Document 9L4nxaDe9dxO9q1wJEn1w9BRL

Castleman File: American Petroleum Institute w/c = with cover letter or memo If DATE = 0, undated CD-ROM Document #:API DATE __ published article from trade journal __ published advertisements __ newspaper article c/" published government report __ government inspection results __ unpublished or internal report __ unpublished presentation from conference letter memorandum industry warning labels industry sales literature industry recommended practices meeting minutes (with attachments) membership list BC notes 111 h1.1c Health .Mmm'crapii \n. T> A Quest Into The Environmental Causes Of Cancer Of tlie Lung l". S. DEPARTMENT of HEALTH. ED EC AT ION. and WELFARE Pvblic Health Service Public Health Monographs edited and issued by Public Health Reports G. St.J. Perrott Chief. Division of Public Health Methods Managing Director Marcls Rosenbllm Executive Editor TaftS. Feiuan Managing Editor Ja'-'Et Easdale Monograph Editor BOARD OF EDITORS Edw ard G. McGavran, M.D., Chapel Hill Chairman Gaylord W. Anderson. M.D., Dr.P.H. Minneapolis Margaret G. Arnstein, R.N., M.P.H. Washington H. Trendley Dean, D.D.S. Chicago Halbert L. Dlnn, M.D., Ph.D. Washington Martha M. Eliot. M.D.. Sc.D. Washington Harold M. Erickson. M.D.. M.P.H. Portland. Oreg. Lloyd Florio. M.D.. Dr.P.H. Denver Vernon G. Mackenzie Washington Victor H. Haas, M.D. Bethesda Basil C. MacLeas. M.D., M.P.H. Hevc York City Seward F.. Miller. M.D. Washington Leo \V. Simmons. Ph.D. .Vfsc Haten, Conn. U. S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Marion B. Folsom. Secretary PUBLIC HEALTH SERVICE Leonard A. Scheele, Snejeoh General API 06399A 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 1912. Public Health Service Publication No. 452 (Issued concurrently with the January 1956 issue of Public Health Reports. \ol. 71, No. 1) Library of Congress Catalog Card No. 55-60064 Received for publication April 1955 UNITED STATES GOVERNMENT PRINTING OFFICE, WASHINGTON, D. C., l^5 For sale by the Superintendent of Documents, U. S. Government Printing Office Washington 25, D. C. - Price 45 cents API 06400 Contents Introduction.................................. ................... .............................................. General epidemiological considerations..................................... Occupational evidence and respiratory carcinogens................................... Epidemiological data on large industrial groups_______ _____________ Occupational respiratory cancers and carcinogens................................. Scope of environmental lung cancer hazards....... ............................. Pattern and types of respiratory cancer hazards.. ...................... Occupational respiratory cancers____________________ Physicochemical state of atmospheric carcinogens and topograph ical distribution of cancers in the respiratory tract_____________ Specific carcinogens.......................................... .. ............ ... .... Inorganic chemicals................................................. Xickel............................................ Chromium................. ...................................... .............. Arsenic........................ Iron.......................................... Beryllium___ _____ _________________ _________________ _ _____ Organic chemicals........ ......... ............................................................... Combustion and distillation products of coal.. ........................... Petroleum, shale oil, and natural gas..____ ___________ _______ Carbon and silicon polymers..... .................. ........................._____ Asbestos____________________ Isopropyl oil................. Mustard gas............................... Radioactive chemicals....... ................................................................. Comments and conclusions_____________ _____________ Bibliography.............. Page 1 1 15 15 18 18 21 21 22 23 23 23 24 27 29 30 31 31 33 35 35 38 38 39 43 46 API 06401 Introduction .ciei)tiiicaily acceptable, any theory T ptiologv of lung cancer must reflect a balanced, and competent analysis of .n1'1 'tjrt, epidemiological, medical, and exth* e (di evidence concerning the types and ^ninental distribution of and contacts all known or suspected exogenous agents *|l` :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 respirator}' 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 V real, definite, and progressive increase in ,j,,, frequency of lung cancer started in most mJustrialized countries around the turn of tfrfe iurv (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 cognized by pathologists of Central Europe Jaring the early 1920's through a study of ycropsy data collected during the first two jfttdes of the 20th century and was subse quently confirmed and elaborated upon by luostatistical investigations from America and Europe which mainly used cancer mortality hu (fig- DPublished records indicate that this develop- sent revealed marked variations in the time i onset of lung cancer, in its relative degree of rverity. and in its progression rate for different 'ocalities and countries. In Germany, for innce. an increase in the incidence of lung incer was first noted in Saxony and Central Germany only. As late as 1931, Fischer re ported that lung cancer represented 11.3 per- of all cancers in Saxony against 6.6 percent * the rest of Germany. In Denmark, accord1 to Clemmesen, a rise in lung cancer frelency 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 mortality rates 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 API 06402 Author Period Number of Total Absolute autopsies carcinomas No. i 1852-76 Fuchs..................... _ .................................... 1854-85 Wolf .................................................................. 1877-84 Passler.................................................................. 1881-94 Wolf ................................................................ 1885-94 1885-97 1887-96 1889-99 Feilchenfeld_____________ _________________ 1895-1900 Riechelmann..................................................... 1895-1901 Sehrt...................... ...........................-................ 1899-1903 1886-1906 8, 716 12; 307 4, 172 9, 246 7, 228 1, 946 5, 022 7, 790 1, 741 3, 337 Redlich................................................................ 1900-05 2, 002 1900-06 Karrenstein___________________ __________ / - 1900-07 16, 272 1900-11 1900-11 .................... 1904-08 Probst.................................................................. 1906-10 2, 739 1907-13 Briese...................................................... ............ 1898-1916 12, 971 Bejach............................................ .................. 1908-13 6,808 Bejach........... ............ ......................................... 1900-12 5, 801 1906-16 4, 754 Rau.............................. ........................ .............. 1909-14 i 816 Berblinger..................... ............ ............ .......... 1910-14 2, 347 Materna......................... ................ ................... 1912-14 866 1912-14 Probst............................................................... .. 1911-15 3, 448 1914-18 1912-22 Materna.................... ........ ................................. 1915-17 1,667 Breckwoldt...................................... .......... ........ 1914-19 6,083 Rau...................................................................... 1915-19 5,518 Berblinger........................................................... 1915-19 3,280 Probst................................................. ................ 1916-20 4, 989 Materna................................... ......................... 1918-20 1, 609 Kikut.h .......... . 1912-23 1916-22 3, 336 1915-23 1920-21 1919-23 Berblinger......................................................... 1920-24 2, 429 Materna.............................. ................ .............. 1921-23 1,049 Breckwoldt...................................... .................. 1929-25 6, 359 Probst.............................. ................................... 1921-25 3, 697 StAehelin ..... .. . 1924 749 1850-1900 5 8 9 870 16 31 9 4 10 511 22 711 27 159 3 6 1900-1925 496 934 566 715 265 1, 287 692 586 552 363 48 218 389 31 32 90 12 20 3 60 33 29 6 15 8 1 11 13 70 554 580 337 392 94 755 8, 301 287 75 892 502 5 21 27 10 24 5 146 10 38 458 24 6 26 36 5 Lung cancers Percent of all cases 1" Percent of all 1 autopsies L 83 1.27 i3 3. 8 1. 88 a 057 .OSS .21 .17 -48 . 10 . 2t .07 .24 .3$ . 17 . 18 6. 3 5. 1 3. 42 3. 8 Z1 Z 7S 1. 13 6. 88 4. 51 4. 8 4. 95 2. 7 Z2 Z 08 5. 0 3. 34 11. 23 7. 14 3. 7 4. 8 2.9 6. 12 5. 31 5.8 4. 9 5. 4 & 75 83 80 Z7 7. 17 4. 9 is . 6/ .31 .37 . ii .9 .48 . 45 .5 . 13 .31 . 34 .n .38 1. 01 . 19 .38 . 36 . 49 .30 . 0" . 31 . 5 .3 . 99 . o* . 3* 1946-49, wii mortality rat Groups of adj occupied dwt London,E Birminghs Bromwi Manchestf Liverpool, Leeds, Bri Sheffield, with Newcastle and dwellings -- Aggregate of 6 occupied dw Aggregate of 3 occupied dw Aggregate of 40.000 occnj Aggregate of 30.000 occuj Aggregate of 20.000 occu: In Ohio, McFarlane, Table 2. F* Author Fischer-Waseil Simross Schairer and i niger. Peters Koch........ ...... Gerbe______ Buschbekl..! Dormanns___ oimross___ Peters___ ~ Gerbe . _'. Koch__ ^eber and'E ochairer and ; pF-wnic?here- r-^a^ Knorr__ 21 EmcningeraD ' f*lt. Koch___ _ Kiacher. ~ Koch ~~ ~ Environmental Causes of Cancer of the Luflf Prom 5, Publi, Hea& API 06403 49, with deviations from the average lity rate set at 100, as follows: of adjacent town* with over 200,000 upied dwellings: London, East Ham, West Ham,Croydon.. 'Birmingham, Smethwick, Walsall, West Bromwich____ ____________ Manchester, Salford, Stockport...................... |j Liverpool, Bootle, Birkenhead, Wallasey... Leeds, Bradford, Halifax...................... 156 134 159 162 132 eld, with 124,000 occupied dwellings........... castle and Gateshead, with 87,000 occupied (-dwellings................................... ............................... ate of 6 towns, each with 50,000 to 85,000 occupied dwellings....... ................... ggregate of 3 towns, each with 40,000 to 50,000 % occupied dwellings......... ....................................... Aggregate of 12 towns, each with 30,000 to 40.000 occupied dwellings..................................... Aggregate of 13 towns, each with 20,000 to 30.000 occupied dwellings 100 Aggregate of 29 towns, each with less than j. 30,000 occupied dwellings. _________________ 135 114 113 107 104 ^ 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: Metropolitan counties (8)________________ _____ 122 9 Urban counties (7)..................................................... 81. 8 Rural counties (73)................................................... 68. 6 The standard mortality ratio is Observed deaths . 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 of lung canoers in autopsy material of German pathological institutes, 1906-51!1 orway 4ALES DRWAY MALES 7 I j males and females and cancer of the larynx f 0f m#les but not of females. This relation is l ^eD apparent when comparing relative lung ggr death rates in the United States and gpgjand with the relative population density thes countries. Whereas, in the United states, a population of 45 persons per ( ^uare mile, 1 lung cancer death occurs per 000 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 r*b|e 3. Lung cancer rates in necropsy material of various German institutes of pathology for the period 1895-1925 Period Total cancers Lung cancers 1 Percent of 1 lung cancers among all ; cancers , i Range Average 7. 475}10- 276 { 15, 431 2m}398 { 832 3>-8'{ 5. 2 1. 9-0. 2 i 2. 1-5. 0 1 3. 0-7. 0 <yure 2. Age-adjusted death rates for respiratory cancer per 100,000 white males in the United States, 1950. (Lew) 25 St Onr 1RLANO S i WALES U. S.A. ALES LAND :s 14-e 1950 sneer of the Lung ^Mie Health Monograph No. 36, 1955 368108--35----- 2 Table 4. Incidence of respiratory cancer, morbidity rates per 100,000 population for 9 metropolitan centers by sex, 1937 and 1947 Morbidity rate# Primary site and city Males Females Total 1937 1947 Percent increase 1937 1947 Percent increase 1937 1947 Percent increase Bronchus and lung: Atlanta...................... .. New Orleans............. .. Dallas......................... .. Birmingham.............. .. Denver.:................... .. San Francisco........... .. Chicago...................... .. Pittsburgh................ .. Detroit....................... .. Larynx: Atlanta...................... .. New Orleans............. .. Dallas......................... .. Birmingham.............. Denver....................... .. fian Francisco........... Chicago...................... Pittsburgh................. ... Detroit....................... .. 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 1 66 186 105 : 96 4 82 i 83 j 1. 0 2. 8 .5 2. 1 4. 2 3. 9 4. 3 4. 9 2. 3 .3 .4 1. 5 .0 .0 .2 .4 : .4 .4 : 5. 0 400 4. 2 50 6. 4 1. 180 3. 9 86 8. 1 93 8. 1 108 7. 0 63 5. 5 12 5. 7 148 0. 3 1. 0 150 . 4 73 1. 3 . 8 1 300 . 6 50 . 8 100 . 3 -25 2. 9 7. 6 3. 1 3. 3 6. 6 9. 8 8. 8 7. 3 7. 6 .9 5. 6 2. 3 .7 .9 2. 4 3. 5 2. 4 .2. 0 8. 9 20. 8 17. 2 11. 0 1*. 8 20. 8 18. 0 15. 6 19. 0 2. n 7. 6 2. 7 2. 6 2. (1 4. 6 3. 7 4. 4 3. 4 207 174 455 233 124 112 105 114 150 122 36 17 271 122 92 6 83 70 by 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. 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 j figures by Blacklock, Kennaway, Lewis, and . Urquhart that about 16 mg. of 3,4-benzpyrene # 4 Table S. Cancer of lunfj: and larynx, England and- Wales 1946-49 (Kennaway and Kennaway) * Type of community Lung can- Larynx can cer ratio1 cer ratio1 Males re males Males males Greater London............. .. 100 100 100 Countv borough............ .. 129 137 125 Other urban districts...... 160 156 148 Rural districts..................1 233 185 170 TOO 59 42 1 Number of persons producing 1 death. 6 Environmental Causes of Cancer of the Luo* API 06407 . eancer death rates ia 23 States of the gLt*a*t"e** 1946 and 19+8, crude death rates per 1946 Industrialized States 1948 Figure 3. Cancer of the lung in males aged 25 vears and over, England, 1921-30. Reproduced by permiaaion of the British Empire Cancer Campaign. ................... >-*York'::::............................................... j 10.4 97;} 1e0.o2 states with regional industrialization 1946 1948 "f these nstrated amounts fated by r polluu _ssociat pheric xh&ust ftables 8 m these '.vis, and nzp>Tene tiand and -ay) ynx canr ratio1 no*rI--..... Louis**114......... ............ ; wtfo*o-taunna-............................. , Vehrask*............................................... 7.3 1,0.70 ' Agricultural States 6.5 1946 1948 ^ I-Kama......... Aztanaa*.......... Jiew Mexico... jforth Carolina, (forth Dakota.. Ongon Joath Carolina. Washington----Wyoming.......... 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 St*," those for the year 1948 were produced by the National Office of Vital Statistics. " rsfaie 7. Lung cancer mortality rates, per 1,000 deaths by aex, in Austria, 1954 (Herfaich and Veubold) 1 Community 1 Total ! Males j Fe males ifietina......... Wee 60.000-1,000.000 A`ts 20,000-60.000 I*an**nder of Austria___ - 32. 7 18. 2 18. 4 10. 3 59. 0 31. 6 32. 3 17. 3 Mud aortdity percent of that expected fiw the dhtribuoan af papulation by age and dan <tdiitrid era n - as - iso - in - no - ms Figured. Obaerred and expected lung cancer deaths in urban and rural Ohio, 1947-51. (T. F. Mancuso) ' /eatjatiMW ^"1 _ 1 ** r----- 1 VJ fee="*{vQKaatrr--ai * Mrroaa )Iaa"Muaal^-c Lung cancer dealAt 8 counties Remainder of Ohio Obterved 1, 550 728 Expected l. 261 1, 017 the LaW B*Wi Monograph No. 36, 1955 API 06408 Table 8. Estimated amount1 of aromatic hydro carbons in 1-minute samples of gasoline exhaust with varying engine revolution speeds (Kotin) Revolutions per minute Pyrene Com pound X | Benz1 pyrene i Benzperylene Anthanthrene 500............... 1.000............ 1,500............ 2,000............ 2.500............ 3,000............ 3,500............ 225 439 507 374 346 121 48 289 1 325 266 1 142 1 127 i 25 1 5i 1 120 61 33 40 25 13 10 235 177 60 73 70 85 39 1 Quantities are expressed in igm. at 0 load. 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 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- 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 > * ? I | * Table 10. Annual age-adjusted increase of fre quency of lung cancer mortality Percent increase Sex ' 1914-30' ; 1931-40' 1933-44 Males................ __ Females.-......... ... 1 Dorn. 1 Potter. 10. 5 8. 0 8. 5 2. 5 5. 8 2. 0 Table 9. Estimated amount1 of aromatic hydrocarbon in 1-minute samples of diesel exhaust with varying load and engine revolution speed and writh fuel-injection inefficiency (Kotin) Revolu tions per minute Load Condition Pyrene ! Compound ;X Benz pyrene Benz- . Anthanpervlene threne 1 1 1,000 1, 200 1, 400 0 Compression release............. .... A .........do.................................... ___ ____ do.................................... ___ K .........do.................................... ___ A .........do.................................... ___ 0 ____ do.................................... ___ A ___ A .........do.................................... .. -. ____ do.................................... ___ ____ do.................................... ___ 0 .........do.................................... ___ A ____ do............................ _ ___ A ___ y* _____do.................................... ___ y< ____ do.................................... ___ i 1 Quantities are expressed in agm./min. 137 i 267 i 536 : 1,800 2,500 208 257 448 888 1, 912 > 188 1 177 : 220 734 822 ! 22 76 175 640 639 0 0 278 488 614 . 0 56 76 337 346 146 465 772 1, 320 876 9 47 437 432 1. 706 80 78 1. 372 982 1. 687 22 42 124 610 1. 265 79 40 171 930 976 0 0 368 1. 071 944 0 43 223 472 469 4. 3 24 197 320 944 20 16 69 577 666 __ _ 1 > the act* Of 6" Tab l: t 3; y.sr SuoDta. Ass 'Gar Tits: Can- Asr Erg. Bek 1*.; Jits'. Km 35m -fait H.jr 8 Environmental Causes of Csncer of the Lung API 06409 ccounteii for by fjj smoking habits or merely reflect -^ostic acumen of ,j in the availabj],^ ities- y pome even less te annual age-ad Dg cancer deaths*^ 1931-44 (table ^ eased cigarette ^ years should *ion rate above ,V* od. It has beet, ** j) that this parad0^ I rates is attribuu,7 ette smokers J' a Iung canc^ from eo< to be ehcitef] pi increaae of j mortality at increase 11-40 1 1933--h , t with varyiag | AnthanM I th retie . -of cases by i;igarette smoking, iorlt; Statistical evidence. explanation conveniently disposes Nation challenging the validity of the c-r distribution of lung cancer in the SU*** *n<1 foreign countries. Year Author Malefemale ratio ft**1 States- yencans Sor**>' tanria....... (Jertnany-. - - rw*....... Canada........ jU|entina..- ..... 1953 Dorn............... 1951 Moore............. 1947 Humphreys... 1950 Beeler et al__ 194(5 Lindskog........ 1951 Carlisle et al.. 1941 Halpert......... 1951 McBumey et al. 1949 O'Keefe.......... 1941 Farberowand Baslow. 1935 Xeelv.............. 1953 Steiner............ 1953 Krevberg........ 1925 ...do................ 1947 Henschen........ 1931 Clemmesen... 1945 .. .do................ 1953 ' Denk. ........ 1953 Grosze............ 1850-1899 __ do................. 1900-1919 .. .do................ 1920-1929 '...do................ 1930-1939 .. .do................. 1940-1949 ...do................ . 1952 Lemoine 1948 Gagnon........... 1947 Santas............. . 1949 Mason, 1949 Fulton............. 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. 4:1 1:1 2:1 5:4 3:1 15:1 6. 6:1 1. 8:1 3. 1:1 3. 8:1 3. 8:1 5. 4: l 10:1 8:1 50:1 10:1 7. 3:1 i Mencans living in Los Angeles. cigarette theory and may perhaps momentanlv satisfy the protagonists of this concept, although it cannot be taken seriously by anyone tvho 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 spread of the 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 countriesi 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. Male-female sex ratio of lung cancers in Germany, 1886-1927 and 1940-50 1940-50 1 :O 0 City 43 Author j Ratio <5? Author Ratio 1 | 223 472 469 Dnsden.............. ... Wolf............................... 6. 7:1 1 Dresden...................... Lickint...................... ... Laiprig-............. __ Sevfarth.......................... . 5. 3:1 | Leipzig........................ Knorr..................... ... 15:1 11:1 24 197 320 944 JO 16 69 O. a 666 Do............... Chemnitz............ ... ieriin................. ... Do... . Do.. . Do............... Eoein.......... Briese........ .................... Wahl............................ km............ . : Bilx.................................. Hamburg............ 2. 5:1 !.........do......................... 2. 9:1 | Zwickau..................... 3. 7:1 i Berlin______ ______ _ 2. 3:1 Potsdam..... ................ 3. 6:1 Koeln........................... 5. 2:1 Muenchen.................. 4. 7:1 __ do______________ 1. 5:1 do...................... 8. 0:1 Jena 1. 8:1 , Hamburg Merkel..................... ... Gerbe....................... ... Berg.......................... ... Hollmaon................. ... Breyer____________ ... Anaclcer___________ ... Kautzsch__________ ___ Frey.......................... Kuntzen___________ ... Letzius.............. ....... ... 15:1 7:1 9:1 19:1 21:1 7:1 18:1 24:1 49:0 12:1 the Laat fctte 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 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 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 Table 13. Histological types of occupational respiratory cancers, according to carcinogenic agent Agent Organ Squamous I cell carci: noma with 1 or without | cornifica- tion Round cell or oat cell carcinoma Anaplastic or polyraor- Adenocarphic carci- , ciooma noma : i 1 i3 ___ ' 4 3: 0 Asbestos ............................... ........ do......................... ___ 1 11 2o Radioactive gases and dust. . ___ ! 14 9 7 Nickel.-..................................... Nares and nasal sinus____ i 3 ....................... 6 Radioactive gases and dust..,.........do.................................. 3 .............................................. Isopropyl oil............................. ...........do...........................................................1........................ 4 .............. f \ 1 f i 1 1 i 10 Environmental Causes of Cancer of the Lung Public Health API 06411 , MinuaJ tobacco consumption in pounds per capita, Great Britain, Norway, Switzerland. Turkcv, * and the L nited States, 1900-50. before 1920, or even before 1900, readily estab lishes the fact that during those years squamous cell carcinomas of the bronchi were by no means rare occurrences (Wolf, 1895--8 squamous cell Table 14. Consumption of tobacco in pounds per head-year, New Zealand and United Kingdom, 1900-1950 (Eastcott) Year Pounds of tobacco per head-vear New Zealand United Kingdom 1900....... ......................... 1910...................................... 1920................... .................. 1930...................................... 1940........... ......... ................ 1950...................................... 2. 3 2. 69 3. 59 3. 28 3. 87 5. 36 1. 95 2. 22 2. 99 3. 31 3. 97 4. 22 carcinomas among 15 lung cancers; Probet, 1927--25 percent squamous cell carcinomas be. tween 1905 and 1918; Watsuji, 1903--23 percent squamous cell carcinomas between 1892 and 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 Conf., 1949--44 percent squamous cell carci nomas in males; 11 percent in females. While adenocarcinomas are more frequent in females than in males, they also are more fre quent in young persons than in old ones (Lindskog; Proc. First National Cancer Conf., 1949), The evidence on hand scarcely supports the contention that adenocarcinomas arc of endog enous causation (Lickint) or that they have an etiology differing from that of squamous ceE carcinomas (Kreyberg). The male-female sex Table 15. Average death rate per year per million persons (males) from cancer of the lung, 1932-52, v New Zealand compared with England and Wales (Eastcott) I Age Period Country i 1932-36________ _______ New Zealand_______ ______ ____ - -- i 1 1937-41........................... - ____ do....... ...................................... ........... 1940-41............................. England and Wales....................... ...........; ! 35-44 ; l i 13 | i 33 ! 126 ; 45-54 | I i 87 i1 108 1 424 1 55-64 i 158 235 802 65-74 204 283 715 1942-46 ..................... 1942-46 ........................... : .. 1947-51 ....................... New Zealand....... ........................ _ ........... 1947-51 ......................... England and Wales....................... ......... 46 132 43 i 166 ! 168 466 635 466 . 1, 072 1, 032 287 j 732 1, 014 781 : 1,682 ! 1,857 1952-53............................. New Zealand....... .......................... ........... 1952-53 ....................... England and Wales....................... ........... 61 175 305 1. 027 1. 456 858 2, 171 2. 650 1 75 and , over 62 21S 448 > 326 527 735 1,073 1, no i. ass Table 16. Observed and expected mortality from cancer of the lung according to place of birtb. } New Zealand or the United Kingdom (Eastcott) :------------------------------------------------------------------------------------------------------------- Age at entry to United Kingdom Place of birth Observed deaths United Kingdom..................... 632 369 Expected deaths 721. 8 279. 9 Under 30 , 30 and over Observed deaths Expected deaths Observed deaths Expected death? I 201 i '' 229.2 168 . 139. f Note: The significance of the difference between observed and expected deaths in the two countries is p<0.001- ` 12 Environmental Causes of Cancer of the Lon# API 06413 ! f-'igure . Trfnii* in -elected environmental factor*. Lai ted Mate*. Lm*0--.*^1 (Humnnind). STATE ASPHALT highways* MOTOR FUEL CONSUMPTION tre more fre. 1 ones (LindCon!., 1949). supports the xre of endog. they have an juamous cell le-female sex lung. W32-33, 300 200F 100 ,y CIGARETTE CONSUMPTION PER ADULT / / FUEL OIL SALES // / ^ MOTOR VliHICLE . f'' S REGISTRATION ___ COAL CONSUMPTION i-74 75 and over 204 283 715 635 -.032 ,14 .857 . 456 '.650 62 213 448 326 527 735 1.073 1, 110 1. 688 lace of birth, lorn :id over Expected deaths ries is p<0.001. t of the Lane '1900 1910 1920 1930 ii i<Ii i i i> I ti i<ii i 1940 1950 i960 ,,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 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 CaUie Health Monograph No. 36, 1955 348108--S3----- S 13 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 f Alps might be related to climatic-atmospheric > Figure 7. Rise in annual production or consumption of cancer-related industrial chemicals between 1900 and 1948. ' PRODUCT UNIT l. HTUMNU5 COAL-PROOUCTON IN U.5.. 2 ruCL WNLUONS Of NCT TONS BUQUCTS-TOTAL PRODUCTION. orthousands nct tons 3. CARBON BLACK - PRODUCTION IN MILLIONS Or POUNDS 4. PETROLEUM - PROOUCTON OP CRUDE PETROLEUM, MLLIONS Or BARRCLS 5 PETROLEUM , ASPHALT - PRODUCTION OF ASPHALT (rrom petroleum), thousands or SHORT TONS e. COAL TAR- PRODUCTION-THOUSANDS OF OWLLONS 7. ISO PROPANOLs. ASBESTOS - PRODUCTION,- THOUSANDS OF POUNDS APPARENT CONSUMPTON, THOUSANDS OP SHORT TONS,(M.YRBK-l]a) 0. ARSENIC to. CHROMITE - PROOUCTON AND BIPORTS; THOUSANDS Or SHORT TONS TOTAL SUPPLY, THOUSANDS OF TONS i l i i1 I conditions winds, whi air of Vie Alpine regk Similar v prevailing lung canoe: Midlands v and Neubo cancer xnai communits where them: fumes from dust and fe the inhabit: remote frm rise in 1cm increase m constructs? Oe The cone or contrib by epideni evidence rates of v*r as well as & specific an# number off well-defines: Epidemiol Industrial Epidemic lung cancer groups ana: existence *' of persons cancer of1 striking aS list some m responsible 1000 1005 WO IMS 1*20 1025 1030 1035 1040 1045 V Table SI. for seven i 14 Environmental Causes of Cancer of the Lsmf Public **' *V '* lissi,rrii^a_ ` fo'">tcit.rihN11 I^ls which to the direction of prevailing bring tne industrially polluted altho|-ie*hh> : K'vV*'ienn"a into the valleys of the northern 4 ftPPrroo**i*nnaatu4r? "of a^arretui tbe h,gh luh ople living in J* era slope 0f .J* atic-atmosphej S>*e^jj^r observations on the influence of the 5 ailing winds upon the relative frequency of cancers in different areas of the English K^ds were reported by Stocks. Herbich ^veubold, moreover, found that the lung r mortality rates were twice as high in ic-1* b*`ween ^jQunitie3 located along main highways, cf\the atmosphere was polluted with exhaust es from gasoline and diesel motors and the i and fumes of asphalted roads, than among habitants of villages and towns situated ote from such traffic arteries. In fact, :he . jjj lung cancers follows more closely the ^ase in consumption of motor fuel and the cstruction of asphalted highways than the 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 jncer of the The concept that environmental factors cause contribute to pulmonary cancers is supported by epidemiological, medical, and experimental jnience obtained from analysis of lung cancer nue of various occupational population groups well as by studies of lung cancers and their specific and different causal agents present in a number of restricted worker groups and in veil-defined industrial operations. Epidemiological Data on Large Industrial Groups Epidemiological studies on the frequency of lung cancer among members of large industrial poupg and trades have brought to light the aistence of marked variations in the liability of persons engaged in different occupations to oncer of the lung. Tables 17-19 supply wiring illustrations of these differences and bt some of the factors which may possibly be foponsible for them. Table 17, which lists lung cancer death rates I* aeven industrial groups in Ohio, shows a Health Monograph No. 36, 1955 striking difference between the rates for agri cultural laborers and for employees in the nonferrous 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 males, 1947 (Mancuso) Industry j Death j rate Nonferrous metal.................................. _______1 : Rubber and plastics..__ __________ 1 .............i .......1.53 Agriculture ......_______________ .............' Stone, clay, glass.................................. .............; Total........................................... _______| I 3. 22 2.18 .82 .66 1.76 2.91 2. 34 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 dust, 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, nonstandard- ized (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 and grain dockers. In the experience of l Dunner and Hicks, these workers showed an f excessive liability to cancer of the lung. Twen- l Table 18. Frequency of lung cancer among operating and nonoperating railroad workers Railroad Period Total lung cancers Type of railroad worker Operating Nonoperating Undetermined Number I Percent . Number Percent ! Number Percent 24 59 83 i 57 155 I 17 14 30 29 Table 19. Occupational groups with excessive incidence of lung cancer ty-four hug 5,000 dock' Occupational group Potential respiratory carcinogens Investigator 2,500 were* 10 boiler sc Metal workers, welders, metal grind Metal dust, lubricating oil mist___ Kennawav and Kennaway; Turner exception ers and polishers, wire makers, tool and die makers, foundry workers, metal moulders, lathe workers, etc. and Grace; Muller; Dublin and Vane; Wvnder and Graham; Mc Laughlin; Breslow and associates. radiological only 5 bad! Cigar manufacturers and tobacco Tobacco dust, insecticides, soot -- Seyfarth; Kennaway and Kennaway; nists. Engineers, mechanics, machinists, Metal dust, soot, lubricating oil-- upon histoftr cers were oi plumbers, crane operators in smelt Turner and Grace; Muller; Wynder ers, etc. and Graham. Painters, decorators--------- ---------------- Metal pigments, coal tar dyes, BECC 1 1944; Moller; Dublin and not exposed that boilers I i carbon black, asphalt paints, solvents, vehicles (lacquers, res ins, synthetic plastics). Vane; Fulton; Wynder and Gra ham. ' sure to cba; " ere used as Tar workers, road workers, asphalters, paviours, stokers, patent fuel workers, furnace men, foundry laborers, rollers, etc. Tar and pitch fumes and dust, soot. Kennaway and Kennaway; Fulton; BECC1 1952; Registrar-General (1938); McLaughlin. ( workers sue iron oxide, or some cam such as rask 1 Report of the British Empire Cancer Campaign. processing c 16 Environmental Cauaca of Cancer of the Long Public HeriUl Trie n large railro^ ratio, it appPafs nonstandard, .. about 75 peK lroad employee* ,r group, whirtj total number of ul workers ^ ,kemen. conduc. iouse personnel, inhalation of coal engines and fuel tain carcinogenic called attention ps, boiler scalers experience of kers showed an lie lung. Twen- i workers Fiur* 8. NASA-. rVjSEi .AR.'NX ' UNO L'ndetermined imber Percent HEATING SOOT, PITCH,TAR, ASP-tA-T jUiT MINING URANIUM ORE REFINING igator KenDaway; Turner uller; Dublin and and Graham; Me- and associate;, y and Kennaway; BriDkmann. ' l(?o2; Gillespie: Muller; Wvnder iller; Dublin and Vynder and Gra- ennawav; Fulton; Registrar-General hlin. nicer of the Lun( 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 only 5 had a slight degree of pneumoconiosis upon histological examination. No lung can cers were observed among dockers who were not 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 workers 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 recent observation of Faulds on the excessive fre quency of pulmonary cancer among English iron ore workers employed in mining activities at two different locations. Necropsies performed on these miners during 1932-53 showed a lung cancer incidence of 9 percent (192 necropsies with 17 lung cancers), while 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 Health Monograph No. 36, 1955 17 (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 Abrams on 518 histologically proved cases of lung cancer in California suggested the existence of an increased liability to lung cancer for members of the following occupational groups: welders, sheet metal workers, steamfitters, boilermakers, crane operators, and nonferrous metal smelter workers, that is, individuals who are exposed to metal dusts and fumes; oilers, oil field workers, wipers, and marine engineers, who 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 information available on the occupation*! I aspects of lung cancer causation are deplorably m defective because of an absence of extensive and prolonged analyses of lung cancer deaths among various industrial groups for specific causij factors. The evidence on hand nevertheless i* adequate for demonstrating that the wide varia tions in lung cancer frequency apparently existing between different industrial population i groups are attributable to differences in more or less well-definable occupational exposures and not to differences in cigarette smoking habits. respiratory can related general t justly be assumi sent the cause o cancers among n tion, especially highly industrial Table 20. Occupa 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 of Environmental Lung Cancer Hazard* An indiscriminate acceptance of the figures given in table 20 as reflecting the actual scope of 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 , occupationaUlung 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 or subjected to identical or similar working condi- ^ tions are subject to the same hazards. 1 | contrast to the apparently low carcinogenic potency of the suspected, but unidentified, j agent presumably contained in tobacco smoke, ^ the occupational respiratory carcinogens are | evidently highly potent, as shown by their hi?*1 > respiratory cancer attack rates (table 21). ! Since environmental carcinogens have been j shown to produce cancers wherever they operate in adequate intensity and duration, and oon- i sidering the fact that many of the occupation^ Arsenic.................. .Asbestos................ Chromates............ Nickel.................... Coal tar..... ........... Petroleum oils... Isopropyl oil____ Radioactive chemit Total___ . Carcinog< Aromatic hydrocari Coal tar fumes.. Petroleum oils.. Carbon and silicon Isopropyl oil__ Asbestos............ Metal.-: Arsenic.. . t- hromates Nickel ... hmizing radiation: Itadioactive ores 18 Environmental Came* of Cancer of the kn** pU,tic Health Me API 06419 ;upationft| ieplorab|v '"^"e anrj 1 nHg -fic caua^j rtheless ja ide varia, ipparently wpulatio^ in more 0p sures and : habits. jirawrv oan'mogens occur as industry*j^ed general atmospheric pollutants, it may be assumed that these pollutants reprei j tbe cause of a significant portion of lung *Dcerg among members of the general popula^ especially those who live and work in ^]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 Occupational respiratory carcinogen* and cancers recorded during past 75 years, their causes, sites, and numbers ' Agent Site of cancer Year dis covered Number of recorded cases United Other States countries 10tal -tence of lental Pe. d by the ntal data cancers, spiratory ents, and 9. Hazards le figures 1 scope of spiratory sepipusly j iral Ru-oCrtz; others). f specific is so far d worker odIv lin- r worker igents or ig condirds. In inogenic entified, smoke, ;ens are ieir high 1). ive been f operate ffld connational .-enic.......................................... Lung................................................ Ubestos................................................... do............................. ..............., chromates-.............................---------- do............. ................................ $kel....................................................... do.............................................. Xares and naaal sinus. Coal tar......................................... Lung..................... Petroleum oils.............................. Lung and larnyx........ Isopropyl i>.................................. Lung..............I........... . Larynx.... ..................... Nasal sinus. ............... Radioactive chemicals................. Lung_______ _______ Nasal sinus. ............... Total. 1930 1934 1932 1932 1936 1936 1946 1879 1931 125 | 1.001 i 1, 126 Table 21. Respiratory cancer attack rates, by environmental carcinogens Carcinogen Sites of cancers Attack rates Incidence in population at risk ! i Percent ; Rate per 100.000 ; of all i_ cancer ' : deaths Morbidity | Mortality Aromatic hydrocarbons: . Coal tar fumes...................... Lung........................; 500:100,000 Petroleum oils...................... Lung_______ _____ 2,000:100,000 Carbon and silicon polymers: Irs.,,o,,p_ro__py' l o.l......................... \ f Pa^rmanyaxs.al sinuses,' 1 ">:100 |............ !.mlj56(.5nr' Asbestos................................ Lung...................... Metals: Arsenic___ Chromates. Xickel____ Naree, paranasal sinuses. Lung....................... Ionising radiation: Radioactive ores.................. I Lung. 329:100, 000 574:100, 000 (42 X nor mal) (20X nor mal). (13.2-20 percent usbestosis autopsied (0.8-2.4 percent normal)). 145.7 males (10.9 nor mal.) 146-338 (50-80 percent of all deaths). Wife 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 Dumber 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 aD 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 ator}- 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, aDd 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 (Neu- 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- i schowsky). A cutaneous as well as parenteral j introduction of coal tar and several polycyclic ^ hvdrocarbons as well as of urethane resulted `% Environmental Cautefi of Caneer of the Lunf i a precocious a ber of pulmon Pattern and If a map of centration of lutaDts were p exhibit a sort the general at nish the oven depth betweet rural district atmospheric p scribed field irregularly ar shaped spots superimposed It stands to i exposure pan portant influe! acter and inri of various re carcinogens w ological scatn spread of cat production fo The followi to environmet be distinguish 1. General posures to c hydrocarbons incomplete and industrial exhaust fume? abrasion prod from asphaht arsenicals eon f burned co-. metal smeltet Use of arseni radioactive n from t he soil c the atmc ^plosions. 2. Special j exposurp to < Public Health 348106--3 API 06421 al (0 I,.4' fin (Jipsscrs 3 t the survpv^` at thorp \v^f ating r,.fjn * victims of ^ led to tho t. h* existonoP ivTTe n>nPh tade m .SchnPB3 ,rpr- lining 0. n for 10 to on :ld the ^*nitpd rations of `d in Bpteiu* icial record 0f s an)nS tho 10 existing roo. cancers may at pulmonary n from agents liratory route, inogens are of dialed as air estivgjoccupaat' 'idence ea other lung cancers. . record which -.ration of ariividuals with ancers (Xeuleen observed iffering from icer (AItiller) agestive. and id vapors of unines. The ignificance of experimental <0 percent of tviamino- ami an increased num0l pulmonary tumors in mice putterr and Types of Respiratory Cancer Hazards jf a map distribution and relative con- trad011 different carcinogenic air pol- ^aDts were prepared for a given area, it would 'diibit a sort of crazy quilt pattern to which e. ^neral atmospheric pollutants would fur- the overall background color, varying in foth between darker urban areas and lighter ^al districts. Other types of carcinogenic jtmospheric pollutants having a more eircum- ^ribed field of distribution would appear as j^gularly arranged aDd variously sized and haped spots and islands of different colors .uperimpsed 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 ter and incidence rates of pulmonary cancers 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 |)c 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 usenicals contained in the mineral ash and soot of burned coal and in the effluents of certain metal smelters, and related to the large-scale use 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 explosions. 2. Special and locally restricted atmospheric 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, Dot 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. 21 Physicochemical State of Atmospheric Carcino gens and Topographical Distribution of Cancers in the Respiratory Tract for the cancers of the bronchi. The bronchiogenic cancers found among chromate manufac turers. asbestos workers, and coke oven and gas sinuses, and lai the list of em were the lung 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 saccula- 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 faeturers (19)15 arsenic worker- tors (1936). tile nasal sinuses, smelter workei nasal sinuses (1931), the car and lung am (1946i. and e among worke sprays or mist- tions. such as the paranasal sinuses and the peripheral bronchiolar regions of the lung, in genic pollutants and the localization of cancers within the various parts of the respiratory tract, Specific Care which inhaled carcinogenic matter may accu mulate. condense, and precipitate. The traffic consideration also must be given to the fact that gaseous and liquid carcinogens may become ad- ! 1 pattern of air pollutants in the respiratory tract sorbed to the surface of carcinogenieally inert 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 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 I 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. Nickel, one < metals and p district of On alloys (iron, cobalt); molyl facture of stai forgings, casts tubing, rods, plating; catah 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 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--the cancerous nature of the lung diseases prevalent among the radioactive-ore miners in Schneeberg. Saxony. This discovery. ( pigments in p; and so on. Exposure to metallic, nieke carbonyl vapo trial workers o tions. While The excessive incidence of larynx cancer of historical importance and great present sig salts not infre< among mule spinners inhaling carcinogenic nificance, attracted little attention at the time 1 f an apparet shale oil sprayed from the revolving spindles because radioactivity was still an unknown fact inhalation of likewise provides another example of this mech and cancers of the lung were comparatively rare , been responsil anism because it is likely that the relatively before the turn of the century and therefore of acute and of I large droplets of this oil are arrested in the upper little medical interest. > monary manii I portions of the respiratory tract, making the It was not until the third and fourth decades > tion of alveol narrows of the larynx the part of main exposure. of this century that additional, well-defined exudation int Dusts or mists composed of particles having occupational activities and environmental eosal hemorrb a diameter below 4 microns, on the other hand, agents were again related to the causation of 1 to the toxic penetrate into the deeper parts of the respira cancer of the lung and other parts of the respira- > formed from tory system and therefore are mainly responsible tory tract, that is, the nasal cavity, paranasal bony) upon tl Environmental Causes of Cancer of the Lun* I API 06423 Public Health 'intiti1 nianufa,.^ and t1 iis typp- q|ants of gaseo\4S ictrate into the uses, where they tion into solirls sition into solirf^ -ation and poly, (aliphatic epo*. anol liquor). p between the spheric carcinoation of cancers spiratorr tract, ito the fact that may become adogenically inert under such cons. Such comi relation to the dsorbed to rock s concerning the ihatic and poly, ns adsorbed to industrial dust ilk/itsoot. 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 1. well-defined environmental le causation of s of the respiravity, paranasal cer of the Lung es. aim larynx. Among these additions to ist of environmental respiratory cancers were the lung cancers among chromate manuturer* (1935). of asbestos workers (1935). of |*cL.enic workers (1930), and of coke oven opera*r\ (i936i. the cancers of the nasal cavity, para- sinuses, and lung among copper-nickel " elter workers (1932). the carcinomas of the ' j sinuses among luminous-dial painters l931)> ^c cancers of the nasal sinuses, larynx, ^ ^ Jung among isopropanol manufacturers (946). and cancers of the larynx and lung sniong workers exposed to lubricating oil sprays 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 he pulmonary structures. Krafft -uggesteil that these reactions are the re-ult of a nickel allergy having the lung as its shook 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 Gydach 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 iE. 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 aDd 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). Xo 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 (Lpken). 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, Pablie Health Monograph No. 36, 1955 23 Dor 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 (L0kenj. 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 f 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- coniotic 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- ' 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 V unknown. Likewise, no definite opinion can be expressed as to the possible existence and t extent ofrespiratory 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 is 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. 1 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. Environmental Cause* of Cancer of tie Lunf blueprintei chromate r on makers workers, g ers, pottei battery m; ers. ink m ers, photo* workers, s canizers. v welders, u railroad ei stallations. An ena tion with from the trial waslrefineries catalyst fo environme follow the agents in coating industrial!; a corrosiv and/or inh developme nasal sept proof of .i menting oi tions amoi chromium Factories <t his report hazards in as well as for it wouli is not reo< been done relearnt an This refl appropriat existence individuals tr>al opera fished data The obs connected especially two tyj rhromates Pul>lic Heal API 06425 prr,,|^u u v le. *&?* 'fresPir*w -ampbell f p0uM hf) fithese, em t0 demon! oogenic Pr pufe metal|ip TO the fem0ral ,,<lous tissUp of 0 sit* of injnr. a carcinog,.n;,. and following rtam- It mav aki and Mu* kic method*, ers of various nt ranged from umor tissue t0 f 'pationj t the data rkers at risk i* opinion ran existence and "ds for person* ct with dust, -cel or its rom- r compound is try. It is for und variety of ium and chrostricted group* possibly be.e form of dust, solids (Bourne kely to be ex* impounds are .ers, bleachers. rtr of the ttfl . .[t,|-s. chronic workers, chromium platers. |lu*Pr manufacturers. chromite miners, cravV^lers. dye workers, electroplaters, enamel irlass and pottery frosters, glass color*f*e ttery glazers. artificial flower makers, **' ^ makers, linoleum workers, paint mak- ']. makers, painters, photographic work*** ' [jotoengravers. polishers, printers, rubber ^ P steel workers, tannery workers, vul- ^ waterproofers of textiles and paper, Users of chromate antirust agents in iiad engines, automobiles, steam heat inl*l^onSi and bitumen and oil refinery workers, environmental atmospheric contamina` ^(h chromium compounds may result ll0D the release of chromium-containing indus- wastes of chromate plants and of oil ' fineries using a chromium-containing silica ^talvst for the catalytic cracking of oils. An imnmental spread of chromates may also follow the use of such compounds as antirusting a^nts in automobiles and for anticorrosive ^ting f airplanes. Since many of the pdustriaOv used chromium compounds exert , corrosive action on tissues, skin contact jnd'or inhalation of such agents results in the jjyelopment of chrome ulcers of the skin and tff.i septum which in turn provide definite pjaof of an existing health hazard. Corn waiting on the appearance of such manifestadons among workers in new industries using chromium compounds, the Chief Inspector of Factories of England and Wales remarked in hk report of 1944 that "the control of old haxards in new industries is of interest to others m well as to the student of industrial health, for it would seem that in many cases the hazard a not recognized until damage to tissue has been done, when old principles have to be relearnt and adapted to new uses." This reflective observation seems to be quite ppropriate when contemplating the possible existence of respiratory cancer hazards for individuals employed in the numerous indusihai operations for which no pertinent pubfidied data of any kind exist at the present time. The observation of apparently occupationwmected cancers of the respiratory organs, ^ecially the lung, has been limited so far <o two types of operations, the production of 'fuotnates 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 causallyinvolved, 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, bi chromates, and zinc chromate) are most often incriminated. Mancuso 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 (Mancuso 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 trivalent 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 femora] 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. Age distribution of cases of chromium cancers of the lung, according to type of worker Type of worker Age [years 21-30 31-40 . 41-50 51-60 61-70 71-80 Total American chromate..... .............................. ...... 0 8 16 19 10 1 M German chromate................ ...................... ........... 1 3 7 14 12 1 35 German chrome pigment........ .................. 531 1 to terer. Niedln Hueper). Spx 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 cases fr< reported as ulcers. Chromium accompany t lung in chroa facturers. It the pneumom or modifying process or wl of coincident Arsenicals product of tl zinc, silver, nickel, tin, a in the smeltc extensively 5 ing past deco vermicides 1 bait, rat pois ly for clearin are applied a and are dus eorn, soybeat ployed as tv facture of <. bronzing an and cosmeti and its con "En vironme: for 35,251 u 26 Environmental Causes of Cancer of the Lunl publi, Health l i API 06427 ft ill eXCiSSiv, J ^iedhardt and Klett; Mancuso and established ^ laePer ' ^Pdnna-el^ recentlv noted a peculiar ;n Germany I'jjjyior of the chromium content of the blood j\ Caroz^j. |2 urine in chromate workers before and after e and Jona*. 2de?elPment f f*111? cancer. It wa9 found isch: Alwet^ 2t in chromate workers the normal urinary , agstaff) an<j ^yetion of chromium ceases with the develop- d Gregorius. jat of lung cancer while simultaneously the 'ancuso and Sood chromium level becomes elevated. If Occupational ^ufirmed, this observation may have distinct 'cel and in jjpportanee in causal, metabolic, and diagnostic v (Baader; r^pe<'ts- . , dbardt and ^pith the exception of 2 cases--1 cancer of case of lung d,e nares (Newman) and l cancer of the of the chest ^axillary sinus (Goldblatt and Wagstaff)--the - employed mug was the exclusive site of respiratory cancers plants, while observed among chromate workers. The total ird to chro- number of these cancers is at present around ts in other 125 cases from all sources. None has been Italy, and ^ported as originating from nasal septum cy of lung which, ar ranges from ry of lung illation, an is strongly Btribution articularlv 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 the pDeumonoconiotic process plays an essential or modifying role in the specific cancerization process or whether it is merely a phenomenon of coincidental coexistence. t among ` 50 per is before rs of unent (table 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 ium con ns with in the smelter fumes and slag heaps. They are extensively produced and used, especially dur ing past decades, as insecticides, fungicides, and ported by vermicides (sheep and cattle dip, grasshopper onas; Let- bait, rat poison), as well as a herbicide, especial ly for clearing railroad rights-of-way. Arsenicals orker 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 Total 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 decides 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 Lung flUic 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 Neubauer 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 factor}', 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 Table ^ 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 anc 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, lc 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 5 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 a the human race made the adjustment to arsenicism. arsenic in the environment and that only \ such eviden* rarely, when associated with other contributing cism 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 rium"; and further "that the handling of arsenic trioxide in the industry studied does smokers wit it is most i dust, fumes, not produce a significant change in the cancer mortality of the plant employees; hence other production < of these pop factors in addition to arsenic must be con sidered significant in the causal relationship to cancer." 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 % 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 The exten 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 coe> the lung ha Environmental Cauaes of Cancer of the Lunf ' Public Hcali API 06429 <i to -OrkP i a>3Sent Pec*ficha2ar'l anc* Schil] d' *-`nce obtaa;inatj `to arseni als, Pa squam O'!* nidemiologi, "'as made ies of cam al metallUr f the to 'orded duri cancer of ( in the lun| this eviden t biological ljustment "I that on r contributing emic disease, it ion. it may igical equili^. handling 0f studied does in the cancer : Wee other a oe con i ciationship ercent of all one plant surthe long, the rly suggest a -enic trioxide the exposed the data of >rted by the among the in Montana ere operated pational and aosphere and nhalation of ; to produce of the lung * connections Table 23 Luna cancer mortality in several Montana counties, 1947-48 (Lull and Wallach) 1 County and total `populatton 1940 Major industry Xumber lung cancers Total Male Fe male Total cancer deaths Percent lung cancer Annual '.ung cancer death rate 100,000 Male Fe male Male1 Fe male Copper smelting 1 Copper mining 1................ Copper mining, smelting3. ' Agriculture 21 27 20 1 0 21 98 30. 8 0. 0 145. 7 0. 0 2 29 259 22. 6 1. 5 ` 48. 6 3. 9 5 25 299 12 7 3. 5 46. 3 12. 3 01 81 3. 0 . 0 i 5' 2 .0 t personal communication of unpublished data, s The'estimated crude death rate for lung cancer among white males in the entire United States in 1947 was . 0 [*r 100.000 population. 1" i The workers employed in copper ore mining and smelting inhale dust and fumes of arsenic contained in the j released as a byproduct and waste product during the smelting process, of jjjould be acknowledged only when there ^jjted at some time clinical and, if possible, ystoloeical and biochemical evidence of chronic ^nicism. 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 jinuses, and lung, and among excessive tobacco snokers with cancer of the larynx and lung, jt is most unlikely that exposure to arsenic Just, fumes, and vapors plays any role in the production of respiratory cancers in members of these population groups. iron- The extensive production and use of various types of iron and of diverse iron products offers frequent opportunities for the inhalation of dust and fumes of iron and its various alloys sad 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 Fe203 or of Fe304H20. respectively, is considered an inert form of pneumoconiosis which does not cause disability tnd which at least in part seems to be revers ible. The deposition of iron oxide particles does not 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 among 192 iron ore miners coming to necropsy 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 lung does not produce a special predisposition to lung cancer. The uncertainty existing in this respect is further illustrated by statistical data provided by J. W. Brower, Deputy State Registrar, Minnesota Department of Health, on the num ber of deaths from lung cancer among iron 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 of the Lunf Health Monograph No. 36, 1955 29 Table 24. Deaths due to cancer of the lung among iron ore miners and residents of Minnesota, (Brower) 1950-54 Year Number of deaths Death rate per 100,000 Minne sota resi dents St. LouisItasca County miners Minne sota resi dents St. LouisItasca County miners 1950.... .. 1951.... .. 1952.... .. 1953.... .. 1954.... .. 328 289 329 367 345 0 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 berylliumnickel alloys, glass, phosphors in fluorescent 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 ngteworthy, that beryllium apparently , once inhaled is retained over a long period of time in the human body, since beryllium has 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 sulfate and beryllium fluoride; the lungs retain the bulk of beryllium if the compounds are in soluble, such as beryllium oxide. Experiments of Aldridge, 3 shown that : certain tissue plasma prot blood. Thes from being p The metab pounds obtai fact that Gat tion of osteo intravenously ing powders burn silieatquently conf and other oxide, beryl) introduced k respiratory r Sissons; Hoar Largent. and period for tin Comment! osteogenic sa of beryllium noted the fa dying with b able amount following cr years, consit been exposes 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 rab' 0Pment of . administratii direct introd ioto the fern' oavity, and : 30 Environmental Caue of Cancer of the Lon? Public Health API 06431 .nnrr ;jro<|s|f,( f f ^Jdridge. Barnes, and Denz, moreover, have ui)e uir^W" I that beryllium ions react rapidly with ,^hers, ^ | jtftin tissue proteins and form complexes with 11 ion thj j*sjna proteins when introduced into the osea to the if, jjood- These complexes protect the beryllium beryllium ar) 0 being precipitated by phosphate ions. *n recognfc j'jie metabolic peculiarities of beryllium com- lese manifestft -onic nature ^ .ere concerned chronic Pne(K mids obtain special importance in view of the pit that Gardner in 1946 reported the produc- of osteogenic sarcomas in rabbits injected Intravenously with insoluble beryllium-con tain- Uiosis). Sonjg .pg powders (beryllium phosphate, zinc beryl arcoid" in rjp_ lium silicate). Other investigators subse-.ar, pulmonar^ uently confirmed these results with the same .ble moreover ^d other beryllium compounds (beryllium eared not oniv 0pde, beryllium silicate, metallic beryllium) 50 among peN Introduced into rabbits by the intravenous or of fluorescent juratory routes (Sissons; Barnes, Denz and ieir bervlliUrn_ jggons; Hoagland. Grier and Hood; Nash; Dutra, Berghout and [urgent, and Roth; Barnes). The preparatory )ustan, Stead- period for the sarcomas was 11-24 months. Commenting on the successful production of rational bervl. rmany, Italy, . Not infrelesions have the body after n of beryllium osteogenic sarcomas in rabbits after inhalation of beryllium oxide, Dutra, Largent, and Roth noted the fact also that the bones of persons Jving with berylliosis contained not inconsiderble amounts of beryllium. They came to the following conclusions: "During the last 20 aosphors from ; of the n! requent est -eactions. been found in ar structure, 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 tm apparently of poorly soluble compounds of beryllium may long period of 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 tent, 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 far, only rabbits have responded with the devel i aerosols are opment of osteogenic sarcomas following the ^llium sulfate i 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 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 ea 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 COMBUSTION AND DISTILLATION PBODUCTS Or COAL The apparent innocuousness of coal and, possibly, graphite dust as respiratory carcin ogens is not shared by the incomplete combus tion, distillation, and hydrogenation products f the Lung hilic Health Monograph No. 36, 1955 31 of coal (pitch, tar. soot, creosote oik, anthracene oils, tar oils, and highly viscous oily and tarnfractions 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 established beyond any doubt. Although the bulk of the casuistic and epidemiological human evidence of occupa tional coal tar and pitch cancers has come from England and Germany, it cannot justly be assumed that American-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 lumber, chimney sweeping, cork brick manu facture, electrolytic metal production, and so on). Since the high boiling fractions of synthetic oils produced by the direct hydrogenation of coal through the Bergius process have been shown to be highly carcinogenic to the skin and hr subcutaneous 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 been operative for some 20 years in Germany and have recently been constructed by several industrial concerns in the United States. Not only the environmental, but also to a greater degree, the occupational inhalation of dust, soot, and fumes produced by the incom plete combustion of coal results in the develop ment of a "soot lung," called bituminosis, 32 which is characterized by the deposition of finely dispersed carbon 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. j 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 liability , 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 t 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 subjected to clinical and X-ray examinations, although there were S' 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, thereby 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 by Koelscb (blacksmith, tar worker), Rodenacker (briquette factory 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 Cauei of Cancer of the Lung j the other ham f 100> lung c;r following oreut gas stokers. 2^ crane opera tor? 136: printers., asphalt worke painters. 129; 3 and automohli. moreover, a n among employ., Additional s vided by the oh generator gas plants and am Canada and E Kawahata; On investigators f, cases of lung workers who w hot tar fumes i lung cancer n employed in m general incidei generator gas 3 employed. N occurred in wr (33 percent apt lung cancers) varied from 9 being 16.6 yet recently made 3 ers. Of 14 casworkers, 6 wen cancer of the ethmoid sinuse upper and low. It is likely t] rates may exis Foliowing a vj25 skin cancerhad been obsi during an S-yw of lung cancer, company officii cancers in this cases of cancer From the ev, the inhalation < of certain open plants, gas plar Public Health M API 06433 I L  (position hand, nnti-i 1 that an ahove-avoriisp '`ontaminaf ranrar frequency existed for the 'ed in Cr)( ,-ins: occupations: gashouse workers. 129; .e. |l'". jtokers. 284: gas producers. 202; gasworks ar i-n th' e l'ut-i"J'l e*5 operators. 138; gasworks superintendents, to high cone*, l,S; printers. 119; chimney sweeps. 119; ded. "While jjphalt workers, 164: metal polishers. 174: .11 to moderat sinters. 129: tanners, 141: streetcleaners. 169: such as is cor^ jDd automobile drivers. 149. They recorded, if industrialize, jnoreover, a ninefold increase of lung cancer ireciable fibroij, jjflotig employees of a Canadian gas plant. >f soot particl additional supporting information was pro r be associate,) vided by the observations made among Japanese itial connects, venerator gas oven workers employed in steel t formations 0|, plants and among gashouse retort workers in >g exposure tumes with the lung is n0r rsial. vposure to coal -eased liabilitv d. Kennawav )al tar in the i roads, domestree, does not ence of cancer ent was made and Biiimann ap^-the lung ; try and mce of tarred id any lung rers subjected >ns, although ancer among enz recently iss gas plants d. 21. or 22.6 tes, thereby rience that panada and England (Kawahata; Kuroda and gawahata; Cruickshank: Doll). The Japanese investigators found, within a 6-year period. 21 eases of lung cancer among generator oven workers who were exposed to the inhalation of j,0t tar fumes when stoking coal. An excessive lung eaneer 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. Seven these 21 lung cancers occurred in workers aged 40 years or younger (33 percent against 18 percent in cryptogenetic lime cancers) (Hueper). 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 ns have an had been observed among the 300 workers neral. Iso during an 8-year period, there was found 1 case in workers of lung cancer. Subsequent inquiries made by fumes were company officials brought the number of lung ar worker), orker), and cancers in this and other tar operations to 6 cases of cancer of the lung. From the evidence available, it appears that aths among oups for the nnaway, on the inhalation of tar fumes sustained by workers of certain operations (coke oven, generator gas plants, gas plants, tar distilleries) seem to have of tlie Lung Public Health Monograph No. 36, 1955 an excessive liability to I'ancer of the respiraiorv tract. It is not unlikely that a more thorough and competent analysis of the death records of other workergroups, which have so farbeen 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). PETBOLEtJM, SHALE OIL, AND NATURAL 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 (Wood; 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. Rosch observed three primary cancers (skin, stomach and lung) in a paraffin worker. Touraine and Bout 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 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 years or more in the industry. Since the majority 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 hased 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 anthracosis; 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 I j | , . ' k prolong the dut carcinogenic ch Since our ch been built arou basic carbonae tives. it does n plete protectio carcinogenic ch prophylactic en practical and < There is. howe remains to he < are still rathet maximal amou sure to the resj carbon? con tail substance? met Carbti Recent studi dry. Homer. Rose, and Wa a new and in combinations o through the linkages betwe' chemicals and chromosomes, from evidence < genesis by nitn ethvleneimines. view of the far by which the? specific action zation. it is ass chains might mucoproteins < linkage with m by cause mito' action of one < nieric molecule ttiay start a pr< followed by a epoxide groups These concej "'ith respirato reasons. Since Druckrey and shown that s various polyi 34 Environmental Causes of Cancer of the Lung Public He*hb M API 06435 .1 (horoufjfj ip-^?rouPs f SOoti r>, carhop it. and jnJ. iters; diesel nu/acturpj^ mudgo pot ^rsJ is an conclusions a survpy of on evidence of the 677 ovpcI for the majormoors have *. 10 v**ars used on 79 U to reason Is of former i a different re based on ions would > existence, li might be ding finelv tar. pitch, and cutting n/'"^ators, ci . steel k factories, as exposure tie engines, cupational arcinogenic agents oons are certain ich not inirtides giv- or ant-hra>ily matter i the lungs, >f the lung, ally related onioses acsis by arorimary and hough the tensity and 7I |011^ rhe duration ot the effect of the specific I ^'inogenic chemicals on the lung tissues. I c>^0ice our civilization and economic life has I " built around the production and use of the J idc carbonaceous substances and their deriva- I te ipt rdooteescti.noont saegeam.infsetaseibxlpeostoureattatoin tch. oemse ureinogenic chemicals with the preventive and ''r^pbylactic engineering and sanitary measures ^radical and economical at the present time. Jpjjere is. however, no doubt that a great deal .mains to be done in this respect and that we still rather far removed from having the fuaxinud amount of possible reduction in expo- ,ure to the respiratory cancer producing hydro carbons contained in the various carbonaceous mbstances mentioned. Carbon and Silicon Polymers Recent studies of English investigators (HenJjy. Homer, Rose, and Walpole; Hendry, Rose, 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 macromolecular 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 view 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, polyethylene, poiy vinyl eliloruie. polymrthvl methacrylate, polyamide. TeHon. and othersi into rats and mire 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 respiratorv 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 of the Lung Pohlic Health Monograph No. 36, 1955 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 (Desmeules, 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 25). 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: Age ** C<ue$ of lung ' cancer 25-34.......... 2 35-44............................................... 45-54................................................. 55-64___________________________ 65-75 5 Total 51 Table 25. Causes Lung cancer 1-----Other respiratory < With mention ol Without mentiot Neoplasms, other i All other diseases3 11 All ca16uses.. 17 1 Including 1 i Including pu > Including 2 not thought to hat 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: Ezpoturetime (jeart) I-3........................................... 4-10.......... II-20........ Caeet of lung cancer 4 6 4 1 | | i age of 128 nonwas only 44.2 1 conclude from these individua tosis before the develop (Linzb Additional s between ashesiderived from tl among 266 cast 1924-46, 31 ca lung (11.65 pen 21 and over_______ 7 of lung cancer Total.............. .................... ............................ 21 The exposure time of this series covers a wade years among 6 cent) which ca that asbestosis range (1-23 years), indicating that type and 14 cases, or 15.2 intensity of jgxposure ,to asbestos as well as perhaps an individual susceptibility to asbesto on which new the normal rai sis play an important role in determining the material was es development of this pneumoconiosis and thereby Lanza, Vonva the possibility of a secondary carcinomatous quite skeptical sequela in the lung. an excessive There were 37 males and 15 females among ^ asbestosis to 1 the 52 cases for which information on sex was Homburger an available. The maleifemale ratio is thus Other investigi 2.5:1, which represents a marked shift toward cept or consi< the female side when compared with the usual relation as hi sex ratio of 5:1 to 10:1 for lung cancers of (Kennaway; M unknown etiology. Equalization of carcino ' Hueper; Gross: genic exposure as represented by asbestosis, for Linzbach and 1 the two sexes, thus resulted in a trend toward [ Welz; DoD). equalization of liability to lung cancer. The histolog It is of importance to note that the mean Environmental Causes of Cancer of the Lung Public Health M API 06437 ' 4" . While. 44jL.y.'ars irar> ie was 7;p t. ... many ca ' ree interval ran& t ears before t| Wedler: Wye^ V .j.jbk - t.aure of death among male asbestos workers compared with the mortality experience of all men in England and Wales (Doll) ' Cause of death Number of deaths Number observed Expected on England and Wales rates Test of -ienificance of difference between observed and expected rvalue of P.i estosis cancer ^ rM)'""nH<ceqO,'f ....... ....... 2 ............ n ................. ie ............... 17 '................. > ............... 51 j,t)B& cipiratorv diseases 1 and cardiovascular diseasesmention of asbestosis.................. .......................... .. without mention of asbestosis........ ................................ " Lms, other than lung cancer.................................... goPtber diseases _...................................-.......................... All causes.............................. ...................................... 11 0. S <0. 000001 14 6 7. 6 <0. 001 4 4 i. 3 4. 7 >0. 1 39 15. 4 <0. 000001 ' i Including 1 case with pulmonary tuberculosis t Including pulmonary tuberculosis. not tihIonucgluhdt itnogh2avceasbeesen(baencigonntsritbriucttourrye coafuesesoopfhadgeuastha. nd septicaemia) in which ^bestosis was present but was n etiology occurs re of 40 and since ancers appeared hat there exists a r age groups for osis of the lung, rosis lung cancer, ther. was: Cajr lung cancn ................ 4 ................ 6 ------ 4 ------------- 21 ies covers a wide r that type and stos as well as >ility 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 earcinoiy asbestosis, for a trend toward cancer. that the mean jje of 128 noncomplicated cases of asbestosis 'as only 44.2 years (Merewether). One may conclude from this observation that some of t[jese individuals apparently died from asbesyjsis before their lung cancer had a chance to develop (Linzbach and Wedler). Additional support for a causal relation t^tween 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 14 cases, 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 an 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; Nordmann; 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 Ritterhoff 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 vrsrkers doubtlessly sustains either no exposure or only a low intensity exposure and thus does not develop asbestosis of the lung, which is the prerequisite for the subsequent cancerous development. Asbestosis must be considered as the essential stigma of an effective exposure. It is, moreover, necessary to know the sex and age distribution of the worker population studied and evaluated as well as to know the duration of employment and exposure. A marked labor turnover in the industry is not inducive for obtaining reliable information on ncer of the Lung hklic 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. 1BOFBOPYL OIL Through the recent discover}- of cancers of the paranasal sinuses, larynx, and lung among isopropanol manufacturers, the occurrence of carbonpolymer cancers has probably been exextended 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, I 2; and lung 1) came to observation among 71 I 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." MXJBTABD QAB 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; Derischanoff; Hiinermann; Reiche). Residuals of warfare gassing were noted by Matz in 10 out of 138 j cases of pulmonary cancer among American l World War I veterans. Four out of 64 cases of lung cancer, recorded by Brockbank, were gassed badly during this war. Macklin 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 bf 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, such as that seei with these gase belong to the gr A possible ct gas upon the b hand, may be i radiomimetic eff that demonstra animals exposes mustards of al According to t. cepts. the caus these cancers n 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. Him these observetii 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-linkit rubbers, rosins., brings a consult lation into dim type. It seemstudy these j coming decades particularly ti system. B< L'p to some Z sure to radioac tively small gi sional workers active ores, ini S8 Environmental Causes of Cancer of the Lung Public Health M API 06439 '.'-v 4; iiirv|,y ii\h.*u among 7 ' : ' '* hose H.hf) t. -opropan^j 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 ro^lthank. were ' din noted ed 5 percent among males, v 2 percent of Koelsch concancer exhibited o war gas injury, aused also two r; Tilley). No time as to the e various gases e acceptance at nic viewpoint, d to the various dally Lewisite, 1 sulfide). The ed, theoretically hemical damage Iso may produce '.ogenic reaction, neer of the Lang as that seen exceptionally after skin burns ?Uth l^ese pases- dancers of such an origin f'loQcr to the group of arsenic cancers. ^ possible carcinogenic action of mustard ^ upon the bronchial mucosa, on the other jjand. may be related to its cross-linking and ^diotnimetic effect, and may be identical with jbftt demonstrated to exist for experimental 4nia*5 exPosed 10 several sulfur- and nitropustards of aliphatic and aromatic nature, ^cording to the mentioned theoretical con cepts. the causative mechanism operative in t(jese 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 t,aIU-er were observed among long-term em ployees 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 0|d. All three suffered from chronic war gas poisoning due to contact with mustard gas (Vamada, Hirose, and Miyanishi). In view of these observations, the distinct probability of carcinomatous effects upon the lung following exposure to mustard gets 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 of radioactive substances--_ras 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; Engelstad; 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 Public Health Monograph No. 36, 1955 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 Joachimsthal 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 (Henekel: 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; Lindemann: Doubrov; Brandt; Brezina. Although the miners of the uranium ore mines in Joachimsthal (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; Puritan 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 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 | used medicinally, when such materials become ; arrested in the lung. j 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 were,part, 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 radk more, no valid ev of arsenic-, chror containing ores ai a rate even rem among the two ra The attack ra* Schneeberg mine tween 75 and SO of the Joachims!) range from 40 t< incidence rate nn recent statement during the period of lung cancer w sable diseases am 323 miners emph* ering the fart t period of lung <. ranges from Id tr sumed that thesi in a miner popul. 400 members wo 1920 and 1930. : at Schneeberg is years for the majt ally to be as short Srhraub, and Ka The total num died from' cancer 1939, according t approximately 41 achimsthal miner has reached 225 numher of these at a relatively ea data given in tal the definite shift -M easurements Sehnoeberg and . nstrated that, h have an excessiv Passing many tin fJoachimsthul .3 Behounek and I Lorenser: Lan; B was suggestei f pneumatic Ai 40 Environmental Causes of Cancer of the Lung Public Health Moi API 06441 unoction 'urrenro ominous ases re in. antj ingested ^posited ircomas, h. thus, of the recently i at an ely not tiye-exm d. oq were (Love), at- these ncerned weight, nvnronhen the able for tstes at inactive neeberg he fact ry neounder workers populaunsthal, figment hmorl). ^vi'essiw lung i-ancer attack rate, also, has found among the miners of the nearbv ^(,snn Georgenstadt region, where the mines ^ - low radioactivity. Thoeroe ;isc, f,urther- ore, no valiil evidence on record that miners [ arsenic-, chromium-, nickel-, and bismuth^Dtaining ores are affected by lung cancers at 1 rate even remotely approaching that seen ^joDg the two radioactive ore miner groups. The attack rate of lung cancer among the ^neeberg miners has consistently been be^een 75 and 80 percent since 1879, while that ,f the Joachimsthal miners has been stated to from 40 to 50 percent. However, this ^.jdence rate may be too low. considering the ^eat statement of Baader, who noted that Juring 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 vj3 miners employed at Joachimsthal. Consid?rlDg the fact that the exposure and latent period of lung cancer in Joachimsthal miners } ranges from 13 to 23 years, it may justly be as sumed that these lung cancer cases originated in a miner population of approximately 300 to 400 members working at these mines between 1920 and 1930. The exposure and latent period at 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 by uHTeit.-iutr 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 fSrhmidtmann; 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 ehalicosis, 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-euggestive, 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, Eschenbrenner, 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 I 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 be little, 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 ore miners in miners suffer from more or less intense anthra- 1 Whether it ha? cosilicosis and that this condition was causing or favoring the development of the bronchial cancers, Rostoski and Saupe stated in 1930 that cancerization ] the establishei Finally, it m 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. Hueck, on the other hand, remarked that silicosis does not represent a precancerous con cancers vary a turo. Many t others, round while a few w. The radioacth this respect t other occupatb dition for the Schneeberg lung cancers. .Some The rapidly of the miners had silicosis but not lung cancer, radioactive m while others had lung cancer but not silicosis. tioned, marke' Similar discrepancies seem to prevail con limited worket cerning the Joachimsthal miners. Ziel in 1935 population to i reported that marked silicosis among these radioactive mi 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. Thereft 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 effluent 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 silieofibrosis 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 contpi chest X-ray study of 398 Joachimsthal miners analysis of th conducted in 1939. He found that 43.4 percent and experimet of these miners presented roentgenological evidence of pulmonary silicosis. However, silicosis was of minor degree among the < enous respirm leave no doul occupational miners who were suspected of having pul general popub 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 miens*? untlirtto^o mp-^as rausi^ ,f hronohi^ tea in 1930 that very extensive ,{ the relative!, imors. Rostosltj uosis may sloty ,{ the tumors, remarked th&t (cancerous con. cancers. Sortie -iot lung cancer, t not silicosis, to prevail con- Ziel in 1935 ' among these iat ashed lungs ixide. Pirchan ntained that n0 . in spite of an ling, and that ie production of was shared bv communication ome degree of >rigin could, 0f 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 & msthal miners t 43.4 percent entgenological . However, ;imong the 7 having pul- contradictory, play any sig)Utory cause of e radioactive- 1 miners in ''luieeberg and Jouehimsthul. & tjjer it has an antagonistic effect upon the ^erizatin process or modifies the course of ! ^p-tablished cancer remains problematical. ^ irinally, it ma-v mentioned that these lung cers van' a great deal in histological struc- ^ >Iany were squamous cell carcinomas; tUf^rS. round cell or anaplastic carcinomas; ^Ljje a few were of adenocarcinomatous type. JrT radioactive lung cancers, thus, follow in YL respect the general pattern set by all ^er occupational cancers. The rapidly growing production and use of .^active material and the thereby condi- ^jjed, markedly increased exposure of some Ijjpited worker groups as well as the general initiation to gases, dusts, and mists containing radioactive matter of long half-life doubtlessly ^presents a potential respiratory cancer hazard uf serious 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 ihe degree of exposure to atmospheric radiojr-tive contaminants for worker groups and neighborhood populations of radioactive plants uid operations, and the continuous and strict supervision concerning the amounts of radiowtive effluents emitted from such establish ments, are urgently necessary for safeguarding the health of these individuals. Table 26. Latent periods of environmental respira tory cancers, in months (Hueper) Cancer of -- Agent LuDg Xares and nasal sinuses Average Range Average Range latent of latent latent of later period period period periov Asbestos Chromates................. Nickel........................ Tar fumes...... ........... Isopropvl oil_______ Ionizing radiation__ 18 15 22 16 25-35 15-48 . 5-47 6-30 9-23 .. 7-50 a 10 25 3-26 6-16 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 PaMic Health Monograph No. 36, 19S5 43 nduw'ri to a specific industrial operation. Epi demiological. medical, and experimental data concerning these respirator.- 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 respirator,- 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 cancers 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 TLipschitz. who reported in HI:'. 1 that the autops, records of a large -Jewish hospital in Warsaw gta Poland, showed a lung cancer frequency of $.9 prfl Lpercent of all cancers for Jews against a fre quency of 15.3 percent for non-Jews, especially evi of in view of the fact that Eastern Jews are par cai ticularly prone to develop thromboangiitis obliterans, which has the best established causal relations to tobacco smoking. poi lar of The claimed absence of a positive associa tion th* between lung cancer and the habit of inhaling cigarette smoke also is inconsistent with the rule that the incidence rate of occupational cancers increases with the intensity of exposure r to a carcinogen. The medical considerai ions on cigarette smoke cancer of the lung thus reveal a number of serious and fundamental > defects and contradictions. iThe best that can be said about the experi mental evidence on hand regarding carcinogenic properties of tobacco tar is that it indicates the carcinogenic agents in some cigarette tars tthrough 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 Enriromnecitai Cmw of Cancer of the Long Pi UtOpsy arsan-, of 8.9 a freecially _e par- ingiitis >lished 'is tion Wing h the ltbnal epidemiological evidence but also | tactically the entire factual and conclusive i jndence available on specific exogeneous causes 1 respiratory cancers indicates that these (tocers are either of occupational origin or points to industry-related factors. Not only Jarge occupational groups but also the members of the general population have contact with these agents in various forms and intensity. Finally, it may be noted that the evidence on hand justifies the viewpoint that, in arriving at a judgment (Baader; LickintJ 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. ai ions ' thus . lental xperi'genic *`S the tars .mals. >ns of mice pra^ is nee. .periwith incer i I irent stive n of t in and sive. .and preung in .lost live v of <-en>en- rop1 of the um- I I ) i I [ T' r 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 Baader, E. W.: Der Lungenkrebs als gewerbemedi- Bidstrup, P. L bronchi. Longmans, Green A Co., 1912, p. 39. London. zinisches Problem. Verhandl. d. deutsch. Kongr. f. Inn. Med. 57. 322-332 (1951). and chromat Hyg. 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' nkrebs. Deutsche renkrebs. ?chwei2 M2). ' T. \V.: Quest f0r . Arch. Industr 1952). ' r den Berufskrebg epathol. 11; 53^_ .inonary fibrosis .0 ` Fortschr. f * > ma of both lungs :iia. Radiology Med. J. 25: 631- t Tobacco smoking n bronchiogenio -336 (1950). tiologic factors in ci^Lteference to r 4 Occup. . Troninger, A. B.: na with cigarette (1953). anishi, M.: An ma found in a al mustard gas . ' s bei den Berg- (linik 31: 1535 i , I ugung maligner 1 lurch Druckreiz ] r. f. Path, u ^ r of the Lung Current Titles Public Health Monographs No. 19. Medical service areas and distances traveled for phvsician 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. 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(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. 27. Roof rat populations in southwest Georgia. Dean H. Ecke. (Public Health Service Publication No. 373) 1955. 18 pages. Illustrated. 20 cents. [Published concurrently with Public Health Reports 70: (4): Bee pages 413-414 for summary.] No. 28. Tularemia in sheep and in Bheep industry workers. William L. 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 Sidney J. Cutler. (Public Health Service Publication No. 418) 1955. 121 pages. Illustrated. 65 cents. [Published concur 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 firet 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. Bailev, 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 S COVLRNMEKT RHIHIlNC OFfICC: llll API 06457 ildw ited. 1 L. ition shed -721 and 418) icur- for t D. am. lges. faith wvn ann. iges. alth rton >hnges. 'alth in* 953. with TV.] h J. tion hed :47- ise, i)lic . C. A55, vith I 1 Public Health Monographs are edited and issued by Public Health Reports under the general direction of 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 review1 if they submit three copies of their manu scripts, double spaced, wdth each page beginning with a new paragraph. Public Health 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 I American Medical Association), and in the Current List of Medical Literature LArmed Forces Medical Library). Single copies of most Public Health Monographs are available upon re quest to the Public Inquiries Branch. L". S. Public Health Service, ^ ashington 25. D. C. Orders for quantities should be sent to the Superintendent of Documents, U. S. Government Printing Office, Washington 25. D. C.. where thev are available at the prices shown, with a 25-percent reduction on orders for 100 or more. In ordering, give title, monograph number, and Publir Health Service publication number and enclose cash, check, or money order. Stamps are not acceptable. Public Health Service Publication- No. 4S2 API 06459 I