Document rpR8YZYeVwkOeKoEY76oQx6Ev

FILE NAME: Oil Industry and American Petroleum Institute (API) DATE: 1956 DOC#: API127 DOCUMENT DESCRIPTION: US Dept of Health Report - A Quest Into the Environmental Causes of Cancer of the Lung P i hi . i c H e a l t h M o x o c k a p i i \ n . V* A Quest Into The Environmental Causes Of Cancer Of the Lung P u b lic H e a l t h M o n o g r a p h s edited and issued by Public Health Reports G. St.J. P errott Chief. Division of Public Health Methods Managing Director M arcus R osenblum Executive ^Editor T a f t S. F eiuan Managing Editor J anet V. E asdale Monograph Editor BOARD OF EDITORS E dward G. M cG avran, M.D., M.P.H.. Chairman Chape! Hill G aylord W. Anderson. M.D., Dr.P.H. Siinruapolis M argaret G. A rnstein, R.N., M.P.H. ff'ashington H. T rendley D ean, D.D.S. Chicago H albert L. D unn, M.D., P h .D. Wash ington M artha M. E liot. M.D.. Sc.D. Il'ashington H arold M. E rickson, M.D.. M.P.H. Portland. Oreg. L loyd F lorio. M.D.. Dr.P.H. Denver V erndn G. M acK enzie Washington V ictor H. H aas, M.D. Bethesda Basil C. M acL ean. M.D., M.P.H. Here York City Seward E. M iller. M.D. Washington L eo \V. Simmons. P h .D. Here Haren, Conn. U. S. D E P A R T M E N T OF H EALTH , ED UC A TIO N, A N D WELFARE M arion B. F olsom. Secretary PUBLIC HEALTH SERVICE L eonard A. Sc h e e l e , Surgeon General v i API 0 6 3 9 9 ^ The Author Dr. Hueper is head of the Environmental Cancer Section of the National Cancer Institute. Public Health Service, chairman of the Cancer Prevention Committee of the International Union Against Cancer, and a past president of the American Society for the Study of Arteriosclerosis. In his SO years of clinical, research, and teaching experience, Dr. Hueper has become well known both in Europe and in the United States as an authority on environmental cancer and on arteriosclerosis. He is the author of more than 200 publications in these and related fields, including the book " Occupational Tumors and Allied Diseases," published in 1942. Public Health Service Publication Xo. 452 (Issued concurrently w ith the Jan u ary 1956 issue of Public H ealth Reports. \ ol. 71, No 1) L ibrary of Congress C atalog C ard No. 55-60064 Received for publication April 1955 U N IT E D ST A T E S G O V E R N M E N T P R IN T IN G O F F IC E , W A SH IN G TO N , D. C., l95o For sale by th e S uperintendent of D ocuments, U . S. G overnment Printing Office W ashington 25, D. C. - Price 45 cents API 06400 C ontents Pife Introduction..................................... 1 General epidemiological considerations........................................ 1 Occupational evidence and respiratory carcinogens..................................... 15 Epidemiological data on large industrial groups..... .................................. 15 Occupational respiratory cancers and carcinogens................................... 18 Scope of environmental lung cancer hazards....... ............................... 18 Pattern and types of respiratory cancer hazards. _ ....................... 21 Occupational respiratory cancers___________________ 21 Physicochemical state of atmospheric carcinogens and topograph ical distribution of cancers in the respiratory tract____________ 22 Specific carcinogens............................................... ..................... . . . . 23 Inorganic chemicals................................................................................... 23 X ick el...................................................... 23 Chromium..........................-.C........................... ............ _ ............... 24 Arsenic.......................... 27 Iron............................................. 29 Beryllium___ _____ __________ ______ _________ _______ _ ___ 30 Organic chemicals....................... .................. .............. ............................. 31 Combustion and distillation products of coal.. .......................... .. 31 Petroleum, shale oil. and natural g a s ..____ __________ _______ 33 Carbon and silicon polymers________ . . . ............. .......... . . . _____ 35 Asbestos____ ______________ 35 Isopropyl o i l ............... .................... 38 Mustard g a s................................. 38 Radioactive chemicals.................................. 39 Comments and conclusions. ___________ 43 Bibliography............... 46 API 06401 Introduction ^ ;cientiikally acceptable, any theory T etiology of lung cancer must reflect a ,< balanced, and competent analysis of .nl`c epidemiological, medical, and ex- th* e [ai evidence concerning the types and F^nuiental distribution of and contacts <Kl' 1 ^ known or suspected exogenous agents |l1 nated in respiratory carcinogenesis for environmental, occupational, or medical reasons. It is only through such scrutiny 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 facts and observations form an im portant and integral part of such an assessment. General Epidemiological Considerations Vreal, definite, and progressive increase in ,j,e frequency of lung cancer started in most gjustrialized countries around the turn of tfrfe ^mry (tables 1-3), that is. at a time when ^rette smoking was still a habit of minor sigmficanc* (Probst: Berblinger; Grosze, Kahlau; Fischer: Lickint). This rise was first clearly ,,pognized by pathologists of Central Europe Joring the early 1920's through a study of ,,cropsy data collected during the first two jrtides of the 20th century and was subse quently confirmed and elaborated upon bv luostatistical investigations from America and Europe which mainly used cancer mortality iU(fig. 1). Published records indicate that this develop- sent revealed marked variations in the time i onset of lung cancer, in its relative degree of verity, and in its progression rate for different 'ocalities and countries. In Germany, for innce. an increase in the incidence of lung -sneer was first noted in Saxony and Central Germany only. As late as 1931, Fischer re ported that lung cancer represented 11.3 per t of all cancers in Saxony against 6.6 percent * the rest of Germany. In Denmark, accord1 to Clemmesen, a rise in lung cancer freP*ency was still doubtful during the first three Erodes of the 20th century and only became definite after 1930. Similar observations as to a 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 same country (fig. 2). In England, for instance, 25 percent of all cancers in males involve the lung; the corresponding figure for Norway is less than 6 percent. Similar discrepancies exist for lung cancer morbidity rates for different metropolitan areas in the United States as well as for their relative progression rates (table 4). Another example of the existence of striking regional variations in lung cancer frequency is presented by the remarkable differences in lung cancer mortalityrates between urban-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. McFa r land, and Porterfield; Levin, Kraus, Goldberg, and Gerhardt) and were reported from England and Wales by Stocks; Kennaway and Kennawav; Fulton; and Philipps. Stocks reported the comparative mortality ratios for males in Health Monograph No. 36, 1953 1 A uthor Period N u m b er of- T otal autopsiescarcinomas Absolute , j No. Percent j Percent ' of all ! of all i cases j autopsia 1852-1900 R e in h a r d ............... ............................................. 1852-76 8, 716 F uchs......................................................... .......... 1854-85 12| 307 W olf....................................................................... 1877-84 4, 172 Passler................................................................... 1881-94 9; 246 870 W olf.................................. .................................... 1885-94 7, 228 P e r u t z .__________________ ____________ 1885-97 M archesani____ ______ _________________ _ 1887-96 1, 946 1889-99 Feilchenfeld................................... ............ ........ 1895-1900 5, 22 511 R iechelm ann........................................ .............. 1895-1901 7,790 711 S e h rt...................................................................... 1899-1903 1,741 159 M archesani. ................. ................... 1886-1906 3,337 5 8 a.o0s875 9 .21 16 . 83 .17 31 48 9 1. 27 . 10 4 .28 10 .07 22 i 3 .24 27 3. 8 3 1. 88 6 1900-1925 R edlich___ S ey fah rt__ K arrenstein K ik u th ____ S taehelin... B ejach......... P ro b st......... S ey fah rt__ B r ie s e .......... B ejach......... B ejach____ M archesani. R a u .............. B erb lin g er.. M a te rn a __ S t a e h e l i n __ P ro b st____ S ey fah rt__ A ssm ann... M a te rn a __ B reck w o ld t. R a u _______ Berblinger. _ P ro b st......... M atern a__ K ik u th ........ M archesani. S ta e h e lin ... Lu b a rs c h ... S ey fah rt__ B erb lin g er.. M a te rn a __ Breckwoldt. P ro b st......... S ta e h e lin ... 1900-05 1900-06 1900-07 1900-11 1900-11 1904-08 1906-10 1907-13 1898-1916 1908-13 1900-12 1906-16 1909-14 1910-14 1912-14 1l 2-14- 1911-15 1914-18 1912-22 1915-17 1914-19 1915-19 1915-19 1916-20 1918-20 1912-23 1916-22 li -sa 1020-21 1919-23 1920-24 1921-23 1929-25 1921-25 1924 2, 002 l, 272 2, 739 12, 971 6, 808 5,801 4, 754 4i 816 2,347 866 3, 448 1,667 6,083 5, 518 3, 280 4, 989 1, 609 3, 336 2, 429 1, 049 6, 359 3,697 749 496 934 566 715 265 1,287 692 586 552 363 48 215 389 70 554 580 337 392 94 755 ftf 301 287 75 892 502 31 6. 3 1.5 5. 1 . 6/ 32 a 42 .31 90 3. 8 .37 12 2 1 20 2 7S 3 1. 13 .li 6. 88 .9 60 4. 51 .4 33 4. 8 .45 29 4. 95 . 5 6 . 13 15 2 7 .31 8 2 2 . 34 1 2 08 . H H 5. 0 13 a 34 . 38 11. 23 1.01 . 19 5 7. 14 21 3.7 27 4. 8 10 2 9 24 6. 12 5 5. 31 146 5.8 10 38 4. 9 458 5. 4 .35 . 36 . 49 * 5g9 3| 1 . 58 1 .3 * .. 1 & 75 24 83 6 8.0 26 2 7 36 7. 17 4. 9 . 99 . 57 . 3 . 97 1 v Groups of adj occupied dwt London, Birtningi Bromuri Manchester Liverpool, Leeds, B n Sheffield, w ith Newcastle and dwellings -- Aggregate of fi occupied d Aggregate of 3 occupied dw Aggregate of 40.000 OCCU.J Aggregate of 30.000 occuj Aggregate of 20.000 occcc In Ohio, McFarlane, T able 2. F** A u th o r ^ tuger. P eters____ K och_____ G erbe____ Buschbekl^ D orm anns. oim ross___ P eters___ G erbe__ _ K och___ Weber and" chairer an obrer ^oherlW a K och___ K norr. Emtninger" .. `alt. K och... E isch er.. K och.. " Weber and '^ h la u . _ 1From 3t Eublic Be^h 2 Environmental Causes o f Cancer c f the Luff API 06403 9, with deviations from theaverage 'ty rate set at 100, as follows: of adjacent town* w ith over 200,000 pied dwellings: 'London, E ast H am , W est H am , C ro y d o n .. 156 Birmingham, Smethwick, Walsall, W est B ro m w ic h .................. 134 Manchester, Salford, S to ck p o rt................ 159 Liverpool, Bootle, B irkenhead, W a lla se y ... 162 Leeds, Bradford, H alifax.................... 132 eld, with 124,000 occupied dwellings............ 135 castle and G ateshead, w ith 87,000 occupied dwellings.................................... 114 ate of 6 towns, each w ith 50,000 to 85,000 occupied dwellings....... .................... 113 ggregate of 3 towns, each w ith 40,000 to 50,000 *3 occupied dwellings......... ........................................ 107 Aggregate of 12 towns, each w ith 30,000 to 40.000 occupied dwellings..................................... 104 Aggregate of 13 towns, each w ith 20,000 to 30.000 occupied dwellings___ _____ 100 Aggregate of 29 towns, each w ith less th a n ^ 20.000 occupied dwellings. ________________ 89 In Ohio, for the years 1947-51 (Mancuso, McFarlane, and Porterfield), the standardized mortality ratios for lung cancer mortality of selected sites among white males 25-64 years of age in urban and rural counties were: M etropolitan counties (8)____ ________________ 122 9 U rban counties (7).................... ................................. 81. 8 R ural counties (73)................ ......................... .......... 68. 6 The standard mortality ratio is Observed deaths X 100. Expected deaths The type of county is defined, according to degree of urbanization, as follows: Metropoli tan county-- containing cities with 1950 popula.tions of 100,000 or more (91 percent urban); urban--containing cities with 1950 populations of 50,000-100,000 (66.2 percent urban); rural-- containing communities with 1950 populations below 50,000 (41.4 percent urban). Curwen, Kennaway, and Kennawav only recently recorded fresh evidence supporting 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 lun^ Frequency rates o f lu n g cancers in autopsy m aterial o f G erm an pathological in stitu te s, 1906-52 1 API 06404 i W ALES orw ay 4A L E S DRWAY M ALES fI / ml females and cancer of the larynx / [ males, ^ut not ^emalea- This relation is l apparent when comparing relative lung ^jjCer death rates in the United States and gpgjand with the relative population density . jjjese countries. Whereas, in the United tateSi with a population of 45 persons per jquWe 1 luog cancer death occurs per gljOO inhabitants, in England these figures stand at 755 persons per square mile and 1 cancer death per 3,300 inhabitants. It has recently been observed that the lung cancer death rate for white males living in the downtown area of Pittsburgh is excessively high--twice the rate for moles living elsewhere in the city. It is somewhat uncertain whether this observation carries the same implication as the observations made in Ohio and in England and Wales. Such an interpretation is suggested f*b*e 3' Lung cancer rates in necropsy material o f various German institutes of pathology Itor the period 1895-1925 Period . Total cancers Lung cancers 1 Percent of : lung cancers among all : cancers Range Average I gril05::::::::::::::::::::::::::: t 10-276i{ sl}398 { I:}3-8 f{ z U 'o i} **-.! - ji&-25........................................................... 15,431 i 832 5.2 3.0-7. 0 ; IRLAND S i* W/ ALES U. S.A . ALES land :s 14-8 1950 jn cer of the tu n | Table 4. Incidence o f respiratory cancer, morbidity rates per 100,000 population for 9 m etropolitan centers by sex, 1937 and 1947 M orbiditv rate# Primary site and city Males Females Total 1937 1947 Percent increase 1937 1947 iPnecrrceeanset 1937 1947 iPnecrrceeanset Bronchus and lung: A tlanta................... .. New O rleans............. .. D allas........................ .. Birm ingham.............. .. D e n v e r.; ................... .. San Francisco........... .. Chicago.................... .. P ittsburgh............... .. D etro it..................... .. Larynx: A tlanta..................... .. New Orleans........... .. D allas..................... . .. Birmingham............ .. D enver..................... .. San Francisco......... Chicago.................... P ittsb u rg h............... . . . D etro it..................... . . 5. 0 13.1 5. 9 4. 5 9. 1 15. 6 13.3 9. 7 12.6 1. 4 11.3 3. 2 1.4 2. 0 4. 5 6. 7 4.4 3. 5 13. 4 39. 1 29. 0 18. 9 21. 9 34. 3 29. 5 26. 1 32. 0 4. 0 14. 9 5. 3 4. 0 4. 1 8. 8 7. 0 8. 0 6. 4 168 198 392 320 141 120 122 169 154 186 ; 32 ; 66 186 105 : 96 4 82 i 83 j bv the 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 cutaneous and respiratory cancers. An additional expression of this urban-rural pattern of lung cancer rates is contained in the recent report of Lew, who found that these rates were 30 to 50 percent higher among indus trial policyholders of the Metropolitan Life Insurance Company than among males holding general policies. Lew found, on 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 lower-income brackets and include a high proportion of men engaged in manufacturing, mechanical industries, mining, transportation, and personal service. In con trast, the general policyholders are drawn mostly from middle- and higher-income groups engaged in nonhazardous occupations. 1. 0 5. 0 400 2. 9 8. 9 2 8 4. 2 50 7. 6 20. 8 . 5 6. 4 1. 180 3. 1 17. 2 2. 1 3. 9 86 3. 3 11. 0 4. 2 8. 1 93 6. 6 1. 8 3. 9 8. 1 108 9. 8 20. 8 4. 3 7. 0 63 8. 8 18. 0 4. 9 5. 5 12 7. 3 15. 6 2. 3 5. 7 148 7. 6 19. 0 207 174 j 455 233 124 112 ; 105 114 150 ' . 3 0. 3 . 9 2. 0 . 4 1. 0 150 5. 6 7. 6 1. 5 . 4 73 2. 3 2. 7 . 0 1. 3 . 7 2. 6 . 0 . 0 . 9 2. 0 . 2 . 8 300 2. 4 4. 6 .4 : .6 50 3. 5 3. 7 . 4 . 8 100 2. 4 4. 4 4 ; . 3 -25 .2. 0 3. 4 122 36 j 17 271 1 122 ,, 92 6 , 83 1 70 ; i The apparent causal significance of these epidemiological findings has been demonstrated ; by several investigators. Appreciable amounts of 3,4-benzpyrene have been demonstrated by Waller and Cooper (R. L.) among the air pollut ants of English cities; by Kotin and associates in the particulate phase of these atmospheric constituents in Los Angeles, and in the exhaust fumes of gasoline and diesel engines (tables S and 9). It has been estimated from these figures by Blacklock, Kennaway, Lewis, and Urquhart that about 16 mg. of 3 ,4-benzpyrene Table S. Cancer o f lung and larynx, England and- Wales 1946-49 (Kennaway and Kennaway) * Type of community Lung can Larynx can cer ratio 1 cer ratio 1 Males Fe males Males Fe males 100 100 100 100 129 137 125 5-1 Other urban districts___ , 160 156 148 233 185 170 59 4'-' 1 Number of persons producing 1 death. Environmental Causes o f Cancer of the Luni API 06407 -ncer death rates ia 25 States of the i Loot 1046 and 19+8, crude death rates per Sttc*' 1946 1948 Industrialised States .... , *5 ratBtc t i c u t . ........................... , & } f"7 ? fu '2< '2 >ii I.V| '22 17 -71 '*2 4 S3 70 >f tlie* nstrated amounts fated by ir polluu ^jsociau pheric thaust <tables g m these wis, and nzpyTene 'land and -ay) ecba#**......... ; 5. 7 ....... ::::::::::: 1 >/..... 'll States with regional industrialization 1946 : 1948 florid*........... ^uioiana----gj*oun......... x 00 tan*......... Sehr***----- ....................... 6.8 ..................... 6. 5 Agricultural States " 1946 7. 4 S. 5 9.4 8. 8 8. 0 -- 1948 ' Usijsms......... tita n * * ............ X* Mexico--. Vorth Carolina. Vorth Dakota.. Omton -- ----joath Carolina. fsshington---- Wyoming.......... 4. 0 5. 1 3. 6 5. 4 2. 6 3. 0 3. 1 4. 0 5. 6 4. 1 4. 1 4. 4 3. 6 3. 7 5. 1 4. 2 4. 9 3. 9 The death rates for the year 1946 were taken from The American Cancer Society, Inc., 1949, Cancer Death Rates for each State in the United States by Ste," those for the year 1948 were produced by the S'ational Office of Vital Statistics. vnx canpratio1 Table 7. Lung cancer mortality rates, per 1,000 deaths by sex, in Austria, 1954 (Herbich and Veubold) Total Males Fe males Tienna........ ...................................... iCHies 60.000-1,000.000 iptiei 20,000-60.000....................... rniiDder of Austria................... 32. 7 18. 2 18. 4 10. 3 59. 0 31. 6 32. 3 17.3 Figur 3. Cancer of the lung in males aged 25 years aad over, England, 1921-30. Reproduced by per* raiaaion o f the British Empire Cancer Campaign. Csuntia indudm? County lorougK o Adwlaortatity percent of that expectedtna thedWribidMA <t papulation by a ^ anddan <tdiitrid w r io n - u - loo - " - no - k i^ Figure 4. Observed and expected lung cancer death* in urban and rural Ohio. 1947-51. (T. F. Mancuso) --- I ---- jo.CML-- ifTT- r-----j V-f-- f e r 5!OMWKrf--* .ftarron fI " Lung cancer death 8 counties Remainder of Ohio Obeerved 1, 550 728 Expected 1. 261 I, 017 the La"* Health Monograph No. 36, 1955 API 06408 Table 8. Estimated am ou n t1 of aromatic hydro carbon* in 1-m in u te sample of gasoline exhaust with varying engine revolution speed* (Kotin) Revolutions per minute Pyrene Com ! Benz- pound X | pyrene ! Benzperylene 500............... 225 289 ! 120 235 1,000............ 439 325 61 177 1,500............ 507 266 ' 33 60 2,000............ 374 142 l 40 73 2.500............ 346 127 i 25 70 3,000............ 121 25 13 85 3,500............ 48 5 1 10 39 ' 1 Quantities are expressed in pgm. a t 0 load. Anthanthrene 153 102 36 27 31 14 15 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 (0.4 micrograms) capable of producing cancer in mice upon subcutaneous introduction. It should be emphasized in this connection that 3,4-benzpyrene is only one ofThe several car cinogenic chemicals isolated from atmospheric pollutants and that, therefore, the actual total amount of atmospheric carcinogens 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, to reconcile the obvious causal significance of this factual evidence with the claim that such regional, and especially urban-rural, differences in lung cancer frequency are totally accounted for by differ- , ences in the cigarette smoking habits of the two population groups or merely reflect local 1 discrepancies in the diagnostic acumen of urban and rural physicians and in the availability of diagnostic medical facilities. Such explanations become even less tenable > in view of the fact that the annual age-adjusted increase in frequency of lung cancer deaths was } higher in 1914-30 than in 1931-44 (table 10), whereas the markedly increased cigarette con sumption during previous years should have boosted the annual progression rate above that ? seen during the earlier period. It has been sug- I gested (Lickint; Hammond) that this paradoxi cal behavior of progression rates is attributable to the fact that many cigarette smokers did not live long enough to develop a lung cancer | because of their precocious death from coronary * sclerosis, which also is assumed to be elicited in Table 10. Annual age-adjusted increase of fre quency of lung cancer mortality Percent increase Sex ; 1914-30' ; 1931-40' 1933-44 M ales................. 10.5 8. 5 5. 8 Females............. . . _ 8. 0 2. 5 2. 0 1 D orn. 1 Potter. Table 9. Estimated a m o u n t1 of arom atic hydrocarbon in 1-m inute sam ples o f diesel exhaust with varying load and engine revolution speed and with fuel-injection inefficiency (Kotin) Revolu tions per minute id ' Condition Pyrene !Compound ! X Benz pyrene Benzperviene Anthanthrene 1,000 1, 200 1, 400 80 Compression release............. ___ 137 i 22 146 22 0 X ......... do..................................... ___ 267 ! 76 465 42 43 K : 175 772 124 223 .........do..................................... . . . . 1,800 640 1, 320 610 472 K .........do..................................... ___ 2,500 639 876 1. 265 469 0 ____ d o ................................... ___ 208 0 9 79 4. ___ .d o ...... .............................. ___ 257 0 47 40 24 'A .........do..................................... . . . . 448 278 437 171 197 % ___ 888 488 432 930 320 v, . . . . d o .................................... ___ 1. 912 ' 614 . 1. 706 976 944 0 .........do..................................... ___ 188 ' 0 80 0 20 4 ____ do................................... ___ 177 : 56 78 0 16 ___ 220 76 1. 372 368 69 ____ do..................................... ___ 734 337 982 1. 071 577 % ____ do..................................... ___ 1 822 ! 346 1. 687 944 666 1 Quantities are expressed in jigm./min. 8 Environmental Causes o f Csncer of the Lung the a c t? o e Taft l'. Vml 3; TSar S ue- D t Ask (Ser Pia: CanAtgf ag. DW? l*t; QeJitr! 35 35m -3eii H.T. Phi/ API 06409 ccourited for by fjj smoking habits or merely reflect "^ostic acumen of ^ in the availabilj,'11 ties- * ome even less tei) i annual age-adj,^ ig cancer d eath ,N 1931-44 (table ^ eased cigarette ^ years should Bion rate above a '* It has been 1) that this parade?irates is attribu *i. tte smoker . gelopp * '* th from co ro n j - to be elicited jj f i increae of f I m ortality ict increase 1-40 ` 1933-441 E- 8.5 I 2.5 i* it t with varyia I AnthanM I threne . 0f cases by cigarette smoking. ,0rlto statistical evidence. explanation conveniently disposes tK^ Ovation challenging the validity of the Jiatribution of lung cancer in the ^ ll< g^tc* and elected foreign countries. Year Country Author Malefe male ratio (^ed State- Mexicans Vor**5 Jaeden - - - paiinaj*-'latdfman..y............... ..... Cnd*........ irentina... gagUcd...... 1953 1951 1947 1950 1946 1951 1941 1951 1949 1941 1935 1953 1953 1925 1947 1931 1945 1953 ' 1953 1850-1899 1900-1919 1920-1929 1930-1939 1940-1949 1952 1948 1947 1949 1949 D orn................ M o o re ............. H um p h rey s,. . Beeler et a l__ Lindskog......... Carlisle et a l.. Halp e rt........... McBumev et al. O 'K eefe........... Farberowand Baslow. N'eelv............... S te i n e r ............. K re v b e rg ........ . . .d ................. H e n sc h e n ........ C lem m esen.. . . . .d o ................. D enk... ........... G ro s z e ............. __ d o................. . . .d o ......... . . .d o ......... . . .d o ......... . . . d o ......... Le moine.. Gagnon. . S an tas__ M ason__ F ulto n__ 5.1 6. 6:1 7:1 11. 5:1 4. 5:1 29:1 14:1 29:1 20:1 13. 5:1 1:1 1:0. 7 4:1 1:1 2:1 5:4 3:1 15:1 6. 6 : 1 1. 8:1 i Meccans living in Los Angeles. cigarette theory and may perhaps momentarilv satisfy the protagonists of this concept, although it cannot be taken seriously by anyone who has any competence in the study of arteriosclerosis (Hueper). It is remarkable, moreover, that after a considerable increase in lung cancer frequency in Russia observed during the first decades of this century, this development seems to have come to a halt during recent years, according to Anfilogow (cited by Lickint). Considering the recorded strikingly irregular epidemiological behavior of lung cancer in diff erent countries, states, provinces, communities, and population groups, it is obvious that this pattern scarcely corresponds with the pattern presented by the degree and sipread of tin* cigarette smoking habit. If the action of en vironmental carcinogens other than those pos sibly contained in cigarette smoke should mainly account for the remarkable increase in lung cancer frequency and for the causation of a major portion of lung cancers, industrial and industry-related carcinogens would well fit this pattern since the growth of industrial establish ments and the use of their products in the economic life of different countries have greatly lacked uniformity in time, type and extent. This concept receives support from a crit ical evaluation of the data on the sex distri bution of lung cancers, the changes in the sex ratio during recent decades, and the probable reasons underlying at least a part of these phe nomena (tables 11 and 12). Considering the remarkable variations which the male-female ratio of lung cancers has shown at different Table 12. M ale-female sex ratio o f lung cancers in Germany, 1886-1927 and 1940-50 1940-50 City Author City Author Dnsden..................... Wolf. D resden.......................: Lickint. Laprig................ ...... Sevfarth Leipzig............ - .........., K n o rr.. Do S eh rt............................ .. 2 .5 :1 .........do_____________ Merkel. Chemnitz, Briese........ .................. .. 2. 9:1 Zwickau .................: G erbe.. leriin___ W ah l-"........................... 3 .7 :1 i Berlin........ .................. Berg Do... B ejach........................... - 2 .3 :1 P otsdam ........................ ; Hollmann. Do... H a n f.............. ................. 3 .6 :1 Koeln............................. !Breyer----- Do... Redlich............................ 5. 2:1 M uenchen.................. .: A nacker... Udn__ Eichengnten and Essen. 4. 7:1 ___ d o ............................: K autzsch.. Haenchen F u c h s ............- ............... i. 5:1 ___ do........................--j Frey.......... 66 m....... Hamburg. Bilz................................... K ikuth...............- ............ 8.0:1 1.8:1 Je n a __________ i K untzen.. H am burg.......................j Letzius---- Ratio the Laa* h U c Health Monograph No. 36, 1955 API 06410 times, in different localities, and in different demographic 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 affecting the members of the two sexes to 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 be come 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 carcinogenic air pollutants into the distal portions of the respiratory tract, thereby increasing the frequency and degree of exposure. 4. Males more often than females work through the entire span of their occupational life within urban areas with proved carcino- genic atmospheric pollution, while females stay for larger portions of their lives in the cleaner suburban dormitory communities. These considerations provide substantial sup port to the concept that local differences in general and occupational industrial air pollu tants may more plausibly account for an ap f preciable portion of the observed differences in attack rates for the two sexes rather than do local variations in their smoking habits. The doubts as to the unrestricted validity of the cigarette theory are deepened if critical evaluation is made of another dubious link in the chain of claims advanced to bolster this concept. It has been maintained (Graham) that squamous cell carcinomas of the bronchial mucosa are a specific response to cigarette smoking since (a) this histological type of bron chogenic carcinoma was allegedly rare before \ 1920; (b) it has increased considerably since that date in relative frequency in comparison 1 to other histological types of carcinoma, es pecially adenocarcinoma; and (c) it is more often found in males than in females. The facts are as follows: Bronchiogenic squamous cell carcinoma has commonly been found with all known occupational respiratory cancers (table 13). However, many of these agents have also elicited other types of pul monary carcinomas, such as undifferentiated, round cell carcinomas and adenocarcinomas. Thus, there is no evidence supporting the view that any specific respiratory carcinogen elicits ! a specific and characteristic type of cancer. A study of lung cancer records of cases observed i Table 13. Histological types o f occupational respiratory cancers, according to carcinogenic agent t Agent Organ i Squamous ; cell carci- : Anaplastic t noma with ' Round cell or oat cell or without I carcinoma or polvmor- Adenocarphic carci- , cinoma cornifica- I noma : tion . Figure 3. Ann. Pourwh Dtf CODitO 6 T ar fum es.............................. Lung.....................................' 3 N i c k e l .......................................... ___ do................................... 1 4 C hrom ium ............................. ___ do................................... ! Asbestos................................. ___ do................................... I 11 2 Radioactive gases and dust ___ do................................... ! 14 9 Nickel..................................... Nares and nasal sinus___ j 3 Radioactive gases and dust ___ do.................................. 3 Isopropyl oil.......................... ___ d o.................................. 3 : 2 6 7 1 6 1 4 1900 0$ 10 Environmental Causes o f Cancer of title Lung Public Health API 06411 before 1920, or even before 1900, readily estab carcinomas among 15 lung cancers; Probet, lishes the fact that during those years squamous 1927--25 percent squamous cell carcinomas be. cell carcinomas of the bronchi were by no means tween 1905 and 1918; Watsuji, 1903--23 percent IN rare occurrences (Wolf, 1895--8 squamous cell squamous cell carcinomas between 1892 and Table 14 C onsum ption o f tobacco in pounds per hbeeasd-year, New Zealand and United Kingdom, 1900-1950 (Eaatcott) 1899; Adler, 1912--approximately 40 percent squamous cell carcinomas among 181 lung car cinomas collected from the literature with ade quate histological data; Proc. First Nat. Cancer Pounds of tobacco per head-year Conf., 1949--44 percent squamous cell carci nomas in males; 11 percent in females. Aear While adenocarcinomas are more frequent in NeoZealand United Kingdom females than in males, they also are more fre quent in young persons than in old ones (Lind- 1900................................ .. 1910....................................... 1920...................................... 1930....................................... 1940...................................... 1950....................................... 2. 3 2. 69 3. 59 3. 28 3. 87 5. 36 skog; Proc. First National Cancer Conf., 1949), 1. 95 2. 22 The evidence on hand scarcely supports the 2. 99 contention that adenocarcinomas arc of endog 3. 31 3. 97 enous causation (Lickint) or that they have an 4. 22 etiology differing from that of squamous ceE carcinomas (Kreyberg). The male-female sex Table 15. Average death rate per year per m illion persons (m ales) from cancer of the lung, 1932-51, New Zealand compared with England and Wales (Eastcott) Period Country 1932-36_______ _______ New Zealand............. .................... .... 1937-41.........................................do................................................... 1940-41................. ............ England and W ales............. .............. 1942-46. 1942-46. New Zealand______ England and Wales. 1947-51. 1947-51. New Zealand______ England and Wales. 1952-53. 1952-53. New Z ealand............ England and Wales. Age 35-44 45-54 ; 55-64 65-74 75 sod I I over as:. 13 1 8 7 , 158 204 ' 62 33 ! 108 235 126 . 424 1 802 283 213 2 715 448 I* 46 132 43 1 166 ! 61 175 168 466 635 ! 326 h. 466 1,072 1,032 : 527 vi 287 ; 732 1,014 i . 735 > *v 781 ; 1, 682 ! 1,857 ! 1,073 > 305 1, 027 1.456 1 1, no * 858 2, 171 2. 650 i. ass Tahlc 16. Observed and expNeecwtedZeamlaonrdtaolirtythefrUomnitecdanKcienrgdoofm t(hEeasltucnogtt) according to place of birtb. w. CJ Age at entry to United Kingdom a Place of birth Odbesaetrhvsed Edxepaetchtsed Under 30 , 30 and over P Observed Expected Observed Expected . deaths deaths deaths death? V United Kingdom............. ........ 632 721. 8 t I 369 279. 9 i 201 i 229. 2 b t 168 139- % N ote: The significance of the difference between observed and expected deaths in the two countries is p<0.001- 12 Environmental Causes o f Cancer of the Loo# API 06413 "Haf * w nt int `g caN -'at.CanCer 15 cel1 carcj. idles. ' e frequent n ire more fre, 1ones (Lindl Conf., i 949) supports the ire of endog. they have an [uamous Cej| lo-female se* lung, 1932-33( f i g u r f . Tremi-* in - e l e c t e d e n v i r o n m e n t a l f a c to r , f a i l e d M a t e * , l o o n - v t i H j n i m m i d ) . i-74 and over 204 i 283 ' 715 : 635 1 -.032 : /14 ! .857 j .456 1 '.650 62 213 448 326 527 735 1.073 1. 110 1. 688 lace of birth, lorn :id over Expected deaths 139. S ries is p<0.001. t of the Lane j*tio of lung cancer (1:0.7) among Mexicans living in Los Angeles, as well as the ratio of 2.5:1 for asbestosis cancers (Merewether), do not support the view that women have any hormonal protection against the action of en vironmental respiratory carcinogens if identical conditions of exposure prevail. The claim that squamous cell carcinoma of the bronchi is in any specific way related to cigarette smoking thus may be laid to rest, since no special histological type of bronchiogenic carcinoma bears any consistent connection with any of the recognized respiratory car cinogens. Finally, it may be mentioned that there does not exist any parallelism between the annual per capita consumption of tobacco in different countries and their respective pulmonary cancer death rates (Herbich and Neubold; Gilliam) (fig. 5). It has been calculated that the English lung cancer rate is apparently double that of the United States, although the English smoke 30 percent fewer cigarettes per capita than Americans. This interesting and perhaps sig nificant observation, which fails to support the Mdie Health Monograph No. 36, 1955 348108--S3-----S 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-year 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 broncho genic 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 API 06414 immigrants, but for those who were 30 years of age or more on entering New Zealand, the risk is 75 percent higher, according to Eastcott. 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 fre quency between cigarette consumption and lung cancer mortality for Upper Austria and Kaernten, on the one side, and for Steiermark and Tyrol, on the other side, although in all four provinces there prevailed approximately the same per capita consumption of cigarettes. These authors suggested that the high lung cancer mortality among the people living in the marginal regions of the northern slope of the Alps might be related to climatic-atmospheric > Firurr Rise in annual production or consum ption o f cancer-related industrial chem icals between 1900 and 1948. PRODUCT - UNIT ' I. BITUMNU5 COAL-PRODUCTION IN U .5 .. MLUON3 Of NCT TONS 2 rUCL BRIQUETS-TOTAL PRODUCTION. thousands o r n e t tons 3. CARBON BLACK - PRODUCTION IN MILLIONS OT POUNDS 4 PETROLEUM - PROOUCTON OT CRUDE PETROLEUM, M LLIONS O r BARRELS or 5 PETROLEUM , ASPHALT - PROOUCTON OF ASPHALT (fr o m p e t r o l e u m ) , t h o u s a n d s SHORT TONS 6. COAL T A R - PRODUCTION,- THOUSANDS OT DALLONS 7. ISOPROPANOL- PROOUCTON-THOUSANDS OT POUNDS conditions winds, whi air of Vie Alpine regie Similar > prevailing lung canoe: Midlands v and Neufee cancer m a comm units where thea: fumes fnois dust and fe the inhabit: remote frm rise in Itm increase in constructs? Oe I ) t > 1 ` SO , The cone or contrib by epidesm evidence 6 rates of v*r as well as B specific aM number off well-defines: EpidemioS Industrial Epidemic lung cancer groups and: existence i f persons cancer of1 striking aS list some m responsible Table 1 for seven i 14 Environmental Causes o f Cancer of the U m t P u b lic H csi API 06415  >*' A i s r p^ I tioiis anii to the direction of prevailing fo '">.tcit.rihNH > althugh ,*^* 1 ^ which bring tne industriallv polluted Vienna into the valleys of the northern 4 ftpPrx n au i " 0f aretti* tbe h*gh i^ ople living in > * le reg>onsinijll^rr observations on the influence of the 5 filing winds upon the relative frequency of p** jancers in different areas of the English em slope 0f Elands w'ere reported by Stocks. Herbich atic-atmosphe^; ^7>`eubold, moreover, found that the lung *r mortality rates were twice as high in ic!. betwen ^ t*inunHte3 located along main highways, c<f \ tjje atmosphere was polluted with exhaust es fro and diesel motors and the t and fumes of asphalted roads, than among lusthabitants of villages and towns situated the ' ^aote from such traffic arteries. In fact, :he . a lung cancers follows more closely the ^ in consumption of motor fuel and the struction of asphalted highways than the (OB! consumption of cigarettes 'fig. 6. Hammond; fig. 7, Hueper; and is similar to the increase in production of other cancer-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 sug gests that several, if not many, environmental factors acting in varying degrees and combina tions 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 epidemio logical pattern of lung cancer, points to an important role which industry-related factors and the growth of modern industry may have assumed in these respects. Occupational Evidence and Respiratory Carcinogens 1945 I*80 in c e r o f tbe The concept that environmental factors cause contribute to pulmonary cancers is supported by epidemiological, medical, and experimental jridence obtained from analysis of lung cancer nue of various occupational population groups Hveil as by studies of lung cancers and their specific and different causal agents present in a number of restricted worker groups and in ell-defined industrial operations. Epidemiological D ata on Large Industrial Groups Epidemiological studies on the frequency of hmgcancer among members of large industrial {maps and trades have brought to light the ahtence of marked variations in the liability of persons engaged in different occupations to oncer of the lung. Tables 17-19 supply nking illustrations of these differences and rit some of the factors which may possibly be foponsible for them. Table 17, which lists lung cancer death rates 1* aeven industrial groups in Ohio, shows a btofc Health Monograph No. 36, 1955 striking difference between the rates for agri cultural laborers and for employees in the non ferrous metal industry, with rates for trans portation 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 m ales, 1947 (Mancuso) Industry ; Death j rate Nonferrous metal................................... ............. : ............. 1 .......___! .......1.53 .............: Stone, clay, glass................. - ................ ............. ; T o ta l............................................ ______ | ! 3.22 2.91 2. 34 2.18 .82 .66 1.76 15 skin cancer and the relationship between low concentrations of carcinogenic air pollutants and lung cancer. Nonferrous metal workers, on the other hand, often have contact with duBt, fumes, and vapors of some carcinogenic metals, such as chromium and nickel, or with arsenicals which are impur ities in many nonferrous metals (copper, zinc, 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 rubber and plastics industry may possibly be attributable to the use of coal tar, petroleum oils, and tars, furnace black, mineral pigments of carcinogenic chemi cals, and aromatic amino-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 ent from the figures listed in table 18. The employment ratio of operating to nonoperating 1 railroad workers in one of two large railroad companies was 1:4. From this ratio, it appears } that, on the basis of the crude, nonstandardized (sex, age) figures presented, about 75 per cent of the lung cancers in railroad employees occurred among the operating group, which . * supplied only 25 percent of the total number of ' employees. Operating railroad workers in cluded engineers, firemen, brakemen, conduc tors, switchmen, and roundhouse personnel, that is, workers exposed to the inhalation of coal soot and oil fumes from diesel engines and fuel ' and lubricating oils, which contain carcinogenic . polycyclic hydrocarbons. Dunner and Hicks recently called attention to two additional worker groups, boiler scalers j and grain dockers. In the experience of l Dunner and Hicks, these workers showed an f excessive liability to cancer of the lung. Twen- Table 18. Frequency of lung cancer am ong operating and nonoperating railroad workers Railroad ; Period Total lung cadcers Type of railroad worker Operating Nonoperating Undetermined Number ; Percent . Number Percent i Number Percent A - - 1940-50 29 B ............................... 1939-49 104 24 ; 83 i 5 1 17 .................... ............... 59 57 15 | 14 30 29 ! 1 ; Table 19. Occupational groupa with excessive incidence of lung cancer > ty-four buy 5,000 dock' Occupational group Potential respiratory carcinogens Investigator 2,500 went* 10 boiler sc Metal workers, welders, metal grind Metal dust, lubricating oil m ist___ Kennawav and Kennaway; Turner exception ers and polishers, wire makers, tool and die makers, foundry workers, and Grace; Muller; Dublin and Vane; Wynder and Graham; Mc radiologies! metal moulders, lathe workers, etc. Laughlin;' Breslow and associates. only 5 had! Cigar m anufacturers and tobacco Tobacco dust, insecticides, soot__ Seyfarth; Kennaway and Kennaway; upon hisUslk nists. Engineers, mechanics, machinists, Metal dust, soot, lubricating oil__ cers were oi plumbers, crane operators in smelt T u rn eran d Grace; Muller; Wynder not exposai ers. etc. Painters, decorators_______________ Metal pigments, coal ta r dyes, and Graham. BECC 1 1944; Mller; Dublin and that boilers i carbon black, asphalt paints, solvents, vehicles (lacquers, res VaDe; F ulton; Wynder and Gra ham. sure to cha; i ins, synthetic plasties). " ere used #: T ar workers, road workers, asphalt- Tar and pitch fumes and dust, Kennaway and Kennaway; Fulton; workers sis ers, paviours, stokers, patent fuel soot. workers, furnace men, foundry B E C C 1 1952; Registrar-General (1938); McLaughlin. tron oxide, laborers, rollers, etc. ( or some caw such as rear > Report of the British Empire Cancer Campaign. Processing c 1 16 Environmental Canses o f Cancer o f the Long Public B e d ! Th. " iMM.ip.-rati ' o large railr0aJ ratio, it appPa^ nonstanda^ .. about 7.5 Per] lroad employe^ Fonp. whlr.b total number 0( ul workers ^ ikemen. conduc. ouse personnel inhalation of COa| engines and fU(!i tain carcinogenic called attention ps, boiler scalers experience 0f kers showed an ite lung. Twen. F i u r* 8. NAGAt. fV jSSt . AP i\X UNS t 'ndetermined imber Percent gator Kennaway; Turner ller; Dublin and and Graham; Mew and associate;, v and Kennaway; BriDkmann. 19-52; Gillespie; Mller; Wvnder iller; Dublin aDd tynder and Gra.ennaway; Fulton; Registrar-General Min. nicer o f the Lune HEATING SOOT, PITCH.TA R, A S P -tA .T DUST MINING URANIUM ORE REFINING ty-four lung cancer cases were found among 5.000 dock workers at Hull. England, of whom 2,500 were exposed to grain dust. There were 10 boiler scalers with lung cancer. With the exception of 1 boiler scaler, none had any radiological evidence of pneumoconiosis and onlv 5 had a slight degree of pneumoconiosis upon histological examination. No lung can cers were observed among dockers who were aot exposed to grain dust. It may be possible that boiler scalers sustain a carcinogenic expo sure to chromate-containing scale, if chromates were used as antirusting agents, or that these orkers sustain a pulmonary deposition of iron oxide. Whether specific vegetable matter or some carcinogenic contaminant of the grain, such as residues of chemical fungicides or other processing or preserving agents, account for the abnormally high fiequency of lung cancer among grain dockers is at present a matter for speculation. Mention also may be made of the receDt 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 post-mortem ex aminations done on 2,378 males of comparable age who were not 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 N blk Health Monograph No. 36, 1955 17 API 06418 (degree of fibrosis in cancerous lungs, 1 plus; in tuberculous lungs, 2 plus; in fibrotic lungs without cancer and/or 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 Schneeberg was analyzed (Hueper). Although the actual causal factor responsible for the lung cancer among iron ore miners remains to be determined, it may be mentioned that Levin and his co-workers recently recorded a positive statistical correlation between an occupational exposure to iron oxide and heat and cancer of the lung. The studies of Breslow, Hoaglin, Rasmussen, and Abramson 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 have contact with oil fumes, mists, and sprays; asbestos workers; construction and maintenance painters, who inhale vapors or various organic solvents, resins, lacquers, plastics, and rubber, as well as finely dispersed inorganic and organic pigments (chromium, nickel, copper and arsenic compounds, carbon black, aniline dyes); and commercial cooks exposed to fumes and mists of overheated vegetable and animal fats and mineral pan greases. A recent study of the causes of death of the members of the International Photoengravers Union raised the suspicion of an excessive lung cancer liability for members of this occupational group. From the different lung cancer death rates listed for the various occupational groups, it is obvious that the total number of workers 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 pro fessions (fig. 8). It is, on the other hand, equally clear that the quantity and quality of 18 information available on the occupation*] aspects of lung cancer causation are deplorably defective because of an absence of extensive and prolonged analyses of lung cancer deaths among various industrial groups for specific causi] factors. The evidence on hand nevertheless is adequate for demonstrating that the wide varia respiratory can related general t justly be assumi gent the cause o cancers among n tion, especially highly industrial tions in lung cancer frequency apparently ' existing between different industrial population . Table 20. Occupa group are attributable to differences in more or less well-definable occupational exposures and not to differences in cigarette smoking habits. Agent Occupational Respiratory Cancers and Carcinogens Conclusive evidence of the existence of exogenous carcinogens and environmental re spiratory cancer hazards is provided by the epidemiological, medical, and experimental date concerning occupational respiratory cancers. A general view of the occupational respiratory cancer panorama, including causal agents, and organs affected is presented in table 19. Scope oj Environmental Lung Cancer Hazard* An indiscriminate acceptance of the figures given in table 20 as reflecting the actual scop>eof these identified and recognized respiratory cancer hazards, however, would be seriously misleading, despite views expressed by several protagonists of the cigarette theory (Ringertz; Wynder and Graham; Levin; and others). Although a definite demonstration of specific \ occupationaLiung cancer hazards has so far been made for only relatively restricted worker groups, the evidence on hand is not only un equivocal but also indicates that other worker groups exposed to the same causal agents r subjected to identical or similar working condi- ^ tions are subject to the same hazards. ID contrast to the apparently low carcinogenic potency of the suspected, but unidentified, | agent presumably contained in tobacco smoke, ^ the occupational respiratory carcinogens arc j evidently highly potent, as shown by their hi?*1 > respiratory cancer attack rates (table 21). ! Since environmental carcinogens have been | shown to produce cancers wherever they operas , in adequate intensity and duration, and con- i sidering the fact that many of the occupational Arsenic................ .Asbestos.............. Chromates.......... Nickel................ Coal ta r. ............. Petroleum oils... Isopropyl oil___ Radioactive chemit Total Carcinog, Aromatic hydrocari Coal tar fum es.. Petroleum oils.. Carbon and silicon Isopropyl oil__ Asbestos............ Metals: Arsenic........ .. C h ro m a te s........ Nickel ............. Ioniz,n? radiation: ttadioactive ores Environmental Came* o f Cancer o f the L** ; p*,Uc Health Me API 06419  upationft| irawry I'dri'inopens occur as industry- eplorab|v I general atmospheric pollutants it mav 5e assumed that these pollutants repre- I antj nHg r the cause of a significant portion of lung .fie capa^j ^eers among members of the general popula- rtheless js ggpecially those who live and work in .-ide varia. ^ j y 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 co-workers. From a survey of 1,503,204 workers employed in all industries of 10 States, it was found that 7,976 were exposed to fumes and dusts of chromium compounds and ipparently wpulatio in more 0p T*^ 20. Occupational respiratory carcinogens and cancers recorded during p sst 75 years, their causes, sites, and numbers ' sures and : habits. Agent Site of cancer Year dis covered Number of recorded eases United States Other countries Total stence of tental re d by the >ntal data cancers, spiratorv ents, and 9. Hazard le figures 1scope of spiratory secipusly ; :ral Ru-^crtz; others), f specific is so far d worker odIv unr worker gents or ig condirds. In nogen ic entitled, smoke, :ens are leir high 1). tve been f operate tad con ditional :c ................................. Lung.......................... 1930 ........ . . . .d o ..............................- .............. 1934 . I.r ............................................ Prtroleuin o ils ............................... i " "" "............................. Radioactive chemicals................... Vares and nasal sinus................................-- Lung................................................ 1936 Lung and larnyx.......................... 1936 1946 Vasal sinus. .................................. Lung.......... .................................. 1879 Vasal s i n u s ................................. 1931 Total.......................................... - ...................... - --------- ---------- 125 I 1.00 1 i 1, 126 Table 21. Respiratory cancer attack ratea, by environm ental carcinogens Carcinogen Sites of cancers Incidence in population at risk Attack rates i ; Percent : ; of all cancer deaths R ate per 100.000 ; Morbidity | M ortality Aromatic hydrocarbons: Coal tar fumes....................... Petroleum oils....................... Csrbon and silicon polymers: [sopropyl o i l . . ..................... Asbestos................................. L ung........................ ; Lung_______ _____ /Paranasal sinuses, l_ larayx. Lung. 500:100,000 2,000:100,000 10:100 Metals: L u n g .___________ Nickel...................... .............. Varee, paranasal sinuses. L u n g ...................... Ionising radiation: ------ . w..........................1 - ........................... 329:100.000 574:100,000 : 134.5 ( nor- | . mal 6.5). (13.2-20 percent asbestosis autopsied (0.8-2.4 percent 145.7 males (10.9 nor mal.) (42X nor- 146-338 mal) ] (20 X nor mal). (50-80 percent of all deaths). 4e Lmg b il ie Health Monograph No. 36, 1955 19 API 06420 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 indi viduals 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 theactual number of occupational respir atory 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 opera tions of the same country. The following ob servations may illustrate this point. The existence of an excessive liability to can cer 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 re ports 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 (Ger many, 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 in formation 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, al though 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 20 and cooling oils have so far totally originated from Europe, despite the fact that American * industries offer ample opportunities for identical exposures, that an excessive liability to lung cancer has been noted for paraffin pressers em ployed in oil refineries, and that the survey of one oil company has shown that there was g marked predominance of operating refinery ' workers among the lung cancer victims of this , particular organization. r Finally, attention may be called to the fact that the entire evidence as to the existence of lung cancer hazards for radioactive-ore miners has come from the observations made in Schnee berg and Joachimsthal. However, mining of , uranium ores has been carried on for 10 to 20 years in the Congo, Canada, and the United States and extensive milling operations of the African ores have been conducted in Belgium for many years without any official record of similar respiratory complications among the workers employed. Additional incompleteness of the existing rec ords on occupational respiratory cancers may be related to the possibility that pulmonary , cancers may have their causation from agents entering the body by an extrarespiratorv route. While, all known respiratory carcinogens are of environmental origin and are inhaled as air pollutants, there exists some suggestive occupa tional, medicinal, and experimental evidence indicating that agents introduced by other routes may be effective in eliciting lung cancers. ^ Several cases of lung cancer are on record which > developed after an or.al administration of ar senicals and which appeared in individuals with arsenical dermatoses and skin cancers (Xeu- bauer). Lung cancers also have been observed | in some aniline dye workers suffering fro primary occupational bladder cancer (Muller) ^ following prolonged cutaneous, ingestive, and j respiratory exposure to dusts and vapors of certain carcinogenic aromatic amines. The possible scientific and practical significance of ^ these findings is suggested by the experimental ( observation of lung cancers in 10 percent of > rats given the potent carcinogen, 2-acetylamino- | fluorene by an extrarespiratorv route (Biel' j schowsky). A cutaneous as well as parenteral * introduction of coal tar and several polycyclic ^ hvdrocarbons as well as of urethane resulted i ` \ Environmental C iutet of Cancer o f the U "* 1 a precocious a ber of pulmon Pattern and If a map of centration o f ' lutants were p exhibit a sort the general at nish the over; depth betweet rural district atmospheric p scribed field irregularly ar shaped spots superimposed It stands to i exposure patt portant influe! acter and inri of various re carcinogens v ological scatn spread of cat production fo The followi to environmei be distinguish 1. General posures to c hydrocarbons incomplete c( and industrial exhaust fume?abrasion prod from asphaltt arsenicals con of burned co*. metal smeltet use of arsent radioactive n from the soila mg the atmc explosions. 2. Special a exposure to < Public Health 348106--3 API 06421 .t >' v : P ^ f 'hui Ame wtP1 s V t.0,.ious uppouranco and a n increased num - pre 0( pulmonary tumors in mice. aii!* Kltoni.r'*n 1 bep'attern and Types of Respiratory Cancer fin (Jiosscrji N Hazards i the survpy^J 0 a map of the distribution and relative con at thoro w. ' a tio n of the different carcinogenic air pol raung refj ' la n ti were prepared for a given area, it would victims of thibit a sort of crazy quilt pattern to which *' cenerai atmospheric pollutants would fur- iod to tho fa tic existcnoo of ive-ore mir* mde in SchnoP. vcr- mining 0J n for 10 to 20 :id the L nitprf rations of thP od in BolgiUni icial record 0f . among thP the overall background color, varying in j^ptii between darker urban areas and lighter districts. Other types of carcinogenic jtnl0spheric pollutants having a more circum^.ribed field of distribution would appear as irregularly arranged aDd variously sized and ,^8ped spots and islands of different colors Superimposed upon the general background. jt stands to reason that such locally differing exposure patterns are bound to exert an im portant influence upon the epidemiological char t e r and incidence rates of pulmonary cancers ic existing rec. cancers may at pulmonary i from agents liratory route, mogens are of ihaled as air stiveoccupant' 'idence ea ,, other lung cancers. . record which Tation of ariividuals with ancers (N'euen observed jffering from icer (Muller) igestive, and id vapors of mines. The tgnificance of experimental U percent of etvlaminoftute (Biel- 0( various regions; each one of the various rarcinogens would produce its own epidemi ological scatter pattern showing a diminishing spread of cancers from multiple carcinogenic production foci. The following three main types of exposure to environmental atmospheric carcinogens may be distinguished: 1. General environmental atmospheric ex posures to certain aliphatic and polycyclic hydrocarbons released into the atmosphere as incomplete combustion products of domestic and industrial and ship fuels, as parts of the exhaust fumes of gasoline and diesel engines, as ibrasion products of rubber tires, and as dust from asphalted and oiled roads; exposure to usercals contained in the mineral ash and soot of burned coal and in the effluents of certain metal smelters, and related to the large-scale ose of arsenical pesticides; and exposure to radioactive material either naturally released from the soil and from bodies of water or pollut ing the atmosphere as the result of nuclear plosions. 2. Special and locally restricted atmospheric exposure to carcinogenic pollutants of the air exists in the vicinity of nonferrous metal smelt ers releasing in their effluents and from their slag heaps fumes and dust containing nickel, arsenicals, chromium compounds, and berylli um. Similar exposure exists in the vicinity of carbon black plants, oil refineries, tar distilleries, gas plants, and similar industrial establish ments producing large amounts of soot or other polycyclic hydrocarbon containing effluents, and in the vicinity of radioactive 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 are strongly suspected of being responsible for the appearance of cancers of the nares, paranasal sinuses, larynx, and lung among members of certain occupational 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 carci nogenic activities are not associated with all atmospheric pollutants. Occupational Respiratory Cancers The respiratory cancers of recognized or strongly suspected occupational origin are im portant, not only as industrial disease manifes tations but also as prototypes of etiologicallv and topographically identical cancers affecting workers in other, similarly hazardous occupa tions as well as of those cancers involving an indefinite portion of the general population sus taining for environmental reasons contacts with the same industry-related carcinogens. 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 (a) the 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 s&ccilla tions. such as the paranasal sinuses and the peripheral bronchiolar regions of the lung, in which inhaled carcinogenic 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 con dition largely influences the site or sites of chief exposure to an atmospheric carcinogen. Car cinogenic 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-nickel 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 respira tory system and therefore are mainly responsible for the cancers of the bronchi. The bronchiogenic cancers found among chromate manufac turers. asbestos workers, and coke oven and gas retort workers are representative of this type of exposure. Atmospheric pollutants of gaseous and vapor types not only penetrate into the lungs but also into the nasal sinuses, where they may be deposited by degradation into solids (radioactive gases), by decomposition into solids (nickel carbonyl), or by condensation and poly merization into liquids or solids (aliphatic epox ides contained in crude isopropanol liquor). In assessing the relationship between the physicochemical status of atmospheric carcino genic pollutants and the localization of cancers within the various parts of the respiratory tract, 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 binations, for instance, occur in relation to the exposure to radioactive gases adsorbed to rock dust in uranium mines as well as concerning the inhalation of liquid or solid aliphatic and poly cyclic carcinogenic hydrocarbons adsorbed to the surface of mineral road and industrial dust or of carbon constituting the bulk of soot. The first evidence indicating the existence of causal relations between environmental factors and the development of cancers of the lung was recorded in 1879, when Harting and Hesse established-ihe cancerous nature of the lung diseases prevalent among the radioactive-ore miners in Schneeberg. Saxony. This discovery, of historical importance and great present sig nificance, attracted little attention at the time 1 because radioactivity was still an unknown fact and cancers of the lung were comparatively rare before the turn of the century and therefore of little medical interest. It was not until the third and fourth decades of this century that additional, well-defined occupational activities and environmental agents were again related to the causation of cancer of the lung and other parts of the respira tory tract, that is, the nasal cavity, paranasal inuscs. and lai the list of ern WPre the lung facturei'# (19)35 arsenic worker? tors (1936). the nasal sinuses, smelter workci nasal sinuses (1931 i . the car and lung am (1946i. and r among worke spravs or mist- Specific Care Nickel, one* metals and p district of On alloys (iron, cobalt); molyl facture of stai forgings, casts tubing, rods, plating; catah pigments in p; and so on. Exposure to metallic, nicke carbonylvapo trial workers o lions. While salts, not infre< f an apparei inhalation of been responsil acute and of monary mani! lion of alveol exudation int eosal hemorrli t the toxic formed from bonyl upon tl zz Environmental Cauies o f Cancer o f the Lun* H ealth API 06423  n ia ir matiufa,. ''"-'"n an<l gai, " 'y p p 0f ints of g a sa c i etrate into th uses, where the* lion into solici sition into sol), sation and poly, (aliphatic epo.y, unol liquor). :p between the ispheric carcino. ation of cancers spiratory tract, trio the fact that may become ad. ogenically inert under such con- Such cornt relation to the dsorbed to rock s concerning the ihatic and poly, ns adsorbed to industrial dust ilk^&lsoot. tl stence of nmental factors of the lung was ing and Hesse re of the lung radioactive-ore This discovery. >at present sigon at the time . unknown fact paratively rare id therefore of fourth decades I. well-defined environmental e causation of s of the respira vi ty, paranasal cer o f the Lung ^ and larynx. Among these additions to ^Ust of environmental respiratory cancers 1 e the lung cancers among chromate manu*e,turers (1935). of asbestos workers (1935). of ^-enic workers (1930), and of coke oven opera*r*3(i936i. the cancers of the nasal cavity, para- sinuses, and lung among copper-nickel Bielt'er workers (1932). the carcinomas of the ?asal sinuses among luminous-dial painters 1931). the cancers of the nasal sinuses, larynx, lung among isopropanol manufacturers i[946). anc* cancers of the larynx and lung niong workers exposed to lubricating oil *prays or mists (1936. 1949). Specific Carcinogens Inorganic Chemicals NICKEL vfickel, one of the most industrially important metals and principally mined in the Sudbury district of Ontario, Canada, has many uses: alloys (iron, copper, chromium, aluminum, cobalt); molybdenum (employed in the manu facture of stainless steel, heat resisting steels, forgings, casts, wires, sheets, structural shapes, tubing, rods, bars, strips, and so on); electro plating; catalysts; ceramic enamels and colors; pigments in paints and inks; storage batteries, and so on. Exposure to nickel fumes and nickel dust of metallic nickel and its compounds or to nickel carbonyl vapors is, therefore, frequent for indus trial workers of many types and in many opera tions. While skin contact to nickel and nickel salts not infrequently results in the development of an apparently allergic type of dermatitis, inhalation of the volatile nickel carbonyl, has been responsible for an appreciable number of acute and often fatal poisonings. The pul monary manifestations (congestion, desquama tion of alveolar epithelium, fibrinous acellular exudation into alveolar spaces, bronchial mu cosal hemorrhages) are apparently attributable to the toxic action of finely dispersed nickel formed from the disintegration of nickel car bonyl upon fee pulmonary structures. Krafft suggested that these reactions are the re-iilt of a 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 Gvdach plant of the International Xickel Company, located at South Wales, England, was made by Grenfell in 1932, although the first appear ance of these neoplasms among the nickel refinery workers was noticed in 1924 (Baader). Subsequent reports dealing with these cancers were made by Stephens; Amor; Cooper i'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 recon struction of the plant had been carried out. The average exposure period for the nasal can cer 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 naso pharynx was observed at Clydach. The nasal cancers involved the turbinates, nasal septum, and paranasal sinuses (ethmoids). 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 (L0ken). 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 smelters in Canada, although several cases of nasal sinus cancers were recently seen in one Canadian nickel plant. Amor pointed out that the majority of indi viduals employed at Clvdach 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 roaster (L0ken). More recent data communi cated by Morgan confirmed this observation, although exposure to nickel carbonyl vapors had occurred more frequently among the af fected workers than was apparent from the data previously given by Amor. The rela tively high incidence of cancer of the nasal cavity indeed suggests that a rather coarse par ticulate dust readily arrested at the region of the turbinates may have been active in the production of cancers at this particular site, while nickel-containing vapors or a very small particulate dust m^st likely account for the cancers of the lung and nasal sinuses. As to the causative agent, various theories have been advanced. Amor favored the con cept that the inhalation from arsenic-containing sulfuric acid used in the refining process was the active carcinogenic agent. It is most unlikely that this is correct because the nickel refinery workers do not suffer from perforated nasal septa and display no evidence of chronic arsenicism such as dermatosis and cutaneous cancers, which almost always have accompanied the occurrence of lung cancer among workers exposed to arsenical dusts or fumes (Hueper). Amor stated that the refined nickel-copper ores are free from radioactive matter. The res piratory cancers observed among nickel refinery workers thus are not identical in etiology with those seen in miners employed in the radioactive mines of Schneeberg and Joachimsthal. Workers employed at the roasters, in the nickel carbonyl operation, and in other parts of the plant, on the other hand, become exposed to the inhalation of dust, fumes, or vapors con taining nickel. Nickel is the common denomi nator for all of them. It thus is most probable that the respiratory carcinomas observed among 24 nickel refinery workers are reaction products to l more or less finely dispersed nickel particles or ] vapors. There is no evidence available, how- ever, which indicates that the inhalation of nickel in particulate or vaporized form is ac companied by pulmonary changes of a pneumo- coniotie nature. , The concept of a nickel etiology of respiratory cancers was tested in animals bv Campbell, who ' exposed mice to the inhalation of powdered nickel matte and observed that these animals had a lung tumor incidence significantly higher than that of the unexposed control mice. The . i recent experiments of Hueper seem to demon strate more conclusively the carcinogenic prop- 1 erties of metallic nickel. When pure metallic nickel powder was implanted into the femoral and pleural cavities and subcutaneous tissue of 175 rats, cancers developed at the site of injec tion in 50 of them. Whether or not nickel assumes a carcinogenic 1 role for cancers of other organs and following exposures by other routes is uncertain. It may . be mentioned, however, that Araki and Mure demonstrated, by spectrographic methods, nickel in human and animal cancers of various types and sites. The nickel content ranged from 6.273 mg. per kilogram of fresh tumor tissue to 0.2 mg./kg. ' , No assessment of the degree of occupational nickel cancer hazard can be made from the data available since the number of workers at risk is unknown. Likewise, no definite opinion can be expressed as to the possible existence and t extent ofirespiratory cancer hazards for persons j having for other reasons contact with dust, fumes and vapors containing nickel or its com- [ pounds. CHROMIUM | Chromium as a metal, alloy, or compound i? used for many purposes in industry. It is for j this reason that a large number and variety of workers have contact with chromium and chro- > mium compounds and that even restricted group? of the general population may possibly be- * come exposed to these agents in the form of dust. ' vapor, fumes, mist, liquids, and solids (Bourne and Rushin). Workers most likely to be ex posed to chromium and its compounds are v acetylene workers, aniline workers, bleachers. blueprint chromate r on makers workers, g ers, pottei battery m: ers. ink m ers, photo workers, s canizers. v welders, u railroad er stallations. An ein ti on with from the trial wasl* refineries catalyst fo environm-e follow- the agents in coating industrial!; a corrosiv and/or inh developme nasal sept proof of ,i menting oi tions amoi chromium Factories his report hazards in as well as for it woult is not rec< keen don' relearnt an This refl appropriat existence individuals trial opera fished data The obs connected esPecially to two tyj chromates Environmental Cause of Cancer of tie Luni Public Heal API 06425 p rr,,|^ u u v le. I, i n > * ? * 4oi` fresP iraw -ampbell ^ t? powder5; fitheSe, jol amnitclye Th em t0 demon; ingen ic pr purue n>etal|iP TO the fem0ral W0US tissu e of 0 s i* o f njflp_ a carcinogen,,, and followine rtain- 11 niav akl and Mu* Inc method* ers of variou* nt ranged from nmor tissue i0 f 'pation] t the data rkers at risk i* ' opinion ran existence and "ds for person* ct 'with dust, vel or its rom- r compound is try. It is for ;ind variety of ium and chro'tricted group* possibly be.e form of dust, solids (Bourne kely to be exompounds are .ers, bleachers. itr o f the t t f l chrome workers, chromium platers. |lu*Pn1^ manufacturers. chromite miners, crav- *!2ers. dye workers, electroplaters, enamel ad01 ^jass and pottery frosters, glass eolor- <of*e ttery gazers, artificial flower makers, * makers, linoleum workers, paint mak- ^^n'k ronkcrS' painters, photographic work*** 'jjotoeiigravers. polishers, printers, rubber iri-P stee, workers, tannery workers, vul- waterproofers of textiles and paper. users of chromate antirust agents in engines, automobiles, steam heat in- ,*l^dons, and bitumen and oil refineryworkers. !*i ^1 environmental atmospheric contamina- ` chromium compounds may result tl0D the release of chromium-containing indus- wastes of chromate plants and of oil neries using a chromium-containing silica ^talrst for the catalytic cracking of oils. An inininental spread of chromates may also folio- the use of such compounds as antirusting ,,ents in automobiles and for anticorrosive (aating of airplanes. Since many of the pdustrially used chromium compounds exert , corrosive action on tissues, skin contact ,,'or inhalation of such agents results in the jgeelopment of chrome ulcers of the skin and tff.i septum which in turn provide definite of an existing health hazard. Com- *aiting on the appearance of such manifesta- qoqs among workers in new industries using chromium compounds, the Chief Inspector of Fictories of England and Wales remarked in hk report of 1944 that "the control of old haxards in new industries is of interest to others mwell as to the student of industrial health, forit would seem that in many cases the hazard a not recognized until damage to tissue has been done, when old principles have to be rekarat and adapted to new uses." This reflective observation seems to be quite ppropriate when contemplating the possible nmtence of respiratory cancer hazards for individuals employed in the numerous indus trial operations for which no pertinent pub- fidieddata of any kind exist at the present time. The observation of apparently oecupation- roonected cancers of the respiratory organs, ^ecially the lung, has been limited so far mtwo types of operations, the production of dtrotnates fronT chromite ore and the manu facture nf .i>rtain chromium pigments zinc chromate, barium chromate, lead chromate). In these operations, both water-soluble and insoluble chromium compounds are inhaled by the exposed workers. The chemical nature of the actual carcinogenic agent which is respon sible for the excessive liability of chromate and chromium color workers to cancer of the lung is still controversial. Although all investigators believe that some chromium compound or compounds are causally involved, it has remained uncertain whether the compounds suspected are hexavalent or trivalent, water soluble or insoluble, mono chromates or dichromates. Water soluble chromium compounds (monochromates, diehromates, and zinc chromate) are most often incriminated. Maneuso and Hueper recently pointed out that it may be more likely that carcinogenic effects are elicited by chromium compounds which are either not soluble in water or are only slightly so, because such chemicals, when inhaled as dust, would be retained and deposited in the lung and thus exert a prolonged effect upon the pulmonary tissues. Such chromium compounds present in a chromate plant would be represented by chromite ore and its early conversion products preceding the formation of monochromates. These little water-soluble trivalent chromium compounds occur in the material present in mixers and roasters and are contained in the slag which usually is stored for future use in the yard area of the plants. Supporting this concept as to the chemical nature of the carcinogenic chromium compounds is the fact that workers as well as animals ex posed to the inhalation of chromite ore dust have not only a high chromium content of the lungs but also an excessive blood chromium level (Maneuso and Urone). Recent experi ments on rats which inhaled finely powdered chromite ore dust showed that after 18 months a chromium level of 13.0 and 17.0 gamma, re spectively, in 100 cc. of blood was found in 2 rats studied. This finding, moreover, definitely establishes the fact that a fraction of the chro mium contained in chromite ore is solubilized in the pulmonary tissues and discharged into the blood. Health Monograph No. 36, 1955 25 Additional support of a causal role of triva lent compounds may be derived from 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 build ing). 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: Buckell 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 pneumonconiotic condition called chromitosis was described by Andrievskaya and Mislavskaya in chromite ore miners, and by Lukanin; Letterer, Xeidhardt, and Klett; and Mancuso and Hueper in chro mate manufacturers. It was produced experi mentally 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 im planted 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 excessive liability to lung cancer has been established so far only for chromate workers in Germany (Pfeil; Alwens and Jonas; Teleky; Carozzi; Gross and Koelsch; Alwens. Bauke and Jonas; Lehmann; Martineck: Gross: Koelsch: Alwens and associates; Goldblatt and Wagstaff) and in the L'nited States (Machle and Gregorius; Gregorius; Baetjer; Hueper: Mancuso and Hueper; Imprescia; Division t>f Occupational Health, U. S. Public Health Service; and in chrome pigment workers in Germany (Baader; Gross and Koelsch; Letterer, Xeidhardt and Klett). Bidstrup found a single case of lung cancer upon X-ray examination of the chest of 321 chromate manufacturers employed for more than 10 years in English plants, while no data exist on this point in regard to chro mate-producing or -consuming plants in other countries, such as Switzerland. Italy, and France. Apart from the excessive frequency of lung cancers among chromate workers which, ac cording to American observations, ranges from 13 to 31 times the normal frequency of lung cancers among the general male population, an occupational origin of these cancers is 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 the age of 40 years, when lung cancers of un known etiology are relatively infrequent (table 22). The quantitative data on the chromium con tent of various organs and blood of persons with chromium lung cancer have been reported by several investigators (Alwens and Jonas: Let- Table 22. Apre d istrib u tio n of cases o f ch ro m iu m cancers of th e luna- according to type of worker Tvpe of worker ' 21-30 Age iyears' 31-40 . 41-50 51-60 61-70 71-80 Total American chrom ate..... ........................................... 0 1 8 16 19 10 1 German chrom ate.................................................... 1 3 7 14 12 1 3> German chrome pigment 5 3 1 1 . to terer. Niedln Hueper). Spt behavior of tl and urine in c the developmi that in chron excretion of cl ment of lung blood chroma confirmed, th importance in respects. With the e the nares ( maxillary sim lung was the -< observed am< number of tl 125 rases fr< reported as ulcers. Chromium aorompany t lung in chroa facturers. It the pneumom or modifying process or wl of coincident Arsenicali product of tl zinc, silver, nickel, tin, a in the smeltc extensively 3 ing past decit vermicides 1 bait, rat pois ly for clearin are applied a and are du? corn, soybeai ployed as tv facture of ; bronzing an and cosmeti and its eon "Environme: for 35,251 tv 26 Environmental Caute o f Cancer of the Lunl p ubii, Health I i API 06427 t, AU tWiVSsi established <n Gerrnar / ; Caro2? e and Jona isch; Alwer .,'agstaff) ari d Gregor,' u, ancuso \iedhardt and Klett; Mancuso and t i oerl- Spannagel recently noted a peculiar or chromium content of the blood urine in chromate workers before and after ^development of lung cancer. It wa9 found in chromate workers the normal urinary tjon of chromium ceases with the develop- of lung cancer while simultaneously the chromium level becomes elevated. If ^^gpned, this observation may have distinct importance in causal, metabolic, and diagnostic ^ p e c ts. , With the exception of 2 cases-- 1 cancer of nares (Newman) and l cancer of the ^axillary sinus (Goldblatt and Wagstaff)--the |unf wa8 lhe exclusive site of respiratory cancers observed among chromate workers. The total number of these cancers is at present around 125 cases from all sources. None has been ^ported as originating from nasal septum ulcers. Chromium pneumoconiosis thus seems to jccompanv the development of cancer of the lung in chromate and chrome pigment manu facturers. It is uncertain, however, whether die pDeumonoconiotic process plays an essential or modifying role in the specific cancerization process or whether it is merely a phenomenon of coincidental coexistence. Total 1 : 54 1 38 !0 ARSENIC Arsenicals represent a byproduct or waste product of the smelting of many ores (copper, zinc, silver, cobalt, antimony, iron, bismuth, nickel, tin, and lead). Arsenicals are present in the smelter fumes and slag heaps. They are extensively produced and used, especially dur ing past decades, as insecticides, fungicides, and vermicides (sheep and cattle dip, grasshopper bait, rat poison), as well as a herbicide, especial ly for clearing railroad rights-of-way. Arsenicals are applied as sprays to orchards and vineyards and are dusted from airplanes upon cotton, corn, soybean, and potato fields. They are em ployed as wood preservatives, in the manu facture of glass, lead-base alloys, dyestuffs, bronzing and paint pigments, and medicinal and cosmetic preparations (Mote). Arsenic and its compounds constitute, according to "Environment and Health," a health hazard for 35,251 workers employed in American in dustries. This definitely is a very conservative estimate of the number of exposed workers, considering the long, although incomplete, list of different occupations entailing contact with arsenicals given by Chamberlain. The estimate, moreover, does not include the rather consider able number of persons who are exposed to arsenicals for purely environmental reasons by ingesting arsenicals with foodstuffs contami nated with arsenical insecticide residues, by consuming drinking water polluted with arsen icals leached into drinking water supplies from mine and smelter dumps, or by inhaling arsen icals released into the air from industrial establishments or by small- or large-scale dust ing operations of arsenical pesticides. From the published evidence, it appears that environmental and nonoccupational contacts with arsenicals have been responsible in recent decades for the majority of cases of chronic arsenieism and cutaneous arsenical cancers (Neubauer; Hueper; Arguello, Tello, Macola and Manzano; Butzengeiger: Baader; Nieberle; Hofmann; Prell; Holmquist; Montgomery and Waisman; Cannon; Arhelger and Kremen; Straube; Bohnenkamp; Hanser and Simon; Gonnet; and many others). While the causal role which arsenic plays in the production of cancers of the skin on the basis of chronic arsenieism of occupational, medicinal, or environmental origin has long since been firmly established, it is rather recently that exposure to arsenicals has seriously been considered as a principal causal agent of cancers of the mucous membranes, such as those of the bronchi, stomach, and bladder. Indeed, today there exists as yet only highly suggestive but not conclusive evidence linking cancer of the lung with an occupational exposure to arsenical dust. However, in' almost all cases of lung cancer for which such claims were made, there existed stigmata of chronic arsenieism in the form of arsenic dermatosis with or without skin cancers. The inhalation of arsencial dust and fumes induces rather frequently the develop ment of perforated nasal septa as well as chronic irritative conditions of the bronchi, thereby creating a symptomatic cancerigenic pattern similar to that seen in chromate workers. Under such circumstances, the existence of a causal relationship between cancer of the lung the Lunf f lU k Health Monograph No. 36, 1955 27 and chronic arsenicism appears to be a reason able conclusion. Chest and X-ray examina tions of 40 workers employed in an arsenic smelter revealed a mild degree of pneumoconi osis (Saupe). Although Saupe himself did not discover any evidence of lung cancer among the workers studied--even though they often were afflicted by hyperkeratoses of the skin and perforated nasal septa--he 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 cancer 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 Xeubauer to wonder whether this is mere coincidence, because only 2 cases of lung cancer were observed among 143 cases of medicinal arsenic cancers of the skin (Russell and Klaber), or whether under occupational conditions the irritation of the respiratory tract by arsenical dust was responsible for the phenomenon. 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 pres ence of cancers of the left foot, abdominal wall, and lung in a furnaceman in a sodium arsenite factory. Analyzing the mortality ex perience 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 28 to an excessive frequency of cancers of the T able - lung and skin, which were confined to workers in the chemical processes and were absent among members of the general group who would be unlikely to be exposed to any specific hazard. Perry, Bowler, Buekell, Druett, and Schilling County am population concluded from the clinical evidence obtained that, after many years of exposure to arsenicals. these sheep dip workers may develops squamous cell carcinoma in the bronchus: The most recent addition to epidemiological Deer Lodge, U Silver Bow, 53 Cascade, 41.49! Gallatin, 18,26! investigations on arsenic cancer was made by Snegireff and Lombard in studies of cancer deaths among employees of several metallurgi cal plants of unidentified type. Of the total of 109 deaths from all causes recorded during i Personal ! The estin 10.9 per 100.00 3 The worl ore and release the last 25 years, 12 were due to cancer of all sites, and of these, 6 were located in the lungs. should be The investigators concluded from this evidence existed at s< that "there are indications that biologically : histological it the human race made the adjustment to arsenicism. arsenic in the environment and that only \ such evideix rarely, when associated with other contributing I eism among endogenous factors such as systemic disease. [ by cancers or possibly factors such as radiation, it may sinuses, and be capable of upsetting the biological equilib smokers wit rium" ; and further "that the handling of it is most i arsenic trioxide in the industry studied does dust, fumes, not produce a significant change in the cancer production < mortality of the plant employees; hence other of these pop factors in addition to arsenic must be con sidered significant in the causal relationship to cancer." The exten In view of the fact that 50 percent of all cancer deaths among employees of one plant sur veyed were caused by cancer of the lung, the observations made in fact strongly suggest a carcinogenic action of inhaled arsenic trioxide upon the tissues of the lung of the exposed workers. This interpretation of the data of Snegireff and Lombard is supported by the k high incidence of lung cancers among the population of several counties in Montana where copper smelters and mines were operated for many years, creating an occupational and environmental pollution of the atmosphere and soil with arsenicals. Prolonged inhalation of arsenical dust and fumes appears to produce an increased liability to cancer of the lung (table 23). However, the existence of such connections I types of iror frequent op dust and fu and compou grinders, pc workers. The resul' pulmonary respectively pneumoconi and which ible. The does not el marked fib dust also siderosilicos The coo the lung ha Environmental Causes o f Cancer of the Lunf ' Public Heali API 06429 Ml'V.p; . . T able 23. L u n a c a n c e r m o r t a l i t y in se v e ra l M o n t a n a c o u n t i e s , 1947-48 ( L u ll a n d W a lla c h ) 1 ,, . abs*n ** 7 * obtaiZ l to arsenioa) 0P a s quam0lli raidemiologip^ "'as made lef of anfp| al metallur^ ' '(' ''orded during cancer of a)j l m the lung, this evidence t biologiea||v ljustment to 1,1 that only r contributing emic disease, ition. it maj! sdcal equilib. handling 0f studied does in the cancer : W e e other mtionship ercent of all one plant surthe lung, the -ly suggest a -enic trioxide the exposed the data of Tted by the among the in Montana ere operated pational and aosphere and nhal&tion of ; to produce of the lung connections , ,,ntv and total ^ i a t . n 1940 Major industry Xumber lung cancers Total Male Fe male Total cancer deaths Percent lung cancer Annual '.ung cancer death rate 100.000 Male mFaele M ale3 mFaele todee, 13,627......... Copper smelting 1--------- 21 D**r go-, 53.207........... Copper mining 1............... 27 yile r. 41,499................ Copper mining, sm elting3 20 C W jf' 18.269................ Agriculture--------- ------- 1 C,*U*U _________ 0 21 2 29 D 25 0 1 98 30. 8 0. 0 145. 7 0. 0 259 22. 6 1. 5 48. 6 3. 9 299 12 7 3. 5 46. 3 12. 3 81 3. 0 . 0 5. 2 . 0 "^Tpersonal communication of unpublished data. The"estimated crude death rate for lung cancer among white males in the entire t'n ited States in 1947 was ,, 0 -jr 100.000 population. |0'a iThe workers employed in copper ore mining and smelting inhale dust and fumes of arsenic contained in the *nd released as a byproduct and waste product during the smelting process. or* Jjould he acknowledged only when there ^ (cd at some time clinical and, if possible, (jstoloeical and biochemical evidence of chronic jjsenicism. In view of the absence of any -uch evidence associated with chronic arseni,jsm among the nickel refinery workers affected br cancers of the nasal cavity, paranasal uses, and lung, and among excessive tobacco snokers with cancer of the larynx and lung, H is most unlikely that exposure to arsenic Just, fumes, and vapors plays any role in the pnxjuction of respiratory cancers in members of these population groups. IRON' The extensive production and use of various types of iroD and of diverse iron products offers frequeDt opportunities for the inhalation of dust and fumes of iron and its various alloys snd compounds by iron ore miners, arc welders, grinders, polishers, silver finishers, and metal workers. The resulting red or black siderosis caused by pulmonary retention of Fe20 3 or of Fe30 4H20 . respectively, is considered an inert form of pneumoconiosis which does not cause disability ud which at least in part seems to be revers ible. The deposition of iron oxide particles does Dot elicit in the lungs a progressive and marked fibrosing reaction unless the inhaled dust also contains silica, producing then a siderosilicosis. The coexistence of siderosis and cancer of the 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 Kennawav reported a 2.25-fold 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 amoDg 192 iroD ore miners coming to Decropsy between 1932 and 1953 there were 17 lung cancers (8.85 percent). Ehrbardt and Giithert, on the other hand, noted that red siderosis of the luDg 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 num ber of deaths from lung cancer amoDg iroD ore miners residing in St.'Louis and Itasca County (total 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 5-year period than that noted for Minne sota residents (table 24). Experimental studies on animals exposed to iron oxide and hematite, respectively, gave con tradictory results as to the production of lung tumors. While Vorwald and Karr, using guinea pigs and rats, failed to obtain lung cancers with r o f the Lunf NUk Health Monograph No. 36, 1955 29 Table 24. Deaths due to cancer o f the lung among iron ore miners and residents o f M innesota, (Brower) 1950-54 Year Number of d e a th , ! " " I" Minne- 1StI.taLsocuais- > Minne sodtaenrtessi- : Countv sodtaenrtessi St. LouisI tasca County miners 1950......... . . 328 1951____. . . 289 1952........ . . 329 1953........ . . 367 1954......... . . 345 5 11. 0 4 9. 7 12 11. 0 6 12. 3 6 11. 6 37. 6 30. 0 90. 1 60. 1 60. 1 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 epi demiological 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 signifi cant 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 (berylliumcopper, beryllium-aluminum, and beryllium nickel alloys, glass, phosphors in fluorescent 30 lamps and neon tubes, atomic energy products, ceramics, refractories, X-ray tube windows, vitreous enamel, radio tubes, textile fibers, gas mantles). It is evidently for this reason that untoward effects in persons exposed to the in halation of dusts and fumes of beryllium and its various compounds have been recognized only during the last decade. These manifesta tions were of both acute and chronic nature as far as the respiratory organs "were concerned (acute beryllium pneumonitis, chronic pneumoconiotic granulomatosis, berylliosis). Some investigators used the term "sarcoid" in de scribing the histologically peculiar, pulmonary manifestations. It is remarkable moreover, that chronic berylliosis has appeared not only among exposed workers, but also among per sons living in the neighborhood of fluorescent lamp factories and inhaling their berylliumcontaining effluents (Eisenbud. Berghout and Steadman; Eisenbud, Wanta, Dustan, Stead man, Harris, and Wolf). Similar observations on occupational beryl liosis were reported from Germany, Italy. England, Russia, and Canada. Not infre quently, similar granulomatous lesions have been observed in other parts of the body after the usually traumatic introduction of beryllium dust, especially of beryllium phosphors from broken fluorescent tubes. The skin of the fingers and hands was the most frequent extrapulmonary location of these reactions. Beryllium granulomas have also been found in the nose and in the anterior ocular structure. } It is noteworthy that beryllium apparently , once inhaled is retained over a long period of time in the human body, since beryllium hss been detected in the urine up to 10 years after cessation of exposure (Klemperer, Martin, and Van Riper) and has been demonstrated in the lungs of rats 1 year after the inhalation of v beryllium oxide (Dutra, Largent, Cholak. Hubbard and Roth) as well as in their bones (Stokinger, Steadman and Root; Barnes'where it may replace calcium. The skeleton retains the bulk of the beryllium in the body (50-80 percent) if the inhaled aerosols are soluble compounds, such as beryllium sulfste and beryllium fluoride; the lungs retain the bulk of beryllium if the compounds are in soluble, such as beryllium oxide. Experiment; of -Aldridge, 3 shown that : certain tissue plasma prot blood. Thes from being p The metab pounds obtai fact that Gar tion of osteo intravenously ing powders lium silicatquently conf and other oxide, beryl) introduced b respiratory r Sissons; Honi Largent. and period for tin Comment! osteogenic sa of beryllium noted the fa dying with b able amount following cc years, consii been exposer pounds of throughout fact that cas been reporte' of poorly sol eventuate in sumably. tin would be co rabbits, anc over a perio> whether per beryllium ar Barnard a coma from Possibly be far. only rah" pment of administratii direct in trod into the fern' cavity, and : Environment] Caute of Cancer o f the Lunf Public Heallt API 06431 .*rcy ;jro (| une indo^.' ^ bers' Sa, 11 son that osea to the jj, yjdndue . Barnes, and Denz, moreover, have that beryllium ions react rapidly with "ain tissue proteins and form complexes with jLjna Protehis when introduced into the r -J These complexes protect the beryllium beryllium ar)(j -en reeogni^lj *jjj being precipitated by phosphate ions, ^ b e metabolic peculiarities of beryllium com- ese manifesta^ mids obtain special importance in view of the romc nature ^ ere concert^ chronic pne(K that Gardner in 1946 reported the producof osteogenic sarcomas in rabbits injected ptr&venously with insoluble beryllium-contain Uiosis). Som^ arcoid" in r|e_ '.ar. pulmonary ble moreover eared not only er powders (beryllium phosphate, zinc beryl[iUJnB silicate). Other investigators subseque,intly confirmed these results with the same other beryllium compounds (beryllium ,,side, beryllium silicate, metallic beryllium) 50 among PeN Induced into rabbits by the intravenous or o f fluorescent eir beryllium juratory routes (Sissons; Barnes, Denz and qggons; Hoagland, Grier and Hood; Nash; Dutra, Berghout and bjrgent, and Roth; Barnes). The preparatory )ustan, Stead- period for the sarcomas was 11-24 months. Commenting on the successful production of rational bervlrmany, Italy, . Not infre- lesions have the body after m of beryllium osteogenic sarcomas in rabbits after inhalation of beryllium oxide. Dutra, Largent, and Roth noted the fact also that the bones of persons ring with berylliosis contained not inconsiderle amounts of beryllium. They came to the following conclusions: "During the last 20 aosphors from . of the nf requent est -eactions. been found in ar structure, m apparently long period of rears, considerable numbers of persons have been exposed to dusts of poorly soluble com pounds of beryllium in various industries throughout the United States. Despite the fact that cases of cancer of this type have not been reported, it is possible that the inhalation of poorly soluble compounds of beryllium may eventuate in osteogenic sarcoma in man. Pre beryllium has sumably, the incubation period of such tumors 10 years after vould be considerably longer in man than in r, Martin, and rabbits, and observations may be required strated in the over a period of years before it will be known inhalation of whether persons who have been exposed to rent, Cholak, * beryllium are prone to have such tumors." in their bones Barnard also suggested that osteogenic sar oot; Barnes), coma from compounds of beryllium "might The skeleton possibly be another industrial hazard." So n in the body (ar, only rabbits have responded with the devel 1 aerosols are opment of osteogenic sarcomas following the allium sulfate ' administration of beryllium compounds. The retain the > direct introduction of powdered beryllium metal ds are in- into the femoral cavity of rats, into the pleural xperiments cavity, and inter the paranasal sinuses failed to of the Lung PsUic Health Monograph No. 36, 1955 elicit a sinsrle neoplastic response at the site of injection in any 1 of the 85 animals used within an observation period of 2 years (Hueperi. 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 dis covery and identification of this pneumoconio sis was definitely facilitated by the distinctive and definitive histological features of the dis ease. 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 carcinogenic ity 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 car cinomatous developments in persons with pre vious exposure to beryllium, some consideration also may be given to the toxic effect exerted by beryllium e the liver leading to the develop ment 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 C O M B U ST IO N AN D D IST IL L A T IO N PB O D U CTS O r COAL The apparent innocuousnees of coal and, possibly, graphite dust as respiratory carcin ogens is not shared by the incomplete combus tion, distillation, and hydrogenation products 31 of coal (pitch, tar. soot, creosote oik, anthracene 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 dktillation products of coal on man and experi mental animals has been establkhed 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-made 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 carcinogenic 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 construc tion and repair work, roofing, brickmaking, foundries, furnace attendance, railway engine driving, roundhouse operations, pickling of lumher, chimney sweeping, cork brick manu facture, electrolytic metal production,and so on). Since the high hoiling fractions of synthetic oils produced hy the direct hydrogenation of coal through the Bergius process have been shown to be highly carcinogenic to the skin and hr suhcutaneous tissue of mice and rats, respectively, certain types of workers manu facturing 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 heen operative for some 20 years in German}' and have recently been constructed hy several industrial concerns in the United States. Not only the environmental, but also to a greater degree, tbe occupational inhalation of dust, soot, and fumes produced by the incom plete combustion of coal results in the develop ment of a "soot lung,'' called bituminosis, 32 which is characterized by the deposition 0f finely dispersed carhon particles contaminated with hydrocarbons normally contained in coal tar in the interstitial lung tissue. Roent genological changes may appear in the lungs after many years of exposure to high concen trations 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 j 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 extensive and is in part controversial. The human evidence relating exposure to coal tar dust and fumes with an increased liahility , to cancer of the lung is equivocal. Kennaway and Kennaway stated that "coal tar in the atmosphere, whether derived from roads, domes tic chimneys, or any other source, does not cause an exceptionally high incidence of cancer i of the lung." A similar statement was made i by Hugounenq and by Husted and Biilmann : in regard to the liability to cancer of the lung for workers employed in the tar industry and in the construction and maintenance of tarred roads. McLaughlin did not find any lung cancer among 3.059 foundry workers suhjected to clinical and X-ray examinations, although there were T deaths from lung cancer among 64 deaths from all causes. Menz recently reported that of 93 workers in Swiss gas plants who died during the 1926--46 period. 21, or 22.6 percent, died from cancer of all sites, therehy confirming previous English experience that workers in tar and pitch operations have an excessive liability to cancer in general. Iso lated observations of lung cancer in workers exposed to the inhalation of tar fumes were made hy Koelscb (hlacksmith, tar worker), Rodenacker (briquette fsetory worker), and 1 Mullschitzky (tar worker). In an analysis of lung cancer deaths among members of different occupational groups for the years 1933-38 Kennaway and Kennaway, on t Environmental Caiuei of Cancer o f the Lung the other ham (1001 lung nr following ocru: gas stokers. 2*> crane operator? 136: printers., asphalt worke painters. 129:3 and automobli" moreover, a n among employ. Additional s vided hy the oh generator gas plants and am Canada and E Kawnhata: Cri investigators f< cases of lung workers who w hot tar fumes -i lung cancer n employed in ot general incidtu generator gas 3 employed. N occurred in wr (33 percent agt lung cancers) varied from 9 heing 16.6 yer recently made a ers. Of 14 casworkers, 6 wen cancer of the ethmoid sinuse upper and low< It is likely tl rates may exi? Following a vis 25 skin cancerhad heen ohs, during an S-yci of lung cancer, company officii cancers in this cases of cancer From the ev, the inhalation< of certain open plants, gas plar Public H eallk M API 06433 I L '* i.-position -s 'ontaminai ,v^ ' e d in Cr]( - -e. Roen ar in the In, to high concfl ded. While ^ il to modera,' such as is cot^ -f industrially' ireciable fibro!/ >f soot particl^ r be associate,) itial connectiv, r formations 0| i? exposure fumes with the lung is nof rsial. xposure to coa| "eased liability d. Kennawav )al tar in the i roads, domesirce, does not ence of cancer ent was made and Biiimann eiy-M he lung ; try and mce of tarred id any lung rers subjected ms, although ancer among enz recently iss gas plants d. 21. or 22.6 tes, thereby rience that ns have an neral. Iso in workers fumes were ar worker), orker), and aths among oups for the nnaway, on o f the Lunf 0ii)t-r hand. noti'i 1 that an above-average I'linccr frequenev existed for the Hiwimt occupations: gasho'use workers. 129; f stokers. 2S4; gas producers. 202; gasworks operators. 138; gasworks superintendents, printers. 119; chimney sweeps. 119; halt workers, 164; metal polishers. 174; ^inters. 129: tanners. 141; street.cleaners, 169: ^od automobile drivers. 149. They recorded, jnoreover, a ninefold increase of lung cancer employees of a Canadian gas plant, additional supporting information was pro-' vided by the observations made among Japanese ,,enerator gas oven workers employed in steel plants and among gashouse retort workers in panada and England (Kawahata; Kuroda and g flwahata; Cruickshank: Doll). The Japanese investigators found, within a 6-year period. 21 fases of lung cancer among generator oven workers who were exposed to the inhalation of j)0t tar fumes when stoking coal. An excessive lung cancer rate was absent among workers employed in other parts of the steel mills. The general incidence of lung cancer among the venerator gas workers was 5 per 1,000 workers employed, ^cven of these 21 lung cancers occurred in workers aged 40 years or younger (33 percent against 18 percent in cryptogenetic lime cancers) (Hueperj. The exposure time varied from 9 years to 23 years, the average being 16.6 years. Similar observations were recently made among Canadian gashouse work ers. Of 14 cases of cancer among retort house workers, 6 were due to cancer of the lung, 1 to cancer of the larynx, and 1 to cancer of the ethmoid sinuses (57 percent were cancers of the upper and lower respiratory tract). It is likely that similar lung cancer incidence rates may exist among American tar workers. Following a visit to a tar distillery where some 25 skin cancers and more than 80 pitch warts had been observed among the 300 workers during an 8-year period, there was found 1 case of lung cancer. Subsequent inquiries made by company officials brought the number of lung cancers in this and other tar operations to 6 cases of cancer of the lung. From the evidence available, it appears that the inhalation of tar fumes sustained by workers of certain operations (coke oven, generator gas plants, gas plants, tar distilleries) seem to have Public Health Monograph No. 36, 1955 an excessive liability to 'ancer of the respiraiory tract. It is not unlikely that a more thorough and competent analysis of the death records of other worker groups, which have so far been found to lack such tendencies, might extend the types and number of tar and pitch workers having, an abnormally high respiratory cancer rate. A recent observation of lung cancer in a worker exposed to heated pitch and asphalt points to another source of occupational pulmonary tar cancer of definite practical importance (Patch). PE T R O L E U M , SH A LE O IL , AND N A TU RA L GAS The carcinogenicity of certain high boiling fractions of petroleum and oil shale, as well as of the combustion products of some of these petroleum derivatives, such as oil shale and natural gas. have definitely been demonstrated not only on experimental animals but also on workers developing cancers of the skin after prolonged contact with these agents. Known carcinogenic chemicals, moreover, have been isolated from these petroleum derivatives as well as their combustion products (Berenblum and Schoental; Fischer, Priestley. Eby, Wattless and Rehner; Falk, Steiner. Goldfein, Breslow and Hykes; Waller; Rehner; Kotin and as sociates.) In addition to skin contact with carcinogenic petroleum derivatives many workers are also exposed for occupational reasons to an inhala tion of oil mist or fumes (workers in paraffin pressing operations, certain groups of oil refinery workers, spinners, metal lathe workers, foundry workers, metallurgical workers, printers, and so on). In spite of this established occupational respiratory exposure to petroleum and shale oils, there are on record only three cases of oil pneumonia Among suoh workers, although such conditions have rather frequently been observed after repeated medicinal instillations of mineral oil containing nasal drops (oil aspiration pneu monitis or paraffinoma of the lung). In fact, two cases of cancer of the lung apparently developing on the basis of a medicinal mineral oil pneumonia have been described (^ood; Sante). The occupational evidence available or pub lished on this aspect of cancer of the lung is rather scanty and in part controversial. Kennaway and Kennaway found a relatively high 33 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 cancers 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 1 was an engineer. Huguenin and his associ ates concluded that their observations indi cated 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. Rsch observed three primary cancers (skin, stomach and lung) in a paraffin worker. Touraine and B out 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 cancer inci dence among employees of a large oil refinery, the surprising observations were made that there was not only a highly excessive incidence of scrotal cancer among employees of the paraf fin pressing department but that incidence of cancer of the lung was also excessive. Paraffin pressers, who represent about one-tenth of the total employed worker group, furnished 56 percent of the lung cancer observed. Since soot as a waste or commercial product has been found to be carcinogenic and to contain known carcinogenic hydrocarbons, a thorough and competent survey of occupational groups particularly exposed to the inhalation of soot (operating railroad personnel; stokers; carbon black manufacturers; rubber, paint, and ink makers; painters; soot burners; printers; diesel engine drivers; carbon electrode manufacturers and users in aluminum plants; smudge pot operators; phonograph record makers) is an urgent necessity. The negative conclusions I reached by Ingalls as the result of-a survey of the carbon black industry are based on evidence \ of dubious merits, because only 79 of the 677 evaluated workers have been employed for 10 j 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 reason 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 also add to our knowledge as to the existence, extent, and type of bituminosis which might be expected to exist in workers inhaling finely ' dispersed soot particles. ; At the present time, exposure to tar, pitch, asphalt, heavy fuel oils, lubricating and cutting oils, soot from domestic furnaces, incinerators, industrial power plants, oil refineries, steel plants, metal smelters, carbon black factories, oil dumps and smudge pots, as well as exposure to the effluents of diesel and gasoline engines, represents the' most widespread occupational and environmental contact with carcinogenic 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 giv- ( ing rise, when inhaled, to bituminosis or anthra- cosis; or they are constituents of oily matter which, when inhaled and retained in the lungs, cause oil pneumonia or paraffinoma of the lung- Since pure anthracosis is not causally related to cancer of the lung, the pneumoconioses ac companying respiratory carcinogenesis by aro matic hydrocarbons do not play a primary and essential role in this process, although the pneumoconioses may lower the intensity and prolong the dui carcinogenic ch Since our cr been built arou basic carbonac tives, it does n pete protectio carcinogenic ch prophylactic en practical and < There is. howe remain? to he < are still ratliot maximal arnou sure to the res] carbons contaii substances met Carb<i Recent studi dry. Homer. Rose, and T7a a new and in combinations o through the ' linkages bet we chemicals and chromosomes, from evidence < genesis by nitn ethyleneimines. view of the fac by which the? specific action zation. it is ass chains might mucoproteins < linkage with m by cause mito' action of one * meric molecule may start a pn followed by a epoxide groups These conce] with respirato reasons. Sin Druckrey and shown that s various polyi 34 Environmental Causes of Cancer o f the Lung P u b lic H e a lth It) API 06435 ! *' .1 f J i o r o i i f f j j f SOot, t>; carhop it. and inJt iters; diesel nu/aeturpj^ mudge pot kers) is an ronrlusions a survey of on evidence of the 677 ovi'd for the majorineers have "* 10 vears used on 79 is to reason Is of former i a different re based on ions would < existence, li might be ding finelv tar. pitch, and cutting ' S v a tors, ci . steel k factories, as exposure tie engines, erupational ureinogenie agents conJare certain ich not inirtides giv- or anthra>ily matter i the lungs, >f the lung, ally related onioses acsis by arorimary and hough the tensity and I , 10112 the duration ot the effect of the specific me hemicals on the lung tissues, I I c&c`inoge since our ncivilization and economic life has I built around the production and use of the j .f carbonaceous substances and their deriva- it does not seem feasible to attain com plete protection against exposure to these ^.jiogenic chemicals with the preventive and '^pbyiactic engineering and sanitary measures ^ ,tical and economical at the present time, ^ r e is. however, no doubt that a great deal .mains to be done in this respect and that we jcc -till rather far removed from having the maximal amount of possible reduction in expo- ,ure to the respiratory cancer producing hydro carbons contained in the various carbonaceous substances mentioned. Carbon a n d S ilic o n P o lym ers Recent studies of English investigators (Hencv. Homer, Rose, and Walpole; Hendry, R<Cse, and Walpole; Haddow) have furnished &new and intriguing concept as to possible combinations of carcinogens with tissue proteins through the postulated formation of cross linkages between certain types of carcinogenic chemicals and the maeromoleeular fibers of chromosomes. This hypothesis was evolved from evidence obtained in the study of carcino genesis by nitrogen-mustards, diepoxides, polvethyleneimines, and related compounds. In new of the fact that one of the various means br which these substances may exert their specific action in the cells is through polymeri zation, it is assumed that polymerized epoxide chains might interreact with proteins or mucoproteins of chromosomal origin, by cross linkage with multipoint attachment, and there by cause mitotic aberrations. The initial re action of one of the epoxide groups of mono meric molecules with the cell component also may start a process of polymerization by being followed by a self-condensation of the free epoxide groups into a polyetheneoxy-structure. 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, of the Lung Pohlic Health Monograph No. 36, 1955 polyethylene, poivvmyl .iiloruie. poiymet hvl methacrylate, polyamide. TeHon. ami 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 respiratone cancer hazard to man. The more immediate importance of these concepts, however, lies in their application to the production of occupational respiratory can cers 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, more over, is supported by observations of lung cancers among Japanese mustard gas manu facturers. ASBESTOS Asbestos differs from the ordinary giant molecular crystalline silicates not only in its chemical and physical properties, but also in the anatomical aspects of the pneumoconiosis produced by it. In contrast to the tridimen sional polymerized silica crystals in which no oxygen atoms are left earning charges to attract positive ions, asbestos consists of giant fibrous molecules composed of polymerized silico-oxygen tetrahydra which are arranged in chains or bands (Parkes). Depending on the origin of asbestos, the fibrils may be short or long. Italian. South African, and Australian asbestos (amphibils) consists of fibrillar or ra diating crystals of calcium-magnesium silicate or sodium iron silicate (40 percent iron oxide). Canadian, Russian, German, and French as bestos is hydrated magnesium silicate, which contains small amounts of iron oxide (5.75 per cent). Canada furnishes about 75 percent of the world production of asbestos. Canadian asbestos, because of its long fibers, is especially 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- 35 duces asbestosis only if the inhaled fibers are sufficiently long. In the absence of fibrous structure, the dust is said to be inert (Wyers; Vorwald, Durkan, and Pratt). Since the larger fibrils are arrested in the bronchioles (Gardner), the granulomatous reactions form peribronchiolar fibrous cuffs with giant cells and asbestos bodies. These have a fibrillar core and an iron staining proteinic or colloidal silicic acid sheath. Whether the iron in the sheaths 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 of asbestos workers upon the presence of asbes tosis and in view of the possibility that the proteins of the lung tissue may specifically interreact with free groups of the filamentary asbestos molecules (Druckrey and associates). The coexistence of asbestosis with cancer of the lung was first reported by Lynch and Smith in 1935 (1 case). 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 case; Holleb and Angrist, 2 cases; and Homburger, 3 cases); from Canada (Des meules. Rosseau, Gilroux, and Sirois, 2 cases; Cartier, 4 cases; Rousseau, 1 case); from Eng land (Gloyne. 17 cases; Harrison, 3 cases; Merewether, 31 cases; Cureton, 1 case; Owen, 1 case), and from Germany (Nordmann. 2 cases; Linzbach and Wedler, 1 case; Homing, 1 case; Welz. 2 cases; Bohme, 1 case; Domenici, 2 cases; and Baader, 1 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 8 cases 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 2.5). Merewether noted that the mean age of males with asbestosis cancer of the lung was 55.2 years (range 22-72) and that their mean expo 36 sure time was 20.1 years (range 6-40), while the mean age of female cases was 44.6 years (range 32-71) and their mean exposure time was 7.6 years (range 0.5-48). However, in many cases there elapsed a long exposure-free interval rang ing from several months to 20 years before the lung cancer became manifest (Wedler; Wyers). The age distribution of asbestosis cancer of the lung was: ** C ate Of A p e (feeri) lung ' cancer 2 5 - 3 4 .......... 2 3 5 - 4 4 ........... 11 45 -5 4 ............... 16 5 5 - 6 4 _________ IT 6 5 - 7 5 ___________________________ 5 T o tal............ ................................................ 51 Since lung cancer of unknown etiology occurs rather frequently before the age of 40 and since 26 percent of the asbestosis cancers appeared before the age of 44, it seems that there exists a moderate shift toward younger age groups for cancers associated with asbestosis of the lung. The exposure time for asbestosis lung cancer, excluding the series of Merewether. was: E x p o su re tim e (yea ri) I - 3 ........................................ 4 -1 0 ........... I I - 20....... 21 and over......... ......................... C a te t of lu n g cancer 4 6 4 7 Total....... ...................... 21 The exposure time of this series covers a wide range (1-23 years), indicating that type and intensity of jgxposure .to asbestos as well as perhaps an individual susceptibility to asbesto sis plat' an important role in determining the development of this pneumoconiosis and thereby the possibility of a secondary carcinomatous sequela in the lung. There were 37 males and 15 females among the 52 cases for which information on sex was available. The male:female ratio is thus 2.5:1, which represents a marked shift toward the female side when compared with the usual sex ratio of 5:1 to 10:1 for lung cancers of unknown etiology. Equalization of carcino genic exposure as represented by asbestosis, for the two sexes, thus resulted in a trend toward equalization of liability to lung cancer. It is of importance to note that the mean Environment! Causes o f Cancer of the Lung T able 25. Lung cancer 1----Other respiratory < With mention ol Without mentiot Neoplasms, other t All other diseases3 All cause?.. ` Including 1 1 s Including pu Including 2 not thought to hat age of 128 nonwas only 44.2 y conclude from these individua tosis before the develop (Linzb Additional s between asbestderived from tl among 266 cast 1924-46. 31 ca lung (11.65 pen of lung cancer years among 6. cent) which ca that asbestosis 14 cases, or 15.2 on which necrc the normal rat material was es Lanza, Yorwt quite skeptical an excessive asbestosis to 1 Homburger an Other investigi cept or consit relation as hi (Kennaway; M Hueper; Gross: Linzbach and 1 Welz; Doll). The histolog Public H ealth M API 06437 ' 4" . \v|iil,, 44-lL.yi'ars irar, Sb ie "'as 7 f r. ... many na ' ree interval ran& rears before t( Wedler: W y e ^ estosis cancer 0| `"nQ nnctr 2 U ie 17 5l n etiology occurs re of 40 and since ancers appeared hat there exists a r age groups for osis of the lung. :osis lung cancer, ther. was: C alleiTrieqof cancer 4 6 4 ----------- 21 ies covers a wide : that type and stos as well as uility to asbestodetermining the iosis and thereby carcinomatous females among tion on sex was ratio is thus .ed shift toward 1 with the usual lung cancers of ion of carcinoiy asbestosis, for a trend toward cancer. that the mean ncer of the Lung Cause of d e a th am ong m ale asbestos w orkers com pared w ith th e m o rta lity experience of all m en J* in England and Wales (Doll) Cause of death Number of deaths Number observed Expected on England and Wales rates Test of henificance of difference between observed and expected rvalue of P.i cipiratorv diseases ` and cardiovascular diseases'nention of asbestosis........................................... .. w thout mention of asbestosis....................................... " `L m s, other than lung cancer.................................. goPtber diseases ......... ......................... - ............. - ......... U1 causes...................................................................... 11 14 ___ 6 4 4 39 . . S 7.6 } in 15. 4 <0. 000001 <0. 001 >0. 1 <0. 000001 ""Tincluding 1 case with pulmonary tuberculosis. , including pulmonary tuberculosis. i including 2 cases (benign stricture of esophagus and septicaemia) in which asbestosis was present but was thought to have been a contributory cause of death. jge of 128 noncomplicated cases of asbestosis as onlv 44.2 years (Merewether). One may include from this observation that some of ^ese individuals apparently died from asbesjpsis before their lung cancer had a chance to develop (Linzbach and Wedler). Additional support for a causal relation between asbestosis and cancer of the lung is derived from the fact that Merewether found, among 266 cases of asbestosis observed during 1924-46, 31 cases of coexisting cancer of the lung (11-65 percent), while there were 91 cases of lung cancer with an average age of 59.4 years among 6,884 cases of silicosis (1.32 per cent) which came to autopsy. Wedler noted that asbestosis cancer of the lung occurred in 14cases, or 15.2 percent of 92 cases of asbestosis on which necropsies were performed, whereas the normal rate of lung cancer in autopsy material was estimated to be 2-6 percent. Lanza, Vorwald, Warren, and Cartier are all quite skeptical as to the actual existence of m excessive liability of individuals with isbestosis to lung cancer, and Cureton and Homburger are undecided on this question. Other investigators, however, favor this con cept or consider the existence of a causal relation as highly probable or established (Kennaway; Merewether; Telekv; Xordmann; Hueper; Gross;Lecoeur; Smith; Saita; Wegelin; Linzbach and Wedler; Stoll, Bass, and Angrist; Welz; Doll). The histological types of lung cancers 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 Ritterhoflf reported the combination of an asbestosis with a sarcoidosis of the lung which, however, was not compli cated 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 dcmbtlessly 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 N U ic Health Monograph No. 36, 1955 37 the actual number of lung cancers and asbestosis cases which may result from effective exposures. For these reasons, no 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 (Bohme). Kennaway and Kennaway reported that 8 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 compen sable disease (Tabershaw). The experimental approach to the problem has so far given equivocal results. Vorwald and Karr, using guinea pigs which were exposed to asbestos dust, obtained negative results. Nordmann and Sorge employed mice for this purpose and claimed to have produced bronchiogenic carcinomas with pulmonary fibrosis in two mice. This observation needs to be con firmed before it can be accepted. 1BO FBO PY L O IL Through the recent discover}- of cancers of the paranasal sinuses, larynx, and lung among isopropanol manufacturers, the occurrence of carbonpolymer cancers has probably been ex extended to man. Isopropyl oil--the crude liquid from which isopropyl alcohol is distilled and which is a slightly turbid, viscous liquid, slowly turning, upon standing, into a brownish to blackish tarry material--contains polypropy lene compounds as well as propylene ether, which may be oxidized into propylene peroxide and propylene epoxide having a tendency to polymerize. Polypropylene, merchandised as Opponol K, is used commercially as an oil for cable filling. Workers employed in isopropanol manufac ture have been exposed to the inhalation of vapors, mist, and dust of isopropyl oil escaping from leaky pipe connections, defective pumps, and gaskets, or spilled on the floor at the occur rence of breaks in pipelines and during repairs on pipes, pumps, and stills. Weil, Smyth, and Nale reported that, between 1928 and 1950, a total of 7 neoplasms affecting various parts of the respiratory tract (nasal sinuses, 4; larynx, 2; and lung 1) came to observation among 71 employees, or in 8.4 percent of those who worked more than 5 years in the isopropanol plant. Five additional cases were observed in another isopropyl alcohol plant, making a total of 12 cases, 7 of which involved the nasal sinuses, 4 the larynx, and 1 the lung. It was calculated that the incidence rate-of cancer of the nasal sinuses and larynx for the second group was 134.5 per 100,000, against a normal rate of 6.3, and that the incidence of these can cers exceeded the expected incidence 21.3 times. From the evidence available it is likely that these cancers as well as those associated with asbestosis belong to the new class of "polymer cancers. M VBTABD GAB The alleged carcinogenic action of war gas poisoning figured prominently in the specula tions as to the cause of the increase in lung cancers observed during the early 1920's (Kikuth; Brockbank; Klotz; Derisehanoff; Hiinermann; Reiche). Residuals of warfare gassing were noted by Matz in 10 out of 138 cases of pulmonary cancer among American World War I veterans. Four out of 64 cases of lung cancer, recorded by Brockbank, were gassed badly during this war. Maeklin noted that war gas poisoning occurred in 5 percent of 164 cases of lung cancer among males, while it was present in only 2 percent of Boldiers without this disease. Koelsch con ceded that a few cases of lung cancer exhibited a doubtful etiological relation to war gas injury, which was claimed to have caused also two cancers of the larynx (Spamer; Tilley). No distinction was made at that time as to the particular chemical nature of the various gases used during World War I. These contentions found little acceptance at that time. From a carcinogenic viewpoint, special interest has to be attached to the various arsenic-containing gases, especially Lewisite, and to mustard gas (dichlorethyl sulfide). The arsenical war gases, when inhaled, theoretically may not only cause nonspecific chemical damage to the respirator}- tissues but also may produce there a specific delayed carcinogenic reaction, S8 Environmental Causes o f Cancer of the Lung such as that seei with these gase belong to the gr A possible ci gas upon the b hand, may be i radiomimetie eff that demonstra animals exposec mustards of al According to t. cepts. the caus these cancers rt possibly active i During the 1 bronchiogenic c; cancer were ol ployees of tlxManufacturing Lewisite and Y:] workers was 30 old. All three poisoning due (Yamada. H im these observatii carcinomatous > exposure to mu products deserv While the fur cancers" is a t supported by at data are sufficiet attention from" viewpoint. Th production and natural and sy and cross-linkii rubbers, rosins., brings a eonsidt lation into dim type. It seemstudy these j coming decades particularly tl. system. R< Up to some 1 sure to radioac t-ively small gi sional workers active ores, im Public H ealth M API 06439 .--V 4; i a r v ] lV ;ii.*u among 7 r hose whf) t. .opropan0 re observed making a tota| olved the nasa[ ae lung. It was rate of cancer 0f for the second against a normal nee of these can. dence 21.3 times. ' it is likely that associated with lass of "polymer tion of war gas in the specula, increase in lung e early 1920's : Derischanoff uals of warfare n 10 out of 138 mong American iut of 64 cases of roijkhank. were ' din noted ed 5 percent among males, v 2 percent of Koelsch concancer exhibited 0 war gas injury, aused also two t ; Tilley). No time as to the e various gases e acceptance at nic viewpoint, d to the various dally Lewisite, 1sulfide). The ed, theoretically hemical damage Iso may produce '.ogenic reaction, neer of the Lunf that seen exceptionally after skin burns ?Utk these gases. Cancers of such an origin f'loQit to the group of arsenic cancers. ^ possible carcinogenic action of mustard ^ upon the bronchial mucosa, on the other and. may be related to its cross-linking and 0mimetic effect, and may be identical with at demonstrated to exist for experimental jnintftl5 exposed to several sulfur- and nitronustards of aliphatic and aromatic nature, cording to the mentioned theoretical con cepts, the causative mechanism operative in ese cancers resembles in some respects that possibly active in polymer cancers. During the last few years, three cases of bronchiogenic carcinoma and 3 cases of larynx cancer were observed among long-term em- plovees of the Japanese Army Poison Gas Manufacturing Plant on Okuno Island, where Lewisite and Yperite were made. One of these workers was 30 years old and a second, 53 years 0ld. All three suffered from chronic war gas poisoning due to contact with mustard gas (Vamada. Hirose, and Miyanishi). In view of ese observations, the distinct probability of carcinomatous effects upon the lung following exposure to mustard gas or chemically related products deserves serious consideration. While the fundamental concept of "polymer cancers'' is a tentative one and needs to be supported by additional evidence, the available data are sufficiently important to require serious attention from both a scientific and a practical viewpoint. The Tapidly expanding industrial production and industrial and general use of natural and synthetic polymerized substances and cross-linking chemicals in plastics, films, rubbers, rosins, adhesives, textiles, and so on, brings a considerable part of the working popu lation into direct contact with chemicals of this type. It seems to be advisable, therefore, to study these population groups during the coming decades for the occurrence of cancers, particularly those affecting the respiratory system. Radioactive Chemicals Up to some 10 years ago, occupational expo sure to radioactive agents was limited to rela tively small groups of industrial and profes sional workers (miners and refiners of radio active ores,' industrial and medical consumers Public Health Monograph No. 36, 1955 of radioactive substances--ms mantle manu facturers. luminous dial painters, radio tube makers, physicists and their assistants, radiolo gists and their assistants). Since the advent of successful atomic fission and the ready produc tion 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, pharma ceutical, and other industrial research workers employing radioactive isotopes, as well as operators handling directly or indirectly ma terials or technical devices giving off ionizing radiation, such as radioactive static eliminators (Silson; Berman and Ernest; Bryan and Silver man), 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 blood forming organs have resulted from excessive exposures to radioactive substances affecting the organism or parts of it by various routes. There exists a great deal of highly suggestive, if not conclusive, epidemiological and experi mental 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, X-radiation) alone may produce in man and experimental animals a fibrosis of the lungs (Kalbfleisch; Doenecke; Belt; Bergmann and Graham; En gelstad; Warren and Gates; Leach, Farrow, Foote and Wawro; McIntosh; Warren and Spencer; Widmann; Bauer; Bauer and Schraer; TongeS'and Kalbfleisch; Freid and Goldberg), occupational exposure to radioactive dust and gases has often been complicated by simul taneous inhalation of dust containing various metals (chromium, nickel, iron, arsenic, cobalt) as well as silica. Pulmonary cancers observed among radioactive-ore miners, therefore, have been 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 radium refinery workers has been doubted by some investigators, who felt that one of the various nonradioactive metals or the silicosis represented the main causal or an important contributory agent (Schinz; Lorenz; Schmorl; Rostoski and Saupe) or that the available evi dence did not provide absolute proof of a radio active genesis (Lacassagne). Several investi gators felt that the lung cancers among the radioactive-ore miners in Schneeberg and Jo achimsthal were principally attributable to a hereditary predisposition created by inbreeding of the mining population (Macklin and Maeklin; Lorenz; Yesin). 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 sub sequently mentioned by other investigators (Henckel: Scheffler; Thiele). However, it was not until 1879 that its malignant neoplastic character was correctly recognized (Harting and Hesse). This judgment was, subsequently confirmed by Cohnheim; Aucke; Arnstein; Uhlig; Risel; Schmorl; Beyreuther: Rostoski. Saupe and Schmorl; Lange; Xeitzel: Dohnert; Baader: Teleky: Hueck; Rostoski, Saupe, and Schmorl; Thiele; Weber; Koelsch; Linde mann: 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 (Lowy). 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. Lowy reported 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 radiodermatitis, leukemia, and lung cancer. A similar observation was recorded by 40 Teleky and bv Xeitzel in a German technician of a radium laboratory. The cancerous lung was found to be radioactive. Four cases of lung cancer have recently been observed, according to Baader, among the workers employed in the radium ore processing plant in Belgium, where the occurrence of such complications was pre viously said to be absent (Maisin, citing Delaet i. 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 that lung j cancers may originate from radioactive material j used medicinally, when such materials become ; arrested in the lung. ) Mention may also be made in this connection j of a report of Martland relating the occurrence of cancer in the ethmoid cells in a luminous dial painter, and of two additional cases re- | 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 paranasal sinus. The four cases of cancer of the lung recently ' reported in an industrial population at an k atomic pile site, however, are definitely not causally related to any specific radioactive ex posures sustained by the workers concerned. In these cases exposure and latent period were insufficiently long to cause lung cancer (Love). On the other hand, the argument that these workers w e r e , p a r t , not directly concerned j with radioactive material carries little weight. Doubtlessly, they had at times environ mental contact with such a material when the meteorologic conditions were unfavorable for the ready dispersal of radioactive wastes at this particular operation. . In favor of an occupational and radioactive origin of the lung cancers among the Schneeberg and Joachimsthal miners is, moreover, the fact that the excessive liability to pulmonary neo plasia is limited to the workers employed under ground and is absent among the workers employed aboveground, and among the popula tion at large of Schneeberg and Joachimsthal. including the employees of the cobalt pigment plant using the Schneeberg ores (Bauer; Schmorl). An excessive lung not been found an Johann Georgens' have a low radi< more, no valid ev of arsenic-, chror containing ores ai a rate even rom among the two ra The attack rat Schneeberg mine tween 75 and 80 of the Joachimstl range from 40 t< incidence rate mt recent statement during the period of ltmg cancer w sable diseases am 323 miners ernplo ering the fact t period of lung <: ranges from Id tr sumed that thes< in a miner popul400 members wo 1920 and 1930. : at Schneeberg is years for the majt ally to be as short Sehraub, and Ka The total num died from' cancer 1939. according t approximately 4' achimsthal miner has reached 22c nurr.her of these at a relatively ea data given in tal the definite shift M easurement? Schneeberg and onstrated that, ii ha ve an excessiv passing many tin (Joachimsthal 5 Behounek and I Lorenser: Lan; It was suggestet of pneumatic dt Environmental Cause* o f Cancer of the Lung P u b lic H ealth Moi API 06441 ;"^Jnns ' n? ; . inR '(i thp 11 -IiPr* v^as per.. Oplapf i )ilv e o la r ars aftor lorotra 1'at ]un^ materia] beoome 'mcction 'urrence ominous uses rern. an<l ingested ppositei] ircomas, ii. thus, of the recently i at an ely not ti>-es:>' d. oa were (Love), it- these ncerned "'eight, nvironhen the able for istes at inactive neeberg lie fact ry neounder workers populatmsthal, figment hmorl). eisivc Inns i-ancer attack rate. also, has been found among the miners of the nearby Georgenstadt region, where the mines a low radioactivity. There is, furtherno valid evidence on record that miners ("arsenic'' chromium-, nickel-, and bismuth^Dtaining ores are affected by lung cancers at 1 ^te even remotely approaching that seen * ioDg the two radioactive ore miner groups. pbe attack rate of lung cancer among the .,hDeeberg miners has consistently been be fen 75 and 80 percent since 1879, while that the Joachimsthal miners has been stated to from 40 to 50 percent. However, this ^idence rate may be too low. considering the ,ent statement of Baader, who noted that jurine the period 1939-43, a total of 180 cases 0f lung cancer were acknowledged as compen^ble diseases and that in 1929 there were only >13miners employed at Joachimsthal. Consid ering the fact that the exposure and latent period of lung cancer in Joachimsthal miners 1 rn?es from to 23 years, it may justly be as sumed that these lung cancer cases originated n a miner population of approximately 300 to 400 members working at these mines between 1920 and 1930. The exposure and latent period 4t Scbneeberg is stated to vary from 15 to 18 rears for the majority of the cases, but occasion ally to be as short as 7 years (Baader; Rajewsky, Schraub, and Kahlau). The total number of Schneeberg miners who died from cancer of the lung between 1879 and 1939. according to available records, stands at approximately 400, while the number of Jo achimsthal miners who fell victim to this disease has reached 225 (1926--13). An appreciable number of these miners died from lung cancer at a relatively early age as is evident from the data given in table 19 (page 16), which shows the definite shift toward younger age groups. Measurements of the radioactivity of the Schneeberg and Joachimsthal mines have dem onstrated that, in both places, mine air and dust have an excessive degree of radioactivity sur passing many times the maximal tolerance dose Joachimsthal 30 times (Peller); Behounek; Behounek and Fort; Tschelnitz; Ludewig and Lorenser; Lange; Rajewsky; Stocklasa). It was suggested that the recent introduction of pneumatic drills -into these mining opera tions aggravated the hazard hy iiicfvit.-uisr tne production of fine particulate dust containing solid radium. Repeated attempts have been made to pro duce cancers of the respiratory tract in experi mental animals exposed to the inhalation of radium emanation and/or radioactive mine dust iSrhmidtmann; Lowv; Campbell; Dohnert; Kahlau; Rajewsky, Schraub. and Kahlau). Schmidtmann obtained neither pneumoconiosis nor pulmonary cancer in animals exposed for 2 years to the inhalation of Schneeberg mine dust collected from drill holes. Campbell, on the other hand, reported that mice which inhaled dust of Czechoslovak pitchblende displayed a significantly increased number of pulmonary tumors. In experiments of Dohnert 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 "ab normally" high percentage of the exposed animals. However, the actual number of affected animals was small, and the interpreta tion of the results as to their significance was therefore difficult. Kahlau and Rajewsky, Schraub, and Kahlau subjected mice to the inhalation of radon. Many of the animals developed bronchial lesions characterized by an atypical epithelial lining as well as by pulmonary adenomas (in 7 of 12 mice of the test series, against 1 in the control series). While they concluded from this evidence that the radioactive origin of lung cancers in Schneeberg and Joachimsthal miners was confirmed, it seems to be advisable to con sider the evidence obtained by these investi gators as highly-suggestive, but not conclusive, because great variations in the incidence rate of lung tumors occur among different groups of mice belonging to noninbred strains. Additional, mildly suggestive observations have been reported by Lorenz, Heston, Eschen brenner, and Deringer as well as by Henshaw, Riley, and Stapleton. Both groups of investi 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 he Lung hU ie Health Monograph No. 36, 1955 41 API 06442 greater significance in this connection are the findings of Liseo and Finkel, who found meta plastic and neoplastic proliferations of the bronchial epithelium in rats inhaling an aerosol of radioactive cerium. Similar results were obtained with plutonium brought into the lungs of rats. Since uranium ore miners inhale not only radon and radium dust but also uranium, which may be retained in the lungs, Hueper, Zuefle, Link, and Johnson injected metallic uranium powder dispersed in lanolin into the pleural and femoral cavities of rats and obtained sarcomas at the sites of injection in 13, or 24 percent, of the 54 rats surviving the minimal latent period of 6 months. Evidence thus produced shows that focal accumulations of uranium, which is an alpha-radiation emitter, may exert a cancerigenic action upon the surrounding tissues, but it does not discriminate between the influence of metal toxicity per se and radioactivity in the genesis of these lesions. From a critical evaluation of the epidemio logical. clinical, and experimental evidence available, it appears that a prolonged inhalation of radioactive gases and/or dust may elicit pulmonary cancers in man (Martland; Evans). In commenting on the production of lung cancer by atmospheric carcinogens, an editorial (Lancet, 1952) remarked, "radioactivity of Joachimsthal mines is stated to be 30 times the tolerance dose. It is scarcely surprising, there fore. that in the past more than half the miners died of lung cancer." It Btands to reason that this effect on the lungs of workers will prevail wherever similar conditions of exposure to radioactive gases and dust exist. The excessive suicide rate observed in the past among the miners in Joachimsthal (Sikl) aptly reflects the human misery produced if such hazardous working conditions are permitted to persist. While there thus can belittle, if any, doubt of the principal role of ionizing radiation in the production of lung cancers among radioactive ore miners and similarly exposed occupational groups, some comments on the possible signi ficance of pneumoconiosis in eliciting or modi fying this effect may be indicated. Reports on the occurrence of pneumoconiosis among the miners in Schneeberg and Joachims thal are contradictory. While Schmorl as well as Rostoski, Saupe, and Schmorl in their early reports (1926, 1928) noted that Schneeberg 0re miners in miners suffer from more or less intense anthra- 1 Whether it bar cosilicosis and that this condition was causing cancerization ] or favoring the development of the bronchial cancers, Rostoski and Saupe stated in 1930 that pneumoconiosis was usually not very extensive in cancerous lungs. Because of the relatively slow course of the pulmonary tumors, Rostoski and Saupe felt that pneumoconiosis may slow the intrapulmonary growth of the tumors. the establishei Finally, it m cancers vary a turc. Many t others, round while a few w. The radioacth Hueck, on the other hand, remarked that silicosis does not represent a precancerous con this respect t other occupt! dition for the Schneeberg lung cancers. .Some of the miners had silicosis but not lung cancer, The rapidly radioactive m while others had lung cancer but not silicosis. tioned, markc' Similar discrepancies seem to prevail con limited workci cerning the Joachimsthal miners. Ziel in 1935 population to i reported that marked silicosis among these radioactive m; miners is quite frequent and that ashed lungs I represents a p> contain large amounts of silicon oxide. Pirchan I of serious prop and Sikl, on the other hand, maintained that no | cancer from su pneumoconiosis could be found, in spite of an , to past expen abundance of pneumatic drilling, and that ores. Thereh pneumoconiosis has no role in the production of the degree of the lung cancers. This opinion was shared by active contan Lowy. Sikl, in his most recent communication neighborhood on the subject, stated that some degree of and operation fibrosis suggestive of silicotic origin could, of , supervision co course, be seen in the cancerous lungs, and there active effluem were single cases of marked silicosis combined ments, are ur<. with cancer. On the whole, however, silicosis the health of t was not a prominent feature in cases of cancer: on the other hand, the lungs most heavily 1 affected with silicofibrosis were generally free from malignant growth. Behounek and Fort noted thaf pneumoconiosis was recorded as the cause of death in only 8.2 percent of 63 miners who came to autopsy between 1929 and 1938. This statement contrasts strikingly with the observations made by Saupe during a The compj chest X-ray study of 398 Joachimsthal miners analysis of th conducted in 1939. He found that 43.4 percent and experime? of these miners presented roentgenological enous respirm evidence of pulmonary silicosis. However, silicosis was of minor degree among the < leave no doul occupational miners who were suspected of having pul general popuh monary neoplasms. Although the data are in part contradictory, contacts with For most o it seems that silicosis does not play any sig nificant role as a direct or contributory cause of cancer of the lung among the radioactive- sive proof of by epidemiok data. One < 42 Environmental Causes of Cancer of the Lunf Public Health API 06443 ,Ah, idienie uritf ' 7 p^ af rausinfc ,f hron^ia| le a in 1930 th 4, ' very extensive f the relatively amors. RostosC liosis may si0^ *f the tumors remarked that ecaneerous Con cancers. Some' tot lung cancer t not silicosis. ' io prevail Con. s. Ziel in 19.35 among these iat ashed lungs ixide. Pirchan ntained that no . in spite of an ling, and that ie production of was shared bv communication ome degree of rigin could, of ungs, and there eosis combined >W silicosis -a. jf cancer; most heavily generally free unek and Fort ts recorded as percent of 63 ween 1929 and strikingly with upe during a msthal miners t 43.4 percent entgenological However, among the 7 having pul- contradictory, play any sigmtory cause of e radioactive- Ln ''imeeberg and Joachimsthal. tttkiter.s. has an antagonistic effect upon the ether ^ r i z ftt'on Proress or mdifies the course of if**1 ,tablished cancer remains problematical. ^finally1 mav ment,ined that these lung ^ers vary a great deal in histological struc- ^ ylanv were squamous cell carcinomas; Hire- - roun d cell or anaplastic carcinomas; 'Tie a few were of adenocarcinomatous type. T radioactive lung cancers, thus, follow in respect the general pattern set by all ^er occupational cancers. fbe rapidly growing production and use of inactive material and the thereby condi- Ded, markedly increased exposure of some limited worker groups as well as the general Ouiation to gases, dusts, and mists containing dioactive matter of long half-life doubtlessly ^presents a potential respiratory cancer hazard f serions proportions. The attack rate of lung ^ncer from such sources is very high, according w past experience with miners of radioactive oreS, Therefore, a competent assessment of jje degree of exposure to atmospheric radio^ v e contaminants for worker groups and ,,eighborhood populations of radioactive plants md operations, and the continuous and strict supervision concerning the amounts of radiosctive effluents emitted from such establish ments, are urgently necessary for safeguarding (he health of these individuals. T able 26. L ate n t periods of e n v iro n m en tal resp ira tory cancers, in m o n th s (H ueper) Cancer of -- Agent LuDg Xares and nasal sinuses Average Range Average Ranee latent of latent latent oflater period period period periox. Asbestos__________ 1 18 Chrom ates................. 15 N ickel......................... 22 Tar fumes...... ............ 16 Isopropvl o il_______ Ionizing radiation__ 25-35 15-48 5-47 6-30 9-23 7-50 11 3-26 10 6-16 25 19-32 Intensive studies also are needed for deter mining whether, through radioactive fallouts, the inhalation of highly radioactive dust par ticles diffusely settling in the bronchial mucosa and producing there minute foci of high inten sity 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 The comprehensive panoramic view and analysis of the total epidemiological, medical, and experimental evidence available on exog enous respiratory carcinomas and carcinogens leave no doubt of the fact that not only large occupational population groups but also the general population have definite and prolonged contacts with one or several of these agents. For most of these agents, adequate conclu sive proof of their carcinogenicity is provided by epidemiological, medical, and experimental data. One of several specific carcinogenic chemicals-has been isolated from several agents representing variable chemical mixtures (soot, 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 cir cumscribed total populations at risk is suffi ciently reliable to prove the presence of an occupational respiratory cancer hazard causally -er of the Lung Pahlic Health Monograph No. 36, 19SS 43 Mutt'il to u specific industrial operation. Epi demiological. medical, and experimental data concerning these respiratory carcinogens attest their high carcinogenic potency under occupa tional conditions, particularly when acting on humans. It is therefore reasonable to assume that inhalation of the same agents, in a miti gated form as air pollutants, by the general population is responsible for a considerable portion of the lung cancers attributable to such contacts. If this coherent and logical picture presented by the evidence supporting the various occupa tional respiratory cancers and, especially, the coal tar fume cancer of the lung, is compared with that available for the cigarette smoke lung cancer, even upon superficial examination, several additional serious defects and inconsis tencies not previously pointed out become apparent. It is surprising to note the absence of positive statistical associations between lung cancer and cigarette cough, although this latter symptom is clinically characteristic of chronic chain smokers. Despite the fact that the lips and oral mucosa are constantly bathed in the tarry liquor oozing from the tip of the cigarettes and despite the contact of these parts with the smoke coming from the cigarettes, there is no consistent statistical association with cancer 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 brown-stained 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 cancere of the hands for which records are available. In an attempt to provide an explanation for 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 clude upon a sort of racially conditioned tissue immunity for explaining the observation of Lipschitz. who reported in 1931 (hat tin* sumps, records of a large -Jewish hospital in Warsaw Poland, showed a lung cancer frequency of $.9 I qpuerecnecnyt ooff 1a5l.l3 cpaenrcceernst ffoorr nJoewn-sJeawgsa,inesstpeaciaflrley l in view of the fact that Eastern -Jews are par ticularly prone to develop thromboangiitis obliterans, which has the best established causal relations to tobacco smoking. The claimed absence of a positive associa tion between lung cancer and the habit of inhaling i , cigarette smoke also is inconsistent with the rule that the incidence rate of occupational cancers increases with the intensity of exposure to a carcinogen. The medical considerations on cigarette smoke cancer of the lung th u s rdeevfeecatls aannducmobnetrradoifctsioerniso.us and fundamental > The best that can be said about the experi f mental evidence on hand regarding carcinogenic properties of tobacco tar is that it indicates the carcinogenic agents in some cigarette tars through the use of hyperreactive animals. There is no evidence that these observations of the skin of a strain of selectively inbred mice have any equivalent in man. Thus the prac tical importance of these observations as to cancer of the human lung is at present uncer tain, especially since Passev, in recent experi ments on mice painted for 16 months with tobacco tar, was unable to elicit a single cancer of the skin. From' these considerations, it is apparent that any final decision concerning the relative role of cigarette smoking in the causation of cancer of the human lung should be kept in abeyance until a great deal of additional and more valid, and especially medically conclusive, evidence becomes available. The data on hand make it unlikely that cigarette smoking repre sents a major factor in the production of lung cancer and in its recent phenomenal rise in frequency. For these reasons, it would be most injudicious mainly to base the future preventive control of lung cancer hazards on a theory of such doubtful scientific merits and to concen trate the immediate epidemiological and experi mental efforts on this apparently overprop agandized concept. The apparent wisdom of such an attitude is readily apparent from the fact that not only a great deal of the circum- 44 Environmental C ja w i ot Cancer of the Taut Utopsy arsaw, of 8.9 a freecially e parangiitis lished epidemiological evidence but also ^ctically the entire factual and conclusive jridence available on specific exogeneous causes gl respiratory cancers indicates that these oncers are either of occupational origin or points to industry-related factors. Not only lirge occupational groups but also the members of the general population have contact with lEtion these agents in various forms and intensity. hiding 'h the iti anal nosure ai ions ' thus . lent al xperigenic *-s the tars ; .mais. >ns of mice pra^ is net. .periwith incer irent rtti V i li of t ill and rive, and i preung in .lost uve y of <-en>enrop- T' l of the um- r Finally, it may be noted that the evidence on hand justifies the viewpoint that, in arriving at a 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. Public Health Monograph No. 36, 1V55 45 Beyreuther, H einem Fall vo enkrebs und Bibliography Anat. u. Phy Bidstrup, P. L.: Brit. J. Indu: Adler, I.: Primary malignant growths of the lungs and bronchi. Longmans, Green 4 Co., 1912, p. 39. London. Baader, E. W .: Der Lungenkrebs als gewerbemedi zinisches Problem. Verhandl. d. deutsch. Kongr. f. Inn. Med. 57. 322-332 (1951). B idstrup, P. L and chromat Hyg. Md. d A lfflldge;'^, Barnes. J., and Denz, F. A.: Experimental Baader, E. W., and Holstein. E.: Gewerbekrankheiten. Bielschowsky, beryllium poisoning. Brit. J. Exper. Pathl. 30: 375 389 (1949). Neue Deutsche Klinik, 7. Erg. Bd., Berlin-W ien, 1940-1941. > aminofluoren Exper. Path Alwens, W.: Der Chromatlungenkrebs. Proc.. 8t.h Baetjer. A. M .: Pulm onary carcinoma in chromate Blacklock. J. 5 Internat. Kongr. f. Unfallmed. u. Berufskrankh., workers. Parts I and II. Arch. Indust. Hyg. 4 1 and Urquha Budapest, 1938. Leipzig, Georg Thieme, 1939, p. Occup. Med. 2: 505-516 (1950). ' human lunc- 973-982. Barnard. C. I.: Rockefeller Foundation. A review for 8:40-55 (19V Alwens. W., Bauke, E. E., and Jonas, W .: Auffallende 1949. New York, The Foundation, 1950. Bloomfield. J. Hufung von Bronchialkrebs bei Arbeitern der Barnes, J. M.: Experim ental production of malignant R. T.. and 3 chemischen Industrie. Arch. f. Gewerbepath. 7 :6 9 tum ors by beryllium. Lancet 1: 436--464 G950). ' the industria 84 (1936). Barnes, J. M., Denz, F. A., and Sissons, H. A.: Beryl Pub. Health Alwens. W., and Jonas, W .: Der Chromatlungenkrebs. lium bone sarcomata in rabbits. Brit. J. Cancer Boemke, F.: Acta Unio Internat. Contra Cancrum 3: 103-114 4: 212-222 (1950). staublunee. (1938V Bauer, K. H .: D as Krebsproblem. Berlin, J. J. 1 Bhme, cited 1 Alwens, W., and Jonas. W .: Ein weiterer Beitrag zr Springer, 1949, p. 758. Am. J. Path. 16: 657-658 kreb.-. Deu Frage des gewerblichen Lungenkrebses. Arch. f. (1940). . 1 Bohnen kamp. Gewerbepath. 7: 532-537 (1936-37). Amor. A. J.: Growths of the respiratory tract. Proc. Bauer, J. T., and Schraer. P. H.: Late pathological 1 effects of high voltage X-rays upon the human lung. In Proc.. > Berufskrank 8th Internat. Congr. Industr. Med. 2: 941-958(1938). Bauke, F., and Alwens. W.: ber rntgenologische ` Thieme. 193 Anor. A. J . : Nickel carbonyl. In Occupation and Lungen-und insbesondere Lungenwurzelvernder Bourne. H. G. health. An encyclopedia of hygiene, pathology and ungen bei Arbeitern der chemischen Industrie. 1 lution in rtn welfare. Supplement. Geneva, International Labour Verhandl. d. deutsche Gesellsch. f. inn. Med Kong. Med. 4 Sun. Office, 1938. Looseleaf, pp. 1-5. Andrievskaya, Z. M., and Mislavaskaya, M. M.: 48: 199-202 (1936). ' Behounek, F .: Verhltnisse der Radioaktivitt im Bourne, H. G. a chroman Silicosis in a chromite mine and its prophylaxis. Gig. Uranpecherzbaurevier von St. Joachimsthal. Bhm. Indust. Mec I. Sanitr. Moscow 5: 28-30 (1949). Physik. Ztschr. 28:333-343 (1927). | Brandt. A.: B Araki, M., and Mure. K.: Spectrographic analysis of tissues: On quantitative analysis of nickel in tum or tissue. Gann 40: 76-79 (19491. Behounek, F., and Fort. M.: JoachimsthalerBergmanns krankheit. Strahlenther 70:487--498 (1941). Belt, T. H.: b e r tdliche Lungenfibrose bei gewerb auf Veranla: bekiimptung Ztschr. f. Ki Arguello, R. A., Tello, E. E., Macola, B. A., and Man licher Radiumschdieung. Frankf. Ztschr. f. Path. ! Breslow. L.: zano, L .: Cutaneous cancer in chronic endemic 42: 170-187 (1931-32). ' Pub. Health regional arsenicalism in the Province of Cordoba, Berblinger. W .: Die Zunahme des Primren Lungen Breslow. L.. H Argentine Republic. Rev. Fac. cienc. med. Univ. krebses io -d e n Jahnen 1920-24. Klin. Wchschr. ` H. K.: O er Cordoba 8: 409-432 (1950). 4: 913-916 (1925). in lung cat Arhelger. S, S., and Kremen. A. J.: Arsenical epithe Berblinger, W.: Zunahme des Lungenkrebses und (1954 . lioma of medicinal origin. Surgery 30: 977-986 (195]'. ' Staublungenkrankheiten. Med. Klin. 27:1337 (1931) Berenblum, I.: Carcinogenic constituents of coal tar. ' Brezina. I..: krankheitei Arnstein. A.: Sozialhygienische Untersuchungen ber die Bergleute in den Schneeberger Kobaltgruben, insbesondere ber das Vorkommen des sogenannten Schneeberger Lungenkrebses, sterr. San. Wes. Wien Beiheft 25: 64-83 (1913.) Aub, J., Evans, R. D., Hempelmann, L. H., and M artland. H. S.: The late effects of internally deposited radioactive materials in man. Medicine 31: 221-329 (1952). Aucke: Der Lungenkrebs in den Schneeberger Gruben. Inaug. Diss. Mnchen, 1884. Baader. E. W., Berufskrebs. In Neuere Ergebnisse auf dem Gebiet der Krebskrankheiten, edited by C. Dam and H. Auler. Leipzig, S. Eirzel. 1937, p. 104-128. Brit. J. Cancer 1: 157-165 (1947'. Berenblum, I., and Schoental. R.: Carcinogenic con stituents of shale oil. Brit. J. Exper. Path. 24: 232- r 239 (1943). Bergmann, M.. and Graham, E. A.: Pneumonectomy for severe irradiation damage to lung. J. Thoracic Surg. 22: 549-567 (1951). Berman, F. A., and Ernest, E. P .: Use of radioactive static eliminators in printing. Indust. Med. 4 Surg. 19:229-230 (1950). Beutel, A., and Woldrich, A.: Klinische und rntgeno logische Beobachtungen ber die Entwicklung des Joachim sthaler Bronchialcarcinoms. Ztschr. f. Krebs forsch. 34: 109-122 (1931). Bridge. J. C.~. and work-1 Office. 1931 Brockbank. cancer. Q' Bryan. F. A... hazards freu devices. 3 Aua. 12. lb Buckeil. M >tudy of t) Med. 8:2: But zengeiger.. der Winzer 46 Environmental Catueg o f Cancer o f the Lung Public Healt iS*-,.-* - API 06447 ' gewerbemedi.. 'utsch. Kongf' rbekrankheiten .. Berlin-W ien' a in chrom ate ndust. Hyg. 4 .. A review f0r 1950. m of malignant 1--464 (1950V H. A.: Beryl. Brit. J. Cancer Berlin, J, j h. 16:657-658 te pathological 'ip hum an lung, mteenologische vurzelveranderhen Industrie. n. Ivied. Kong. ioaktivitt im msthal. Bhm, M e ' Tnanno. 1. -e bei gewerh'schr. f. Path. ihren Lungenin. Wchschr. nkrebses und '7:1337 (1931V .= of coal tar. inogenic con'ath. 24: 232- 'u m o n e c to m y .1. Thoracic f radioactive Med. & Surg. md rntgeno.wicklung des -ehr. f. Krebs- J .fguther. H.; Multiplicitat von Carcinomen bei ^eiue F8** V0D i 0 8enftnnCem- "Schneeberger'' Lung,,krebs und Tuberkulose. Virchow's Arch. Pathol, f knat. u. Physiol. 250: 230-243 G924V n dstrup, P. L .: Carcinoma in lung of chromate workers, grit. J. Indust. Med. 8 : 302-305 (1951'. Bidstrtip, P. L .: Cancer of the lung in nickel, arsenic #nd chromate workers. Arch. Biges d. Med. Soc., jjvp. Med. d Trav. et M id. L ie. 8 : 500-500 (1950V gjeischowsky, F.: D istant tumors produced by 2aminofluorene and 2-acetylaminofluorene. Brit. J. xper. Path. 25: 1--t (1944). glacklock, j . W. S., Kennaway, E. L.. Lewis. G. M., and L'rquhart, M. E.: The carbon content of the human lungs and bronchial glands. Brit. J. Cancer g: 40-55 (1954). Bloomfield, J. J., Trasko. V. M., Sayers, R. R., Page, r . T., and Peyton. M. F.: A preliminary survey of the industrial hygiene problem in the United States. Pub. Health Bull. No. 259., 1940. p. 132. Boemke, F.: Das Lungenkarzinom in der Asbest staublunge. Med. Monatsschr. 7: 77-81 (1953). Bhme, cited by H. W. Wedler, Asbestos und Lungen krebs. Deut. med. Wchnschr. 69:575-576 (1943). Bohnenkamp, H.: ber chronische Arsen Vergiftung. ln Proe., 8th Internat. Kong. f. Unfallmed. u. Berufskrankh., Budapest, 1938. Leipzig, Georg Thieme. 1939, vol. 2. p. 1069-1072. Bourne. H. G., and Rushin, W. R .: Atmospheric pol lution in the vicinity of a chromate plant. Indust. Med. <fc Surg. 19:568-572 (1950). Bourne, H. G., and Yee, H. T .; Occupational cancer in a chromate plant: An environmental appraisal. Indust. Med. & Surg. 19: 568-572 (1950). Brandt, A.: Bericht liber die im Schneeberger Gebiet auf Veranlassung des Reichsausschusses fr Krebs bekmpfung durchgefhrten Untersuchungen. Ztschr. f. Krebsforsch. 47: 108-111 (1938). Breslow, L .: Occupational factors in lung cancer. Pub. Health Rep. 6 8 : 286-288 (1953). Breslow, L., Hoaglin. L., Rasmussen, G., and Abrams, H. K.: Occupations and cigarette smoking as factors in lung cancer. Am. J. Pub. Health. 44: 171-191 (19541. Brezina. E.: Internationale bersieht ber Gewerbe krankheiten. Berlin, J. J. Springer, 1929. Bridge. J. C .: Annual Report chief inspector of factories and workshops. London, His M ajesty's Stationery Office. 1931, 1936, and 1941. Brockbank, VV.: Occupational incidence of primary lung cancer. Quart. J. Med, 1:31--40 (1932). Bryan, F. A., andSilverm ann, L. B.: Internal radiation hazards from the use of polonium in static eliminator devices. U. S. Navy Med. News Letter 14: 22-26, Aug. 12, 1949. Buckell, M., and Harvey, D. G.: An environmental study of the chromate industry. Brit. J. Indust. Med. 8:298-301 (1951). Butzengeiger, K. H.: Die chronische Arsen Vergiftung der Winzer. Xrztl. Wchenschr. 4 : 365-369 (1949). Campbell. J. A.: Cancer of the -km and increase on incidence of primary tum ors of the lung in mice ex posed to dust obtained from tarred roads. Brit. .1. Exper. Path. 15: 285-294 (1934), Campbell. J. A.: Cancer of the human lung and animal experiment. J, Indust. Hyg. 19:449-456 11937V Campbell, J. A.: Lung tum ors in mice and man. Brit. Med. J. 1: 179-183 (1943). Cannon, A. B.: Chronic arsenical poisoning. Symp toms and sources. New York State Med. J. 36: 219-241 (1936). Carozzi, L .: Le cancer professionnel. Arch, d 'lctr. md. 42: 85, 118, 155 (1934). Cartier, P .: Discussion on asbestosis cancer of the lung. Arch. Indust. Hyg. & Occup. Med. 3: 262 263 (1953). C artier. P.: Some clinical observations of asbestosis in mine and mill workers. Arch. Indust. Health. 11: 204-207 (1955). Chamberlain, C. W.: Arsenical poisoning in industry. Indust. Med. 4 Surg. 3: 286-288 (1934). Clemmesen, J .: Bronchial carcinoma. A pandemic. Danish Med. Bull. 1: 37-46 (1954). Clemmesen, J., Nielsen, A., and Jensen. E.: The in crease in incidence of carcinoma of the lung in Denmark, 1931-1950. Brit. J. Cancer 7:1-9 (1953). Cohnheim, cited by H. R. Dhnert: Experimentelle Untersuchungen zur Frage des Schneeberger Lungen krebses. Ztschr. f. Krebsforsch. 47:209-239(1938). Cooper, E. H.: An im portant factor in the causation of industrial cancer. Med. Press 187:397-398 (1933'. Cooper, R. L .: Atmospheric pollution in Salford. Chem. & Industry 1364-1365 (1953). Cruickshank, W. H.: Report on cancer in industry. Ontario, Canada, Division Industrial Hygiene, 1941. p. 14. Cureton, R. J. R.: Squamous cell carcinoma occurring in asbestosis of the lung. Brit. J. Cancer 2: 249--253 (1948). _ Curwen, M. P., Kennaway, E. L,, and Kennaway, N. M,: Cancer of the lung and larynx in town and country. Acta Internat. Unio C ontra Cancrum 10:104-109 (1954). Denk, W.: Bemerkungen zum Bronchialkarzinom. Beitr. z. klin. Chir. 186: 282-290 (1953). Derischanoff. S. M.: Zur Statistik und Genese des Lungenkrebses. Ztschr. f. Krebsforsch. 35: 481-491 (1932)."' ' Desmeules, R., Rousseau, L., Giroux, M., and Sirois, A.: Amiantose et cancer pulmonaires. Semaine d. Hop. Paris 231: 1820-1823 (1947). U. S. Public H ealth Service: H ealth of workers in chromate producing industry. Public Health Service Pub. No. 192. Washington, D. C., U. S. Govern m ent Printing Office, 1953, p. 131. Doenecke, F.: ber tdliche Lungenfibrose hei gewer blicher Radiumschdigung. Frankf. Ztschr. f. Path. 42: 161-169 (1931-32). Dhnert, H. R.: Experimentelle Untersuchungen zur Frage des Schneeberger Lungenkrebses. Ztschr. f. Krebsforsch 47: 209-239 (1938). o f the Long Public Health Monograph No. 36, 19SS 47 Doll, R .: The causes of death among gas workers with special reference to cancer of the lung. Brit. J. Indust. Med. 9: 180-185 (1952). Doll, R.: Mortality from lung cancer among asbestos workers. Brit. J. Indust. Med. 12: 81-86 (1955). Doll, R .: The m ortality of doctors in relation to their smoking habits: A preliminary report. Brit. Med. J. 1: 1451-1455 (1954). Doll, R .: Study of the aetiology of carcinoma of the lung. Brit. Med. J. 2: 1271-1285 (1952). Doll, R., and Hill, A. B.: Bronchial carcinoma: Inci dence and aetiology. Brit. Med. J. 2: 521, 585 and 590 (1953). Domenici. cited by F. Koelsch in Krebs der Luftwege und seine berufliche. Verursachung. Arch. f. Gewerb- epath. u. Gewerbehyg. 5:455-470(1935). Dorn, H. F.: Incidence and prevalence of cancer of the lung. Pub. Health Rep. 58: 1265-1271 (1943). Doubrov, S.: Les cancers du poumon d 'origine pro fessionnelles. Paris mdd. 1: 287-290 (1931). Dreyfuss. T. R.: Lungencarcinom bei Geschwistern nach Inhalation von eisenoxydhaltigern Staub in der Jugend. Ztschr. f. klin. Med. 130: 256 (1936). Druckrey, H.. and Schmhl, D.: Cancerogene Wir kungen von Kunststoff-Folien. Ztschr. f. N atur forsch. 7b: 353-354 (1952). Dnner. L.. and Hicks. M. S.: Bronchial carcinoma in dusty occupations in boiler scales and grain dockers. Brit. J. Tubere. 47:145-151 (1953). D utra. F. R., and Largent, E. J.: Osteosarcoma induced by beryllium oxide. Am. J. Path. 26: 197-202 (950).' Dutra. F. R.. Largent. E. J., and Roth, J. L.: Osteo genic sarcoma after inhalation of beryllium oxide. Arch. Path. 51:474-479 (1951). ' D utra. F. R.. Largent. E. J.. Cholak, J., Hubbard, D. M., and Roth, J. L.: Persistence of beryllium oxide in lungs after inhalation of dust. Arch. Indust. Hvg. A Occup. Med. 4:65-73 (1951). Eastcott. D. F.: Medical statistics of New Zealand for the year 1953. Wellington. New Zealand, D epart ment of Health, 1955. . Editorial: Atmospheric Carcinogens. Lancet. 2: 30 (1952). E hrhardt. W.: Differentialdiagnosis von Silikose und Lungenkrebs, und die Frage urschlicher Bezie hungen beider Erkrankungen. Arch. f. Geschwulst forsch. 1: 249 (1949). Eisenbud, M.. Berghout, C. F., and Steadman, L. T.: Environmental studies in plants and laboratories using beryllium. I. Indust. Hyg. A Occup. Med. 30: 281-285 (1948). Eisenbud. M.. W anta, R. C.. D ustan. C.. Steadman. L. T.. Harris. W. B., and Wolf. B.: Nonoccupational berylliosis. J. Indust. Hyg. A Occup. Med. 31: 282 294 (1949). ' Engelstadt, R. B.: ber die Wirkungen der Rntgen strahlen auf die Lungen. Acta Radiol. Supp. 19, 1934. pp. 1-94. Evans. E. H .: Casualties following exposure to zinc chloride smoke. Lancet 2: 368-375 (1945). 48 Falk. H., and Steiner, P. E.: The adsorption of 3, t 4-benzpvrene and pyrene by carbon black. Cancer FaRlke,sH. .1,2:an4d0-S43tei(n1e9r5,2P!.. E.: T' he identification of aro t matic polycyclic hydrocarbons in carbon blacks. Cancer Res. 30-33 (1952). Falk, H. L-, Steiner, P. E.. Goldfein, S., Breslow, A., and Hykes, R.: Caroinogenic hydrocarbons and related compounds in processed rubber. Cancer Res. 11: 318-324 (1951). Faulds. J.: Pulm onary disease in iron ore miners. An Exhibit. W ashington, D. C., Sept. 4-8, 1954. In ternational Conference Geographic Pathology. Faulds. J., cited in G. M. Bonser, J. Faulds, and M. J. Stew art: Occupational cancer. Am. J. Clin. Path. 25: 126-134 (1955). Fischer, H. G. M., Priestley, W., Eby, L. T., Wanless, G. G., and Rehner, J., Jr.: Symposium on cancer control program for high boiling catalytically cracked oils. Arch. Indust. Hyg. A Occup. Med. 4: 315-324 (1951). ' Fisoher, W.; Gewchse der Limgen und des Brustfells. Henke-Lubarsch; Handbuch der speziellen patholo gischen Anatomie und Histologie. Berlin, J. J. Springer, 1931, vol. III/3 . . Freid, T. R., and Goldberg, H .: Post-irradiation changes in lungs and thorax. Am. J. Roentgenol. 43: 877-895 (1940). Frommei. E.: Les tats pulmonaires prdisposant au cancer, considerations sur l'tiologie du cancer du poumon. Rev. d. md,, Paris, 44: 31 (1927). Fulton, J. S.: Carcinoma of the lung. Proc. Roy. Soc. Med. 42: 775-782 (1949). Gaffer, W. M., and Sitgreaves, R .: Disabling m or bidity and mortality from oancer among male em ployees of an oil refining company. Pub. Health Rep- 55: 1517-1526 (1940). Gardner, L. U. : Generalized pulmonary granulomatosis occurring among workers believed to be exposed to beryllium. In Transactions, 11th Annual Meeting, Industrial Hygiene Foundation of America. P itts burgh, The Foundation, '1947. t Gardner, L. U. : Osteo-sarcoma from intravenous beryl lium compounds in rabbits. Federation Proc. 5: 221 (1946). Gilliam. A. G.: M ortality attributed to lung cancer in the large cities of the United States in 1948 and 1949. J. N at. Cancer Inst. 15: 1307-1312 (1955). Gilliam, A. G.: Some aspects of the lung cancer problem Proc. 61st .Ann. Cong. Mil. Surg. of the United States. Washington, D. C., The Congress, 1954. Glovne, S. R .: A case of oat-cell carcinoma of the lung occurring in asbestosis. Tubercle 18: 100-101 (1936). Glovne, S. R .: Squamous cell carcinoma of the lung occurring in asbestosis. Tubercle 17: 5-10 (1935). G oldblatt, M. W., and Wagstaff. V. A.: Aspects of industrial medicine and hygiene in German chemical factories. British Intelligence Objective Subcom mittee. Final Rep. 1501, Item 24. London. The Subcommittee, 1948. Gnnet. M L.: 1 nasale chez des d. mal. profess. Goulden, F.. and identification oi means of the fb 3: 157-160 (194 Goulden, F., Ken Arsenic in the s Cancer 6: 1-7 ( Graham. E . A.: P consideration o Med. 27: 261-2 Gregorius. F.: 3 Arch. Indust, b Grenfell, cited by Le mdd. du tra Gross. E . : b e Wchenschr. 15 Gross. E .: Das f a pat ho logen. A Gross. E. and Alv Chromat her-' Kongr. f. Unf (1939). Gros-, E . . and h der Chromfarl 12: 164-176 il Grosze. H.: Hut Pathologischen Arch. f. Gescin G iithen. H .: Lui Xrztl. Wchnsci Haddow. A.: Tb. carcinogenesis. Fr. Homburge Paul B. Hoebei H arting, F. H.. * Bergkrankheit jahrsschr. b. i (N. S.) 30: 102 Hammond. E . C Cancer 7: 110( Hammond. E . C tween human M. A. 155: 13 Hanser. R.. and chronischer Ar 51: 305-321 (1 Harrison. C. V.. rent British a tumor problen 5: 242-263 (1! Heady. H.. and attributed to 3 : 3 ] 1-320 il" Henckel. K. F.: Freiberg. 1728 Hendry. J. A.. H A. L.: Cyto 6: 235-255. 3? Environmental Caiue* o f Cancer o f the Lung Public Health 1 API 06449 I n ..f ,3 tiiack. l'aneer 1 m of aro. caroon black? Breslow, A., anfl >ns and related ancer Res. 11 . ire miners. An 4-8. 1954. In. athology. uilds, and M. J . Clin. Path. 25; L. T.. Wanless, -ium on cancer ytically cracked `led. 4; 315-324 1 des Brustfells. ziellen patholo- Berlin, J. J Post-irradiation Roentgenol. 43; irdisposant au du cancer du 1927). Proc. Roy. Soc. Disabling mornong male em- Health granulomatosis be exposed to :inual Meeting, merica. Pitts- -avenous berylation Proc. 5; lung cancer in !948 and 1949. 55). ancer problem 1'nited States. 4. na of the lung 10-101 (1936). a of the lung 5-10 (1935). V: Aspects of rman chemical 'tive SubcomLondon. The ,,ier M L.: 15*"ix cas de perforation de la cloison l t a ale e h e d e s uiivrier- manipulant l'arsenic. Arch. mal profess. 9; 227-229 11948V -'ulden. P.. and Tipler. M. M.: Experiments in the f L,den(ification of 3: 4-benzpyrene in domestic soot by ( means of the fluorescence spectrum. Brit. J. Cancer 157-160 (1949). - u|den, P" Kennaway. E. L.. and Crquhart. M. E.; 0 arsenic in the suspended m atter of town air. Brit. J. > C ancer 61 1--( (19o2). -raham. E. A.: Prim ary cancer of the lung with special i consideration of its etiology. Bull. New York Acad. Med. 27: 261-276 (1951). Gregorius. F.: Lung cancer in chrom ate industry. ' 4rch. Indust. Hyg. 4 Occup. Med. 5: 196-197 (1952). Grenfell, cited by L. Carozzi. in Le cancer professionnel. Le md. du trav. 6: 1. 95 (1934). E.: ber beruflichen Limgenkrehs. Klin. W'chenschr. 15: 323 (1936). (ross. E.: Das Carcinom vom Standpunkt des Gewerbe pathologen. Angew. Chem. 53: 368-372 (1940). Gross- E. and Aiwens. \V.: Lungenkrebs durch Arbeit in I Chromat lierstellenden Betrieben. Ber. Internat. ) Koner, f. Cnfallmed. u. Berufskrankh. 2: 966-982 . 1939). Gross. E.. and Koelscli. P .: ber den Lungenkrebs in der Chromfarbenindustrie. Arch. f. Gewerbepath. 12: 164-176 11943). Grosze. H.: Hundert Jahre Luneenkrcbsstatistik des Pathologischen Instituts Dresden-Friedrichstadt. Arch. f. Geschwulstforsch. 5: 318-334 (1952). Gthert. H.: Lungenkarzinom und Lungentuberkulose. Xrztl. Wchnschr. 4: 513 949V Haddow. A.: The chemical and genetic mechanisms Ln carcinogenesis. In the phytopathology of cancer by Fr. Homburger and W. H. Fishman. N'ew York. Paul B. Hoeber. 1953, pp. 441-551. Hrting. F. H., and Hesse. W .: Der Lungenkrebs, die Bergkrankheit in den Schneeberger Gruben. Viertei jahrssehr. b. gerichtl. Med. u. ffentl. Sanittsw. (X. S.) 30: 102-132.296-309: 31: 313-321 (1879). Hammond. E. C.: Lung cancer and common inhalants. Cancer 7: 1100-1109 (1954). Hammond. E. C.. and Horn. D.: The relationship be tween human smoking habits and death rates, J. A, M. A. 155: 1316-1328 (1954). Hanser, R., and Simon, L.; Carcinom auf der Basis chronischer Arsenvergiftung. Ztschr. f. Krebsforsch. 51: 305-321 (1940-1941). Harrison. C. 5"., cited by W. E. Smith. Survey of cur rent British and European studies of occupational tumor problems. Arch Indust. Hyg. 4 Occup. Med. 5: 242-263 (1952). Heady, H.. and Kennaway, E. L .: Increase in deaths attributed to cancer of the lung. Brit. J. Cancer 3: 311-320 (1949). Henckel, K. F.: Von der Bergsucht und H uettenkrtze. Freiberg, 1728. Hendry, J. A., Homer, R. F., Rose, F. L.. and Walpole, A. L.: Cytotoxic agents. Brit. J. Pharmacol. 6: 235-255* 357-410 (1951). Hendry. J. A.. Rose. F. L.. and Walpole. A. L.: C yu- toxic agents. Brit. J. Pharmacol. 6: 201-234. .Line 1951. Henry. S. A.: Cutaneous cancer in relation to occupa tion. Ann. Roy. College Surg.. England 7: 425-454 (1950). ' Henry. S. A.: Cancer of the scrotum In relation to occupation. London. Oxford University Press, 1946. p. 112. ' Henshaw, P. S., Riley. E. F.. and Stapleton. G. E.: Plutonium project. Biologic effects of pile radiation. Radiology 49: 349-359 (1947), Herbich. J., and Xeubold, R .: Incidence and distribution of lung cancer in Austria. Ztschr. f. Krebsforsch. 60: 139-160 (1954). Hill, A. B,, and Faning, E. L.: Studies on the incidence of cancer in a factory handling inorganic compounds of arsenic. Brit. J. Indust. Med. 5: 32-36 (1948). Hoagland, M. B., Grier. R. S., and Hood, M. B.: Beryllium and growth. Beryllium induced ostoegenic sarcoma. Cancer Res. 10: 629-635 (1950). . Hofmann, P .: Die Gefhrdung der Tierwelt durch In dustrieabgase. Arch. f. Gewerbepath. 7: 670-672 (1937). Holleb. H. B., and Angrist. A.: Carcinoma in associ ation with pulmonary asbestosis. Am. J. Path. 18: 123-135 (1941). Holmquist. I.: Occupational arsenic dermatitis. Acta dermat-venereol. 31: (supp. 26) 1-214 (1951). Homburger, Fr.: The co-incidence of primary carcino ma of the lungs and pulm onary asbestosis. Am. J. Path. 19: 797-807 (1943). . Hopkins. R., and Van Studdiford. M. T .: Multiple epitheliomas and pigm entary dermatosis in a Xegro boy. Arch. Dermal. 4 Syph. 29: 408-421 (1952). Horning, R .: Betrachtungen zur Frage des Berufskrebses der Asbestarbeiter. Ztschr. f. Krebsforsch. 47: 281-- 287 (1938). Hueck. W .: Kurzer Bericht ber Ergebnisse anato mischer Untersuchungen in Schneeberg. Ztschr. f. Krebsforsch. 49: 312-315 (1939). Hueper, W. C.: Environmental cancer hazards caused by industrial air pollution. Arch. Indust. Hyg. 4 Occup. Med. 2: 325-328 (1950). Hueper, W. C .: Environmental lung cancer. Indust. Med. 4 Surg. 20: 49-62 (1951). Hueper, W. C .: Xickel cancers in rats. Texas Rep. Biol. dTMed. 10: 167-186 (1952). Hueper, W. C.: Occupational tum ors and allied diseases. Springfield. Illinois, C. C. Thomas, 1942, p. 896. Hueper. W. C.: Air pollution and cancer of the lung. Rhode Island Med. J. 36: 24-52 (1953). Hueper. W. C.: Environmental lung cancer Indust. Med. 4 Surg. 23: 463-467 (1954). Hueper, W. C.: Recent developments in environmental cancer. Arch. Path. 58: 360--399, 475--523, 645-4)82 (1954). Hueper. W. C.: Occupational and environmental pul monary cancers with special reference to pneumo coniosis. Proc., 7th Saranac Symposium on Pneu moconiosis, 1952. In press. of the Lung ( Public Health Monograph No. 36, 1955 49 Hueper, W. C.: Environm ental lung cancer. Ca nadian Cancer Conference, 1954. New York, Aca demic Press, Inc., 1955. vol. 1, p. 186-236. Hueper, W. C.: An analysis of the environmental causes of lung cancer. In Proc., Pharm aceutical M anu facturers Association. 1954, p. 149-178. Hueper, W. C. : Environm ental cancer. I n th e phvsio- pathology of cancer. E dited by F. Homburger and W. Fishman. New York, Paul B. Hoeber, p. 730- ill. Hueper, W. C., Zuefle. J. H.. Link, A. M., and Johnson, M. G.: Experimental uranium cancers in rats. J. N at. Cancer Inst. 13: 291-305 (1952). Hugounenq. L.: Les carbures carcinognes du goudron et de goudronage. Ann. Hyg. Pub. N. S. 17: 1-7 (1939). Huguenin. R.. Fauvet, J., and Bourdin. J.: Rol vent uel des nbulisations de certaines huiles industrielles dans l'tiologie due cancer bronchopulmonaire. Bull, et mm. Soc. md. hp. de Paris. 65: 1020 1022 (19491. Hnermann. T.: Kehlkopfkrebs nech Gelbkreuzvergift ung. Ztschr. f. Larvngol. 17: 369-376 (1929). Husted. E.. and Biilmann. G.: Prim ary cancer of lungs with reference to frequency, etiology, pathological anatom y and histology of this leBion. Acta path, et mierobiol. Scandinav. 14: 141-196 (1937). Imprescia, S.: Bronchogenic carcinoma and chromates. J. Am Coll. Chest Phys. 22: 347-355 (1952). Ingalls. T. H.: Incidence of cancer in the carbon black industry. Arch. Indust. Hyg. & Occup. Med. 1: 662 676 (1950). ' Kahlau. G.: Experimentelle Erzeugung von Lungen tumoren durch Radiumemanation. Yerhandl. d. deutsch, path. Gesbelsch. 32: 379-385 (1950). Kahlau, G.: D er Lungenkrebs. Ergebn. d. allg. path, u. path. Anat. 37: 258-419 (1954). Kalbfleisch, H. H.: Tdliche Lungenfibrose infolge gewerbicher Schdigung durch Radium. Arch. f. Gewerbepath. 7: 699-701 (1936). Kawahata, K.: ber die berufliche Entstehung des Lungenkresbses bei Generatorgas-Fabrikation. Gann 30: 341-344 (1936). K awahata, K.: ber die gewerblich hervorgerufenen Lungenkrebse bei Generatorgas Arbeitern in den Stahlwerken. GanD 32: 367-387 (1938). Kennaway, E. L.: The data relating to cancer in the publications of the General Register Office. Brit. J. Cancer 4:158-172 (1950). Kennaway, E. L., and Kennaway, N. M.: A study of the incidence of cancer of the lung and larynx. J. Hyg. 36: 236-267 (1936). ' Kennaway. E. L.. and Kennaway, N. M.: Studies of the incidence of cancer of the lung and larynx. Brit. J. Cancer 5: 153-158, (1951). Kennaway, E. L., and Kennaway, N. M.: The incidence of cancer of the lung in coal miners in England and Wales. Brit. J. Cancer 7: 10-18 (1953). K ikuth, W.: ber das Lungencarcinom. Virchows Arch, f. path. Anat. 255: 107-128 (1925). Klemperer, F. W., Martin, A. P., and Van Riper, J.: Beryllium excretion in humans. Arch. Indust. Hyg. A Occup. Med. 4: 251-256 (1951). Klotz, M. O.: Association of silicosis and carcinoma of the lung. Am. J. Cancer 35: 38-49 (1939). Koelsch, F.: Lungenkrebs und Beruf. Acta nio Internat. C ontra Cancrum 3: 243-251 (1938). Kotin, P., Falk, H. L., Mader, P., and Thomas. M.: Aromatic hydrocarbons. I. Presence in the Los Angeles atmosphere and the carcinogenicity of atmospheric extracts. Arch. Indust. Hyg. A Occup. Med. 9: 153-163 (1954). Kotin, P., Falk, H. J., and Thomas. M.: Aromatic hydrocarbons. II. Presence in the particulate phase of gasoline engine exhausts and the carcinogenicity of exhaust extracts. Arch. Indust. Hyg. & Occup. Med. 9: 164-177 (1954). ' Kotin, P., Falk, H. L., and Thomas. M.: Aromatic hydrocarbons. III. Presence of particulate phase of diesel-engine exhausts and the carcinogenicity of exhausts extracts. A. M. A. Arch. Indust. Health 11: 113-125. (1955). Krafft, K.: Nickelcarbonyl Pneumonien. 8th Internat. Kongr. f. Unfallmed. u. Berufskr. 1939. Leipzig, Georg Thieme, 1940, vol. 2, pp. 1054-1056. Krevberg, L.: Occupational influences in a Norwegian material of 235 cases of primary epithelial lung tumors. Brit. J. Cancer 8: 605-612 (1955i. Kuroda. S.: Occupational pulmonary cancer of gen erator gas workers. Indust. Med. 6: 304-306(1937 . Kuroda, S., and Kawahata, K.-. ber gewerbliche Entstehung des Lungenkrebses bei Generatorgas arbeitern. Ztschr. f. Krebsforsch. 45: 36-39 (1936'. Lacassagne. A.: Actualities scientifiques et indust rielles., Paris, Herrmann et Co.. 1945, p. 55. Lange, K,: Krebserkrankungen und geologische Ver hltnisse im Erzgebirge. Ztschr. f. Krebsforsch. 42: 306-310 (1935). Lanza. A. J.: Discussion of YY. E. Smith on A survey of some current British and European studies of occupa tional tum or problems. Arch. Indust. Hyg. Occup. M3. 5: 242-2^4 (1952). Leach, J. E., Farrow, J. H.. Foote. F. \Y.. and Wawro, N. W.: Fibrosis of the lung following roentgen irradiation for cancer of the breast, Am. J. Roent genol. 47: 740-747 (1942). Lecoeur. J.: L 'tude des cancers professionnels est-elle susceptible d 'apporter de nouvelles notions tiologi ques et pathogniques en ce concern le cancer des bronches? Presse md. 50: 415-417 (19421. Lehmann, K. B.: Teerstrassen vom Standpunkt der Hygiene. Arch. f. Hyg. 104: 105-131 (1930,. Letterer, E.. Neidhardt. K., and Klett. H.: Chromat lungenkrebs und Chromatstaublunge. Arch. f. Gewerbepath. 12: 323-361 (1944). Levin, M. L.: The occurrence of lung caDcer in man. Acta Internat, t'nion Contra Cancrum 9:531-539 (1953). 50 Environmental Causes o f Caneer o f the Lung Levin. M. L . hardt. P 1 and sntoki: Am. Pub. 3 Lew. E. A.: cancer stu< 5: 198-203 Lew. E. A.: tory cancer Surgeons. < Lickint. F.: krebses. I kopff. Lindskog. f Surr. 124: Lindemann: 1 Deut, nted Linzbach. A cancer am f. paihol. A Lipschitz. M Lungenkr-l 381 (1931 . Lisco. H.. at pathology j Federation Lwy, J.: D Acta nio (1938). Lwy. J.: < H ealth. Ge Lwy. J.: Med. Klini Laken. A. C Tidsskr. X- Lorenz. E.: 3 review of J and Joachi (1944). Lorenz. E., Eschenbrer. tum ors in irradiation 6: 349-373 Love. R. A.: tion at an A E C -1 62Oak Ridge Ludewig. P. Grubenluft an RadiuT (1924). Lukanin. \Y. mokoniose. Lull. L., and npublish Lynch. K. M and similar 1978 (1937 Lynch, K., a Chest. 14 Public Heait API 06451 a r<'infJrr,a ` * J 1. if. Acta Uni0 I (1938). d Thomas. ,\[ . 'e in the LrJS inogenicity of Hvg. 4 Occijp M.: Aromatic articulate phase carcinogenicity Hyg. it Occup. . M.: Aromatic iculate phase of `inogenicity 0f Indust. Health i. 8 th Internat. 1939. Leipzig 1056. ' i a Xortvegian pithelial lung 1955). 'ancer of gen104-306 C1937). *r gewerbliche Generatorgas36-39 (1936). .es et indust . p. 55. ol' e Verforsch. on A survey of dies of occiipa:list. Hyg. it .. and YY'awro, ring roentgen Am. J. Roent- nnels est-elle ions etiologile cancer des 1942). mdpunkt der 19301. H.: Chroinat,e. Arch. f. mcer in man. urn 9:531-539 \[. 1 . Km \. > . 1iuidbere. I. D.. and Ger- ^han*1- ^ Pri'bicms in the srudy of occupation j uivkimz in relation to lung cancer. In Proc. \ta. Pul)- Keaith Cancer A. Buffalo, Oct. 11, 1954. ` E. A.. Use of life insurance company records for ^ sneer studies. Arch. Indust. Hyg. it Occup. Med. -. [1)6-203 11952). ' " _. E. A.: Recent trends in m ortality from respira- **,ory cancer. In Proc.. Meeting International College urgeons. Chicago, 111., Sept. 8 . 1954. p. 18. Lickin'" Aetiologie und Prophylaxe des Lungen krebses. > kopff' Lindikog. Dresden. 1953. p. 212. Theodor SteinG. E.: Bronchiogenic carcinoma. Ann. ,i'rz. 124: 667-674 il946i. Lindemann: ber Krebserkrankungen der Bergarbeiter. 0 eut. med. Presse 20: 3-6 (1916). Ljnzbach. A. J.. and Wedler. H. YV.: Occupational eancer among asbestos workers. Y'irchows Arch, f. pat hol. Anat. 307: 387-409 (1941). Lipschitz. M.: Bemerkungen ber die Zunahme des Lungenkrebses. Ztschr. f. Krebsforsch. 34: 376 381 (1931). Lisco. H-. and Finkei. M. P .: Observations on lung pathology following inhalation of radioactive cerium. Federation Proc. 8 : 360-361 (1949). Lwy. J-: Der Bronchialkrebs als Berufskrankheit. Acta Unio Internat. Contra Cancrum 3: 182-187 11938). Lwy. J.: Occupational tumors. Occupation and Health. Geneva. Suppl. 1939. Lwy, J . : b er die Joachimsthaler Bergkrankheit. Med. Klinik 25: 141-142 (1929). L#ken, A. C.: Lungencarcinom Hos N'ikkelarbeidere. Tidsskr. Xorske Laegeforen. 70: 376-378 (1950). Lorenz, E .: Radioactivity and lung cancer; A critical review of lung cancer in the miners of Schneeberg and Joachimsthal. J. X at. Cancer Inst. 5: 1-15 (1944). Lorenz, E., Heston, YY". E., Deringer, M. K., and Eschenbrenner, A. B.: Increase in incidence of lung tumors in strain-A mice following long continued > irradiation with gamma rays. J. Xat. Cancer Inst. 6 : 349-373 (1946). ' Love. R. A.: Lung carcinoma in an industrial popula tion at an atomic pile site. Atomic Energy Co.. AECU-1620. Brookhaven Xat. Lab. Tech. Inf. Serv. Oak Ridge, Tenn. Issues 1951. Ludewig, P., and Lorenser, E. : Untersuchung der Grubenluft in den Schnee berger Gruben auf den Gehalt an Radiumemanation. Strahlenther. 17: 428-435 (1924). Lukanin, YY'. P.: Zur Pathologie der Chrom atpneu mokoniose. Arch. Hyg. 104: 166-194, 1930. Lull. L., and Wallach, A. : M ontana State Health Dep. Unpublished data, 1950. Lynch, K. M.: Pulmonary asbestosis. Asbestos body and similar objects in lung. J. A. M. A. 109: 1974 1978 (1937). Lynch, K., and Cannon, W. M.: Asbestosis. Dis. of Chest. 14: 874-890 (1948). ' Lynch. K.. and Smith. W. A.: Carcinoma of the iung in asbestos-silicosis. Am. J. Cancer 24: 56-63 (1935). Lynch, K.. and Smith, YY'. A.: Pulmonary asbestosis: A report of bronchial carcinoma and epithelial metaplasia. Am. J. Cancer 36: 567-573 (1939). Machle. YY".. and Gregorius. F .: Cancer of the respira tory system in the United States chromate-producing industry. Pub. Health Rep. 63: 1114-1127 (1948). Machle. YY'., and Gregorius. F .: Cancer of the respira tory system: Rates and distribution in the chromateproducing industry in the United States. Proc. 9th International Congress Industrial Medicine. London, The Congress, 1948, pp. 464-468. Macklin. M.: Has a real increase in lung cancer been proved? Ann. Int. Med. 17: 308-324 (1942). Macklin. C. C., and Macklin. M. A.: A critical review of the usual methods of investigation of the role of extrinsic causes in producing human cancers, es pecially of the lung. Acta Unio Internat. Contra Cancrum 6 : 1334-1339 (1950). Macklin. M,, and Macklin. C. C.: Does chronic irrita tion cause primary carcinoma of the human lung? Arch. Path. 30: 924-955 (1940). Maisin, J ,: Les cancer professionelles. Bruxelles m id. 14: 544 (1934). Mancuso. T. F .: Occupational cancer and other health hazards in a chromate plant. II. A medical ap praisal. Indust. Med. A Surg. 20: 393-399 (1951). Mancuso, T. F., and Hueper, W. C.: Occupational cancer and other health hazards in a chromate plant. Indust. Med. A Surg. 20: 358-363 (1951). Mancuso, T. F., MacFarlane, E. M,, and Porterfield, T, D.: The distribution of cancer m ortality in Ohio. Am. J. Pub. H ealth 45: 58-70 (1955). Mancuso. T. F., and Urone. P. F .: Personal communi cation. M artland, H. S.: The occurrence of malignancy in radioactive persons. Am. J. Cancer 15: 2435-2516 (1931). M artland, H. S.: Radium poisoning. Cecil, Textbook of Medicine. 7th ed. pp. 582-587 (1947). Martineck: Arbeit und Gesundheit; Heft 29, D ritte Y'erordnung der Unfallversicherung und Berufskrank heiten von 1936. Leipzig, George Thieme. 1937. Matz. P. B.: Incidence of primary bronchiogenic car cinoma. .J: A. M. A.,.111: 2086^-2092 (1938). M cIntosh, H. C., and Spitz, S.: A study of radiation pneumonitis. Am. J. Roentgenol. 41: 605-615 (1939). McLaughlin, A. J. G.: Industrial diseases of iron and steel foundry workers, Great Britain, Factory De partm ent, Ministry of Labour and Medical Services, London. H. M. Stationary Office, 1950. Menz, M.: ber Berufsschdigungen bei Gaswerk arbeitern insbesondere der Gaskokerei Kleinhningen. Schweiz, med. Wchnschr. 77: 895-899 (1947). Merewether, E. R.: Annual report, chief inspector of factories for the year 1947, p. 79-81; 1948, pp. 92-93. of the Lang Pnhlic Health Monograph No. 36, 1955 51 Montgomery, H., and Waisman, J.: Epithelioma at tributable to arsenic. J. Invest. Dermat. 4: 365-383 (1941!. Morgan, G.: Personal communication. Mote, R. H.: Arsenic. In Mineral Year Book, 1946, by E. W. Pehreon and A. I. M atthews. U. S. D epartm ent of th e Interior, W ashington, D. C., U. S. Government Printing Office, 1948, p. 137. Mller, A.: Zwei und dreifache Karzinome bei F arb stoffarbeitern. Helvet. chir. acta 18:1-41 (1951). Mllschitzky, A.: Bronchuskarzinom bei einem Teer arbeiter mit H autkrebs. D erm at. Wchnschr. 109: 973-975 (1939). Xash, P.: Experimental production of malignant tum ors by beryllium. Lancet 1: 519 (1950). Neitzel, E.: Berufsschdigungen durch radioaktive Substanzen. Arbeitsmed. Heft 1, 1935, p. 46. Neubauer, 0 .: Arsenical cancer: A review. Brit. J. Cancer 1: 192-244 (1947). Newman, D. A.: Case of adeno-carcinoma of the left inferior turbinated body and perforation of the nasal septum in the person of a worker in chrome pigments. Glasgow M. J. 33: 469 (1890:. Nieberle, K.: ber endemischen Krebs in Siebbein von Schafen. Zitschr. f. Krebsforsch. 49: 137-141 (1939-40). Nordmann, M.: Der Berufskrebs der Asbestarbeiter. Ztschr. f. Krebsforsch. 47: 288-298 (1938). Nordmann, M.: Lungenasbestose und Lungenkrebs. 8th, Internat. Kongr. f. Unfallmed. u. Berufskrankh. vol. 2, pp. 983-984. Leipzig, Georg Thieme, 1939. Nordmann, M., and Sorge, A.: Lungenkrebs durch Asbeststaub im Tierversuch. Ztschr. f. Krebsforsch. 51: 168-182 (1940). Oppenheimer, B. S., Oppenheimer, E. T., Stout, A. P., and Danishefsky, I.: Malignant tumors resulting from embedding plastics into rodents. Science 118: 305-306 (1953). Oppenheimer, B. S., Oppenheimer, E. T., Stout, A. P., and Eirich, F. R .: Further studies of polymers as carcinogenic agent in animals. Cancer Research 15: 333-340 (1955). Owen, T. K.: Carcinoma and asbestos. Brit. J. Cancer 5: 382-383 (1951). Parkes, G. D .: Mellor's modern inorganic chemistry. New York. Longmans, Green k Co., 1939, p. 684. Passey, R. D.: Experimental soot cancer. Brit. Med. J. 2: 1112-1113 (1922). Passey, R. D., Green, N. H.. et al.: Lung cancer and smoking. British Empire Cancer Campaign. 31st Ann. Rep., London, The Campaign, 1953, pp. 195-- 196. Patch, I. L.: Bronchial carcinoma in dusty occupa tions. Brit. J. Tuberc. 47:145-149 (1953). Pat no, M. E.: Geographic study of cancer prevalence within an urbnn population. Pub. Health Rep. 69: 705-715 (1954). Peller, 6.: Lung cancer among mine workers. Human Biol. 11: 130-143 (1939). Peller, S .: Cancer in Man. New York, International Universities Press, Inc., 1952, p. 556. 52 Perry, K., Bowler, R. G., Buckell, H. M.. Druett, magavo, G., and the lung in pri H . A., and Schilling, R. S. F. : Studies in the incidenc 8aita, G. I.: I. T of cancer in a factory handling inorganic compound professionale. of arsenic. Brit. J. Indust. Med. 5: 1-15 (1948). Pfeil, E.: Lungentumoren als Berufserkrankungen " Sante, L. R.r T t Chromatbetrieben. Deut. med. Wchnschr. 61: 119-' " their possible 1200 (1935). " bronehiogentc Philipps, P. A.: Cancer of the lung and larynx in urba_ 788-797 11949 and rural districts. Brit. Emp. Cancer Campaign Saupe. E.: Ge 30. Ann. Rep., 1952, p. 110. genologische Pirchan, A., and Sikl, H.: Cancer of the lung in miner ' der Arsenikh Freiberg in of Jachimov (Joachimsthal) ; Report of cases observeu ' 582 (1930'. in 1929-30. Am. J. Cancer 16 : 681-722 (1932'. Saupe, E.: be Potter, E. A. : Changing cancer rate. Cancer Research i 7 : 351-355 (1947). krebs und 8 Prell, H.: Die Schdigung der Tierwelt durch die inn. Med. 5- Fernwirkungen von Industrieabgasen. Arch. Gewer- Saupe. E.: Berit bepathol. 7 : 656-670, 1937. Untersuchung Eortschr. a. Probst, R. : Die Hufigkeit des Lungenkarzinoras. (1939). Zeitschr. i. Krebsforsch. 25: 431--453, 1927. Scheffer. C. L .: Proc. First National Cancer Conference. Memphis, ^ nitz, 1770. Tennessee, 1949. New York. American Cancer Society, 1950. Schinz. H. R.: Rajewsky, B.: Bericht ber die Schneeberger Unter der Krebserze suchungen. Ztschr. f. Krebsforsch. 4: 315-340 '070-1073 '19 (1940). Schinz, H. R-. Rajewsky, B., Schraub, A., and Kahlau, G.: Experi Ztschr. f. Kre mentelle Geschwulsterzeugung durch Einatmung i Schmidtmann. von Radiumemanation. Naturwiss. 31:170-171 ber die Wir. (1943). Bronehialepit Rehner, J.: The isolation and identification of fluoran (1930.1. thene from carbon Black. J. Am. Chem. Soc. 62: 2243 Schmorl. G.: F (1940). I cancer. Rep Reiche, F.: Primres Traeheararcinom. Metastase in j Bristol. Eng. der linken Nebenniere. Zentralbl. f. allg. Path. u. , 272-274. Path. Anat. 4: 1-8 (1893). Scott, A.: Oceiq Ringertz, N.: Environm ental factors and smoking in of Scotland si the causation of cancer of the lung. Am. J. Clin. 1109 (1922!. Path. 24: 83 (1954). - Rise], cited by A. Thiele: Die Schneeberger Lunger, krankheit. Fabrikrzte der chemischen Industrie i M erkbltter ber berufliche Erkrankungen Berlin, j J. J. Springer, 1930. Rodenacker, G.: Die chemischen Gewerbekrankheiten und ihre Behandlung. Leipzig, 1951. Rsch, H .: Drei verschiedene Carcinome bei einem Paraffinarbeiter. Virchows Arch. f. path. Anat. 245: 1-8 (1923i. Rostoski, O., and Saupe, E.: Gewerbehygienische and r Siki. H .: bet ' Joachimsthal Krebsforsch. Silson. J. E.r static elimin. 952 1950". Silson, J. E.,, E use of bervi State Depart 1194 9 1. klinisch-rntgenologische Untersuchungen en den Simons, E. J. : 1 Erzbergwerkleuten des Johanngeorgenstdte lil., Y ear Bo Grubenbezirkes in Sachsen. Arch. Gewerbepatho' Sissons. H. A.: 1: 731-734 (1930). in the rabbit. Rostoski, O., Saupe, E., and Schmorl, G.: Die Berg 7: ]71-172 i krankheit der Erzbergleute in Schneeberg in Sachsen. Ztschr. f. Krehsforsch. 23: 360-380 (192G). . Rousseau, L.: Quelques considrations sur lminantose. i Sm. d 'hp. Paris. 23: 1811-1814 (1947). . Russell, B. F., and Klaber, R.: Arsenical lung cancer r plus arsenical medicine dermatosis. Proc. Roy. | Soc. Med. 38: No. 3, Sect. Derm. 128 (1938). . Skavlem, j,, i monary asb. 22: 493-517 Smith. V m . I tional factor Union Agair Environmental Causes o f Cancer of the Lung t Public Health ; 'U ""r-lrirr?^idf.n- t' 'C 00rnPO,,J 3 noig, nrl it-- i`ankunttpn Vhnschr. 6 j. , l" d J*ryns n IJrh Caner C^ P a 1>n' ' the lung n mi rt of cases observ 81-722 (1932) Cancer ReSearch ierwek durch <jj isen. Arch. Ge** * Lnneenkarzinom, 133. 1927. Vrence. M emphjs American Cancer uneehereer Unte,. -c h . 49: 31o-3 4 0 :hla,`- n .: Ex-peri. nirch Einatmung 'iss. 31:170_]72 i.-ation of fluoranitem. Soc. 92: 2243 "m. Metastase i0 f. allg. Path. u. ~ smoking in .im. .1. Clin. 'ebereer Lunger. rischen Industrie itnktingen Berlin, erbekrankheiten ni. inome bei einem f. patii. Anat. 'hygienische and .Imngen en den umgeorgenstdte Gewerbepatho' ri. G.: Die Bergeberg in Sachsen. -0 (19201. sur l'aminantose. 4 i 1947). ideal lung cncer sis. Proc. Roy. 128 (1938). cer of the Lung , u.:;t I. H.. Frequency of cancer of .w*.'"inm: in p n \a te practice. Trax 2: 47-88 1953,. ;!ie ' 1. Tumori primitivi del polmone rii origine :iis. e _ ale. Med. d. lavoro 39: 105-116 <1948), ^ R.: The fate of oil droplets in the lung and ' st"htee"> rno.sfibhlie relationship to the development of broneh -gg-79" ,11949). 1 E.: Gewerbehygiettische und klinisch-rnt- '* ^logische Untersuchungen and den Arbeitern j er Arsenikhtte der staatlichen H ttenwerke bei Freiberg >n Sachsen. Arch. Gewerbepathol. 1: 5g2 11930). ^ -sUpe E.: ber die Beziehungen zwischen Lungenr Ijrebs und Staublungenerkrankung. Zentralbl. f. inn. Med. 54: S25 (1933). 4aupe. E.: Bericht ber eine rntgenologische Relhen" ulltersuchung an Joachimsthaler Bergleuten. Fortschr. a. d. Geb. d. Rntgenstr. 60: 168-171 ,1939b icheffler, ('. L .: E)ie Gesundheit der Bergleute. Chem nitz. 1770. >chiz. H. R -: Der Metallkrebs. Eiu neues Prinzip " der Krebserzeugung. Schweiz, med. Wchnschr. 72: ,070-1073 (1942). rchinz, H. R., and Uehlinger, E.: Der Metallkrebs. Ztschr. f. Krebsforsch. 52: 425-437 (1942). scbmtdtmann, M .: Experimentelle L'ntersuchungen ber die Wirkung des Schneeberger Staubs auf das B ro n c h ia le p ith e l. Ztschr. f. Krebsforsch. 32: 677 11930). ychmorl. G.: Pathological study of Schneeberg lung cancer. Rep. Internat. Cancer C'onf., LondoD, 1928. Bristol. Eng. John W right 4 Sons, Ltd., 1929, pp. 272-274. Scott, A.: Occupation cancer of paraffin and oil workers of Scotland shale oil industry. Brit. M. J. 2 :1 1 0 8 1109 (1922). Sikl. H.: b e r den Lungenkrebs der Bergleute in ' Joachimsthal (Tschechoslovakia). Ztschr. f. Krebsforsch. 32:609-613(1931). silson, J. E.: Hazards in use of radioactive electro static eliminators. Am. J. Pub. H ealth 40: 943 952 i 1950,. Silson. J. E., Benjamin. L. P., and Wilson, S. C.: The use of beryllium in New York State. New York State Departm ent of Labor M onthly Rev. 28:13-16 1949!. Simons, E. J . : Prim ary carcinoma of the lung. Chicago, 111., Year Book, Inc., 1937. Sissons, H. A.: Bone sarcoma produced experimentally in the rabbit. Acta Unio Internat. C ontra Cancrum. 7: 171-172 (1950). Skavlem, j., and RitterhofT, R. J . : Coexistent pul monary asbestosis and sarcoidosis. Am. J. Path. 22: 493-517 (1946). Smith, Wm. E .: An evaluation of claims for occupa tional factors in cancer of the lungs. Acta Internat. Union Against Cancer 9: 50-58 (1953). Public Health Monograph No. 36, 1955 Suegireff. L. S.. and I...,i.i ar-i 11 M \rse,..c a: u cancer. Arc''. Industr. Hyg. ,v t iccup. M -i. 4 . 199-205'1951'. Southam, A. H.: Mule spinner-' eaneer. Rep. Internat. Oonf. Cancer. London. 1928. p. 280. John Wright 4 .Sons, Ltd., Bristol. Spamer, E .: Ein Fall von Primrkarzinom der Kptgluttis bei Vergiftung durch franzsisches Kampfgas. Zeitschr. f. Larvgnol. 10: 44-60 ,1921,. ' Spannagel, H.: Eine L'ntersuchungsmethode zur Bestimmung von Chromium in Blut und l'rin. Zentralbl. f. Arbeitsmed. u. Arbeitsschutz. 1: 15-17 (1951). Steiner, P. E.: Etiological implications of the geo graphical distribution of lung cancer. Acta Internat. L'nlon Against Cancer 9: 24-49 1953). Steiner, P. E.: B utt, E. M. and Edmondson. H. A.: Pulmonary carcinoma revealed at necropsy with reference to increasing incidence in Los Angeles County Hospital. J. N at. Cancer Inst. 11: 497 510 (1950). Stephens. C., An im portant factor in the causation of industrial cancer. Med. Press 4 Circu. 187: 194-200, 216-219, 283 (1933). Stewart, M. J. and Faulds, J. S,, Pulmonary fibrosis in hematite miners. J. Path. & Bact. 39: 233-253 (1934). Stocklasa. J . : Die Bedeutung der Lufradioaktivitt bel der Entstehung der Joachimsthaler und Schneeberger Bergkrankheit. Deut. med. Wochenschr. 59: 1199 1200 (1933). Stocks. P.: Regional and local differences ln cancer death rates. Studies on medical and population subjects. No. 1. p. 46. General Register Off.. London. H. M. Stationary Off., 1947. Stocks, P.: Endemiology of cancer of the lung in England and Wales. Brit. J. Cancer 6: 99-111 (1952). Stocks, P.: Lung cancer, tobacco and atmospheric pollution. Brit. Emp. Cancer Campaign 31st Ann. Rep., 1953 pp. 410-412. Stokinger, H., Steadman. L., and Root. R. E.: Acute inhalation toxicity of beryllium. Arch. Industr. Hyg. & Occup. Med. 1: 379-397 (1950). Stokinger. H. E., Sprague. G. F.. Hall. R. W .: Acute inhalation toxicity of beryllium. Arch. Ind. Hyg. 4 Occup. Med. 1: 379-397 (1950). Stoll. R., Bass, R., and Angrist, A. A.: Asbestosis associated with Jpronchogenic carcinoma. Arch. Int. M7d. 68: 831-834 (1951). Straube, G .: Die Frhdiagnose der gewerblichen Arsen vergiftung. Deut, med. Wochenschr. 65: 334-335 (1939). Tabershaw, I. R .: Report on industrial hygiene in the western zone of Germany. Arch. Industr. Hyg. 4 Occup. Med. 3: 298-315 (1951). Teleky, L,, Occupational cancer of the lung. J. Industr. Hyg. 19:73-85 (1937). Teleky, L .: Krebs der Kromatarbeiter. Deut. Med. Wochenschr. 62:1353-1354(1936,. Teleky, L.: Berufliche Radiuraschdigungen. Wien. Klin. Wochenschr. 50: 619 (1937). 53 I API 06454 Teleky, L.: Der berufliche Lungenkrebs. Acta Unio Warren, S., and Drake. VY. L.: Prim ary carcinoma of internat. Contra Cancrum 3 : 253-273 (1939). the liver in hemochromatosis. Am. J. Pathol. 27' Thiele, A .: M artin Pansa, Sachsens ltester Gewer- 573-609 (1951). . ' bearrt. Zeitschr. f. ffentl. Gesundheitspfl. 6: 348 Warren, S., and Gates, O.: Radiation pneumonitis. (1921). Arch. P ath. 30 : 440-460 (1940). ' Tilley, cited by Lickint, F.: tiologie und Prophylaxe Warren, S., and Spencer, J.: R adiation reaction in des Lungenkrebses. Theodor Steinkopff, Dresden, lung. Am. J. Roentgenol. 43: 682-701 (1940). 1952, p. 46. W atsuji, S. : Beitrge zur K enntnis des primren Horn Tnges. E. and Kalbfleisch, H. K.: Ein zweiter Fall krebses der Lunge. Ztschr. f. Krebsforsch. von tdlicher Lungenfibrose infolge gewerblicher 1: 445-462 (1903-1904). Radiumeinwirkung. Frankf. Zeitschr. f. Pathol. Weber, L. F .: External causes of derm atitis. Arch. To5u0r:ain1e0,0-A12.,2an(1d93B7o).ur, H.: Les cancers par huiles de WeDdelermr, aHt.. AW.S: yApshb.e3st5o:se12u9n-d17L9un(g19en37k)r.ebs. Deutsche N graissage. Rv. md. fran. 20 : 283-292 (1939). med. Wchnschr. 69: 575-576 (1943). Tschelnitz. H.: Bemerkungen zur tiologie de St. Wegelin. C.: Der Bronchial-und Lungenkrebs. Schweiz, Joachimsthaler Lungenkrebses. Strahlenther. 53: 269 med. Wchnschr. 72: 1053-1063 (1942). (1935). Weil. C. S., Smyth, H. F., and Nale, T. VY. : Quest for Turner. H. M., and Grace. H. G.: An investigation of a suspected industrial carcinogen. Arch. Industr. cancer mortality among males in certain Sheffield Hyg. A Occup. Med. 5' 535-547 (1952. X trades. J. H yg .'38: 90 (1938). Welz, A.: Weitere Betrachtungen ber den Berufskrebs Uhlig, M.: ber den Schneeberger Lungenkrebs. Virchows Arch. f. pathol. Anat. 230: 76-98(1921). der Asbestarbeiter. Arch. Gewerbepathol. 11: 536 * 550 (1942). U. S. Public Health Service: Environment and health. Widmann, B. P .; Irradiation pulmonary fibrosis. Public Health Service Pub. No. 84. Washington, Am. J. Roentgenol. 47: 24-38 (1942;. D. C.. l \ S. Government Printing Office. 1951, p. 152. Wolf, K.: D er primre Lungenkrebs. Fortschr. f. Urone. P. F.. and Anders, H. K .: D eterm ination of small Med. 13: 725, 765 (1895). . amounts of chromium in human blood, tissues, and Wood, E. H .: Unusual case of carcinoma of both lungs \ urine. Analyt. Chem. 22: 1317-1321 (19501. Yesin. M. S.: Cancer pulmonaire provoqu par les associated with lipoid pneumonia. 40: 193-195 (1943). Radiology r manations radioactives. Arch. mal. profess. 9: 280 Wyers, H.: Asbestosis. Post-Grad. Med. J. 25: 631 283 (1948). 637, 1950. Volimann. J.: Tierexperimente mit intraossrem Arsen-, Wynder, E. L., and Graham, E. J.: Tobacco smoking Chrom-, und K obaltdepot. Schweiz. Zeitschr. f. as a possible tiologie factor in bronchiogenic I \ allg. Pathol. u. Bakteriol. 1: 440-443 (1938-40). carcinoma. J. A. M. A. 143: 329-336 (1950). i Vrwald, A. J.: Pulm onary cancer in experimental Wynder, E, L., and Graham, E. J.: Etiologie factors in exposures to beryllium. Proc. 7th Saranac Sym bronchiogenic carcinoma with special reference to posium on Pneumoconiosis, 1952. In press. industrial exposures. Arch. Industr. Hyg. A Occup. Vmrwenaltda.l Ast.udJ,,iesDuofrkaasnb. eTst.o, saisn.d PArractht., IPn. dCus.:trE. xHpeyrgi. WMynedde.r,4:E.22L1.,-2G35rah(1a9m51, ).E. A., and Croninger, A. B.: N A Occup. Med. 3: 1-43 (1951). Experimental production of carcinoma with cigarette Vrwald, A. J., and Karr. J. W. : Pneumoconiosis and tar. Cancer Research 13: 855-864 (1953). pulm onary malignancy. Am. J. P ath. 13:654 (1937). Yamada, A.: Personal communication. Vrwald, A. J., and Karr, J. W. : Pneumoconiosis and Yamada, A., -^Hirose. FV, and Miyanishi, M.: An pulmonary cancer. Am. J. Pathol. 14 : 49-58, Ja n apuattoiepnsty scuacsceumofbebdrotnochioaclcucpaartciionnoaml a mfuosutnadrd ingaas l N uary 1938. poisoning. Gann 44: 216-218 (1953). Waller, R. E.: The benzpyrene content of town air. Ziel, R.: Zur Frage des Lungenkrebses bei den Berg Brit. J. Cancer 6: 8-21 (1952). leuten in Joachimsthal. Med. Klinik 31: 1535 Warren. S.: Effects of radiation on normal tissues. Arch. P ath. 34: 443-450. 562-608, 749-787, 917-931, Zo(ll1i9n3g5e)r., H. O.: Experimentelle Erzeugung maligner \ 1070-1084 (1942); 35: 121-139, 304-353 (1943). Nierenkapseltumoren bei der R atte durch Druckreiz Warren, S.: Pathologic aspects of occupational tumors, (Plastic-Kapseln). Schweiz. Ztschr. f. Path, u * Occup. Med. 5: 249-251 (1948). Bact. 15: 666-671 (1952). * X * i 54 Environmental Cause o f Caneer o f the Lung f ! % API 06455 i> meumoniij union reaction j 2-701 (19-10). " ie? primren Horn. f. Krebsforsch' dermatitis. ArCh 37). ' ukrebs. Deutsche renkrebs. Schweiz M2). ' T. W.: Quest f0r . Arch. Industr 1952). ' r den Beruf.sk rebs epathol. 1 1 : .53^ . .inonary fibrosis '2: ` bs. Fort.schr. f ma of both lung3 uia. Radiology t Med. J . 25: 6 3 1- Tobacco smoking n bronchiogenic -336 (1950). tiologic factors in ci^l_teference to . r 4 Occup. ?roninger. A. B.t na with cigarette (1953). anishi, M.: An ma found in a al m ustard gas , . ' I s bei den Berg- flinik 31: 1535 wgung maligner 1 lurch Druckreiz r. f. Path, u | Current Titles Public Health Monographs No. 19. Medical service areas and distances traveled for physician care in western Pennsylvania. Antonio Ciocco and Isidore Altman. (Public Health Service Publication No. 248) 1954. 32 pages. Illustrated. 25 cents. [Published concurrently with Public Health Reports 69: (3); see pages 321-322 for summary article.] No. 20. Gamma globulin in the prophylaxis of poliomyelitis. Report of the National Committee for the Evaluation of Gamma Globulin in the Prophylaxis of Poliomyelitis. IPublic Health Service Publi cation No. 358) 1954. 178 pages. Illustrated. 11.25. [Published concurrently with Public Health Reports 69: (5); see pages 519-520 summary.] No. 21. Whv some sanitary engineers leave the field. Irwin M. Rosenstock and Arthur P. Miller. (Public Health Service Publication No. 359) 1954. 16 pages. Illustrated. 20 cents. (Published concur rently with Public Health Reports 69: (9); see pages 865-866 for summary article.] No. 22. The Bethesda'-Ballerup group of paracolon bacilli. Mary G. West and Philip R. Edwards. (Public Health Service Publication No. 362) 1954. 35 pages. 30 cents. [Published concurrently with Public Health Reports 69: (10); see pages 1012-1013 for summary.] No. 23. Biological factors in the transmission of American arthropod-borne virus encephalitides. Frederick F. Ferguson. (Public Health Service Publication No. 372) 1954. 37 pages. 30 cents. [Pub lished concurrently with Public Health Reports 69: (11); see pages 1095-1096 for summary.] No. 24. Appraising the clinical resources in small hospitals. Faye G. Abdellah and Eugene Levine. (Public Health Service Publication No. 389) 1954. 39 pages. 30 cents. (Published concurrently with Public Health Reports 69 (12); see pages 1215-1216 for summary.] No. 25. Sickness experience in selected areas of the United States. Selwyn D. Collins, Katharine S. Trantham, and Josephine L. Lehmann. (Public Health Service Publication No. 390) 1955. 96 pages. Illustrated. 50 cents. [Published concurrently with Public Health Reports 70: (1); see pages 81-82 for summary.] No. 26. A history of plague in the United States. Vernon B. Link. (Public Health Service Publication No. 392) 1955. 120 pages. Illustrated. 60 cents. [Published concurrently with Public Health Reports 70: (3); see pages 335-336 for summary article.] No. 28. Tularemia in sheep and in Bheep industry workers. William L. j Jellison and Glen M. Kohls. (Public Health Service Publication No. 421) 1955. 17 pages. Illustrated. 20 cents. [Published concurrently with Public Health Reports 70: (7); see pages 720-721 for summary.] No. 29. Mortality from cancer in the United States. Harold F. Dorn and f Sidney J. Cutler. (Public Health Service Publication No. 418) 1955. 121 pages. Illustrated. 65 cents. [Published concur- V rently with Public Health Reports 70: (7); see pages 721-722 for summary.] No. 30. Major causes of illness and of death in six age periods. Selwyn D. Collins, Josephine L. Lehmann, and Katharine S. Trantham. (Public Health Service Publication No. 440) 1955. 22 pages. Illustrated. 25 cents. [Published concurrently with Public Health Reports 70: (9); see page 857 for summary.] No. 31. Illness and mortality among infants in the first year of life. Selwyn D. Collins, Katharine S. Trantham, and Josephine L. Lehmann. (Public Health Service Publication No. 449) 1955. 20 pages. Illustrated. 15 cents. [Published concurrently with Public Health Reports 70: (10); see page 1028 for summary.] No. 32. Disposition of first admissions to a State mental hospital. Morton Kramer, Hyman Goldstein, Robert H. Israel, and Nelson A. John son. (Public Health Service Publication No. 445) 1955. 25 pages. Illustrated. 25 cents. [Published concurrently with Public Health Reports 70: (11); see pages 1135-1136 for summary.] No. 33. Survey and appraisal methods for community fly control programs. H. F. Schoof. (Public Health Service Publication No. 443) 1955. 18 pages. Illustrated. 20 cents. [Published concurrently with Public Health Reports 70: (11); see pages 1137-1138 for summary.] No. 34. Housing rehabilitation and enforcement of housing laws. Ralph J. Johnson and Roy O. McCaldin. (Public Health Service Publication No. 451) 1955. 34 pages. Illustrated. 30 cents. [Published concurrently with Public Health Reports 70: (12): see pages 1247 1248 for summary.] No. 35. A study of selected home care programs. Alice M. Waterhouse, Eleanor C. Bailey, Jeanne T. Palmer, and Mary C. Gillis. (Public Health Service Publication No. 447) 1955. 128 pages. 65 cents. [Published concurrently with Public Health Reports 70: (12); see pages 1249-1250 for summary.] No. 36. A quest into the environmental causes of cancer of the lung. W. C. Hueper. (Public Health Service Publication No. 452) 1955. 54 pages. Illustrated. 45 cents. [Published concurrently with Public Health Reports 71: (1); see interpretive article. U f C0VLRNMEKT MIN1IN6 O FfICt: H I > API 06457 . 1LIK' 1 ited. 1 L. it ion shed -721 and 418) irur. for t D. lam. iges. faith wyn ann. iges. alth rton >hnges. 'alth in. 955. with iry.] h J. tion hed ) !47- ise, idle its. -ee i . C. A55. I vith Public H ealth M ono g raph s are edited and sued by Public Health Reports under the general direction o f the Board of Editors. The monographs present contributions to knowledge in the fields of public health, particularly material that is extensive, detailed, or specialized. All manuscripts considered for publication as monographs receive the same technical and scientific review as papers submitted to Public Health Reports. The opinions expressed are those of the authors and do not necessarily reflect the views of Public Health Reports or the Public Health Service. Trade names are used for identification only and do not represent an endorsement by the Public Health Service. Authors will facilitate review if they submit three copies of their m anu scripts, double spared, with each page beginning with a new paragraph. Public H ealth Monographs are listed in the table of contents of the issue of Public Health Reports with which they are concurrently published. They are also listed in its annual index, in the Quarterly Cumulative Index Medicus IAmerican Medical Association), and in the Current List of Medical Literature EArmed Forces Medical Library). Single copies of most Public Health Monographs are available upon re quest to the Public Inquiries Branch. U. S. Public Health Service, Washington 25. D. C. Orders for quantities should be sent to the Superintendent of Documents, L. S. Government Printing Office, Washington 25. D. C.. where they are available at the prices shown, with a 25-percent reduction on orders for 100 or more. In ordering, give title, monograph number, and Public Health Service publication number and enclose cash, check, or money order. Stamps are not acceptable. API 06458 API 06459