposes Such challenging the validity of the an able able 11 United Sex Sex distribution distribution distribution of of States and selected long caneer in in the foreign countries countries cigarette theory and may perhaps momentarily momentarily satisfy the protagonists of this concept although eamust be tariketa serimisly by anyone who has in the study of arteriosclerosis allax comp Huepers is remarkable Moreover that after a consulerable increase in lung cancer lung in Russia observed during the first Trequenes Trequenes decades of this centurcentury y this development seents 1830-19133 830-1933 wo Country CountCrouyntry Year Year AAuuriroi n on _. ated States , * Mexicans may may sveden.. Alsumark Alsumark Alsumark . : : 1933 1931 1917 1970 Dorto Moore Humphrey's Humphrey's Beeler et al 1951 1951 191 aol page 1911 Lindskog Carlisle et l Ulaskport Ulaskport Ulaskport et McBurney O'Keefe O'Keefe anel FarberowBys ow Bys ow Neely Steiner Kneeberg ... Heuschen Ulenimesl Ulenimesel .he 1958 1958 1850 1900 1919 1920 11993030 1929 11993399 1980-198 1980-198 1932 1978 1917 1949 6161 Benk Cirosze Cirosze Lenroine Lenroine Gagnon Muson Muson Fulton Mexiraus living in Los Angeles to have come to a halt during recent years Marker fetuale BELIZE | nul 74 I ee tke 11 20 according to Aufilogow rited by Lickint strikingly iregular Considering Considering Considering Considering the recorded strikingly irregular epidemiological erent countries countries behavior of states provinces lung cancer in diffprovinces comtumities comtumities and population groups it is obvious that thiwith pattern scarcely corresponds with the presented by by the degree and If spread action pattern of the of cigaret e cigarette smoking smoking habit If the action of en- vironmental carcinogens carcinogens carcinogens other than those pos- 1.08 1.08 18.5 it 1:47 1:47 a il 2 atl oe lacl rere en 3. sibly contained in cigarette smoke should mainly arcount lung remarkable for the increase in causation of caneer frequenes frequenes and for for the causation of a of lung caurers industrial and major portion this fit major carcinogens industry related carcinogens would well fit this the growth of industrial establishe pattern sitee in their ments and the use ofof their products in the eronomie life of different countries have greatly greatly greatly laeked uniformity uniformity uniformity in in time time type type and extent This concept receives support from a erit- distridistri- wos ar Bescl Aud ical ical evaluation evaluation lution of lung of of the data cameers the on the sex distri- distri- changes in the sex tad or 30 10 1 ~ during ratio during recent decades and the probable reasons underlying underlying nomena tables 11 at least a 12. and 12. part of these phe- Considering Considering Considering the Considering remarkable variations which the female ratio of lung cancers has shown at different Table 12. female sex ratio of lung caneers in Germany LB86 192a7 nd 1910 50 1910 50 1886-1927 1886-1927 1940 50 City . ; : * oh cea ve Author Katio wus Wolf Seyfarth Sehrt Briese Wahl Bejari JUB Redlich Eichengren and Essen Fuchs Bilz Kikuth Dom Dom je jo 10 pa | para para be Presaleta Lemzig > Zwickan Berlin 0 dam Koelne Muenchen do the Seb 480304 Sib Hanoburg Author Licking JALOOLEN~fi Merkel Ciorbe Beng |||||||||| Breyer Antieker Kainzsch Frey Kuntzen Letz'ns Ravio 15 31 15 : : 19 : 21 7 18 21 19 12 y * Public Health Monograph No. 36 1935 i oe 3 2% i ve By i a oF 3 4 eS times in different localities and in different demographie groups it is most unlikely that such discrepancies and changes are attributable to fluctuations in the intensity of one single factor such as cigarette smoking Instead they appear to be due to alterations in the type and extent of the action of a broad spectrum of en- vironmental respiratory carcinogens the members of the two sexes to affecting different degrees The marked and growing predominance of males among lung cancer victims seems to be due largely to the following factors 1. Males are more extensively employed than females in occupations which produce and use known or suspected atmospheric carcinogens Also males work more consistently and over longer periods of their lives in such occupations 2. Males predominate in outdoor occupa- tions especially in urban areas where they become exposed to carcinogenic pollutants in the general atmosphere effluents of domestic and industrial furnaces exhaust from gasoline and diesel engines dust from rubber tires and from asphalted and oiled roads 3. Males more often than females perform heavy physical labor requiring deep and fre- quent respiratory movements facilitating the penetration of carcinogenie air pollutants into the distal portions of the respiratory tract thereby increasing the frequency and degree of exposure 4. Males more often through the entire span life within urban areas than females work of their occupational with proved carcino- genie atmospheric pollution while females st for larger portions of their lives in the clear suburban dormitory communities These considerations provide substantial su port to the concept that local differences general and occupational industrial air poll tants may more plausibly account for an a preciable portion of the observed differences attack rates for the two sexes rather than ,, local variations in their smoking habits The doubts as to the unrestricted validit of the cigarette theory are deepened if critid evaluation is made of another dubious j link the chain of claims advanced to bolster th concept It has been maintained Graham that squamous cell carcinomas of the bronch mucosa are a specific response to cigaret smoking since a this histological type of bro chogenic carcinoma was allegedly rare befo 1920 b it has increased considerably sin that date in relative frequency in comparise to other histological types of carcinoma e pecially adenocarcinoma and c it is more oft found in males than in females The facts are as follows Bronchiogen squamous cell carcinoma has commonly be found with all known occupational respirato cancers table 13 However many of the agents have also elicited other types of pf monary carcinomas such as undifferentiate undiferntiae round cell carcinomas and adenocarcinom Thus there is no evidence supporting the vie that any specific respiratory carcinogen clic a specific and characteristic type of cancer * study of lung cancer records of cases observ Table 13. Histological types of occupational respiratory cancers according to carcinogenic agent f Agent Organ Squamions | | cell carci cell Round cell noma | with or without cornifica- carcinoma carcinoma | tion | AAnaplasntic aplastic | or polymorphic carci noma Adenocar cinoms Tar futues 22 Nickel 2022 o.. Chromium ee weed eee Se Ling . .. _do_ a _do_ a a es , Asbestos 00 0 Radioactive gases and dust Nickel Radioactive gases and dust Isopropyl oil _. wee .do .do | . - __! a .do | 4 __! Nares and nasal sinus wee _do_ ee ne. _do_ _do_ a 223 Pr 276 Sen 4 10 fe tae ales stay e cleaner itial sup- cences cences in pollu an ap -rences B than a, 5. Figure 5. Figure Annual Annual Great tobacco consumption in pounds per capita and consumption the pounds UniUtniteed d States States States 1190930 00 Britain 1900 30 3.0 Norway Switzerland Turkey Found's validity if critical s link in Ester th Graham Bronchial cigaret H | of bron- e befoj : : : oly site 1 mparison oma ore often | | | hiogen : spiratory ' . of pu entiates cinoma the view elicits wer A observed . i i | ; \ i = | UNITED CIGARETTE . : ! ' BRITAIN _ | | ent i denocarinoma _ 2 a ae 05 10 15 20 The Jung Public Health Monograph No. 36 1955 1955 a \ are aS ee NORWAY CIGARETTE 70 1925 30 35 | \ s \ NORWAY H \ a a | \v . 40 45 1950 11 . po a NO before 1920 or even before 1900 readily establishes the fact that during those years squamous cell carcinomas of the bronchi were by no means rare occurrences Wolf 1895 s8quamous cell Table Consumption in 600 carcinomas among 15 lung cancers ; Probi 1927-25 percent squamous cell carcinomas b tween 1905 and 1918 Watsuji 1903 23 INDEX pertes squamous cell carcinomas between 1892 1899 Adler approximately 40 perce 600 1900 a 195E0 astcott Year post Pounds of tobacco per year einomas collected from the literature with quate histological data Proe First Nat Conf 1949-44 percent squamous cell nomas in males 11 percent in females ad Cancer | Fs 500 New New ' i Zealand United Kingdom To orem 1900 1910 : oo i 2. 2. 19 1.95 2. 22 1930 aoeee votre eee 1940 1950 Loneeee 3.59 3.59 3.87 5. 36 2.99 2.99 3.97 1. 22 - - While adenocarcinomas are more / Proc frequent th skog Conf Lan females than in males also they they are are more quent in young persons than in old onesones sskogkog Proc FiFrstirFirststNatiNoanatlional CancerCaCnancceerr Conf th th The evidence evidence on hand 1949 scarcely supports the contention that adenocarcinomas are of endog 400 300 200 enous causation Lickint or that they have ak etiology differing from that of squamous rg carcinomas Kreyberg The female i ro Table 15. 1932 Average death rate per year per million persons males from cancer of the i New Zealand compared with England and Wales lung Eastcott : 10C Period ! Country ae : Age ; , 35-44 | 45-54 55-64 ' ~ ~ ~ ~ : _ 1932 36 i New Zealand 222. ae 13 | 87 158 1937-41 do we 1940-41. England and Wales ._ . 1942-46 1942 ' New Zealand 4 En6 gland and Wales 9122 7 ed eee! 01772777 88 126 ' 48 132 | | 108 424 \ 235 802 | 168 466 | 466 1,072 1947-51 1947 51 le New Zealand 1947-51 1947-5 i England and Wales beeeeeee. 1952-53 L 2. . 1952-53 2 New Zealand coe cee eee England and Wales ee eee ee 287 | 166 | i ' 781 61 175 305 858 732 682 i 1.027 171 cae! : ( 65-74 | ant , OYCT Ve. pwratio 204 % living 283 715 . ag 3.5 WE a not Si 635| 1,032 gg bormic 3% vizoni 1,014 1,857 1 gy condit 1,097 The fs 1.456 650 > 1. ee the b 1,68 cigare Table 16. Observed and expected mortality from cancer of the lung New Zealand or the according to place United Kingdom Eastcott Age at entry to United Kingdom Place Place of birtlu Observed | Expected i deaths deaths Under 30 30 and over ; -- . a count : a New Zealand e ee United Kingdom 200d! 4 Note The significance of the 1 Observed + Expected Observed : Expected : ; deaths => deaths deaths deaths | of & 632 369 | ! ae |------ ee 721.8 279.9 | i 201 | : 229.2 229.2 i 168 | : 139 139 ms 3 0.00 F difference between observed and expected deaths in the two countries is : mg death fig 5 lung the [ 30 p Amer nifica 12 Environmental Causes of Cancer of the Lung ; Publi Oe Figure 6 Trends in selceted environmental factors United States 1900 3H 3 ammand STATE ASPHALT HIGHWAYS HIGHWAYS MOTOR FUEL CONSUMPTION - _/7 CIGARETTE CONSUMPTION PER ADULT FUEL OIL SALES ! 4 MOTOR VEHICLE 7 REGISTRATION all a= ea a, . Neva Pe, +e aatte ie sue ee senses eee en grrr ts 0 1900 1910 ee toe 1920 iJ at*"4,.,COAL CONSUMPTION pirtaepetbrdereriic iao p t 196r 0 i 19p 60 1930 1940 1950 1960 of lung cancer 0.7 among Mexicans in Los Angeles as well as the ratio of for asbestosis cancers Merewether do support the view that women have any -onal protection against the action of enmental respiratory carcinogens if identical itions of exposure prevail e claim that squamous cell carcinoma of bronchi is in any specific way related to ette smoking thus may be laid to rest no special histological type of bronchiocarcinoma bears any consistent connection any of the recognized respiratory car- uns milly it may be mentioned that there does rist any parallelism between the annual apita consumption of tobacco in different tries and their respective pulmonary cancer rates Herbich and Neubold Gilliam ) has been calculated that the English cancer rate is apparently double that of United States although the English smoke percent fewer cigarettes per capita than This interesting and perhaps sig- ant observation which fails to support the et oe fe: Health No. 36 1955 348108-M3on5o-graph validity of the cigarette theory is disposed of by its proponents by assuming that exposure to cigarette tar is less severe for Americans who do not smoke cigarettes to the very end than for English smokers who for economic reasons indulge in this questionable habit Recent epidemiological studies of Eastcott in New Zealand provided the most important data on this point It was found that the relative consumption of tobacco in pounds per head for the population of New Zealand and the United Kingdom revealed an inverse relation to their lung cancer death rates tables 14 and 15 Eastcott moreover found when comparing the observed number of lung cancer deaths with the expected number for native New Zealanders of British extraction and for immigrants from the United Kingdom that the immigrant group meets with a much higher incidence of bronchogenic cancer than would be expected on the basis of equity suggesting that the immigrant has an increased susceptibility to lung cancer table 16 The chances of dying of cancer of the lung are 30 percent higher for all United Kingdom 13 oe centoe mmei g re o eet se inal a immigrants but for those who were 30 years of age or more on entering New Zealand the risk is 75 percent higher according to Eastcolt Differences in habits of tobacco smoking are unlikely to contribute to this picture in the opinion of Eastcott Herbich and Neubold pointed out that there did not exist any consistent proportional frequency between cigaretle consumption and climatic lung cancer mortality for Upper Austria Kaernten on the one side and for Steien and Tyrol on the other side although i four provinces there prevailed approxim the same per capita consumption of cigare These authors suggested that the high cancer mortality among the people living ir marginal regions of the northern slope of Alps might be related to Figure 7. Rise in annual production or consumption of related industrial chemicals and 1948 between PRODUCT - UNIT 1 BITUMINUS COAL PRODUCTION IN U.S 2 FUEL BRIQUETS MTIOLTLAILONPSROODFUCNTEITONTONS 3 CARBON THOUSANDS OF NET TONS BLACK - PRODUCTION IN MILLIONS OF POUNDS 4 PETROLEUM - PRODUCTION OF CRUDE PETROLEUM MILLIONS OF BARRELS 5 PETROLEUM ASPHALT - PRODUCTION OF ASPHALT FROM PETROLEUM THOUSANDS OF SHORT TONS 6 COAL TAR PRODUCTION PRODUCTION THOUSANDS OF GALLONS 7 ISOPROPANOL-- PRODUCTION- PRODUCTION- THOUSANDS OF POUNDS 8 ASBESTOS - 7 APPARENT CONSUMPTION 9 - ARSENIC THOUSANDS PRODUCTION TONS -1939 OF SHORT AND IMPORTS M. YR K-1939 10. CHROMITE - THOUSANDS OF TOTAL SUPPLY SHORT TONS THOUSANDS OF TONS SOURCE MINERALS YEARBOOK 1945 ; 3 6 : Austria and Steiermark ough in all roximateroxlimaytely cigarettes high lung iving in the lope of the atmosphere between m conditions and to the direction of prevailing inds which bring the industrially polluted air of Vienna into the valleys of the northern Alpine regions observations Similar observations on the influence influence of the ngprevailing winds upon the relative frequency of cancers in different areas of the English Mailands were reported by Stocks Herbich and Neubold moreover found that the lung ancer mortality rates were twice as high in Mamunities located along main highways re the atmosphere was polluted with exhaust as from gasoline and diesel motors and the fast and fumes of asphalted roads than among cw inhabitants of villages and towns situated squote from such traffic arteries In fact the ~ in lung cancers follows more closely the rease in consumption of motor fuel and the struction of asphalted highways than the consumption of cigarettes fig 6. Hammond fig 7 Hueper and is similar to the increase in production of other related chemicals It is apparent from the numerous observa- tions and facts of general environmental nature cited that there exists an impressive amount of circumstantial evidence of different character and from various sources which strongly suggests that several if not many environmental factors acting in varying degrees and combinations cause or contribute to the development of pulmonary cancers and are involved in their recent rise in frequency Much of the evidence on hand particularly the irregular epidemiological pattern of lung cancer points to an important role which industry factors and the growth of modern industry may have assumed in these respects Occupational Evidence and Respiratory Carcinogens The concept that environmental factors cause contribute to pultnonary cancers is supported w pidemiological medical and experimental lence obtained from analysis of lung cancer nates of various occupational population groups as well as by studies of lung cancers and their | die and different causal agents present in a vamber of restricted worker groups and in -efined industrial operations _ 45 ** _ Epidemiological Data on Large ) dustrial Groups Epidemiological studies on the frequency of _ seg cancer among members of large industrial Fraps and trades have brought to light the sistence of marked variations in the liability * persons engaged in different occupations to a of the lung Tables 17-19 supply ing illustrations of these differences and ast some of the factors which may possibly be onsible for them Table 17 which lists lung cancer death rates be even industrial groups in Ohio shows of the Lang Preble Health Monograph No. 36 1955 striking difference between the rates for agricultural laborers and for employees in the nonferrous metal industry with rates for transportation workers occupying a position directly behind the rates for nonferrous metal workers It seems to be characteristic of inhabitants of agricultural areas to rank first in death rates from cutaneous cancer and last in rates for pulmonary cancer This is in accordance with the relationship between solar radiation and Table 17. Lung cancer death rates per 1,000 deaths from all causes for 7 industrial groups in Ohio 5,309 males 1947 Mancuso Industry Industry Industry | | Death | | rate Nonferrous metal__ 2... ..------------- Transportation Rubber and plastics . Iron and steel 2-2-2 1 e+ Mining and quarrying . Agriculture ....--.-------------------- Stone clay glass- ' Total ween ce vee ce ceeeeeeeeee | I 3. 22 2. 91 2. 34 2. 18 1. 53 .82 .82 .66 .66 76 15 skin cancer and the relationship relationship between low concentrations concentrations of carcinogenic air pollutants and lung cancer cancer Nonferrous metal workers on the other hand often have contact with dust fumes and vapors of some carcinogenic metals such as chromium and nickel or with arsenicals arsenicals which ities in are impur- many nonferrous metals copper zine silver Transportation workers are exposed to the exhaust from gasoline and diesel engines petroleum lubricants and dust from asphalted roads The relatively high death rates of workers employed in the the rubber and plastics industry may possibly be attributable to the use of coal tar petroleum petroleum oils and tars furnace black mineral pigments of carcinogenic chemicals and aromatic antioxidants used in the production of rubber and plastics The actual discrepancy in the lung cancer liability between operating and nonoperating railroad workers is even greater than is appar- Table 18. Frequency of lung cancer cancer among ent from the figures listed in table 18 employment ratio of operating to nonoperat railroad workers in one of two large railr companies was 4 From this ratio it appe that on the basis of the crude nonstanda ized sex age figures presented about 75 cent of the lung cancers in railroad 1 employ occurred among the operating group wh supplied only 25 percent of the total number employees Operating railroad workers cluded engineers firemen brakemen cond tors switchmen and roundhouse personi that is workers exposed to the inhalation of c soot and oil fumes from diesel engines and fi and lubricating oils which contain polycyclic hydrocarbons carcinoge experience Dunner and Hicks recently called attenti to two additional worker groups boiler and grain dockers In the scale Dunner and Hicks these workers showed ; excessive liability to cancer of the lung Twe i operating and nonoperating nonoperating railroad workers Railroad i | Ant A. tlt B. | Period Total , Jung , caneers | 1940-50 1940-50 | 29 1 1939-49 | 104 | Type of railroad worker me ~~ Operating TT ee ee Nonoperating 4 Undetermined 3 ae 24 Percent SLE Number | 24 59 Percent R3 | 57 Number | 5 | 15 Percent Number ! jee 17 14 eee ee 30 Percen Table 19. Occupational groups with excessive incidence of lung cancer Occupational group [| Potential respiratory carcinogens | Metal workers welders metal metal grinders and polishers , wire makers tool and die makers , foundry workers metal moulders moulders lathe workers etc. Cigar manufacturers and tobacco- nists Metal dust lubricating lubricating oil mist Tobacco dust insecticides soot __ Enpgliunemebresrs cmreacnheaonpiecrsatormsacinhisnmiesltts- | Metal dust soot lubricating ...... ers etc. Painters decorators_ Tar workers road workers workers asphalt- ers paviours stokers , patent fuel workers furnace mien laborers rollers etc. foundry Metal pigments coal tar dyes carbon black , asphalt paints solvents vehicles vehicles lacquers res- ins synthetic plastics plastics Tar and pitch fumes and dust sout Investigator Kennaway and Kennaway Kennaway Turi and Grace M^...ller Dublin Vane Wynder Wynder and Laughlin Breslow and associat Seyfarth Kennaway and Kennaw Enger Versluys Brinkmann 4 BECC1 1944 and 1952 Gillesp Turner and Grace M^...llerWynd and Graham d BECC Vane ham 1944 M^...ller Dublin & Fulton Wynder and C Kennaway and Kennaway Fulto BECC 1952 Fulto Registrar 1938 McLaughlin 1 Report of the British Empire Cancer Campaign 16 Environmental Causes of Cancer of the Figure 8 ORE SMELTING CHROME PLATING PIGMENTS PAINTS INK PRINTING ABRASIVE ORE REFINING PLATING BUFFING renee ORE MINING SMELTING CHROMATE NICKEL CARBONYL a nee ARSENIC PESTICIDES PHARMACEUTICALS MINING ASBESTOS ? ISOPROPYL OIL ? ASBESTOS PROCESSING ASBESTOS WEAVING TAR FUMES PRODUCTION MANUFACTURING COKE OVEN SERVICING ASPHALT DUST RADIOACTIVE DUST PITCH TAR PITCH _ HEATING HEATING SOOT TAR ASPHALT DUST NASAL SINUSES LARYNX four lung cancer cases were foutul among 1,000 dock workers at Hull England of whom 1,300 were exposed to grain dust There were $8 boiler sealers with lung cancer With the ception of 1 boiler sealer none had any adiological evidence of pneumoconiosis and valy 5 had a slight degree of pneumoconiosis pon histological examination No lung can mrs were observed among dockers who were not exposed to grain dust It may be possible at boiler scalers sustain a carcinogenic expomure to containing scale if chromates * used as antirusting agents or that these Forkers sustain a pulmonary deposition of Rw oxide Whether specific vegetable matter some carcinogenic contaminant of the grain has has residues of chemical fungicides or other Messing or preserving agents necount for | blic Health Monograph No. 36 1955 the abnormally high frequency of lung cancer among grain flockers is at present a matter for speculation Mention also may be made of the recent observation of Faulds on the excessive fre- quency of pulmonary cancer among English iron ore workers employed in mining activities at two different locations Necropsies performed on these miners during 1932-53 showed a lung cancer incidence of 9 percent 192 necropsies with 17 lung cancers while mortem ex- aminations done on 2,378 males of comparable age who were not employed employed in these mines revealed that only 44 or 1.85 percent had primary lung cancers It is remarkable that there did not exist any parallelism between the degree of pulmonary fibrosis observed in the iron miners and their liability to lung cancer 17 ot pea bety in tuberculous lungs 2 plus in fibrotic lungs without cancer and tuberculosis 3 plus The absence of a positive correlation between pulmonary fibrosis and lung cancer was noted when the evidence on lung cancer among the radioactive ore miners of Joachimsthal and Selineeberg was analyzed Hueper Although the netual causal factor responsible for the lung cancer among iron ore miners remains to be determined it may be mentioned that Levin and his workers recently recorded a positive statistical correlation between an occupational exposure to iron oxide and heat and cancer of nuuoiuun available onl the occupation aspects of lung cancer causation are deplora defective because of an absence of oc upation spiratory spiratory Hated genes as be as extensive stly prolonged analyses of lung cancer deaths unce various ffaactocrs torfactosrs inTdhuestrieavildence hfaonrd specific The evidence evidence groups evidence on on hand cu neverthelessnevertheless the cau pacers amor opacers n esepsecpiaecia nevertheless demonstrating on adequate for his frequency Fg tions in lung cancer that the 5 wide vara F indust appoppaurleantti existing between different industrial 20 Oc Tat^r groups are attributable to differences in _ more less definable occupational . exposures we not to differences in cigarette smoking habits J the lung Occupational Respiratory Cancers The studies of Breslow Hoaglin Rasmussen and Carcinogens and Abrams on 518 histologically proved cases of lung cancer in California suggested the existence of an increased liability to lung cancer for members of the following occupational groups welders sheet metal workers steamfitters boilermakers crane operators and nonferrous metal smelter workers that is individuals who are exposed to metal dusts and fumes oilers oil field workers wipers and marine engineers who Conclusive evidence of the existence exogenous carcinogens and environmental the spiratory cancer hazards is provided by the epidemiological medical and experimental experimental date concerning occupational respiratory cancers A general view of the occupational respiratore cancer panorama including causal agents are organs affected is presented in table 19 gree pouales pouales yeal Laitar Laitar ee oe & petroleum oils opyl opyl | katemctikavtemctieve chch PutaPultal . have contact with oil fumes mists and sprays asbestos workers construction and maintenance painters who inhale vapors or various organie solvents resins lacquers plastics and rubber as well as finely dispersed inorganic and organie pigments chromium nickel copper and arsenie scope Hazaras Scope An given of Environmental Lung Cancer indiscriminate acceptance of the in table 20 as reflecting the actual Hazaras figur these identified and recognized respirate cancer hazards however would be serious misleading despite views expressed by severe & compounds carbon black aniline dyes and commercial cooks exposed to fumes and mists of overheated vegetable and animal fats and protagonists of the cigarette theory Ringeru Wynder and Graham Levin and others Although a definite demonstration of Carci Carci spee e mineral pan greases occupational lung cancer hazards has so te ane A recent study of the causes of death of the been made for only relatively restricted work Arotuatie fume members of the International Photoengravers groups the evidence on hand is not only u Petroleum em Union raised the suspicion of an excessive lung equivocal but also indicates that other worker oii Cartson and sili { cancer liability subjecteedxposed working Et members occupational identicatlhe similar opropyl group for of this occupational groups subjected identical to to identical same similar similar causal agents # working i or con opropyl oiol il AsAbsbeessttooss oo From the different lung cancer death rates tions are subject to the same hazards I listed for the various occupational groups it is obvious that the total number of workers $ contrast to the apparently low carcinogene Metals potency of the suspected but unidentified Arsenie possibly exposed to occupational carcinogens of known or still unknown nature is evidently very large and comprises workers employed in basic and processing industries construction Trans- portation services trades laboratories and professions fig 8 It is on the other hand equally clear that the quantity and quality of agent presumably contained in tobacco smoke the occupational respiratory respiratory carcinogens wi ] evidently highly potent as shown by their hi | respiratory cancer attack rates table 21 . Since environmental carcinogens have been shown to produce cancers wherever they opera F in adequate intensity and duration and cot sidering the fact that many of the occupations & 4. Aromates Nickel Immuung radiati radi t Radioactive o % 18 Public Health Environmental Causes of Cancer of the Las . iret ROMs) 4 ee Pespiratory carcinogens occur as industry- related general atmospheric pollutants it may thebe assumed that these pollutants repre- justly the cause of a significant portion of lung fancers among members of the general popula- who live and tion especially , tion those industrialized industrialized work in ghly industrialized areas The approximate scope of occupational ex- posures to the various respiratory carcinogens may be estimated from data supplied by Bloom- field and his workers From a survey of 1,503,204 workers employed all industries of 1 States it was found that 7,976 were exposed chromium fumes to fumes and dusts of chromium compounds and Table 20. Occupational respiratory carcinogens and cancers recorded during past 75 years their causes sites and numbers pee Agent ; Site of cancer Number of recorded cases dis- Year covered ras United States Other countries Total Total | Asbestos Arsenic ee Arsenic . E Chromates . . - Nickel . . ee eee Lang Wo. eae Dee ~ ow... do do a _do Leen Nares and nasal sinus 1930 1934 cae 1932 1932 0.02... one eee Chaltar Chaltar ee Petroleum oils .. ee . koprkopoyl propyl ee _ io Lung 2... Lung and larnyx Lung_ . Larynx oc... 8. Nasal sinus- oo Lote . 1936 1936 1946 rn . Lee eee Radioactive chemicals ee a Lung Nasal sinus .. . Lee . 1879 1931 . * Total ee eee eee 1-315 1-315 j 1-315 yi a. Qa! ran t 41 u0. 3 | 125 i 16 it G5 51 51 33 33 0: 0 a: 625 0 1.001 23 96 140 84 53 40 H 4 1325 3 1. 126 Table 21. Respiratory cancer attack rates by environmental carcinogens Carcinogen Sites of eneers Incidence population at risk Percent all cancer deaths Attack rates Rate per 100.000 Morbidity Mortality * Aromatic hydrocarbons ~ Coal fumes Lung . Carbon ( Petroleum oils . E Carbon and silicon polymers Lung * Paranasal sinuses \ larnys o* Asbestos 0 022 Lung- le. ; 500 100 000 2,000 100 000 10 : 0 = te 7 * Hetals ~ Arsenie eee .. Lung 0 wae ae : * Chromates__ - Chromates__ Lung a Nares woe. ~ lee ; ge Nickel lee Nares paranasal simsimuusesses ] LLunug Lnungg nn eos } 000 100 000 LE * niting radiation bs Radioactive ores 2... - Lu oe. cen chee eeeeg ceeecere | ! aan __ oo 47 5 a . 134.5 ( normal 6.5 Lo. nas a 13.2-20 percent asbestosis autopsied 0.8-2.4 percent normal cen ; 42 nor- . > mal 145.7 males 10.9 normal 146-338 0... Ul ee eeeelne eee eee eee note | eee 20 normai ee eee ew eee) cece ee hees wese 50-80 percent of all ; deaths | . __ 19 : me BNigecey 4 ; 3,356 to fumes and dusts of arsenicals For industrial workers of all 48 States respiratory health hazards existed from the inhalation of dust fumes mists and vapors for 35,000 individuals employed in asbestos operations in 33,000 having contact with arsenicals in 240,000 inhaling various types of metal dust and in 2.500.000 having cutaneous respiratory and ingestive exposures to various combustion and distillation products of coal tar pitch creosote oil soot and to petroleum fuel oils and lubricat- ing oils greases and cooling oils to name a few The highly defective state of knowledge con- cerning the actual number of occupational respiratory cancers is moreover demonstrated by the fact that information on the existence and number of such cancers in specific industrial operations with recognized respiratory cancer hazards is distinctly spotty not only as to data available from different countries but also concerning those on hand from identical operations of the same country The following observations may illustrate this point The existence of an excessive liability to caneer of the lung from an inhalation of coal tar fumes by retort attendants of gas and coke oven plants has been established by a few reports from Japan Canada and England Apart from these isolated data no others are available for similar operations from these or any other highly industrialized countries Germany United States France Italy Poland Russia Likewise there is no official record available concerning the occurrence of respir- atory cancers among carbon electrode makers and attendants in aluminum manufacturing plants where workers become exposed to dust and fumes from the pitch and petroleum asphalt in the electrodes and where according to information available from four different countries tar and asphalt cancers of the skin have been observed as the result of such contacts It is moreover surprising that data on the occurrence of lung cancers among producers and users of arsenical insecticides have been re- ported almost exclusively from Europe although the United States has been for many years the main producer and consumer of these products Similarly reports as to the existence of respiratory cancer hazards from an occupa- tional inhalation of mists and fogs of lubricating and cooling oils have so far totally origina from Europe despite the fact that Ameri industries offer ample opportunities for identi exposures that an excessive liability to lv cancer has been noted for paraffin pressers ployed in oil refineries and that the survey one oil company has shown that there wa marked predominance of operating refine workers among the lung cancer victims of particular organization R. : Finally attention may be called to the that the entire evidence us to the existence lung cancer hazards for radioactive min has come from the observations made in Schn mining berg and Joachimsthal However uranium ores has been carried on for 10 to years in the Congo Canada and the Unit States and extensive milling operations of } Belgi African ores have been conducted in for many years without any official record similar respiratory complications among workers employed q Additional incompleteness of the existing ords on occupational respiratory cancerms be related to the possibility that pulmons cancers may have their causation from agen entering the body by an extrarespiratory rou While all known respiratory carcinogens are environmental origin and are inhaled as pollutants there exists some suggestive occup tional medicinal and experimental eviden indicating that agents introduced by oth whic routes may be effective in eliciting lung cancer Several cases of lung cancer are on record developed after an oral administration of senicals and which appeared in individuals wi arsenical dermatoses and skin cancers No bauer Lung cancers also have been observe in some aniline dye workers suffering fro significance primary occupational bladder cancer M^...lle following prolonged cutaneous ingestive al respiratory exposure to dusts and vapors q certain carcinogenic aromatic amines Th possible scientific and practical these findings is suggested by the experiment observation of lung cancers in 10 percent polycycl rats given the potent carcinogen acetylamino acetylamino fluorene by an extrarespiratory route Bie schowsky A cutaneous as well as parenter introduction of coal tar and several hydrocarbons as well as of urethane resulted i 20 Environmental Causes of Cancer of the Lu Ree iy cto originated American identical precocious appearance and an increased num- a her of pulmonary tumors in mier identical Y to lung ssers t Pattern and Types of Respiratory Cancer Hazards survey of To was a refinery us of th > the fact istence re miners n Schnes Schnes If map of the distribution and relative con- centration centration of the different carcinogenie air pol- latants were prepared for a given area it would exhibit a sort of crazy quilt pattern to which he general atmospheric pollutants would fur- aish the overall background color varying in aish pth between darker urban areas and lighter eyal districts Other types of carcinogenic atmospheric pollutants having a more circum- mining a 10 to 20 te United ms of th Belgina ribed field of distribution would appear as regularly arranged and variously sized and Japed spots and islands of different colors perimposed upon the general background t stands to reason that such locally differing record nong tin exposure patterns are bound to exert an iminfluence upon the epidemiological char- jeter and incidence rates of pulmonary cancers isting res f various regions , one of the various ers that carcinogens would produce pattern its showing own diminishing epidemi- diminishing diminishing diminishing ulmonary alogical scatter pattern showing a diminishing imagenes imagenes ryrout ns are of spread of cancers from multiple carcinogenic production foci The following three main types of exposure as ad environmental atmospheric carcinogens may e oerupa evidenes by other geahrers geahrers ord which on of at fuals with rs No. observe ing from M^...ller tive mad vapors ! ies The ficance of erimentai percent d tylamine tte Bui arentera i distinguished : 1. General environmental atmospheric ex- psures to certain aliphatic and polycyclic Eydrocarbons released into the atmosphere as complete combustion products of domestic and industrial and ship fuels as parts of the Ahaust fumes of gasoline and diesel engines as abrasion products of rubber tires and as dust from asphalted and oiled roads exposure to arsenicals contained in the mineral ash and soot burned coal and in the effluents of certain tal smelters and related to the large ase of arsenical pesticides and exposure to radioactive material either naturally released from the soil and from bodies of water or pollutng the atmosphere as the result of nuclear explosions 2. Special and locally restricted atmospheric exposure to carcinogenic pollutants of the air polveveis esulted exists in the vicinity of nonferrous metal smelters releasing in their effluents and from their slag heaps fumes and dust containing nickel arsenicals chromium compounds and beryllium Similar exposure exists in the vicinity of carbon black plants oil refineries tar distilleries gas plants and similar industrial establishments producing large amounts of soot or other polycyclic hydrocarbon containing effluents and in the vicinity of radionective ore mills and atomic energy plants The individualized type of air pollution con- nected with the smoking of tobacco with its suspected carcinogenic hazard to the lung in the special form of cigarette smoking may be included in this type of exposure to atmospheric carcinogens 3. During the last 75 years an increasing number of specific chemical and physical agents have either definitely been recognized or arc strongly suspected of being responsible for the appearance of cancers of the nares paranasal sinuses larynx and lung among members of certain ocempational groups These specific occupational exposures are associated with the inhalation of coal tar and pitch fumes and dusts mists and fogs of petroleum derivatives soot vapors of isopropyl oil that is the crude liquor from which isopropyl alcohol is distilled arsenic nickel chromium compounds asbestos and ionizing radiation Since the available evidence establishes such carcinogenic connections with only some but not with all inhalants such as silica or coal dust it is apparent that carcinogenic activities are not associated with all atmospheric pollutants Occupational Respiratory Respiratory Cancers The respiratory cancers of recognized or strongly suspected occupational origin are important not only as industrial disease manifestations but also as prototypes of etiologically and topographically identical cancers affecting workers in other similarly hazardous occupations as well as of those cancers involving an indefinite portion of the general population sustaining for environmental reasons contacts with the same industry carcinogens the Lung Public Health Monograph No. 36 1955 21 248108-55--4 248108-55--4 ay te ae ame ER STE a ina at eke NT g4. fg le eS Cae Physicochemical State of Atmospheric Carcino- gens and Topographical Distribution of Cancers in the Respiratory Tract In agreement with observations made as to reasons for the topographical distribution of environmental cancers in other duct systems urogenous and alimentary canal respiratory cancers of environmental origin are preferably occupying sites where th e flow of the inhaled polluted air is interfered with that is in the normal narrows of the respiratory tract such as the region of the nasal turbinates and the larynx or its bronchial bifurcations or b where the respiratory tract forms dead end saecula- tions such as the paranasal sinuses and the peripheral bronchiolar regions of the lung in which inhaled carcinogenie matter may accu- mulate condense and precipitate The traffic pattern of air pollutants in the respiratory tract thus corresponds to the distribution pattern of respiratory cancers elicited by atmospheric carcinogens The second principal factor which determines the localization of an environmental cancer within the different sections of the respiratory tract is represented by the physicochemical status of a particular carcinogen since this condition largely influences the site or sites of chief exposure to an atmospheric carcinogen Carcinogenic dusts consisting mainly of coarse particles are mainly arrested in the nares where they cause cancers of the turbinates The nasal cancers observed among copper matte refinery workers inhaling the coarse dust of the roasters illustrate this interrelation The excessive incidence of larynx cancer among mule spinners inhaling carcinogenic shale oil sprayed from the revolving spindles likewise provides another example of this mech- anism because it is likely that the relatively large droplets of this oil are arrested in the upper portions of the respiratory tract making the narrows of the larynx the part of main exposure Dusts or mists composed of particles having a diameter below 4 microns on the other hand penetrate into the deeper parts of the respiratory system and therefore are mainly responsible for the cancers of the bronchi The bronchio genic cancers found among chromatechromate turers asbestos workers and coke manufa^ oven and ga retort workers are representative of this type exposure Atmospherie pollutants of gaseon and vapor types not only penetrate into 4: tract lungs but also into the nasal sinuses where the j may be deposited by degradation into radioactive solidi gases by decomposition into solid nickel carbonyl or by condensation and merization into liquids or solids aliphatic eppoort yeport ides contained in crude isopropanol liquor In assessing the relationship between between the physicochemical status of atmospheric carcinos genic pollutants and the localization of cancen within the various parts of the respiratory consideration also must be given to the fact that gaseous and liquid carcinogens may become ad sorbed to the surface of carcinogenically inert solid dust particles and behave under such con ditions more like solid particles Such com 4 binations for instance occur in relation to the exposure to radioactive gases adsorbed to rock the dust in uranium mines as well as concerning inhalation of liquid or solid aliphatic and poly cyclic carcinogenic hydrocarbons adsorbed ta the surface of mineral road and industrial dust ae or of carbon constituting the bulk of soot a The first evidence indicating the existence A 1 of causal relations between environmental factors } and the development of cancers of the lung war recorded in 1879 when H^/rting and Hesse lung established the cancerous nature of the 4 ry diseases prevalent among the radioactive discovery miners in Schneeberg Saxony This Bo 4 a of historical importance and great present sig- & nificance attracted little attention at the time because radioactivity radioactivity was still an unknown fact iv and cancers of the lung were comparatively rare b before the turn of the century and therefore of a little medical interest n environmental It was not until the third and fourth decades t- of this century that additional defined occupational activities and | c agents were again related to the causation te of cancer of the lung and other parts of the respira- fe paranasal tory tract that is the nasal cavity . b 22 Environmental Causes of Cancer of the Lung 7 F Ae ERAS nuses and larynx Among these additions to he list of environmental respiratory cancers the lung cancers among chromate manu- wefarceturers * 1935 of asbestos workers 1935 of Carsenic workers 1930 and of coke oven opera- . tors 1936 the cancers of the nasal cavity para- masal sinuses and lung among copper melter workers 1932 the carcinomas of the msal sinuses among luminous painters 1931 the cancers of the nasal sinuses larynx and lung among isopropanol manufacturers 2 1946 and cancers of the larynx and lung " among workers exposed to lubricating oil sprays or mists 1936 1949 Specific Carcinogens Inorganic Chemicals NICKEL Nickel one of the most industrially important Metals and principally mined in the Sudbury Estrict of Ontario Canada has many uses Probalt Boys iron copper chromium aluminum Probalt Probalt molybdenum employed in the manu- cture of stainless steel heat resisting steels ou rgings casts wires sheets structural shapes Labing rods bars strips and so on electroplating catalysts ceramic enamels and colors ments in paints and inks storage batteries so on Exposure to nickel fumes and nickel dust of etallicnickel and its compounds or to nickel rbonyl vapors is therefore frequent for indus- tal workers of many types and in many opera- sos While skin contact to nickel and nickel not infrequently results in the development i an apparently allergic type of dermatitis halation of the volatile nickel carbonyl has #0. responsible for an appreciable number of and often fatal poisonings The pul- nary manifestations congestion desquamaof alveolar epithelium fibrinous acellular dation into alveolar spaces bronchia mu- the hemorrhages are apparently attributable gu. the toxic action of finely dispersed nickel med ae from the disintegration of nickel carupon the pulmonary structures Krafft suggested that these reactions are the result of nickel allergy having the lung as its shock organ The first report concerning the occurrence of an excessive number of cancers of the nasal passages nasal cavity and paranasal sinuses and of the lungs among workers of the Clydach plant of the International Nickel Company located at South Wales England was made by Grenfell in 1932 although the first appearance of these neoplasms among the nickel refinery workers was noticed in 1924 Bander Subsequent reports dealing with these cancers were made by Stephens Amor Cooper E. H. Carozzi Bridge and Merewether From 1923 to 1948 inclusive there were reported to the Chief Inspector of Factories a total of 47 cases of cancer of the nose and 82 cases of cancer of the lung from the nickel works By the end of 1948. 46 of the workers with nasal cancer and 72 of those with lung cancer had died None of the patients with nasal cancer and only 2 of the patients with lung cancer had commenced work in the nickel refinery after 1924 when a reconstruction of the plant had been carried out The average exposure period for the nasal cancer patients was 23 years range 3-26 years and for the lung cancer patients 25 years range 1-33 years No cases of cancer of the larynx have occurred and only 1 cancer of the nasopharynx was observed at Clydach The nasal cancers involved the turbinates nasal septum and = paranasal sinuses eth- moids Of these the majority were of the undifferentiated cell type 6 some showed a squamous cell character 3 while columnar cell carcinomas were uncommon 1 Of the lung cancers of which histological studies were available in only 4 cases 3 were of the small cell pleomorphic type while 1 was a squamous cell carcinoma Similar observations were recently recorded from a Norwegian nickel refinery where 3 cases of lung cancer were seen L^,ken In one of these cases a squamous cell carcinoma was associated with sarcoid lesions Goldblatt and Wagstaff mentioned that so far cancers of the respiratory tract have not been noted among the workers employed at the German nickel refinery at Ludwigshafen Health Monograph No. 36 1955 23 nor has there been reported an unusual fre- quency of respiratory cancers among the work- ers of the Sudbury nickel ore mines and in Canada although several smelters cases of nasal sinus cancers were recently seen in nickel plant one Canadian signifCiaccamarpnctbitleinylsosglueen containing Amor pointed out that the viduals majority of indi- employed at Clydach who developed respiratory cancers were not exposed to the inhalation of nickel carbonyl but to that of nickel matte dust or dust from the nickel matte matte roaster L^,ken More recent data communi- cated by Morgan confirmed this observation although exposure to nickel had carbonyl vapors occurred more frequently among the al- fected workers than was data apparent from the previously given by Amor The rela- tively high incidence of cancer of the nasal cavity indeed suggests that a rather ticulate dust coarse par- readily arrested at the region of the turbinates may have been active in the production of cancers at this while particular site particulate dust most cancers of the lung and vapors or a very small likely account for the nasal sinuses nickel refinery workers are reaction more or less finely dispersed nickel products vapors There is particles no evidence available hot ever which indicates that the nickel in inhalation particulate or vaporized form is companied by pulmonary changes of a coniotic nature pneum The concept of a nickel etiology of respiratresopirato cancers was tested in animals by respirato exposed mice to the inhalation of nickel matte and observed that powder had a lung tumor incidence these anim than that of the high unexposed control mice 7% recent experiments of Hueper seem to strate more demo erties conclusively the carcinogenic pro of metallic nickel When nickel powder was pure metall implanted into the femor and pleural cavities and subcutaneous subcutaneous 175 rats cancers developed at the sitesite of tion in 50 of them inje Whether or not nickel assumes a ! role for cancers of other organs and followin exposures by other routes is uncertain be It m mentioned however that Araki and Mu demonstrated As to the causative by spectrographic method method method have been advanced agent various theories nickel in human and animal cancers of vario cept that the Amor favored the con- types and sites The nickel content sulfuric inhalation from containing 6.273 mg per kilogram of fresh ranged fro the acid used in the refining process was 0.2 mg tumor tissue d . active carcinogenic agent It is unlikely that this is most No assessinent of the degree of occupation correct because the nickel refinery workers do not suffer from perforated nickel cancer hazard can be made from the available since the nasal septa and display no evidence of chronic unknown number of workers at risk y arsenicism such as dermatosis and Likewise no definite opinion U cancers which almost always have cutaneous be expressed as to the possible an existence the occurrence of lung cancer accompanied among workers extent of respiratory cancer hazards for person having for other reasons exposed to arsenical dusts or fumes Hueper fumes and contact with du Amor stated that the refined nickel copper pounds vapors containing nickel or its com ores are free from radioactive matter The res- piratory cancers observed observed CHROMIUM workers thus among nickel refinery those are not identical identical in etiology with Chromium as a metal alloy or compound seen in minersminers employed in the radioactive mines used for many purposes in industry It is of Schneeberg and Joachimsthal this reason that a large number and variety Workers employed at the roasters in the workers have contact with chromium and chr chr nickel carbonyl operation and in other mium compounds even restricted im of the plant on the other hand become parts of the general population group f$ to the inhalation of dust fumes or vapoerxspocsoend- come exposed to these agents minatyhe pfoosrsmibolfydudu taining nickel Nickel is the common denomi-denomi- vapor fumes mist liquids and solids Bour nator for all of them It thus is most probable and Rushin Bour Workers most likely to be re that the respiratory carcinomas carcinomas observed posed to chromium and its compounds ef Te among acetylene workers aniline workers bleacher 24 Environmental Causes of Cancer of the roducts to blueprinters chrome workers chromium platers facture of articles chromate manufacturers chromite miners miners certain chromium pigments zinc or able how cray- on makers dye workers electroplaters enamel chromate barium chromate lead chromate In these operations both soluble and alation of workers glass and pottery frosters glass color- insoluble chromium irm is ac- ) ers pottery glazers artificial flower makers compounds are intualed by the exposed workers The chemical nature of i pneumo battery makers linoleum workers paint mak- the actual ers ink makers painters photographic work- sible carcinogenic agent which is respon- spiratory ers photoengravers polishers printers rubber for the excessive liability of chromate and bell who workers steel workers tannery workers vul- chromium color workers to cancer of the lung is still controversial powdered powdered canizers waterproofers of textiles and paper Although all investigators believe that animul welders users of chromate antirust agents in chromium some ailroad engines automobiles steam heat in- compound or compounds are causally 100 The stallations and bitumen and oil refinery workers involved it has remained the compounds suspected uncertain whether are hexavalent or " demon An environmental atmospheric contamina- trivalent water soluble nic prop - tion with chromium compounds may result chromates or insoluble mono- from the release of or dichromates Water soluble containing metalic indus- chromium femoral trial wastes of chromate plants and of oil compounds monochromates di- chromates and zine containing tissue of refineries using a silica incriminated chromate are most often atalyst for the catalytic cracking of oils An environmental spread of chromates Manenso and Hueper recently pointed out inogeni may also follow the use of such compounds as antirusting that it may be more likely that carcinogenic effects are elicited by chromium compounds ollowing gents in automob and for anticorrosive compounds It coating of airplanes Since which are either not soluble in water or are may id Mure mdustrially used chromium many of the only slightly so because such chemicals when methods compounds exert $ corrosive action on tissues skin inhaled as dust would be retained and deposited contact in the lung and thus exert a prolonged effect ae various and inhalation of such agents results in the development of chrome upon the pulmonary tissues Such chromium ged from ulcers of the skin and Sre tissue lo Lasal septum which in turn provide definite compounds present in a chromate plant would proof of an existing health hazard be represented by chromite ore and its early tie Com- conversion products preceding the formation Des pational cuting on the appearance of such manifesta- tions of monochromates These little he data among workers in new industries using trivalent soluble Ey t risk 1. chromium compounds the Chief Inspector of chromium compounds occur in the SER Factories of England and Wales material present in mixers and roasters and FE ion cau remarked in ice and Lis report of 1944 that the control of old are contained in the slag which usually is stored persons Lazards in new industries is of interest to others for future use in the yard area of the plants mae. h dust well as to the student of industrial health Supporting this concept as to the chemical eres Is com- for would seem that in many casecs ases the hazard nature of the carcinogenic chromium compounds ON _# not recognized until damage to tissue has is the fact that workers as well as animals ex- Ce been done when old principles have to be posed to the inhalation of chromite ore dust aI } learnt and adapted to new uses have not only a high chromium content of the ME ale und is This reflective observation lungs but also an excessive blood chromium PR tis for seems to be quite - sppropriate when contemplating contemplating the possible level Mancuso and Urone Recent experi- iety of Pustence of respiratory cancer hazards for ments on rats which inhaled finely powdered chr individuals employed in the numerous indus- chromite ore dust showed that after 18 months groupa groupa dy be operations for which no pertinent pubshed data of any kind exist at the present time a chromium level of 13.0 and 17.0 gamma re- spectively in 100 cc of blood was found in RS oJfoduursnte coTnnheectoebdservation of apparently occupation- rats studied This finding moreover definitel2y RL cancers of the respiratory organs establishes the fact that a fraction of the chro- be ev NEL Is are specially the lung has been limited so far two types of operations the production of mium contained in chromite ore is solubilized in the ichers romates from chromite ore and the manu- the blopoudlmonary tissues: and discharged into I Lune Public Health Monograph No. 36 1955 25 -Astarkvarak support lent compounds may of a causal be derived role of trivafrom the ob- servation that 10 of the 20 chromate workers with lung cancer reported on by Alwens and Jonas in 1938 were not employed within the manufacturing buildings or were repair men or maintenance workers blacksmith glazier driver welder or manufacturer of sulfuric and hydrochloric acid produced in a nearby building While all of them probably had some exposure to chromates it is likely that their contact with chromite ore dust or with dust from the slag heaps containing more or less insoluble chromium compounds was much more pronounced Mancuso Urone and Anders Bourne and Yee Buckelf and Harvey As the result of the retention of insoluble chromium compounds in the lung tissues there develops a blackish spotty pigmentation and a spotty fibrous thickening of the peribronchial and interstitial tissue where the chromium dust particles are deposited This pneumouconiotic condition called chromitosis was described by Andrievskaya and Mislavskaya in chromite ore miners and by Lukanin Letterer Neidhardt and Klett and Mancuso and Hueper in chromate manufacturers It was produced experimentally in rabbits by Lukanin Letterer re- ported a chrome silicosis in a polisher in an iron foundry who inhaled silica and chromium oxide dust While the attempts of Gross and Koelsch and of Campbell to produce lung cancer in mice by exposing them to chromate dust were unsuccessful Schinz and Vollmann who implanted powdered chromium metal into the femoral cavity of rabbits observed after more than 3 years 1 animal with cancer of the lung and 1 with cancer of the femur It is definitely surprising that an excess Jonas established liability to lung cancer has been # far only for chromate workers in German Pfeil Alwens and Jonas Teleky ; Carozz Gross and Koelsch; Alwens Bauke and Lehmann Martineck Gross Koelsch Alwer and associates Goldblatt and Wagstaff Gregorius in the United States Machle and and Gregorius Baetjer Hueper Mancuso and Hueper Imprescia Division of Occupationa Health U. S. Public Health Service andOcupationa chrome pigment workers in Germany Baader Gross and Koelsch Letterer Neidhardt and Klett Bidstrup found a single case of cancer upon ray examination of the of 321 chromate manufacturers employed for more than 10 years in English plants no data exist on this point in regard to lung chea while chro producing or -consuming plants in other cForuanntcreies such as Switzerland Italy and Apart from the excessive frequency of lung . caneers among chromate workers which ao cording to American observations observations ranges from 13 to 31 times the normal frequency of lung cancers among the general male population a occupational origin of these cancers is gm: strongly suggested by the shift of the age distribution -_ toward younger age groups This is particularly striking for the lung cancers present among German chrome pigment workers since 50 per cent of the cancers affected individuals before table the age of 40 years when lung cancers of un : known etiology are relatively infrequent Z : 22 > Bs 80 the -- -- * con The quantitative data on the chromium tent of various organs and blood of persons with chromium lung cancer have been reported by several investigators Alwens and Jonas Let Table 22. Age distribution of cases of chromium cancers cancers of the lung according to type of worker Age years Type of worker ee 51-60 71-80 a 21-30 31-40 | 41-50 51-60 61-70 71-80 | ee ae fe nn 673 American chromate | German chromate 0 0 8 ' 673 19 121 l German chrome pigment pigment 1 3. | | 673 14 121 1 008. we. rT eee eee 5 | 673 1 121 te ee . ol ae 26 ; Environmental Causes of Cancer of the Lung Pul : and Klett Mancuso and dustries PD rrip ere uace te of exposed workers Niedhardt estimate of the number list alalpper er Spannacgherlomriecuemntcloyutneonttedofathpeecbulloioard the long although incomplete considering contact with different occupations entailing chavior of tchheromate workers before and after of Chamberlain The estimate estimate urine in was found arsenicals given by the rather consider- of lung cancer be development the normal urinary moreover does not include exposed to workers chromate able number of persons who are hst of chromium ceases with the develop- arsenicals for purely environmental environmental environmental reasons by cretion ment cancer while simultaneously the arsenicals with foodstuffs contami- of lung level becomes elevated UE ingesting insecticide residues by Mood chromium observation may have distinct this nated with arsenical consuming drinking water polluted with arsen- confirmed in causal metabolic and diagnostic icals leached into drinking water supplies from importance mine and smelter dumps or by inhaling arsen- respects el With the exception of 2 cases cancer of and i cancer of the icals released into the air from industrial small- or scale dust- the nares Newman and Wagstaff the sinus Goldblatt establishments or by ing operations of arsenical pesticides that maxillary the exclusive site of respiratory cancers From the published evidence it appears was chromate workers The total and nonoccupational contacts among around environmental in recent observed of these cancers is at present with arsenicals have been responsible number from all sources None has been for the majority of cases of chronic 125 cases from nasal septum decades arsenical cancers reported as originating arsenicismi and cutaneous Tello Macola pneumoconiosis deers thus seems to Neubauer HuBeuptezrengAeriggueerllBoander Nieberle Chromium of cancer of the and Manzano Montgomery and the development Hofmann Prell Holmquist company and chrome pigment manu- in chromate whether hang however Waisman Cannon Arhelger and Kremen Hanser and Simon facturers It is uncertain plays an essential essential Straube Bohnenkamp and many others process the pneumonoconiotic role in the specific cancerization Gonnet causal role which arsenie plays in process modifying it is merely a phenomenon While the of the skin on the whether process process or the production of cancers x e acloincidental coexistence basis of chronic arsenicism of occupational % environmental origin has long ARSENIC es medicinal or established is rather recently n or waste AL Arsenicals represent a byproduct since been firmlyto arsenicals has seriously been that exposure of the smelting of many ores copper considered as a principal causal agent of cancers product +s ine silver cobalt antimony iron bismuth Arsenicals are present membranes such as those of the of the mucous bladder Indeed today ickel tin and lead bronchi stomach and but ja the smelter fumes and slag heaps They are there exists as yet only highly suggestive and used especially dur xtensively produced and fungicides evidence linking cancer of the not conclusive to arsenical with occupational exposure decades as insecticides an ing past and cattle dip grasshopper lung almost all cases of lung vermicides sheep herbicide especial- dust However in made there rat poison as well as a cancer for which such claims were bait 1 Arsenicals hy for clearing railroad rights of chronic arsenicism in the existed stigmata to orchards and vineyards dermatosis with or without skin are applied as sprays and are dusted from airplanes fields upon cotton They are em- form of arsTehneic inhalation of arsencial dust and cancers the develop- gorn soybean and potato fumes induces rather frequently in the manu- ployed as wood preservatives ment of perforated nasal septa as well as chronic i dyestuffs of glass base alloys irritative conditions of the bronchi thereby cture and medicinal = bronzing and paint pigments Arsenic Mote creating a symptomatic cancerigenic pattern in chromate workers and cosmetic preparations to similar to that seen of a raf y and its compounds constitute according the existence Under such circumstances circumstances Environment and Health a health hazard American in- causal relationship between cancer of the lung 35,251 workers employed in = for 27 7 Public Health Monograph No. 36 1955 it iE b Pre oes I er and chronic arsenicism appears to be a reason- able conclusion Chest and ray examinations of 40 workers employed in an arsenic smelter revealed a mild degree of pneumoconiosis Saupe Although Saupe himself did not discover any evidence of lung cancer among the workers studied though they often were afflicted by hyperkeratoses of the skin and perforated nasal septa cited the autopsy observations previously made by Schmorl on 2 arsenic smelter workers who died from cancer of the lung Teleky Frommel briefly mentioned the occurrence of a cancer of the lung in a taxidermist who used an arsenical powder for dusting the pelts of animals Four additional cases of lung caneer in sheep dip workers with arsenic dermatosis noted in one of these were reported by Merewether while Hopkins and Van Studdiford observed in a farmer living near a cotton field sprayed with insecticides arsenical dermatosis epitheliomas and cancer of the lung The occurrence of 5 cases of lung cancer Merewether Hopkins and Van Studdi- ford among only 24 individuals suffering from occupational arsenical dermatosis and epitheli- omas caused Neubauer to wonder whether this is mere coincidence because only 2 cases of lung cancer were observed among 143 cases of medicinal arsenic cancers and Klaber or whether conditions the irritation tract by arsenical dust the phenomenon of the skin Russell under occupational of the respiratory respiratory was responsible for Henry commenting on the occurrence of skin cancers among sheep dip workers 1910-23 recorded 2 additional cases of lung cancers among 10 such workers who had cutaneous cancers He mentioned moreover the presence of cancers of the left foot abdominal wall and lung in a furnaceman in a sodium arsenite factory Analyzing the mortality experience of a sheep dip factory Hill and Faning found that 7 or 31.8 percent of the 22 cancers causing death among members of this group were located in the respiratory organs while 3 or 13.6 percent were situated in the skin There were during the period 1910 43 a total of 75 deaths from all causes among workers in this factory The proportional excess of cancer deaths was mainly attributable Druett to an excessive frequency of cancers lung and skin which of were confined to worken in the chemical processes and were workabsenden absend among members of the general groupgroup who would F. be unlikely to be exposed to any specific hazard Ae Perry Bowler Buckell and Schilling j concluded from the clinical evidence obtained that after many years of exposure to these sheep dip workers arsenicak may develop squamo Be cell carcinoma in the bronchus - : The most recent addition to epidemiological investigations on arsenic : cancer was made br Snegireff and Lombard in studies of cancer < deaths among employees of several q wr? _- Deer Silver Caste Galla 1 : metallurgai evidence cal plants of unidentified type of 109 deaths from all Of the total causes recorded during the last 25 years 12 were due to cancer of sites and of these 6 were located in the lungs The investigators concluded from this 10.9 ! # one ar F ' shoni that there are indications that biologically the human f race made the adjustment : to arsenic in the environment and that onlr- rarely when associated with other contributing F * exist histo arsen such endogenous factors such as systemic disease d relationship or possibly factors such as radiation it mar be capable of upsetting the biological equilib rium and further that the handling of # arsenic trioxide in the industry studied does idk: not produce a significant change in the ; cancer P mortality of the plant employees hence other factors in addition to arsenic must be con Jf sidered significant in the causal to cancer cisi by c BINIS smok it is dust prodi of the In view of the fact that 50 The cancer deaths percent of all & types sur- among employees of one plant veyed were caused by cancer of the lung the E fdruesqtu observations made in fact strongly suggest and c carcinogenic action of inhaled arsenic trioxide F upon the tissues of the lung of the exposed -- gworrikned workers This interpretation of the data of The Snegireff and Lombard is supported by the pulm high incidence of lung cancers among the population of several counties in Montana respec pneu where copper smelters and mines were operated - <- and s for many years creating an occupational and ible environmental pollution of the atmosphere and does soil with arsenicals Prolonged inhalation of mark arsenical dust and fumes appears to produce - < dust lung an increased liability to cancer of the table 23 3 sidero The However the existence of such connections g the lu 28 Environmental Causes of Cancer of the Lung . Public Table 23 Laing cancer mortality in several Montana counties 1947 4L8ull and Wallach| County and total population population 1940 population Major Major industry a i : b Number : - Number lung . : i . Number i caneers _ caneers a Total Total cancer ! Percent hing PePrecrenctent hing cancer * M Maallee 1- FeF - e- oot male ; deaths : Male , 1- . + male ; ca ne Annual lung cancer death rate 100,000 - ee 1 Male; ; FeF- emale ee ee an Cascade Deer Lodge 13,627_ .. Copper smelting 3 LUNE . ver Bow 53,207 53,207 Copper mining smelting LUNE 41,499 2. Copper mining smelting +i LUNE Gallatin 18,26918,269 : Agriculture _o 0.22. LUNE : ; Q; 588- 20 588- 5, 25 QO: 588- 98 | 30. 259 299 | $ j 12.7 3. \ 145. 1. 48. 3. 0 : 46. 5 5. 1 0.0 3. 12. 0 _ ae unpublished communication " Personal communication of data The estimated crude death rate for lung cancer among white males in the entire United States in 1947 was 199 per 100,000 population 3 The workers employedin copper ore mining and smelting inhale dust and fumes of arsenie contained in the are and released as a byproduct and waste product during the smelting process hould be acknowledged only when there * existed at some time clinical and if possible histological and biochemical evidence of chronic senicism In view of the absence of any mch evidence associated with chronic arseni- rism among the nickel refinery workers affected sinuses cancers of the nasal cavity paranasal sinuses and lung and among excessive tobacco mokers with cancer of the larynx and lung is most unlikely that exposure to arsenie st fumes and vapors plays any rolein the production of respiratory cancers in members these population groups s IRON + The extensive production and use of various typesiron and of diverse iron products offers = frequent opportunities for the inhalation of fast and fumes ofiron and its various alloys and compounds by iron ore miners arc welders grinders polishers silver finishers and metal resulting red or black siderosis caused by almonary retention of Fe2O3 or of Fe -OH pectively is considered an inert form of rumoconiosis which does not cause disability id which at least in part seems be revers- y The deposition of iron oxide particles particles Meesnot elicit in the lungs a progressive and marked fibrosing reaction unless the inhaled it also contains silica producing then a The coexistence of siderosis and cancer of te lung has occasionally been observed Stew- art and Faulds 1 case Dreyfuss 3 cases in watchmakers Vorwald and Karr 3 cases in hematite miners Simons 1 case in a blaster of iron casts It may be mentioned moreover that Kennaway and Kennaway reported a 2.25 incidence of pulmonary cancer among metal grinders and that Turner and Grace as well as Campbell noted an excessive frequency of lung cancer among metal workers The most recent contribution to the problem of siderotic cancer of the lung was furnished by Faulds who noted that among 192 iron ore miners coming to necropsy between 1932 and 1953 there were 17 lung cancers 8.85 percent Ehrhardt and G^...thert on the other hand noted that red siderosis of the lung does not produce a special predisposition to lung cancer The uncertainty existing in this respect is further illustrated by statistical data provided by J. W. Brower Deputy State Registrar Minnesota Department of Health on the number of deaths from lung cancer among iron ore miners residing in St. Louis and Itasca County Ototal number of miners 13,313 against that of residents of Minnesota population base 2,982,483 There prevails a consistently higher lung cancer death rate for iron ore miners for the year period than that noted for Minnesota residents table 24 Experimental studies on animals exposed to iron oxide and hematite respectively gave contradictory results as to the production of lung = tumors While Vorwald and Karr using guinea pigs and ruts failed to obtain lung cancers with Health Monograph No. 36 1955 29 ry is i 1 } ee ae A ti OE ret:Maneg \ t eee i Ors e aa = empe rt en OE yee VE Pdatend PRIN et 2 - gite SR ce ee ere eR sere denis AE ee pint Ne Be aes crag ID ie a et Sere ky var Table 24. Deaths due to iron ore miners and Brower 19511 54 cancer of residents the of lung among Minnesota Number Number of deaths ; DeDaetahth rate ppeerr 100,000 eet | Minne- St. Louis Itasca sota resi- | County dents | miners Minne- i sota resi- | dents | County miners eee eee 1950 0S 328 | [ee h 11.0 37.6 1951 1952 . ' 1953 0002. 289 i 329 | 367 4 i 12 Ni. 9.7 9.7 11.0 12.3 30. 0 90. I 60. I 1954 345 ft a 11. 10. hematite dust Campbell reported an increase in the number of lung tumors in mice exposed to iron oxide over that of the control series When the available evidence is viewed criti- cally it is still uncertain whether an exposure to iron dust conveys an abnormal liability to lung cancer Although Warren and Drake recently concluded that the development of primary carcinoma of the liver as a sequela of hemochromatosis apparently depended in part on the intracellular deposition of iron such considerations may not necessarily be applicable to pulmonary siderosis and cancer However thorough and comprehensive epidemiological data on the incidence of lung cancer in workers exposed to iron dust are not available Hence a definite conclusion on this problem must be withheld The availability of conclusive information on this point appears to be urgent in view of the suggestive evidence recorded by Faulds and because of the fact that damages have been allowed in the past by court action in at least one case of cancer of the lung in the production or aggravation of which the inhalation of steel dust was alleged to have played a significant role BERYLLIUM Beryllium is a metal which has found significant industrial use only since about 1920 It was not until about 1940 that beryllium and its compounds were extensively employed for numerous purposes and products beryllium- copper aluminum and beryllium- nickel alloys glass phosphors in fluorescent 30 lamps and neon tubes atomic energy product window ceramics refractories ray tube window th vitreous enamel radio tubes textile fibers g) mantles It is evidently for this that effects in reason untowhalation ard effects in persons exposed to the of Aldridg shown certain tis plasma p T is.bhwed halation of dusts and fumes of is.bhwed is.bhwed is.bhwed beryllium from bein its various compounds have been been during recognized Es The me only during the last decade These manifesta pounds pounds of tions were of both acute and chronic nature respiratory nature concerned that fact far as the respiratory organs were concerned tion of os acute beryllium pneumonitis chronic E moconiotic granulomatosis berylliosis Sore & iin ngtrpavoewndo investigators used the term sarcoid in dum sili dum scribing the histologically peculiar pulmonary & quently c moreover manifestations It is remarkable and othe only that chronic berylliosis has appeared not * oxide be oxide among exposed workers but also among # living in neighborho d among pr introduce sons living in the neighborhood of fluorescent respirator lamp factories and inhaling their beryllium Sissons containing effluents Eisenbud Berghout and r Largent Steadman Eisenbud Wanta Dustan Stead | period for man Harris and Wolf Comme ; berkasteogeni Similar observations on occupational berkasteogeni berkasteogeni Italr liosis were reported from Germany } infre England Russia and Canada Not F quently similar granulomatous lesions hare | been observed in other parts of the body after . the usually traumatic introduction of beryllium berkasteogeni berkasteogeni of berylli noted the able amor following dust especially of beryllium phosphors from - years co broken fluorescent tubes # The skin of the been exp fingers and hands was the most frequent & pounds extrapulmonary location of these reactions FF througho fi Beryllium granulomas have also been found in Y the nose and in the anterior ocular structure fact that been repo It is noteworthy that beryllium apparently FF of poorly once inhaled is retained over a long period of EF eventuat time in the human body since beryllium has sumably been detected in the urine up to 10 years after would be | cessation of exposure Klemperer Martin and Van Riper and has been demonstrated in the _ rabbits p over a } lungs of rats 1 year after the inhalation of $ beryllium oxide Dutra Largent Cholak J Hubbard and Roth as well as in their bones whether beryllium Barna Stokinger Steadman and Root Barnes # where it may replace calcium The skeleton retains 50-80 the bulk percent of if the the beryllium inhaled body in the aerosols are f $ { soluble compounds such as beryllium sulfate and beryllium fluoride the lungs retain the bulk of beryllium if the compounds are in- soluble such as beryllium oxide Experiments coma fr possibly far only opment administ direct int into the cavity a i ia Environmental Causes of Cancer of the Lung 2. Public H Fe Aldridge Barnes and Denz moreover have own that beryllium ions react rapidly with tain tissue proteins and form complexes with fisma proteins when introduced into the These complexes protect the beryllium . being precipitated by phosphate ions The metabolic peculiarities of beryllium comGrounds obtain special importance in view of the that Gardner in 1946 reported the produc- n of osteogenic sarcomas in rabbits injected F travenously with insoluble beryllium ae powders beryllium phosphate zinc beryl- m silicate Other investigators subse- ently confirmed these results with the same de other beryllium compounds beryllium de beryllium silicate metallic beryllium troduced into rabbits by the intravenous or piratory routes Sissons Barnes Denz and tons Hoagland Grier and Hood Nash Dutra Largent and Roth Barnes The preparatory od for the sarcomas was 11-24 months Commenting on the successful production of teogenic sarcomas in rabbits after inhalation 8 beryllium oxide Dutra Largent and Roth ed the fact also that the bones of persons ing with berylliosis contained not inconsider- Rat amounts of beryllium They came to the Mowing conclusions During the last 20 Mowing considerable numbers of persons have ads exposed to dusts of poorly soluble com- ads of beryllium in various industries ughout ughout the United States Despite the Pet that cases of cancer of this type have not is reported it is possible that the inhalation b& poorly soluble compounds of beryllium may etuate in osteogenic sarcoma in man Pre- ably the incubation period of such tumors pedd be considerably longer in man than in bits and observations may be required Wa period of years before it will be known her persons who have been exposed to jum are prone to have such tumors Bernard also suggested that osteogenic surfrom compounds of beryllium might 15 be another industrial hazard So aly rabbits have responded with the develnt of osteogenic sarcomas following the istration of beryllium compounds The ome introduction of powdered beryllium metal the femoral cavity of rats into the pleural and into the paranasal sinuses failed to elicit a single neoplastie response at the site of injection in any of the 85 animals used within an observation period of 2 years Hueper When in 1948 Hueper proposed that the sarcoid pulmonary manifestations of berylliosis might be followed by outright malignant lesions in the lungs this suggestion was received with a great deal of skepticism The recently reported successful production of bronchogenic carcinomas in the lungs of rats which over periods of more than 1 year inhaled dust of soluble and insoluble beryllium compounds Vorwald however makes the appearance of such delayed malignant sequelae in man a distinct possibility especially as several cases with coexisting berylliosis and cancer of the lung have recently been observed Kahlau In view of the established occupational as well as general environmental occurrence of human berylliosis it may be pointed out that the discovery and identification of this pneumoconiosis was definitely facilitated by the distinctive and definitive histological features of the dis- case If these manifestations should be fol- lowed by the development of cancers of the bones and lungs the establishment of causal relations between a previous exposure to beryl- lium and the subsequently appearing cancerous reaction would appear to be rather easy The studies on the toxicity and carcinogenicity of beryllium compounds indicate that the toxic and cancerous manifestations are to be considered as responses to the action of beryl- lium itself and not as the result of the associated anions of its acidic salts Stokinger Sprague and Hall In considering possible future carcinomatous developments in persons with previous exposure to beryllium some consideration also may be given to the toxic effect exerted by beryllium on the liver leading to the development of cirrhosis and to an impairment of the metabolic and detoxicating function of this organ Aldridge Barnes and Denz Hoagland Grier and Hood Organic Chemicals COMBUSTION AND DISTILLATION PRODUCTS OF COAL The apparent innocuousness of coal and possibly graphite dust as respiratory carcinogens is not shared by the incomplete combustion distillation and hydrogenation products Health Monograph No. 36 1955 31 mere ce Tata ete er ret seee mgaree Vr wean pie ny ne Sw ran pet igen ee ea rte er nbe cer toe een ak ee reat pn | a ADEN yee oe te te tearted nga ne e of coal pitch far soot creosote oils authracene oils tar oils and highly viscous oily and tarry fractions obtained by the direct hydrogenation of coal employed by the Bergius process The carcinogenic action of these combustion and distillation products of coal on man and experi- mental animals has been established beyond any doubt Although the bulk of the casuistic and epidemiological human evidence of occupa- tional coal tar and pitch cancers has come from England and Germany it cannot justly be assumed that American coal tars tar oils creosote oils and pitches differ fundamentally in their carcinogenic properties from those manufactured abroad The exposures sustained by the numerous types of American workers in a great variety of occupations and operations do not seem to differ from those found for their European colleagues nor are the carcinogenie which is characterized by the deposition of finely dispersed carbon particles contaminatedcontaminated with hydrocarbons normally contained in coal : tar in the interstitial lung tissue Koentgenological changes may appear in the lungs after many years of exposure to high concen rations of soot in the air inhaled While the pulmonary deposition of small to moderate amounts of soot in the lungs such as is com monly found in inhabitants of industrialized regions does not elicit any appreciable fibrous proliferations massive storage of soot particles in the lung tissues may finally be associated with an increase of the interstitial connective tissue and with pseudoglandular formations of peribronchial alveoli The human evidence relating exposure to coal tar and pitch dust and fumes with an increased liability to cancer of the lung is not the other 100 lun following gas stoke crane ope 136 pri * asphalt painters and auto moreovemorreover among er Additio vided by generator plants ar Canada a Kawahat investiga enses of ' effects on the skin of these workers at variance with European observations However in addition to skin contact with these products of processed coal there exists for some groups of workers a considerable exposure to these agents in the form of dust or fumes tar distilleries tar paint shingle roofing paper paper conduit and battery case manufacture gas works coke oven operations road construetion and repair work roofing brickmaking foundries furnace attendance railway engine driving roundhouse operations pickling of lumber chimney sweeping cork brick manufacture electrolytic metal production and on Since the high boiling fractions of synthetic oils produced by the direct hydrogenation of coal through the Bergius process have been shown to be highly carcinogenic to the skin and subcutaneous tissue of mice and rats respectively certain types of workers manufacturing and using such products and inhaling fumes or mists of these carcinogenic petroleum and tar oil substitutes may have a special lung cancer hazard Manufacturing plants using the Bergius process have been operative for extensive and is in part controversial The human evidence relating exposure to coal workers hot tar fi tar dust and fumnes with an increased liability lung can to cancer of the lung is equivocal Kennawar and Kennaway stated that coal tar in the employed general i atmosphere whether derived from roads domes tie chimneys or any other source does not cause an exceptionally high incidence of cancer generator employed occurred of the lung A similar statement was made by Hugounenq and by Husted and Biimana in regard to the liability to cancer of the lung for workers employed in the tar industry and 33 perc lung can varied fi being 16 in the construction and maintenance of tarred _ recently roads McLaughlin did not find any lung ers Of cancer among 3,059 foundry workers subjected workers to clinical and ray examinations although cancer o there were 3 deaths from lung cancer among ethunoid 64 deaths from all causes Menz recently upper at reported that of 93 workers in Swiss gas plants who died during the 1926-46 period 21 or 22.6 It is li rates mi died from cancer of all sites thereb,, _ Followir percent 25 skin confirming previous English experience that had be workers in tar and pitch operations have an | excessive liability to cancer in general Iso- during a of lung lated observations of lung cancer in workers compan some 20 years in Germany and have recently been constructed by several industrial concerns exposed to the inhalation of tar fumes were made by Koelsch blacksmith tar worker cancers cases of in the United States Not only the environmental but also to a greater degree the occupational inhalation of dust soot and fumes produced by the incom- plete combustion of coal results in the development of a soot lung called bituminosis Rodenacker briquette factory worker and 7 M^...llschitzkytar worker In an analysis of lung cancer deaths among members of different occupational groups for the & years 1933 38Kennaway and Kennaway on } Environmental Causes of Cancer of the Lang From the inha of certa plants Public } 32 excessive liability to cancer of the respiratory hand noted that an average an other It is not unlikely that more thorough he frequency existed for the tract of the death records of lung cancer 100 occupations following gashouse workers 129 202 gasworks and competent analywshisich have far been found other worker groups extend the types stokers 284 gas producers to lack such tendencies might operators 138 gasworks superintendents and number of tar and pitch workers having an flcrane 119 chimney sweeps 119 cancer rate A ; printers abnormally high respiratory asphalt workers 164 metal polishers observation of lung cancer in a worker 129 tanners 141 street cleaners 169 recent heated pitch and asphalt points to painters automoblie drivers 149 They recorded exposed to tar another source of occupational pulmonary and moreover ninefold increase of lung cancer cancer of definite practical importance Patch of a Canadian gas plant among employees Additional Additional supporting information was pro- SHALE OIL AND NATURAL GAS PETROLEUM the observations made among Japanese ided by workers employed in steel The carcinogenicity of certain high boiling well as enerator gas oven workers in fractions of petroleum and oil shale as plants and among gashouse retort and of some of these of the combustion products and England Kawahata Kuroda Canada Cruickshank Doll The Japanese derivatives such as oil shale and petroleum been demonstrated Kawahata within a year period 21 natural gas have definitely but also on investigators - found oven not only on experimental animals ases of lung cancer among generator of the skin after of workers developing cancers workers who were exposed to the inhalation contact with these agents Known when stoking coal An excessive prolonged have been hot tar fumes workers carcinogenic chemicals moreover Ang cancer rate was absent among The isolated from these petroleum derivatives as in other parts of the steel mills their combustion products Berenblum ployedincidence of lung cancer among the general 5 1,000 workers per well as and Schoental Fischer Priestley Eby Wanless Golfein Breslow enerator gas workers was and Rehner Falk Steiner Seven of these 21 lung cancers Waller Rehner Kotin and as- employed occurred in workers aged 40 years or younger in cryptogenetic and Hykes sociates) with carcinogenic {3 percent against 18 percent time In addition to skin contact lung cancers Hueper The exposure workers are also derivatives many varied from 9 years to 23 years the average petroleum to an inhala- for occupational reasons ~ being 16.6 years Similar observations were work- etxiopnosoefd oil mist or fumes workers in paraffin made among Canadian gashouse certain groups of oil refinery teentlyOf 14 cases of cancer among retort house pressing operationsmetal lathe workers foundry . 6 were due to cancer of the lung 1 to workers spinners workers printers and workers of the workers metallurgical cancer + of the larynx and 1 to cancer the so on In spite of this established occupational hmoid sinuses 57 percent were cancers of to petroleum and shale and lower respiratory tract respiratory exposurreecord only three cases of oil upper It likely that similar lung cancer incidence oils there are on such workers although such exist among American tar workers tes may where some distillery pneumonia among been observed conditions have rather frequently instillations of mineral Towing a visit to a tar warts after repeated medicinal had skin cancers and more than 80 pitch oil containing nasal drops oil aspiration pneu- been observed among the 300 workers of the lung In fact had , an year period there was found 1 case monitis or paraffinoma of the lung apparently BBrirnging . lung cancer Subsequent inquiries made by mineral two cases of cancer the basis of a medicinal . mmpany officials brought the number of lung developing on oil pneumonia have been described Wood : in this and other tar operations to 6 ; acers tates of cancer of the lung \ the evidence available it appears that From Se * inhalation of tar fumes sustained by workers certain operations coke oven generator generator gas a * . gas plants tar distilleries seem to have Sante The occupational evidence available or pub- lished on this aspect of cancer of the lung is rather scanty and in part controversial Kenand Kennaway found relatively high naway plants : tod - . { 33 we Public Health Monograph No. 36 1955 e ratio of laryngeal but not of pulmonary cancer in mulespinners who inhale a mist of the carcinogenic shale oil lubricating the spindles Southam noted that mulespinners occasionally develop multiple primary caneers involving the stomach or the lung in addition to cancers of the skin Scott on the other hand stated that he had not observed a single case of lung cancer among shale oil workers Huguenin Fauvet and Bourdin who ana- lyzed a series of 112 lung cancers for possible etiological factors found that 18 or 16 percent were metallurgical workers exposed to the inhalation of nebulized lubricating and cutting oils 8 were chauffeurs 5 were mechanics and was an engineer Huguenin and his assori- ates concluded that their observations indi- ented an excessively high frequency of lung cancer among workers exposed to vaporized or nebulized lubricating oil While the study of Gafafer and Sitgreaves on cancer morbidity and mortality among the male employees of an oil refining company did not reveal any abnormal liability of the members of the occupational group to cancer of the lung this judgment may have to be revised at least for certain types of refinery workers according to more recent and scrutinizing observations R^sch observed three primary cancers skin stomach and lung in a paraffin worker Touraine and Bour also attributed the development of pulmonary cancer among certain worker groups to lubri- cating oil mists Such exposure conditions may account also for the excessive lung cancer mortality among male metal grinders observed by Turner and Grace There is moreover some evidence available indicating that the inhalation of mists or fogs of certain processed petroleum oil fractions also conveys an increased liability to cancer of the lung During a recent survey on deuce among employees of a large the surprising observations were cancer inci- oil refinery made that there was not only a highly excessive incidence of scrotal cancer among employees of the paraffin pressing department but that incidence of cancer of the lung was also excessive Paraffin pressers who represent about tenth of the total employed worker group furnished 56 percent of the lung cancer observed Since soot as a waste or commercial product 34 has been found to be carcinogenic and to contar known carcinogenic hydrocarbons a thorough thorough and competent survey of occupational groups particularly exposed to the inhalation of operating railroad personnel stokers carbon black manufacturers rubber paint and in makers painters soot burners printers diesel engine drivers carbon electrode manufacturer and users in aluminum plants smudge pou operators phonograph record makers is an urgent necessity The negative conclusion reached by Ingalls as the result of a survey of Me the carbon black industry are based on evidence of dubious merits because only 79 of the 677 evaluated workers have been employed for 10 years or more in the industry Since the major ity of known occupational lung cancers have an average latent period of over 10 years Ingalls conclusions are actually based on 79 living and active workers It stands to reasonagen? that an analysis of the death records of former carbon black workers may have told a different story especially if the diagnoses were based on autopsy findings Such investigations would would y ^ also add to our knowledge as to the existence : extent and type of bituminosis which might be expected to exist in workers inhaling finely e = : dispersed soot particles exposure At the present time exposure to tar pitch ae 4 2636 asphalt heavy fuel oils lubricating and cutting ae 442636 oils soot from domestic furnaces incineratori industrial power plants oil refineries stee 442636 plants metal smelters carbon black factories exposure 4 2636 oil dumps and smudge pots as well as a to the effluents of diesel and gasoline engines 442636 represents the most widespread occupational sp $f ch and environmental contact with carcinogenie material The specific carcinogenic agents con- tained in these carbonaceous matters are certain specific aromatic hydrocarbons which not in frequently are attached to carbon particles gir ing rise when inhaled to bituminosis or anthra m cosis or they are constituents of oily matter which when inhaled and retained in the lungs 6 cause oil pneumonia or paraffinoma of the lung " Since pure anthracosis is not causally related to cancer of the lung the pneumoconioses ao 8804 companying respiratory carcinogenesis by aro 8804 matic hydrocarbons do not play a primary 8804 essential role in this process although the 8804 pneumoconioses may lower the intensity and > Environmental Causes of Cancer of the Lang in ze aps DOL 014 uk Sel et's 301 a) of ite 377 30 or tls, the duration of the effect of the specific prolong chemicals on the lung tissues esrcinogenic Since our civilization and economic life has built around the production and use of the been basic carbonaceous substances and their deriva- it does not seem feasible to attain comtires plete protection against exposure to these carcinogenic chemicals with the preventive and prophylactic engineering and sanitary measures practical and economical at the present time There is however no doubt that a great deal remains to be done in this respect and that we still rather far removed from having the are maxinal amount of possible reduction in exposure to the respiratory cancer producing hydro- carbons contained in the various carbonaceous substances mentioned polyethylene polyvinyl chloride polymethyl methacrylate polyamide Teflon and others into rats and mice are followed by the develop- ment of sarcomas at the site of deposition there exists the possibility that the inhalation of vapors mists and dusts of the monomers and polymers of these and related chemicals for occupational reasons may create a respiratory cancer hazard to man The more immediate importance of these roncepts however lies in their application to the production of occupational respiratory cancers by a silicon polymer asbestos possibly also by a carbon polymer contained in isopropyl oil polypropylene or propyl epoxide The probability of such an action mechanism moreover is supported by observations of lung cancers among Japanese mustard gas manu- 79 Carbon and Silicon Polymers S17] facturers ASBESTOS eg ner Recent studies of English investigators Hen- Asbestos differs from the ordinary giant ey0e2.1 dry HaonmdeWralpRoolsee HaandddoWwalphoalvee fuHrennidshreyd molecular crystalline silicates not only in its but also in Rose uld chemical and physical properties 1 new and intriguing concept as to possible anatomical aspects of the pueumoconiosis jee combinations of carcinogens with tissue proteins the to the tridimen- be through the postulated formation of cross psiroondaulcepdolybmyeriitzedInsicloicnatrcarsytstals in which no ely linkages between certain types of carcinogenic atoms are left carrying charges to chemicals and the macromolecular fibers of oxygen chromosomes This hypothesis was evolved attract positive ions asbestos consists of giant ting evidence obtained in the study of carcino- fibrous molecules composed of polymerized OPS from oxygen tetrahydra which are arranged in ee genesis by mustards diepoxides poly- chains bands Parkes Depending on the -teel ethylencimines and related compounds In or be short or view of the fact that one of the various means origin of asbestos the fibrils may ce ure by which these substances may exert their long Italian South African and Australian amphibils consists of fibrillar or ra- Ties sperific action in the cells is through polymeri- asbestos silicate iit zation it is assumed that polymerized epoxide diating crystals of magnesium prt, tiie chains might interreact with proteins or or sodium iron silicate 40 percent iron oxide une mucoproteins of chromosomal origin by cross Canadian Russian German and French as- tain linkage with multipoint attachment and there- bestos is hydrated magnesium silicate which in- mitotic aberrations The initial re- contains small amounts of iron oxide 5.75 per- giv by rause " action of one of the epoxide groups of mono- cent Canada furnishes about 75 percent of lira- merie molecules with the cell component also the world production of asbestos Canadian atter may start a process of polymerization by being asbestos because of its long fibers is especially ngs ung aited ill aroe and Ove and followed by a condensation of the free epoxide groups into a polyetheneoxy These concepts are important in connection with respiratory carcinogenesis for several reasons Since Oppenheimer and associates Druckrey and associates and Zollinger have shown that a parenteral implantation of various polymerized plastics cellophane suitable for textiles Depending on its physical characteristics asbestos finds numerous uses textiles filter material building material gaskets insulating material adsorbants and so on Some 35,000 workers in the United States are exposed to asbestos dust It is asserted that inhaled asbestos dust pro- Lung 35 Public Health Monograph No. 36 1955 og duces ashestosis only if the inhaled fibers are sufficiently long In the absenter of fibrous struetine Vorwald the dust is said Durkan and to be inert Wyers Prates Since the larger tibrils and arrested in the bronchuoles Gardner the granulomatous reactions form peribronchiolar fibrous cuffs with giant cells and asbestos bodies These have a fibrillar core and an iron staining proteinie or colloidal silicie arid sheath Whether the iron in the stiraths originates from the asbestos fibers or is derived from blood or tissue elements is still controversial These two observations de serve special mention because of the apparent dependence of cancerous changes in the lungs asbestos workers upon the presence presence of ashes- tosis and in view of the possibility that the proteins of the lung tissue may juterreact with free groups of the asbestos molecules Druckrey and specifically filamentary associates associates The coexistence of asbestosis with cancer of the bang was first reported by Lynch and Smith in 1935 ( cases They later recorded 3 addi- tional cases Lynch and Smith Lynch Simi- lar observations have subsequently been re- corded from this country Stoll Bass and Angrist 1 rase Holleb and Angrist 2 rases and Homburger 3 cases from Canada Des- meules Rosseau Giroux and Sirois 2 cases Cartier 4 cases Rousseau I case; from England Gl^,yne 17 cases Harrison 3 cases Merewether 31 cases Cureton 1 case Owen case and from Germany Nordmann 2 cases Linzbach and case Welz 2 cases 2 cases and Baader Wedler | ease Horning B^hmeI ease Domenici I case Thus there is at present a total of 80 cases of asbestosis cancer of the lung on record To this number must perhaps be added the S ^'ases of cancer of the lung complicated by asbestosis which Kennaway and Kennaway discovered in an analysis of the death certificates of males registered between 1921 and 1938. Eleven additional cases of asbestosis cancer of the lung in workers in two English plants were recently reported by Doll who felt from his statistical analysis that there exists a definite causal rela- tion between these two conditions table 25 Merewether noted that the mean age of males with asbestosis cancer of the lung was 55.2 55.2 22-72 years range 22-72 and that their mean expo- 36 sure time was 20.1 years range -40 while mean age of female rases was 44,6 years ran 82-71 and their mean exposure time was 7 years range 0.5 48 However in many cas there clapsed a long exposure interval ran ing from several months to 20 years before t lung cancer became manifest Wedler Wyers The age distribution of asbestosis cancer the lung was 25-31 25-31 25-31 35--11 15-51 55-61 55-61 65-75 1upe ftr8 Cases Lung cance - > 1 ss 1 - 1 ose Total an 5 Since lung cancer of unknown etiology occur rather frequently before the age of 40 and sinc 26 percent of the asbestosis cancers appeare before the age of 44 it seems that there exists moderate shift toward younger age groups for caneers associated with asbestosis of the lung The exposure time for asbestosis lung cancer excluding the series of Merewether was 1-3 1-11 Fxposure time years we eee -- 11-20 21 and over | lung ee eee waee Total The exposure time of this series covers a wide range 1-23 years indicating that type and intensity of exposure to asbestos as well perhaps an individual susceptibility to asbesto sis play an important role in determining the development of this pneumoconiosis and thereby the possibility of a secondary carcinomatou sequela in the lung There were 37 males and 15 females among the 52 rases for which information on sex wat available The female ratio is thu 2.5 which represents a marked shift toward the female ide when compared with the usua sex ratio of 5 to 10 for lung cancers of unknown etiology Equalization of carcino genic exposure as represented by asbestosis for the two sexes thus resulted in a trend towardi equalization of liability to lung cancer 3 It is of importance to note that the mean Environmental Causes of Cancer of the Lung Lung 6. Causes of death among male asbestos workers compared with the mortality experience of all men in England and Wales Doll Cause of death __ ancer ee espiratory diseases - and cardiovascular mention of asbestosiscardiovascular out mention of asbestosis . sms other than lung cancer . er diseases 3 . diseases- diseases- All cau2-s 2 -eeee eee ees eeee a a Number of deaths Number observed Expected an England and Wales rates Test of significance of difference difference between observed and expected value of P. 11 S ^ 000001 14 7.6 7 39 15. 0. 090001 ocluding 1 case with pulmonary tuberculosis ncluding pulmonary tuberculosis ncluding 2 cases benign stricture of esophagus and septicaemia in which asbestosis was present but was ought to have been a contributory cause of death 128 noucomplicated cases of asbestosis nly 44.2 years Merewether One may de from this observation that some of individuals apparently died from asbes- before their lung cancer had a chance to op Linzbach und Wedler ditional support for a causal relation Den asbestosis and cancer of the lung is ed from the fact that Merewether found g266 g266 cases of asbestosis observed during 46 31 cases of coexisting cancer of the 1.65 percent while there were 91 cases ing cancer with an average age of 59.4 among 6,884 cases of silicosis 1.32 per- which came to autopsy Wedler noted asbestosis cancer of the lung occurred in ses or 15.2 percent of 92 cases of asbestosis hich necropsies were performed whereus normal rate of lung cancer in autopsy rial was estimated to be 2-6 percent mia Vo rald Warren and Cartier are all keptical as to the actual existence of excessive liability of individuals with Hosis to lung cancer and Cureton and burger are undecided on this question investigators pr consider however favor this con- the existence of a causal Awayas highly probable or established AwaMyerewether Teleky Nordmann AwaGy ross Lecoeur Smith Saita Wegelin and ch Wedler Stoll Bass and Angrist ) histological types of lung caucers ob- served do not deviate essentially in their relative frequency from those seen in cancers of unknown etiology There were 22 squamous carcinomas 7 oat cell carcinomas 4 anaplastic carcinomas and 6 adenocarcinomas In view of the fact that one of the Norwegian cases of nickel cancer of the lung was associated with pulmonary sarcoidosis it may be mentioned that Skavlem and Ritterhoff reported the combination of an asbestosis with a sarcoidosis of the lung which however was not complicated by a carcinoma Attempts have been made to refute the claim of a causal relation between asbestosis and lung cancer by determining the frequency of pulmonary cancer among the total worker population of the asbestos industry Cartier Vorwald Such a procedure is bound to give misleading results It is quite immaterial how many workers employed in the industry develop lung cancer since an undetermined portion of these workers doubtlessly sustains either no exposure or only a low intensity exposure and thus does not develop asbestosis of the lung which is the prerequisite for the subsequent cancerous development Asbestosis must be considered as the essential stigma of an effective exposure It is moreover necessary to know the sex and age distribution of the worker population studied and evaluated as well as to know the duration of employment and exposure A marked labor turnover in the industry is not inducive for obtaining reliable information on Health Monograph No. 36 1955 37 the actual number of lung cancers and asbes- tosis cases which may result from effective exposures For these reasons 310 definite conclusions can be drawn from the observation of Cartier noting 8 cases of lung cancer among 4,000 workers studied for 10 years especially as the frequency of asbestosis among effectively exposed workers increases with the duration of exposure B^hme Kennaway and Ken- naway reported that S lung cancers may be found among 4,000 males of the age range 45-64 years The evidence on hand at any rate has con- vinced the West German Government to make asbestosis cancer of the lung a compensable disease Tubershaw The experimental approach to the problem has so far given equivocal results Vorwald and Karr using guinea pigs which were exposed the respiratory tract nasal sinuses 4 larynk 2 and lung ) came to observation among employees or in 8.4 percent of those who worked more than 5 years in the isopropanol plant Five additional cases were observed another isopropyl alcohol plant making a in of 12 cases 7 of which involved totali B the sinuses 4 the larynx and 1 the lung nasal It wa calculated that the incidence rate of cancer the nasal sinuses and larynx for the of group was 134.5 per 100,000 second against a normal rate of 6.3 and that the incidence of these can- cers exceeded the expected incidence 21.3 From the evidence available it is times that these cancers as well as those likely associated with polymer asbestosis belong to the new class of polymer & cancers to asbestos dust obtained negative results MUSTARD GAS Nordmann and Sorge employed mice for this gu purpose and claimed to have produced bronchio- genic carcinomas with pulmonary fibrosis in lung two mice This observation needs to be con- the firmed before it can be accepted The alleged carcinogenic action of war ; poisoning figured prominently in the specula tions as to the cause of the increase in cancers observed during the Kikuth Brockbank Klotz early 1920 : Derischanoff ISOPROPYL OIL H^...nermann Reiche Residuals of warfare : Through the recent discovery of cancers of gassing were noted by Matz in 10 out of 138 BF the paranasal sinuses larynx and lung cases of pulmonary cancer among American among isopropanol manufacturers the occurrence of World War I veterans Four out of 64 caseosf E lung cancer recorded by Brockbank were carbonpolymer cancers has probably been ex- extended gassed badly during this war Macklin fi: can noted to man Isopropyl the crude that war | liquid from which isopropyl alcohol is distilled gas poisoning occurred in 5 percent sup and which is a slightly turbid viscous of 164 cases of lung cancer among males - data slowly turning liquid while it was present in only 2 percent atle of & upon standing into a brownish to blackish tarry material contains polypropy- soldiers without this disease ceded that a few cases of Koelsch con view prod lene compounds as well as lung cancer exhibited which may be oxidized into propylene ether a doubtful etiological relation to war gas injury natu and propylene peroxide which was claimed to have caused also two and propylene epoxide having a tendency to polymerize Polypropylene merchandised cancers of the larynx Spamer Tilley No rubb as Opponol K is used commercially as an oil for distinction was made at that time as to the particular chemical nature of the various bring latio cable filling gases Workers employed in isopropanol manufac- used during World War I. These contentions found little type . stud ture have been exposed to the inhalation of that time From acceptance at comi vapors mist and dust of isopropyl oil escaping a carcinogenic viewpoint special interest has parti from leaky pipe connections defective to be attached to the various } pumps and gaskets or spilled on the floor at the containing gases especially Lewisite syste rence of breaks in occur- and to mustard gas dichlorethyl sulfide The arsenicar on pipes anpdipelines and during repairs arsenicar gases when inhaled theoretically Up f Nale pumps stills Weil Smyth and may not only cause nonspecific chemical damage sure reported that between 1928 and 1950 a total of 7 neoplasms affecting various parts of - to the respiratory tissues but also may produce f there tively siona ae a specific delayed carcinogenic reaction activi ie 38 aie Environmental Causes of Cancer of the Lung Public nN , that seen exceptionally after skin burns as Cancers of such an origin these gases ith belong to the group of arsenic cancers carcinogenic action of mustard possible A the bronchial mucosa on the other gas upon be related to its linking and hand may effect and may be identical with radiomimetic demonstrated to exist for experimental that to several sulfur- and nitro- exposed mimals of aliphatic and aromatic nature mustards According to the mentioned theoretical con- the causative mechanism operative in epts resembles in some respects that these cancers ~ possibly active in polymer caucers During the last few years three cases of carcinoma and 3 cases of larynx bronchiogenic cancer were observed among long em- L ployees of the Japanese Army Poison Gas Manufacturing Plant on Okuno Island where Lewisite and Yperite were made One of these was 30 years old and a second 53 years workers d All three suffered from chronie war gas due to contact with mustard gas poisoning Hirose and Miyanishi In view of Yamada these observations the distinct probability of these effects upon the lung following carcinomatous exposure to mustard gas or chemically related ; products deserves serious consideration While the fundamental concept of polymer eancers is a tentative one and needs to be upported by additional evidence the available data are sufficiently important to require serious attention from both a scientific and a practical viewpoint The rapidly expanding industrial production and industrial and general use of natural and synthetic polymerized substances and linking chemicals in plastics films abbers rosins adhesives textiles and so on brings a considerable part of the working popu- into direct contact with chemicals of this lation type It seems to be advisable therefore to these population groups during the study fcf.oming decades for the occurrence of cancers % particularly those affecting the respiratory of radioactive substances mantle manufacturers luminous dial painters radio tube makers physicists and their assistants radiologists and their assistants Since the advent of successful atomic fission and the ready produetion of synthetic radioactive substances the number and variety of individuals who have occupational contact with radioactive matter have rapidly and greatly increased uranium and thorium ore miners smelter and refinery workers atomic energy plant employees mili- tary personnel and agricultural biological medical chemical metallurgic oil pharmaceutical and other industrial research workers employing radioactive isotopes as well as operators handling directly or indirectly materials or technical devices giving off ionizing radiation such as radioactive static eliminators Silson Berman and Ernest Bryan and Silverman sewage disposal workers paper and textile manufacturers and so on It is an established fact that cancers of the skin connective tissue and bone and bloodforming organs have resulted from excessive to radioactive substances affecting exposures the organism or parts of it by various routes There exists a great deal of highly suggestive if not conclusive epidemiological and experimental evidence relating an occupational in- halation of radioactive dust and gases to the development of pulmonary cancers Although excessive medicinal and occupational exposure to ionizing radiation radium radiation alone may produce in man and experimental animals a fibrosis of the lungs Kalbfleisch Doenecke Belt Bergmann and Graham Engelstad Warren and Gates Leach Farrow Foote and Wawro McIntosh Warren and Spencer Widmann Bauer Bauer and Schraer T^ngesand Kalofleisch Freid and Goldberg occupational exposure to radioactive dust and has often been complicated by simul- gases taneous inhalation of dust containing various metals chromium nickel iron arsenic cobalt as well as silica Pulmonary cancers observed system . Radioactive Chemicals Up to some 10 years ago occupational expo- ure to radioactive agents was limited to rela- py rely small groups of industrial and professional workers miners and refiners of radio- betive ores industrial and medical consumers among radioactive miners therefore have Yan complicated in an appreciable number of cases by silicosis of a minor to moderate degree It is for these reasons that the radioactive genesis of the cancers of the lung noted among these miners as well as among uranium and 39 TO RCE pec aver: ee T AOS S BUA IT) tmae ae me Soe ne pe OIE Se TY Rw. a gt radium refinery workers has been some investigators who felt that various nonradioactive metals or doubted by one of the the silicosis represented the main causad or an important contributory agent Schinz Lorenz Selumorl Rostoski and Saupe or that the available evi- dence did not provide absolute proof of a radioactive genesis Lacassagne Several investigators felt that the lung cancers among the radioactive miners in Schneeberg and Joachimsthal were principally attributable to a hereditary predisposition created by inbreeding of the mining population Macklin and Macklin Lorenz Vesin The mala metallorum causing death at an early age of the miners in the ore mountains of Saxony was first described by Agricola during the early part of the 16th century and was subsequently mentioned by other investigators Henckel Scheffler Thiele However it was not until 1879 that its malignant neoplastic character was correctly recognized H^/rting and Hesse This judgment was subsequently confirmed by Cohnheim Aucke Arnstein Uhlig Risel Schmort Beyreuther Rostoski Saupe und Schmorl Lange Neitzel D^hnert Baader Teleky Hueck Rostoski Saupe and Schmorl Thiele Weber Koelsch Lindemann Doubrov Brandt Brezina Although the miners of the uranium ore mines in Jo- achimsthal Czechoslovakia also were suffering from a fatal lung disease similar to that observed among the cobalt ore miners in Schneeberg Saxony it was not until 1926 that the cancerous nature of the pulmonary disease among these miners was recognized L^wy Additional confirming evidence was provided later by Beutel and Waldrich Ziel Sikl Saupe Peller Pirchan and Sikl Baader Behounek and Fort and Teleky Evidence supporting a radioactive origin of the lung cancers among these two groups of miners was provided by the observation of lung cancers among employees of radium refineries and radium laboratories L^wyreported the occurrence of two such cases among the workers employed in the laboratories of the Joachimsthal mines where the ores are refined and the puri- fied material is tested One of the cases had chronic cancer, radiodermatitis leukemia and lung A similar observation was recorded by An Teleky and by Neitzel in a German technicia BS of a radium laboratory cancerous The TheThe cancerous lluunng g was found to be radioactive Four cases of lung cancer have recently been observed according JJoohaha Joha de have to Baader among the workers employed in the more radium ore processing plant in Belgium where the occurrence of such complications was om: E: conta viously said to be absent Maisin citing a Deloet Perhaps the development of a bilateral - alveolar carcinoma of the lung in a woman 16 years after the intravenous injection of 75 cc of Thorotrast may also supply suggestive evidence thatlung become cancers may originate from radioactive material # of th used medicinally when such materials arrested in the lung Mention may also be made in this connection rang - incid of a report of Martland relating the occurrence of cancer in the ethmoid cells in a luminous dial painter and of two additional cases me ported by Aub Evans Hempelmann and Martland Dial painters not only ingested radioactive material which became deposited in the bones and produced osteogenic sarcomas but they also inhaled this matter which thus may have produced the carcinoma of the ering _ peric rang paranasal sinus recently The four cases of cancer of the lung reported in an industrial population at a atomic pile site however are definitely not causally related to any specific radioactive er posures sustained by the workers concerned In these cases exposure and latent period were TI insufficiently long to cause lung cancer Love On the other hand the argument that these died 1939 workers were in part not directly concerned with radioactive material carries little weight appr schi Doubtlessly they had at times environ has with material ai mental contact with such a material when the # nun meteorologic conditions were unfavorable for at & the ready dispersal of radioactive wastes al data this particular operation . and Joachimsthal miners is moreover the fact that the excessive ability to pulmonary noo 3 plasia is limited to the workers employed under ground and is absent among the workers including the employees of the cobalt pigment : plant using the Schneebeorregs Bauer Schmor 40 An excessive lung cancer attack rate also hias been found among the miners of the nearby tions aggravated the hazard by increasing the production of fine particulate dust containing not where the mines solid radium Georgenstadt region Johann a low radioactivity have no valid evidence more chromium- There is furtheron record that miners nickel- and bismuth- Repeated attempts have been made to produre cancers of the respiratory tract in experimental animals exposed to the inhalation of af arsenic- containing ores are affected by lung cancers at that seen radium emanation and radioactive mine dust Schmidtmann L^wy Campbell D^hnert rate even remotely approaching the two radioactive ore miner groups Kahlau Rajewsky Schraub and Kahlau ad among The attack rate of lung cancer among the Schmidtmann obtained neither pneumoconiosis E Schneeberg miners has consistently been be nor pulmonary caneer in animals exposed for 2 re 75 and 80 percent since 1879 while that years to the inhalation of Schneeberg mine dust otfwetehne Joachimsthal miners has been stated to collected from drill holes Campbell on the :b from 40 to 50 percent However this other hand reported that mice which inhaled fg t range incidence rate may be too low considering the dust of Czechoslovak pitchblende displayed a statement of Baader who noted that significantly increased number of pulmonary recent during the period 1939--43 a total of 180 cases of lung cancer were acknowledged as compen- sable diseases and that in 1929 there were only 2m3iners employed at Jonchimstbal Consid- ering the fact period of lung that the exposure and latent cancer in Joachimsthal miners - ranges from 13 to 23 years it may justly be ns- sumed that these lung cancer cases originated in miner population of approximately 300 to umors In experiments of D^hnert and of Hueck mice were placed in cages within the mines Some mice developed moderate chalicosis while pulmonary and mediastinal tumors adenomas round cell sarcomas in addition to an occasional squamous cell metaplasia of the alveolar epithelium were seen in an abnormally high percentage of the exposed animals However the actual number of 400 members working at these mines between affected animals was small and the interpreta- 1920 and 1930. The exposure and latent period tion of the results as to their significance was at Schneeberg is stated to vary from 15 to 18 rears for the majority of the cases but occasionally to be as short as 7 years Baader Rajewsky Shraub and Kahlau therefore difficult Kahlau and Rajewsky subjected mice to the Many of the animals Schraub and Kahlau inhalation of radon developed bronchial The total number of Selineeberg miners who lesions characterized by an atypical epithelial died from cancer of the lung between 1879 and lining as well as by pulmonary adenomas in 1939 according to available records stands at approximately 400 while the number of Jo- sthal miners who fell victim to this disease 7 of 12 mice of the test series against in the control series While they concluded from this evidence that the radioactive origin of lung has reached 225 1926-43 An appreciable cancers in Schneeberg and Joachimsthal miners | number of these miners died from lung cancer was confirmed it seems to be advisable to cca- relatively early age as is evident from the data given in table 19 page 16 which shows the definite shift toward younger age groups sider the evidence obtained by these invest gators as highly suggestive but not conclusive because great variations in the incidence rate Measurements of the radioactivity of the of lung tumors occur among different groups of Schneeberg and Joachimsthal mines have demonstrated that in both places mine air and dust have an excessive degree of radioactivity sur- passing many times the maximal tolerance dose . Hoachimsthal 30 times Peller Behounek mice belonging to noninbred strains Additional mildly suggestive observations have been reported by Lorenz Heston Eschenbrenner and Deringer as well as by Henshaw Riley and Stapleton Both groups of investi- . Behounek and Fort Tschelnitz Ludewig and Lorenser Lange Rajewsky Stocklasa It was suggested that the recent introduction -% pneumatic drills into these mining opera- gators found that mice exposed to ionizing whole body radiation revealed in addition to leukemia and ovarian tumors some increase in the number of pulmonary neoplasms Of | 41 Public Health Monograph No. 36 1955 greater significance in this connection are the findings of Liseo and Finkel who found meta- Wheth plastic and neoplastic proliferations of the Wheth Wheth bronchial epithelium in rats inhaling an aerosol the of radionetive cerium Similar results were obtained with plutonium brought into the Fin lungs of rats Sinee uranium ore miners inhale reports 1926 1928 noted that Schneebe miners suffer from more or less intense anthi cosilicosis and that this condition was causi or favoring the development of the bronchi cancers Rostoski and Saupe stated in 1930 th the pneumoconiosis was usually not very extensive cancer in cancerous lungs Because of the relative cancer not only radon and radium dust but also uranium which may be retained in the lungs slow others Hueper Zuefle Link and Johnson injected tumore while metallic uranium powder dispersed in lanolin The into the pleural and femoral cavities of rats and this obtained sarcomas the sites of injection in Som other 13 or 24 percent of the 54 rats surviving the minimal latent period of 6 months Evidence tioned thus produced shows that focal accumulations conlimite of uranium which is an radiation emitter may exert a cancerigenic action upon the radion surrounding tissues but it does not discriminate repres between the influence of metal toxicity per se slow course of the pulmonary tumors Rostos Rostos tur and Saupe felt that pneumoconiosis may the intrapulmonary growth of the this Hueck on the other hand remarked the silicosis does not represent a precancerous come ; lition for the Schneeberg lung cancers of the miners had silicosis but not lung cancer & while others had lung cancer but not silicosis : Similar discrepancies seem to prevail conlimite cerning the Jonchimsthal miners Ziel in 1933 popul reported that marked silicosis among the lune miners is quite frequent and that ashed contain large amounts of silicon oxide Pircha repres and radioactivity in the genesis of these lesions and Sikl on the other hand maintained me cancpears }i From a critical evaluation of the epidemio- pneumoconiosis rould be found in spitethoaft aF to logical clinical and experimental evidence abundance of pneumatic drilling & and that ores production available it appears that a prolonged inhalation pneumoconiosis has no role in the g! the d of radioactive gases and dust may elicit the lung cancers This opinion was shared by active pulmonary caneers in man Martland Evans L^wy Sikl in his most recent r neighl In commenting on the production of lung communication - on the subject stated F that some degree and o cancer by atmospherie carcinogens an editorial fibrosis suggestive of silicotic origin could F supery Lancet 1952 remarked radioactivity of course be seen in the cancerous lungs and then Joachimsthal mines is stated to be 30 times the were single cases of marked silicosis active silcothe tolerance dose It is scarcely surprising there- with cancer combine On the whole however silicothe ments silicothe he fore that in the past more than half the miners was not a prominent feature in cases of cancer died of lung cancer It stands to reason that on the other hand the lungs most heavily this effect on the lungs of workers will prevail # affected with silicofibrosis were generally free wherever similar conditions of exposure to from malignant growth Behounek and Fort & radioactive gases and dust exist The excessive noted that pneumoconiosis was recorded suicide rate observed in the past among the the cause of death in only 8.2 percent of 63 miners in Joachimsthal Sikh aptly reflects the miners who came to autopsy between 1929 and F human misery produced if such hazardous 1938. This statement contrasts strikingly with working conditions are permitted to persist the observations made by Saupe during af The While there thus can be little if any doubt of chest ray study of 398 Joachimsthal minen < analys # the principal role of ionizing radiation in the conducted in 1939. he found that 43.4 percent and e production of lung cancers among radioactive of these miners presented roentgenological Thous ore miners and similarly exposed occupational evidence of pulmonary silicosis However J leave groups some comments on the possible significance of pneumoconiosis in eliciting or modifying this effect may be indicated silicosis was of minor degree among the . miners who were suspected of having puk monary neoplasms F occup. generi conta Reports on the occurrence of pneumoconiosis among the miners in Schneeberg and Joachimsthal are contradictory While Schmorl as well Although the data are in part contradictory | it seems that silicosis does not play any sig- % nificant role as a direct or contributory cause F For sive P by ep as Rostoski Saupe and Schmorl in their early cancer of the lung among the radioactive- data Lang 42 Environmental Causes of Cancer of the . Public id miners in Schneeberg and Joachimsthal Whether it has an antagonistic effect upon the ancerization process or modifies the course of cancer remains problematical established it may be mentioned that these lung Finally ive acers vary a great deal in histological struc- acers cell are Many were squamous carcinomas round cell or anaplastic carcinomas -kibersa few were of adenocarcinomatous type whileradioactive lung cancers thus follow in itt her respect the general pattern set by all B the her occupational cancers in & The rapidly growing production and use of diortive diortive material and the thereby condi- ined markedly increased exposure of some mited worker groups as well as the general 15pulation 15pulation to gases dusts and mists containing sedioactive sedioactive matter of long half doubtlessly SB presents a potential respiratory cancer hazard a serious serious proportions The attack rate of lung 110 ncer from such sources is very high according 32 past experience with miners of radionctive Eint fags, Therefore a competent assessment of ol Be degree of exposure to atmospheric radio- be B tive contaminants for worker groups and onighborhood onighbord onighborhood populations of radioactive plants of and operations and the continuous and strict if pervision concerning the amounts of radio- retive retive effluents emitted from such establish- i ents are urgently necessary for safeguarding te health of these individuals Table 26 Latent periods of environmental respiratory caneers in months Hueper i Cancer of - Agent Lung Nares and nasal sinuses Average ] Average Range Range ! latent latenti latent ioflatent period ee h : Asbestos 200----! Chromates 2. -- |... Nickel 02. 02.2 ee 18 15 22! period ; period period ee ee ! 15-48 toll fees. 5-47 I" 6-30 wees aiai}c 3-26 Tar fumes 02 sopropyl oil --Ionizing radiation 16 | 923 i..--.--------. a 10 6-16 25-35 7-50 25 19-32 Intensive studies also are needed for deter- mining whether through radioactive fallouts the inhalation of highly radioactive dust particles diffusely settling in the bronchial mucosa and producing there minute foci of high intensity radiation may elicit delayed cancerous reactions Since radiation cancers like other occupational cancers have a long latent or induction period table 26 it is essential that all possible precautions be taken against en- vironmental contamination with radioactive matter to prevent a possibly permanent con- tamination of the human environment with dangerous amounts of radioactive matter Comments and Conclusions 1 The comprehensive panoramic view and fyFalysis of the total epidemiological medical ut # and experimental evidence available on exog,E nous respiratory carcinomas and carcinogens t. | leave no doubt of the fact that not only large cupational population groups but also the a+ 9 general population have definite and prolonged , contacts with one or several of these agents For most of these agents adequate conclu- reproof reproof of their carcinogenicity is provided of epidemiological medical and experimental ~ data One of several specific carcinogenic chemicals has been isolated from several agents representing variable chemical mixtures coal tar and pitch petroleum oils gasoline and diesel engine exhaust Wherever a definite identification of a specific causal agent such as isopropyl oil asbestos and chromates has not yet been attained the epidemiological evi- dence based on an evaluation of cancer inci- dence of relatively small occupationally circumscribed total populations at risk is sufliciently reliable to prove the presence of an occupational respiratory cancer hazard causally } Public Health Monograph No. 36 1955 43 demiological medical and experimental data concerning these respiratory carcinogens attest attest their high carcinogenic potency under occupa- kapotitivo kapotitivokapotitivo WI WI KUPA KUPA BUAH THE 1991 GHALO large hospitalVITOWBiIE records of a Jewish in Poland showed a lung cancer frequency & & percent of all cancers for Jews against at tional conditions particularly when acting on humans is therefore reasonable to assume Jews quency of 15.3 percent for Jews especi in view of the fact that Eastern are that inhalation of the same agents in miti- Gicularly prone to develop thromboang te gated form as air pollutants by the general obliterans which has the best establis population is responsible for a considerable mgr portion of the lung cancers attributable to such ee contacts causal relations to tobacco smoking : The claimed absence of a positive associa between lung cancer and the habit of inha Ng If this coherent and logical picture presented rule with by the evidence supporting the various occupa- cigarette smoke also is inconsistent that the incidence rate of occupatio tional respiratory cancers and especially the cancers increases with the intensity of expo lM coal tar fume cancer of the lung is compared to a carcinogen The medical considerat de with that available for the cigarette smoke lung on cigarette smoke cancer of the lung pe cancer even upon superficial examination reveal a number of serious and fundamen ell several additional serious defects and inconsis- defects and contradictions tencies not previously pointed out become The best that can be said about the ex ee apparent mental evidence on hand regarding carcinog oe It is surprising to note the absence of positive properties of tobacco tar is that it indicates statistical associations between lung cancer and carcinogenic agents in some cigarette ff e cigarette cough although this latter symptom is clinically characteristic of chronic chain smokers Despite the fact that the lips and through the use of hyperreactive anim through There is no evidence that these observation the skin of a strain of selectively inbred wg ete oral mucosa are constantly bathed in the barry have any equivalent in man Thus the p we liquor oozing from the tip of the cigarettes and tical importance of these observations as despite the contact of these parts with the cancer of the human lung is at present und smokecoming from the cigarettes thereis no tain especially since Passey in recent exp consistent statistical association with cancer ments on mice painted for 16 months of these parts The assertion that no tarry material exudes from the cigarette tip is belied by the evident fact that chronic cigarette smokers are observed to have stained tobacco tar was unable to elicit a single can of the skin df From these considerations it is appar that any final decision concerning the rela fingers There is on the other hand not a single record available of cancer of the fingers attributable to cigarette tar Such cancers of the fingers would be equivalent to the numerous cases of coal tar cancers of the hands for which role of cigarette smoking in the causation cancer of the human lung should be kept abeyance until a great deal of additional more valid and especially medically conclusi evidence becomes available The data on hi records are available In an attempt to provide an explanation for make it unlikely that cigarette smoking rep sents a major factor in the production of this discrepancy in the carcinogenic behavior between coal tar and cigarette tar Lickint resorted to the speculative assumption that cigarette tar possesses a special tissue specificity so that the skin of the first three fingers although impregnated with cigarette tar is immune to its carcinogenic action It also would be medically unsound to con- cancer and in its recent phenomenal msg frequency For these reasons it would be m prevent injudicious mainly to base the future control of lung cancer hazards on a theory such doubtful scientific merits and to cong trate the immediate epidemiological and expe mental efforts on this apparently overpr agandized concept The apparent wisdom clude upon a sort of racially conditioned tissue immunity for explaining the observation of such an attitude is readily apparent fromcircu fact that not only a great deal of the circu 44 Environmental Causes of Cancer of the Li autopsial epidemiological evidence tically the entire factual and but also conclusive idence available on specific exogeneous causes caneers indicates that these respiratory are either of occupational origin or especiallcers to industry factors Not only parts occupational groups but also the members the general population have contact with agents in various forms and intensity ssociati ssociati : ( inhaling with the upatio upatio . expos ideratio ung -}, dameng dameng ae exper exper cinoge cinoge cates th tle lan antinas rations t red ma the pract ns as t it there t_expre t_expre ths with le canne Finally may be noted that the evidence on hand justifies the viewpoint that in arriving at judgment Baader Lickint in any medico- legal dispute requiring the assessment of li- ability for the development of a respiratory cancer any evidence incriminating specific occupational factors should be given preference over that possibly provided by a cigarette smoking history appare relativ sation si kept wank a: clusiv on hard g reptes of lung rise ta be attest Venur Jeory conce 1 exper erprop erprop sdom om circun he Lung Public Health Monograph No. 36 1955 1955 45 * Bibliography ^' Adler .: Primary malignaut growths of the lungs and bronchi Longmans Green & Co. 1912 p 39 London Altridge W. 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