Document 5DvXak6wDKD12wrryZ8rZnJzJ

Public Health Monographs edited and issued by Public Health Reports G. Sr.J. Parrott Ckirf, Division of Public Health Methods MenasDirector Makci^ Executive Editor Taet S. Fe.iua* Managing Editor Janm V, Kashau Monograph Editor BOARD OF EDITORS Howard G MlGavran, M.O., M.P.II.. Chairman Chapel UiH Gaylord W. Anderson, M.D . Dr.P I! Minneapolis Marlaklt G. Arksikin, R.N., M.P.II. IPashinvu n H. Yrendley Dean, D.D.S. Chu a ,o Halrert L. Duns, M l)., Pu.D. Washington Martha M. Kliot. M.l)., Sc.D. Washington Harold M. Krurson, M.l)., M.P.ii Portland, (Jreg Lloyd Florio, M.D., Dr.P.11 Denver Vernon G. MaiRlkzik Washington Victor ii. Haas, M.D Bftkesdo liAML C. MacLean, M.D., M.P.ii New York City Seward K. Miller. M.D Washington Leu \V. Simmons, Pu.D New Haven, Conn. U. S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Marion U. Folsom, Secretary PUBLIC HEALTH SERVICE Leonard A. Schcrle, Surgeon General A Quest Into the Environmental Causes Of Cancer of the Lung W. C. Hueper, M.D. Public Health Monograph No. 36 Tiie Author Dr. Ilurper i hetul oj the Environmental Cancer Section oj tits National Cancer Institute, Public Health. Service, chairman oj the Cancer Prevention Committee oj the International Union Against Cancer, and a poet president oj the American Society jor the Study oj Arteriosclerosis. In hie SO yeart oj clinical, research, and teaching experience, Dr. Hueper has become veil known boUt in Europe and in the United States as an authority on environmental cancer and on arteriosclerosis. lie is Use author oj more than X00 publications in these and related fields, including the book "Occupational Tumors and Allied Diseases," published in 194. Contents ^ Introduction_____ _________ - General epidemiological considerations................................................... 0<u*ii|mlimml evidence iiikI 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 respirauny tract....................... Specific carcinogens...... ............................................... . . ___ Inorganic chemicals.. ............ --...................... .............................. Nickel..................... Chromium............... ... ............... _.................................................. Arsenic........................... Iron_____ ________ ................. --............................................-- Beryllium..................... Organic chemicals......... .............................................. ................... Combustion and distillation products of cool............................... Petroleum, shale oil, and natural gas........................................ ... Carbon and silicon polymers----------- ----------------- ..--------------- Asbestos...................................... ....................................................- Isopropyl oil............ ...... Mustard gua .. ..................................... .. Radioactive chemicals..................... Comments and conclusions.~................. Bibliography............. ................................................................................... rix 1 1 t.r> 15 18 18 21 21 22 25 23 23 24 27 29 30 31 31 33 35 35 38 38 39 43 4G Introduction To bo scientifically acceptable, any theory on tlio etiology of lung cancer must ri>(loct u critical, balanced, and competent analysis of l In- entire cpideiniologicaL. medical, and ex perimental evidence concerning the types and environmental distribution of and contacts with all known or suspected exogenous agents memninuted in respiratory carcinogenesis for environmental, occupational, or medical reasons. It is only through such scrutiny lliut significant and worthwhile information may be obtained us to the rduLive rule which the various indi vidual respiratory carcinogens have played and arc playing in the production of lung cancer. The following facts and observations form an im portant and integral part of such ait assessment. General Epidemiological Considerations A real, definite, and progressive increase in the frequency of lung cancer started in most industrialized countries around the turn of the century (tables 1-3), that is, at & time when cigare.Uc smoking was still a habit of minor sig nificance (Probsi; Berblingor; Grosze, Kuhluu; Fischer; Liekint). This rise was first clearly recognized by pathologists of Centra! Europe ring the early 1920's through a study of oropsy data collected during the first two dccadiw of the 201 h century and was subse quently confirmed and elaborated upon by hiostatistical investigations from America and Europe which mainly used cancer mortality data (fig. 1). - Published records indicate that this develop ment revealed niarkod variations in the lime of onset of lung cancer, in its relative Jcgree of severity, and in its progression rate for different localities and countries. In Germany, for in stancy an increase in the incidence _of lung canoe*'on first noted in Saxony and Central Germany only. As late as 1931, Fischer re ported that lung cancer represented 11.3 per cent of all cuuecrv in Saxony against ti.O percent in the rest of Germany. In Denmark, accord ing to Clcnuucscu, a rise in lung cancer fre quency was still doubtful during the first throe decode* of the 20tli century and only became definite after 1930. Similar observations as to a lute appearance of this increase were made in Italy. There still exist striking differences in the lung cancer mortality rales of different countries and different regions of the same country (fig. 2). In England, fc instance, 23 percent of all cancers in mules involve the lung; the corresponding figure for Norway is less than 0 percent. Similar discrepancies exist for lung cancer morbidity rales for ilifiorunl metropolitan ureas in the United States us well as for their relulivc progression rules (table 4). Another example of the existence of striking regional variations in lung cancer frequency is presented by the rumorkable differences in lung cancer mortality rales between urbun-industriolizod arcus uiid rural districts. This has b<>cn demonstrated for Kngiund and Wales un,d for the United States, where lung cancer death rates were found to be consistently higher in urban areas than in rural area* (tables 5-7, figs. 2 and 4). Such observations have been made in Ohio, New York, and Connecticut (Mancuso, McFar land, and Porterfield; Levin, Krutis, Goldberg, and Gerhardt) and were rc|K>rted from England and Wah-s by Stocks; Kennaway and Kcnnawuy; Fulton; and Philipps. Stocks reported tlie comparative mortality ratios for males in fiUic Health Bmnsnph No. U, 1955 1 Tabic i. Krn|Miii7 rale* of lung cancer* in aulu|a>; inalcrial (l'ruli) Aulitor ,, . . -Niimlier of, Total > Absolute crion , autopjo* i carcinoma* No. 1Ii l.ung cancer* Percent Percent of all of all case* autopsic.- 1852-1000 lteiiiliard... . Kucli*.......... Wolf.......... ..... Pansier_____ Wolf............. Perm*........... Marelioaani.. Kikmli___ . Koilchenfcld. lUeehclmanii. Sehrt_______ Marelioaani.. lledlieli_____ Seyfahrt____ Karrcuaicin.. Kikutli.......... Staehelin___ Bejach Probat........... Seyfahrt____ Brieae______ Bejach______ Bejach Marchesaui.. Rau________ Berblinaer... Matorna____ Stachclm.. . Prolist........... Seyfahrt____ Aaamanu___ Matorna___ Hreckwoldi.. Rau............... Rcrliliugcr__ Probat........... Matorna____ Kikut.lt__ Marelioaani.. Stachclin___ ljubarscli.. . Seyfahrt____ Berbiinger___ Matorna____ Brockwoidl.. Probat______ BUoiielin.. . 1852-70 1854-85 1R77-84 18KI-04 1885-04 1885-97 1887-90 1889-00 1895-1900 1895--1901 1899-1903 1880-1900 8, 710 12,307 4,172 0, 240 7,228 ................... 870 ]t 94G &022 7,700 1,741 3,337 nil 711 169 a-- 5 ,.. 8 .. 9 .. 10 31 .. 9 4 .. 10 ... 22 27 1 3: 6 !.. 1. 83 1. 27 4. 3 , 3. 8 ' 1. 88 0. 057 . 065 . 21 , 17 . 426 . 10 . 26 . 07 . 24 . 38 . 17 . 18 1900-1925 1900-05 2,002 490 31 { 0. 3 1900-00 ................... 5. 1 \ 905-07 10,272 1900-11 ................... 934 32 ' 3 42 90 3. 8 ' 1900-11 ............... 566 12 Z 1 1904-08 715 20 2. 78 1900-10 2,730 265 3 1. 13 1907-13 6. 88 1898-18)G 12, 971 1,287 60 4. 51 1908-13 6.808 092 33 4. 8 1909-12 1906-16 5. 801 A, 754 586 29 6 , .. 4. 95 .........1 1909-14 4,816 552 15 ! 1910-14 2,347 363 8 2. 2 1912-14 806 48 1 ' 2. 08 1012-14 _ 218 11 5. 0 2,448 389 13 3 34 1914-18 11. 23 1912-22 I91A-17 1,007 70 5 7. 14 1914-10 0, 083 .V*4 21 3 7 1915-19 5,518 580 27 4. 8 1915-19 3,280 337 10 3 9 1010-20 4,989 302 24 fi. 12 1918-20 1,009 94 5 1 3 31 1012-23 .. 140 ' 5.8 . 1910-22 3,330 10 . . 1915-23 1920-21 1919-23 1920-24 2,429 755 38 8,301 458 , ............. ..1 287 24 | 4. 9 5.4 | &8 735 1! . 1021-23 1020-25 1,040 6,359 75 892 6 ! 80 20 2.7 1 1921-25 3,697 602 3G i 7. 17 1024 749 5 4. e * l.: .07 .31 . 37 .a .9 . 40 . 45 .5 . 13 .31 .34 . 11 ,3K 1. 01 . 19 .35 .30 .49 .30 . 59 .31 . 58 .3 .99 . 57 .39 .97 Z Eatrironmmtil Caaaea tf Cancer of the Lung DUP 1142024 I'jlu I'.), wiLli tlovmlKiiiM from the uvri'ufc'u mortality rate sot at 100, os follows: _ Groups of adjacent towns with over 300,000 occupied dwelling*: idon. East Ham, West Him, Croydon.. . iiungluim, Smethwick, Wubuill, West Bromwich.......................... ........ .................n Manchester. Salford. Stockport.150 t.ivcr|>ool, Bootle. Uirkcuhciul. WniUisuy__ l/ocds, Bradford, Halifax' 156 134 103 132 Sheffield, with 124,000 occupied dwellings........... XcwciikUi- mill fiutexheiul, witli 87,000 occupiod dwellings114 Aggregate of 6 towns, each with 50,000 to 85,000 oceufiiml dwellings 113 Aggregate of 3 towns, each with 40,000 to 50,000 occupied dwellingsSi" 107 Aggregate of 12 towns, each with 30,000 to 40.000 occupied dwellings104 Aggregate of 13 towns, each with 20,000 to 30.000 oecupied dwellings100 Aggregate of 20 towns, each with lees than 20.000 oecupied dwellings. _________________ 135 80 In Ohio, for the years 1947-51 (Moncuso, McFarlanc, and Porterfield), the standardized mortality ration for lung caueer mortality of selectod sites among white males 25-04 yoars of age in urban and rural counlius were: Mctro|<olitnn counties (8) 122. 9 Urban counties (7) SI. S Rural oountios (73i..... ............................................ 68. 6 The standard mortality ratio is Olmorvod deaths Expected deaths 100. 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 Kennaway only recently recorded froah 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 lungs Table 2. Frequency rates of lung cancers in autopsy material of German pathological institutes, 1906-52 1 Author City Period Percentage of lung cancers among all canoen Bex Male Female KueluT-WanclA-..., Frankfurt._____ _______ ______ ________ Sehairer and Schoetugcr. Peters____ _____ ___ Koch_____ ________ Gertoc......................... Zwickau___ . _ . _ Uuwhbck.................1 Dreaden Dormann*...............1 Germany......... ......... ......... ......................... Koch...... .................... Weber and Knoll... Scliaircr and Schoeniger. Fischer-Waeelt Kocii.. ................. Knorr........ ................ Emminger and Emfall. Kocii.......................... VVrlK`r.... ............... K'wli....... .. ......... . \VW**r and KuoU... kahUu__ ______ ___ Frankfurt.....___.....J DuMM&dorf............................. UuuMNnhkirf... ....... . ... Frankfurt... __________ ............ Germany---- -------- ------------ ------------------------- 1900 1900-12 1910-14 1913-17 1920-23 1924-27 1924-31 1925-33 1927-31 1927-31 1928-31 1931-40 1932 1932-39 1938 1943-45 1945-18 1945-18 1940-47 1940-48 11MH 1951 1952 1 From Kahlau. 2. 50 2. 2 02 8 61 12. 9 19.79 13.0 9.83 15. 4 13. 0 12. 28 13. 9 12. 0 31.86 13. 0 36.33 13.0 35. 53 38. 0 1. G 12.94 21. 4 23.4 0.97 Z 38 4.8 5. 4 FsUir Health Monograph No. 36, 1955 DUP 1142025 Kiurv 1. ComiMiruiivi' irrmU in rvsiMrutory cancer nurulii), IV24-SU. 4 Eniinnnuii Cnuei of Cancer of the Lung of males uiul females uad cancer of the larynx of males, but not of female' This relation is even apparent when comparing relative lung c*<'"cr death rates in the Unitod States and E .ml with the relative population density in these countries. Whereas, in the United Suites, with n population of 45 persons per square mile, 1 lung cancer death occurs per G,GOO inhabitants, in England these figures stand ut 755 pursuits per squure 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 males living elsewhere in the city. It is somewhat uncertain whether this observation carries the same implication os the observations made in Ohio and in England and Wales Such an interpretation is suggested Table 3. 1-ung cancer rate* in neeropey material of various German institutes of pathology for the period 1093-1923 Period Total canoen Lung efcnoen Pcrcuitl of lung cancers among All eAnoort Bange Average 1895-1805 1906-15.. 191U#>.. fl}l0,276 { IS, 431 M3}388 { 832 tl}TM / \ 5. 2 1.9-6.2 2. 1-5. 0 2.0-7. 0 1. 9-6.2 Figure 2. Age-adjusted death rates for respiratory cancer per 100,000 white males in the United States, 1950. ' (low) Dador 17 3X 17-20 21-24 25 4 Orr Public Health Monograph No. 56, 1955 MStOg--S----- * DUP II42027 Talth* t. Iiiciiiciitv wf rnuiniiurv cmiiult, morindi ly ru per 1UU,UUU population for V tiieLropoliUni OGUli`f by mi, 1937 aod 1947 Morbidity rates Primary site and city ' 1637 =r Male*- Females 11147 Peroent1 inerCHMJ 11137 1047 Percent increase 11137 Totai 10-47 Pereeu* inCJTA'd Broiu'hu* ami lung: Atlanta.. ................. .. 5. 0 13. 4 168 1. 0 5. 0 400 2. li ji>7 New Orleans___ DuUuk. 13. 1 311. 1 11)8 2. 8 4. 2 50 7. 6 20. 8 .V li 21). 0 31)2 . fi 6. 4 1, UWI 3. ! 17. 2 174 45.'. Birmingham________ 4. 5 t& *J 32U 2. 1 3. 0 86 3. 3 11. U 23J Denver.. r............... .. 11. 1 21.1) 141 4.2 8. 1 113 a fi 14 8 124 San Francisco........... IS. f. 34. 3 120 3.11 8. 1 108 1). 8 20. 8 112 Chicago...... ................ 13. 3 211. 5 122 43 7. 0 63 & 8 IS. 0 105 Pittsburgh................. . 11. 7 26. 1 16!) 4.6 5. 5 12 7. 3 is r. 114 Detroit....................... ... 12.6 32. 0 164 2.3 47 148 7. 6 11). 0 Larynx: 150 Atlanta.................... 1. 4 4. t) 186 .3 U 3 . !> 2. n 122 New Orleans............. ... 11.3 14.11 32 .4 1.0 ISO 5. 6 7. r> 3fi Dallas. . .... -; 3.2 5. 3 66 1.5 .4 Birmingham______ . ! 1. 4 4. 0 , I8Ti . 0 1. 3 73 | 2. 3 1 .7 2. 7 2. 0 17 271 Denver'...................... ....... 2. 0 4. 1 105 .<i .0 . 9 2 1) 122 Shu Francisco.... . 4. S H. 8 !M> .2 . 8 300 2 4 4, fi 02 Chicago...... ............... 6.7 7. 0 4 . 4 . 0 50 3. 5 3. 7 6 Pittsburgh............... 4. 4 8. 0 82 . 4 .8 100 2. 4 4. 4 , 83 Detroit....................... ..-L. 3. 5 fi. 4 83 .4 . 3 -25 _ 2 0 3. 4 70 1 by ihc 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 playod by many occupational carcinogens, such as arscnicals, coal tar, petroleum derivatives, and radioactive substances in the production of )>oth cutanoous and rospiratorv cancers. An additional expression of this urban-rural pattern of lung cancer rates is contained in the recent report of Low, who found that these rates were 30 to 50 percent higher among indus trial policyholders of tho Metropolitan Life Insurance Company Ilian umong males holding general policies. Ijow found, on the other hand, that such differences did not exist for female holders of tho two type* of policies. He |>ointcd out that industrial policyholders represent, for the moat part, urban wage earners and their families in the lower-income bruckots and include a high proportion of men engogod in manufacturing, mechanical industries, mining, transportation, and personal service. In con trast, the general policyholders arc drawn mostly from middle- and lughcr-iucomo groups engaged in nonhaxardnus occupations. The apparent causal significance of these epidemiological findings lias been demonstrated by several investigators. Appreciable amounts of 3,4-bcnzpyrene 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 Lo6 Angeles, and in the exhaust fumes of gasoline and diuscl engines (tables 8 and 9). It has been estimated from these figures by Blacklock, Keimawav, Lewis, and Urquliart that about 16 mg. of 3,4-bcnzpyrene Table S. Cancer of lung and larynx, England and Wales 1946-49 (Kennaway and kennaway) Tyi of oouumiiiity Lung can j Larynx cuncer ratio1 1 ocr ratio1 Males Fw mila* 1 Males Frmalcb County lommcli............... Other urban diitriett___ Rural liistricti................... 100 120 100 233 100 i 137 156 ' 185 : 100 125 14K 170 1 Number of persons producing 1 death. 100 55 56 42 6 Environmental Causes of Cancer of (be Lung LgjisgtE attL jets mb Table 6. Luna cancer <lcall> rule* in 25 blalc of the i Lnltal 100,000 Suto, 1M anil 1MI, crude death--n-i-aa per State 1M6 1M8 Induslrialixod States 1 Connecticut____________ __________ M&rvljtnd..___ __________ ___ _____ MlWJCU'hUtfCttK____ _______ ..... Michigan. ____ ..........___ ..... New Hampshire~ New Jiwy... _________........ New Vorlt Ohio.................. JVnnyl v*nia__ ______ ........... Rhode Ialand K5 : ki 6. 5 10. 4 5. 7 7. 4 -- 0. 7 10.2 _ 6. 0 6. 7 8.7 II. . H. 2 K4 10. 2 7. 1 10. I 0. 7 II. 0 7.3 K. 4 7.4 States with regional industrialisation 1946 1946 Jdouuiwim_____ _........ Missouri Montana____ ____________ ........ Ncbnutka................ 6. * as 7. 3 10. 0 5.7 Agricultural States 7. 4 K ft 8. 4 8. 8 8. 0 Alabama N Mexico..... .................... .. 1846 1M8 4. 0 5. 1 3. 6 5. 4 2.0 ^ 3.0 & 1 4. 0 Ji. ti 4. 1 4. 1 4. 4 3. 0 -- 3.7 5. I 4. 2 4. 0 3. 8 The death rates for the year 1046 were taken from "The American Cancer Society, Inc., IMS, Cancer Death Rates for each State in the United States by Sit*'," tliOMr for the yenr IMS were produced by the National Office of Vital Statistics. Sdud asrtadty perasst sf Mas sapsOed lisaHa aMrtkuusn f papuUlian by afcanSdaetf datrtet arxi - ai ms- n> - -i Figure 4. Observed and expected lung cancer deutha in urban ami rural Ohio, 1947-51. (T. F. Mancuso) Table 7. Lung cancer mortality rales, per 1,000 death* by sex, in Austria, 1954 (Herb)eh and Naaabalal) . Community Total Malea Romales Virmm ___ ..... 32.7 Cities (10,000-1,000.000................. 18.2 Cities 20.000-60,000...................... 18. 4 Rciuaiuder of Austria 10.3 50.0 31.0 32. 3 17.3 7. K A0 3.9 3. 7 Remainder of Ohio 728 1,017 FabUrBaalth Maaoograph No. 36, 1955 TIi<` It. faltmulrd imtuiml 1 f ifrimiilt * hyiiruoariiotu in imimic ampin of muylinr nhrnul with varying engine revolution peed (Kotin) Revolution* j*ef minute (Joiu- IW'IIX- Hcu*- Aitt.ltX |ivrune tent rene 500..............._ 225 28(1 120 235 1,000 t:tti 325 ri 177 l.s'iUO............... -- ">07 gWi 33 00 2.000....... - 374 142 40 73 2.500 .,. - ;m< 127 25 70 i 3,000............ __ ,121 25 13 85 3,500............ - 48 5 10 ' 39 1 Quanlilk* are cxprcmctl in *gtiu at 0 load. 153 102 30 27 31 14 15 maty be inhaled mid retained in the lungs from those source* during a lifetime and thul this quantity represents approximately 40,000 time? the dose (0.4 micrograms) capable of producing cancer in ndFe upon subcutaneous introduction. It should be emphasised in this connection tliut 3,4-bcnzpyrene is only one of the several car cinogenic fiieniieuis 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 Ixuupyrene content o[ the uir 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 es|>cciully urbau-riirul, differences in lung cancer freipieucy arc totally accounted for by dilleionccs in the cigarette smoking habits of the two population groups or merely reflect local discrepancies in the diagnostic acumen of urhjin and rurui 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 lu.i, whereas the markedly increased cigarette con sumption during previous years should have boosted the annual progression rate above ihut soon 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 cheat'd m Table 10. Annual ago-adjusted increase of fre quency of tuna cancer mortality Percent increase Sex 1914-30 *1 , 1931-001 1933-44 ' Males...................... ! Females................... 1 Dorn. Poller. 10. S 8.0 8.5 2.5 5. S 2.0 Table 9. Estimated amsunl1 uf aromalic bytlrocarbnn in 1-minulc camples uf tlieeel exhauel with varying load and engine revolution speed and with fuel-injection inefficiency (kotin) Revolu tions |>er i Load minute Condition Pyrene Comiiound! Beni- Beni- ) Anllian- X 1 pyrene . jierylene 1 ii throne 0 Coiujm*toti rtilcAM:..................... -- V _____ do............... ......... do............................................. 0 ____ do........................ -It % _____do............................................. 0 k M % % 137 i 267 : 530 1 800 500 ; 208 257 ] 448 ! 888 ,912 188 1 177 | 220 734 822 22 , 70 : 175 : 040 ! 639 , 0! 01 278 488 | 514 o| 56 ! 70 I 337 1 340 ! 14(i 465 772 1,320 , 870 ; 470 | 437 432 , 1, 706 I 80 78 | 1,372 | 982 1,087 22 42 124 010 1, 265 79 40 171 930 970 0 0 308 1, 071 944 0 43 223 472 469 4. 3 24 197 320 944 2100 09 577 GOG 1 Quantities arc expressed in ngiu./uuu. 8 Environmental Cause* of Cancer of the Lung DUP 1142030 the majority of ouso by cigarette smoking, according to statistical evidence. Such tiu explanation conveniently^ disposes of an observation challenging the validity of tin' 'i'anir 11. Sn ilialriiiuLion of lima coiux-r in Ihv Inilcl Suites ami selected foreign oountries, IH1U-191.S ,, Country Year __ Author 1 Mali - | female ratio Uinied State-. Mexican* 1.. Norway.. Sweden Dcutn&rk__ . Austria.......... Germany_____ < u............... .Mimi_____ Kmiluini............. 10.1.1 1951 1947 1950 1940 19.51 1941 1951 1949 1941 103f> 1953 1953 1925 1947 1931 194.1 1953 1953 IH5U-IHDI) 1900-1919 1920-1929 1930-1939 1940-1949 1952 10-1H 1947 l!M!> 1949 Dorn____ -___ 5:1 Moore_______ <1(1:1 Humphrey*... 7:1 Heeler cl ill__ 11. 5:1 Liudskog_____ 4. 5:1 Carlisle ct al.. 29:1 Halpert Id Mciiumcy et _ 29:1 oi. O'Keefe 20:1 Farlicrow and 13. 5:1 Bcslow. __________ (----1:1 Suminr. ____ 1 :0. 7 Kreyberg........ - . 4:1 . .do. ............. 1 :1 Hensehon____ __ 2:1 CicmmcacM.. -- 5:4 ...do................. _T 3:1 Denk............... 15:1 GmMxc a fi: 1 ...do................. -1. 8:1 ...do................. 3. 1:1 ...do................. .3. 8:1 __ do........... ...... 3. 8:1 ...do................. 5. 4:1 10:1 Council.............. 8:1 SutlULri. ...... 50:1 Mumoii. ...... - 10:1 Kulum ...... . 7.3:1 1 Mexicans liviug m Los Angeles. agurellc Lbeory uud may perhaps momentarily satisfy the protagonists of this concept, although it cannot be taken seriously by anyone who bos any competence in the study of arteriosclerosis (Hueper). It is remarkable, moreover, that lifter tv considerable increase in lung cancer frequency ju Kussia observed tluring the first decades of this eenlury, tills developnieiit seems to have come to u halt during recent years, according to Aniilogow (ciUxl by luckml). Considering the recordotl strikingly irregular epidemiological behavior of lung cancer in diff erent countries, slates, 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 (hau those pos sibly contained in cigarette smoke should mainly account for the remarkable increase in lung cancer frequency and for the causation of u major portion of lung cancers, industrial and industry-related currinogens would well lit this pattern since the growth of industrial establish ments and the use of their products in the economic life of different countries have greatly lacked uniformity in time, type and extent. This concept receives support 1 -om u crit ical evaluation of the data on the sex distri bution of lung cancers, the changes iu the sex ratio during recent decades, and (he probable reasons underlying at least u part of these phe nomena (tables It uud J2). Considering Un remarkable variations which the mole-female ratio of lung cancers hus shown at different Tabic 12. Male-female ki ratio of lung cancers in Germany, lttS'lHi? and 1940-50 City 1880-1927 Author Hallo City 1940-50 Author I Ratio Dresden_____ .. ...1 Wolf.................................... 8 7:1 Leifuiic........... J Soyfurtli____ ___________ 5. 3:1 Do........... 2s 5:1 2s 0:1 ............! Wahl................................... 3. 7:1 2. 3 :1 Do........... 3. G -.l Do .. . Kwih _____ _______ Ktchctigrucii and Kmicu. 4.7:1 Mucnchcu... ; Kuch*__________...........1..5.:1 Jena................ ............, Bits...................................... 8.0:1 Hamburg____ ............I Kikutli................................ 1. 8:1 IxsiiuiK...... ................ ......... do........................... Knorr .... .... Kunlxxcii___________ Frev............. .............. ... i 15:1 ill! 15:1 7:1 9:1 19:1 21:1 7; I 18:1 24:1 49:0 12:1 Fabiie Baallb Monograph No. *6, 19SS 9 limes, iii illiferent local men, and in different dcmograpliir groups, il is most unlikely that uch discrepancies and changes are attributable to fluctuations in the intensity of one single factor, such aa cigarette smoking. Instead, they appear to lie due to alterations in the typo ami extent of the action of a broad spectrum of en vironmental respiralory curcinoguns airoeliiig the members of the two sexes to different degrees. The-marked and growing predominance of mules among lung rancor victims seems Ui In due largely to the following factors: 1. Mules arc 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. Mules predominate in outdoor occupa tions, especially in urban arcus, where they be come excised to carcinogenic |M)llutunts ill 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). M. 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 |>orlions of the respiratory tract, thereby increasing the frequency and degree of cx|M>Kure. 4. Males more often than females work through tlie entire spun 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 llic observed differences in attack rates for the two sexes rather than do iocul variations in llicir smoking habits The doubts as to the unrestricted validity of the cigurcltc theory arc deepened if crilieul evaluation is made of another dubious link in the chain of claims udvancod to bolster tins concept. It has been maintained (Graham that squamous cell carcinomas of the brouchiui mucosa are a specific response to cigarette smoking since (a) this histological type of bron chogenic carcinoma was ollegodly rare before 1920; (6) it has increased considerably since llial date in relative frequency in comparison to other histological types of carcinoma, es pecially adenocarcinoma; and (e) it is more often found in males than in females. The facts are as follows: Broncliiogenic 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, sucli as undifferentiated, round cell carcinomas and adenocarcinomas. Thus, there is no evidence supjKjrling the view that any specific respiratory carcinogen elicits a spocific and characteristic type of cancer. A study of lung cancer records of cases observed Table 13. Histological typo of occupational respiratory cancers, according to carcinoacnic agent Agent Organ Squamous cell carci noma with or without eornlfica tion Round oell or oat oell carcinoma Anaplastic or polymor phic carci noma Adenocardoom* Tir (unM................................... Nickel......................................... Chromium....*.. ________ Ailartat.... ................................ ____ do.................................. Radioactive gases and dust.. Nickel7____________________ Radioactive gases and dust.. isopropyl ill_______________ 3 4 ii 14 3 3 3 2 22 V7 0 ................... ; 2 (i ) 1 M Kariron cranial Causer of Cancer of llie Lung DUP 1142032 M|titna T>. AiiiiiiuI Iniiui mi <*>iimiiiii|i!mmi in iMMiuif- (Wr 'H|iilu. (.rt-iil liriuiut NufwHji) ad the (joiteci Suits, 1*00-50. Turki'Vt I'uUtr Health Uamofnjk No M, 1955 11 -gfti M ijw*W -Hillfci; ^ygglgym before 1VJaiU, or even before 1`JOll, readily estab lishes the fact that during those years squamous cell eareBfomas of the bronchi were by no means rare occurrences (Wolf, 1895-^1 squamous cell Table 14. Consumption of lultaecu in pounds per bead*year. New Zealand and llnilad Kingdom, lWa-lWO (Hastoon) Year Pounds of tobacco per hoad-yoar New Zealand United Kingdom tin........ .................. 1910...................................... 1930....................................... . 1M0....................................... JMO................ ...................... 1N0................ ...................... U 3.09 3.59 1.38 3.87 5.30 1. 95 X 23 199 - 3.81 *.K7 r4.X2 carcinomas among 10 lung cancers, l'robot. 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 moles; 11 percent in females. While adenocarcinomas arc more frequent in fomaloa than in mules, they also arc more fre quent in young persons than in old ones (Lnuiskog; Proc. First National Cancer Conf., 1940). The evidence on hand scarcely supports the contention that adenocarcinomas arc of endog enous causation (Lickrnt) or that they have an etiolog^jdiflermg from that of squamous cell mpriripfies (Kroybcrg). The male-female sex Table U. Anns* death rale per year pm _______ __(___a_le__e)__I_r_a_n_ cancer of the lung, 1932-53, Nnrtalmil eomperni with Kagland end Vain (laalom) Age -44 45-54 i 55-64 65-74 | 75 nd over 193%*6. 1937-41. 1040-41. 1942-46. 1942-40. 1947-51. 1947-51. 1052-53. 1952-53. NewBealand. --.do..................... ........................,.A. England and Wale*........................j*-. New Zealand. Kngiunil and Wnlo New Zealand. England and Walc. New Zealand. England and Wales. 13 33 130 40 r 132 43 106 61 175 87 158 204 : 108 424 | 168 46C j 235 802 400 1,072 283 715 635 ' ],U3J 287 781 j 305 858 1 732 1,682 , 1,027 2, 171 1,014 ! 1,857 j 1.45G 2,650 1 62 213 448 320 .VJ7 735 1,073 1, 111) 1,088 Taldc 16, Ob--crvctl and expected morlalily from cunnrr uf liic lune aocurding Lo place of liirtlt. New Zealand or the United Kingdom (Eaateolt) Age at entry to United Kingdom Place of birth Oiworvcd death* Now Zuniumi________ ___ ___ United Kingdom......... ............ 3oy KX|)UCU.*(1 do*th 721. 8 279. 0 Under 30 Observed deaths Expected deaths 201 229. 2 30 and over Olncrvud Expccu-tl deaths deaths > 168 ' 13U & Non: Tba aignificanoe of the difference between obeorved and expected deaths in the two countries u p<0.001. IX Environmental Causes nf Cancer of tbe Lung DUP.1142034 Kitfurt 0. TrvaiiU in acieeleti envmmmenUti tailed Mlaloh iyw>*53 (Hammond). ratio 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 o'" support the view that women have any i ionol protection against the actionTof 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 bronchio- gcnic 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 tobscco in different countries and their respective pulmonary cancer death rates (Herbich and Ncuboid; Gilliam) (fig. 5). It has been calculated that the English lung cancer rate is apparently double that of the United States, although the English smoko 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 tbit exposure to cigarette tar is leas severj for Americans who do not smoke cigarettes to the very end than for English smokers who, for economic reasons, indulge in this questionable habit. Kocent epidemiological studies of Eastcott in New Zealand provided tho 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, moroover, found when comparing tho observod 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 PakUc Health Moeocraph No. 36, 1955 S4U0S--SS------3 13 DUP 1142035 :.m nj a wr~a ;.iiitfjMih auj immigrants, bul for those wlio were 30 years of age or more on entering New Zealand, the risk, is 75 percent higher, according to Kastcoll. Differences in habits of lohacco smoking are unlikely to contribute to this picture, in the opinion of Eustcott. Herbich and Ncuhold pointed out that there did not exist any consistent proporiiontd fre quency between cigaicttc consumption and lung cancer mortality for Upper Austria am. Kaemten, on the one side, and for Steiermark and Tyrol, on the other side, although in all four provinces there prevailed approximately the some pur cupitu consumption of cigorcllf's Those authors suggested that the high lun.cancer mortality among the people living in the marginal regions of the northern slope of tinAlps might be related to climaiic-atmospiienc Figure Kir in annual iwuduclioii or eutinumillion of amcnr-wUled industrial chemicals between 19UU ^ and lFit. MOPUCT UNIT 1. pttumma com.-MtODucrnN in u.s . MS4J0NS or MET TONS 2. fUCL PMOUCTS-TOTAL RRCOUCTON. THOUSANDS Of NET TONS X CARSON SLACK SNOOUCTtOK IN MHJUONS Of POUNDS A. PETROLEUM - RROOUCTON Of CAUOC PETROLEUM, MLLIONS Of PARRELS S. PETROLEUM, ASPHALT PROOUCTON Of ASPHALT (TNOM PETROLEUM}, THOUSANDS Of JHORT TONS COAL TAR- PRCOUC T ION,- THOUSANDS 0f GALLONS ISOPROPANOL- PRODUCTION- THOUSANOS OT pounos DUP 1 M2036, Jit; i'uikIiIioiik mill u> the direction of prevailing winds, which bring the industrially polluted air of Vienna into the valleys of the northern Alpine regions. ' uilar observations on the influence of the p tiling winds upon tho relative frequency of lung cancers in diilerent areas of the English Midlands were reported by Stocks. Hcrbich and N cuboid, moreover, found that the lung cancer mortality rates were twice as high in communities located along "main highways, where the atmosphere waa polluted with exhaust fumes from gusoline and diesel motors and the dust and fumes of asphalted roads, than among the inhabitants of villages and towns situated remote from such traffic arteries. In fact, the rise in lung cancers follows more closely the increase in consumption of motor fuel and tho construction of asphalted highways than the <-nuKiiiu|>(imi f cigarettcM (fig. 0, Hammond; fig. 7, Hucpcr) and is similar to the incroasc in production of other cancor-relstod 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 differen. character and from various sources which strongly suggests that several, if not many, environmental factors acting in varying degrees and combina tions cause or contribute to the development of pulmonary cancers and aro involved in their recent rise in frequency. Much of tho evidence on hand, particularly the irregular epidemio logical pattern of lung cancer, points to an important role winch industry-related factors and the growth of modem industry may have assumed in these respects. Occupational Evidence and Respiratory Carcinogens The concept that environmental factors cause or contribute to pulmonary cancers is supported 1 epidemiological, medical, and experimental i .cncc obtained from ui tidysis of hmg cancer rates of vurioitH occupational jKtpulalion groups as well as by studies of lung cancers and their spocifk: and different causal agents present in a uumber of restricted worker groups and in well-defined industrial operations. Epidemiological Data on Large Indtsfrial Groups -- Epidemiological studies on the frequency of lung cancer among members of large industrial groups and trades have brought Vo light the existence of marked variations in the liability of persona engaged in different occupations to cancer of the lung. Tables 17-19 supply striking illustrations of theoo differences and list aomo of tho factors which may possibly bo responsible for thorn. Table 17, which lists lung cancer death rates for seven industrial groups in Ohio, shows a PsWe Haakh Monagnph Ns. 56, 1955 striking difference between tho rates for agri cultural laborers and for employees in the nonferrous motal industry, with rates for trans portation workers occupying a position diroctly behind the rates for nonferrous metal workers. It seems to be characteristic of inhabitants of agricultural areas to rank first in death rates from cutanooiu cancer and last in rates for pulmonary cancer. This is in accordance with the relationship between solar radiation and Taldc 17. Luck cancer death ratea per 1,900 death* tiun all eauaca fur 7 iaduatrial group* in Ohio, SJ09 male*, 1947 (Maneuao) Indiiatry Paatii rate Rubber *ud plAnticN............. Total.......................................................... 3.22 2. 91 2. 84 2. 18 1. A3 . 82 . 00 1.70 15 skin nmrrr Ulnl llic rrlul Hilislii[i lirtucrii 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 molals, such os chromium and nickel, or with arseuicais which arc impur ities in many nonferrous metals (copper, zinc, silver;. TruiiBporUilion workers arc 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 block, mineral pigments of carcinogenic chcmiculs, and aromatic amino-anlioxidaDls 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 tu table lb. The employment ratio of operating to nonoperating railroad workers in one of two large railroad companies was 1:4. From this ratio, it appears that, on the basis of the crude, nonstandardized (sex, age) figures presented, about 75 per cent of the lung cancers in railroad employees occurred among tho 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, workore 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 Dunner and Hicks, those workers showed an excessive liability to caDcer of the lung. Twen- Table 18. Frequency of iun( cancer intone operating anti nonoperating railroad worker* Ty|>c of railroad worker Operating N'ono|>crating Undetermined 1 Number | Percent i Number ; Percent i Number ; Percent 5 17 15 14 Table 19. Occupational group* with nwniw incidence of lung cancer Investigator Kennaway and Kcnnaway; Turner and Grace; M Oiler; Dublin and Vane; Wyndcr and Graham; Mc Laughlin; Broalow and aaaociatew. Scyfarth; Kcnnaway and Kcnnaway; Kngor; Voraluya; lirinkmann. BKCC1 1944 and 1952; Gilkapic; Turner and Grace; MOiler; trader and Graham. BKCC1 1944; Mailer; Dublin and Vfraatnne; Fulton; Wyndsr asd^Qra- Kcnnaway and Kennaway; Fulton; BKCC1 1052; Hogistrar-Gencral (103K); Mclumghlin. Farlmaianalnl Cayaea of Cancer of the Long Kigure k. m ORE SMELTING .- .*'- ^ *--- " ^"EPLAT1^ -- PIGGMIfEENTS. PAINTS --.. ` *-Wv -- * 7^MK^PRINTING , . '.ABRASIVE "' ORE REFINING PLATING ^BUFFING ' ' ' -. v-^ -.Cu ' Vl<L* CHROMATE V* -' -/-:- 'X, ; NICKEL CARBONYL'?- .*' .ORE MINING rftMELTING '^PESTICIOES 'PHARMACEUTICALS ARSENIC -r->' ' ASBESTOS (?1 - ` I - NASAL SINUSES LARYNX MINING ISOPROPYL OIL (?) . f^~AS8Estds processing !jfi[a'y*EAViNG ' r<.. LUNG . manufacturing' ' ^^OKE^EN SERVICING . RADIOACTIVE DUST ***&?- PITCH. TAR .......... V^W.TI^ASPH^TJIUS^ . -/ ^ H E3'V, v. ;^ V; - - RV'-" ty-four lung cancer cones were found among 5,000 dock workers al 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 chromalo-coutauung scale, if chromates were used as antirusling agents, or that those 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 presurviug agents, account for the abnormally high frequency of lung cancer among gruiu dockers is at present a matter for speculation. Mention also may bo made of (lie recent observation of F&ulds on the excessive fre quency of pulmonary concur among English iron ore workers omployod in mining activities at two different locations. Necropsies porformod on these miners during 1932-53 showed s lung cancer incidence of 9 percent (192 necropsies with 17 lung cancers), while post-mortem ex aminations done on 2,378 males of comparable ago who wore not omployod in those miiios 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 Pshlk Health Moaocnpfc N*. 36, 1955 17 D.UP 1 M2039 (degree of fibrosis in cancerous lungs, 1 plus; in tuberculous lungs, 2 plus; in fibrolic lungs without cancer and/or tuberculosis, 3 plus). The absence of a positive correlation between pulmonary fibrosis ami lung cancer was noted when the evidence on lung cancer among the radioactive ore miners of Joorhimsthal and Schnechcrg was analyzed (11 neper). Although the actual causal factor rri>onsihlc for the lung cancer among iron ore miners remains to be determined, it may be mentioned that I^evin and his co-workers recently recorded a |>osilivc statistical correlation between an occupational exposure to iron oxide and heat and cancer of the lung. The studies of Breslow, liouglin, Kaamusson, and Abrams on 518 histologically proved cases of lung cancer in California suggested the existence of uu increased liability to lung cancer for memhers of the following occupational groups: welders, sheet metal workers, sleumfillers, boilermakers, crane o]>ertttors, and uouferrous metal smeller workers, that is, individuals who arc exposed to nictal dusts and fumes; oilers, oil field workers, wipers, and marine engineers, who have contact. with oil fumes, mists, ami sprays; asbestos workers; construction and maintenance painters, who inluile vajxjrs or various organic solvents, resins, lacquers, plastics, and rubber, us well ua finely dis|X'rwd inorgunic and organic pigments (chromium, nickel, copper and arsenic ooiiijMnmds, curium block, aniline dyes); ami commercial cooks cx]>ose<l lo fumes and mists of overhauled vegetable and animal futs ami mineral pan greases. A recent study of the cuuwcs of death of the memhers of the International Photoengruvcrs 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 occuj>auomii 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 liand, equally clear that the quantity and quality of information available on the ocrupuuoian aspects of lung cancer causation are deplorably defectivc because of an absence of extensive and prolonged analyses of lung cancer deatlis among various industrial groups for specific causal factors. The evidence on hand nevertheless iadequate for demonstrating that the wide varia tions in lung cancer frequency apparently existing between different industrial population groups are attributable to difference's in more or 1ms wcll-definablo occupational exposures and not to differences in cigarette smoking habit'-. Occupational Respiratory Cancers and Carcinogens Conclusive evidence of the existence of exogenous carcinogens and environmental re spiratory cancer liozords is provided by die epidemiologicnl, medical, and cxperimentaTdata concerning occupational respiratory cancers. A general view of the occupational respiratory cancer panorama, including causal agents, and orgiuis affected is presented in table 10. Scope oj Kneisoomental Luiuj Cancer Hatanli All indiscriminate acceptance of the figures given in table 20 as reflecting the actual scope of these identified and recognized respiratory cancer hazards, however, would he seriously misleading, dospite views expressed by several pmtngnuiKlM of the cigarette theory (Kiugcrlz; Wynder uml Graham; Jxivin; and others;. Although a definite demonstration of specific occupational lung cancer hazards has ao far boon made for only relatively restricted worker groups, tlic evidence on hand is not only un equivocal hut nlso indicates that oilier worker groups exposed to tlie same causal agents or subjected lo identical or similur working condi tions are subject to the same hazard#. In contrast to the apparently low carcinogenic potency of the suspected, hut unidentified, agont presumably oontainod in tobacco moke, tlie occupational respiratory carcuiogens Tire evidently iugidy potent, us shown by tiioir high respiratory cancer attack rates (table 21). Since environmental carcinogens have been shown to produce cancers wherever they operate in adequate intensity and duration, and con sidering the fact that many of the occupational 18 ~ Isrlimsiilil Causa* at Cmmeae at the Lung ruapiriti-iirv i-siivuuigriiN im-i-iii- ur> iiidusln- rcluted general atmospheric pollutants, it, may justly be assumed tliat those pollutants repre sent the cause of a significant portion of lung ..ix among mi-mltcrs of the general populu- t especially those who live and work in highly industrialized arcus. " The u|i|)i-o\iiiiate nco|>c of occupational ex posures to the various ruupiratory earchiogens may be oslimatod from data supplied by Bloom field and his co-workers. From a survey of 1,5(M,204 workers employed in all industries of 10 States, it was found that 7,970 were exposed to fumes aud dusts of chromium eon pounds und Tuttle 20. Occupational ruupiratory carcinogens and cancer* ruuunlod liuriua past 73 yuan*, ltit*ir oiuan, *iu-, tad numbers Agent bite of cuneer 1 !_ i Your diw eovered j j Number of recorded cases United Other StttUv oountntx Total ArM'tiic....................... ............ ! Lung__________ ________ ____________1030 AkIk*hU>k___ _ ___________ 1034 Oiruiiuitou............. ................ 1032 Nickel........ ............ ................ 1032 1 Nares and nasal sinus___________ OoalUir... ........................ ----- 1 Lung................................. ............ 1031. Petroleum oils..................... 1 Lung and larnyx..................................... 1030 Isopropyl oil......................... ----- : Lung.................................................. 1040 | larynx....==................. ......... Nasal sinus'-................ ................ Radioactive chemical*.___ ------ Lung..........hr....................... ........... 1870 : Nasal sinus___ ..... .................. 1931 i j | > l1 i l Tout......................................................................................_......... I.................... ! 7 22 75 0 0 0 7 1 4 <1 0 3 125 j 10 74 <15 84 51 53 33 0 0 0 025 0 1,001 | 23 90 140 84 51 53 40 1 4 u C25 3 1,120 Table 21. Kespiralory cancer attack rales, by environmental carcinagcus Carcinogen Attack rates ! Incidence in Site* of cancers |*t|uilalion i'ercenl Rate |*t 100,000 at rink , of all *1 I cancer | , i deaths , Morliidity ! Mortality Aromatic hvdrocarljons: Coal tar fumes hung............500:100.000 Petroleum oils..................... Lung......................... 2,000:100,000 Carbon and silicon polymers: Isopropyl oil_____________ /Paranasal sinuses, 1 l larnyx. --. 1/ 10:100 AkIjcsUjh.... .............. ............ , Lung......................... Metals: Arsenic___ Chromates Nickel Ionising radiation: Radioactive ores. Lung...................... . Lung_____________ (Naaninsu,aeap. aranasal Lung Lung 320:100,000 ! 574:100,000 I 45 55 134.5 ( nor mal 0.5). (13.2-20 iicrcent m.bcstosis autojwiod (0.8-2.4 percent normal)). . 145.7 males (10.0 nor mal.) (42 X nor- 140-330 mal) (20 X normul). (60-80 percent of all dcutlis). Public Health Monograph Na. 14, 1955 19 3,350, u> fimn'h. tiiuI dust* <f tirMi>iiii'ls. For industrial workers of all 48 S Lalee, respiratory health hazards existed from the initiation of dust, fumes, misLs, and vapors for 35,000 individimls employed in u*lxio& operations, in 33.000 having contact with urseniculs, in 240,000 inhaling various ly|x*. of metal dust, and in 2.500.000 having cutaneous, respiratory, and digestive ex leisures to vtirious combustion and distillation products of coal tar, pitch, creosote oil, soot, and to petroleum fuel oils and lubriouting oils, pem, an<l cooling oils, to name a few. The highly defective state of knowledge con cerning the actual number ofoccupational respir atory cancers is, moreover, demonstrated by the fact that information on iho existence and number of such cancers in specific industrial operations with recognized respiratory cancer hazards is distinctly spotty, not only as to data available from diflorcnt countries but also concerning Those on hand from identical opera tions of the same country. The following ob servations may illustrate tlus point. The existence of an excessive liability to can cer of the lung from an inhalation of coal tar fumes by retort attendants of gas and coke oven plants has l>ccn established by a few re ports from Japun, Canada, and England. Apart from these isolated data, no others ore available for similar operations from these or any other highly industrialized countries (Ger many, United Stales, France, Italy, lJolund, Kiiksiu). Likewise, there is no official nsxtrd uvuiiublc concerning the occurrence of respir atory cancers among carbon electrode makers and attendants in aluminum manufacturing plants, where workers Itocomc exposod to dual and fumes from the pitch and petroleum asphalt in the electrodes, and where, according to in formation available from four dilTcronl countries, tar and asphalt cancers of Lite akin liavc been observed os the result of such eonlucts. It ia, moreover, surprising that data on the occurrence of lung cancers among producers and users of arsonical insecticides have boon re ported almost exclusively from Kuro|>c, al though the United Stales lias bocu for many years the main producer and consumer of these products. Similarly, reports us to the existence of respiratory cuuccr liazards from an occupa tional inhalation of mists and fogs of lubricating and cooling oils lmvc so far totally originated from Europe, despite the fact that American industries offer ample opportunities for identical exposures, that on excessive liability lo lung cancer has been noted for paraffin pressers elnployed in oil refineries, and that the survey of one oil company has shown that there was n marked predominance of operating refinery workers umong the lung cancer victims of this particular organization. Finally, attention may be culled to the fuel that the entire ovidcncc os to the existence of lung cancer hazards for rodiouclive-ore miners lias oomo from the observations made in Sclineeberg and Joachimstliul. However, mining of uranium ores luu been carried on for 10 to 20 yean in the Congo, Canada, and the United States and extensive milling operations of the African ores have boon conducted in Belgium for many yean 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 uxirurespiratory route. While all known respiratory carcinogens arc of environmental origin and are inhaled as air pollutants, there exists some suggestive occupa tional, medicinal, and experimental evidence indicating that agents introduced by other routes may be effective ill eliciting lung ouueers. Several coses of lung cancer are on record which developed after an oral administration of ar senical* and which appeared in individuals with arsenical dermatoses and skin cancers (\oubsuer). Lung cancers also have been observed in some aniline dye workers suffering from primary occupational bladder cuuccr (Muller) following prolonged cutaneous, ingostivc, and respiratory exposure to dusts and vapors of certain carcinogenic aromatic amines. The possible scientific and practical significance of these findings ia suggested by the experimental observation of lung cancers in 10 percent of rata given the potent carcinogen, 2-acctylaminofluonmc by on oxtrurespirulory route (Bielschowtky). A cutaneous as well as parenteral introduction of coal tar and several polycyclic hydrocarbons as well as of urethane resulted in 20 EavifmuMaul Csbm* sf Cancer of the Luas ;iiw . ^BLL u precocious uppcarum u uiui un increased num ber of pulmonary tumors in 'nice. Pattern and Types oj Respiratory Cancer Hazards _ . miip of Uu- distribution and rotative oon- crnlruiiun of l lie different cumnogenitrair pol lutant* wore pic|Mirod for n given area, it woulil exhibit u sort of crazy quilt pattern to winch tlio general ul.mos|>licrir |M>iluluuts woulil furnisli the overall background color, varying in depth between darker urban areas and lighter rural districts. Ollier types of carcinogenic tttinospherie pollutants having a more jiirrumsenbed field of distribution would appear as irregularly arrongetl and variously sized and shaped h|k>U und islands of different colors su]>eriinposcd upon the general background. It stands to reason that such locally differing ex|>osure patterns arc bound to exert an im)M>rlanl influenee upon the epidemiological charaeter and incidence rates of pulmonary runners of various regions; each one of the various eureinogeus would produce its own epidemi ological scatter pattern showing a diminishing spread of cancers from multiple carcinogenic production foci. The following three main types of exposure to environmental atmospheric carcinogens may be distinguished: lenenii environmental atmospheric exiMisures lo certain aliphatic and polycyclic hydrocarbons released into the atmosphere us incomplete combustion products of domestic and industrial and ship fuels, as parts of the exliuust fumes of gasoline and diesel engines, as abrasion products of rubber tirca, and as dust from asphalted and oiled roads; exposure to arw-nicals contained in the mineral ash and soot of burned coal and in the effluents of certain metal smollei-s, und related to the large-scale use of arsenical pesticides; and exposure to radioactive material cither naturally released from t he soil and from bodies of water or pollut ing the atmosphere as the result of nuclear explosions. 2. Special and locally restricted atmospheric ex|M>sun< to carcinogenic pollutants of the air exists m the vicinity of noufemius tuclul smelt ers releasing in their effluents and from their slug heaps fumes and dust containing nickel, arBcnicals, chromium compounds, and berylli um. Similar exposure exists in the vicinity of carbon black plants, oil refineries, tar distilleries, gas plants, und simitar industrial establish ments producing large amounts of soot or other ]>olycyclic hydrocarbon containing effluents, and ill the vicinity of radioactive ore mills und atomic energy plants. The individualized ty)>c of air pollution con nected with the smoking of tobacco, with its suK|>eclcd curciuogeuic. 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 iucroooing number of specific chemical and phyaicol agents have either definitely been recognized or are strongly sus|>eeU'd of being responsible for the uppcuruiicc of cancel's of the nitres, paranasal sinuses, larynx, and lung among members of certain occupational groups. These specific occupational exposures arc associated with the inhalation of coal tar and pilch fumes and dusts, mists and fogs of pctroloum derivatives, soot, vajiore of isopropyl oil, that is, the crude liquor from which isopropyl alcohol is distilled; arsenic, nickel, chromium compounds, asbestos, and ionizing radiation. Since the availubl j evidence eHtablisht's such carcinogenic, connections with only some, but not with oil, inhalants, such as silica or coal dust, it is apparent that carci nogenic activities are not associated with all atmospheric pollutants. Occujxitioiuil Respiratory Cancers Tin* respiratory cancers of recognized or strongly suspected occupational origin are im portant, not only as industrial disease manifes tations but also as prototypes of cliologicaily 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 muons contacts with the suine industry-related carcinogens. PaUic HasUh Mooormpfa Ns. 06, 1955 341108--M------1 21 aTjj^M.'3gg' s? fFflaaa Phytieochemical State of Atmospheric Carcinoym* and Topcrjraphieal Distribution of Concert in tin Respiratory Tract In agreement wiili observations mude u* to reasons for the loiKigruphieul <JiKtril>iiticm of environmental canccm in otlu-r duel systems (urogeliotis uii<Tuiilneiilurv ruiml), respiratory cancers of environmental origin are preferably occupying aitoTwliere (a) llie (low of llie inhaled polluted air isThtcrfored with, that is, in the noniutf narrows of llie respiratory tract, such as the region of the nasal turbinates and the larynx or its bronchial bifurcations, or (b) where tlie respiratory tract forms dead end sacculations, such qs_tlie parunusul sinuses and the peripheral bronchiolar regions of the lung, in which inhaled carcinogenie matter may accu mulate, condense, and precipitate. The traflic pattern of air ^llutunts in the respiratory Iruct thus corresponds to the distribution pattern of respiratory cancers elicited by atmospheric carcinogens. The second principal factor winch determines tin' localization of an environmentul coucer within the different sections of the respiratory tract is represented by the physicochemical status of a particular carcinogen, since tins con dition largely influences the site or sites of chief exiKiRurc to an atmospheric, carcinogen. Car cinogenic dusts consisting maiidy of course particles ure maiidy urrvsled in the nures, where, they cause cancers of the turbinates. The nasal cancers observed among copper-nickel matte refinery workers inhaling the coarse dust of the roasters illustrate this interrelation. The excessive incidence of larynx cancer among mule spinners inhaling carcinogenic shale oil sprayed from the revolving spindles likowisc provides another example of this mech anism because it is likely that the relatively large droplots of this oil are arrestod in the upper portions of the respiratory tract, making the narrows of the larynx the port of main exposure. Dusts or mists ooui]km<h1 of iwrticles having a diameter below 4 microns, on the other liaud, penoIrate into the deeper ports of the respira tory system and therefore are mainly responsible for the cancers of the bronchi. The broiiilm.genie cancers found among chromate manufu> turers, asbestos workers, and coke oven and gu.retort workers arc representative of this type of exposure. Atmospheric pollutants of gaseous and vapor types not only penetrate into lin kings hut also into the nasal sinuses, whore ilu v liiuy bo deposited by degradation into ooluU (radioactive gases), by dn-omposition into solid(nickel carbonyl), or by condensation and poly merization into liquids or solids (aliphatic diox ides contained in crude uopropunol liquor>. In assessing the relationship between tluphysicochemical status of atmospheric carcino genic pollutants and the localization of cuncer^ within the various parts of the respiratory tract, consideration also must be given to the fuel that gaseous and liquid carcinogens may become ad sorbed to tlio surface of carcinogcnically men solid dust particles and beliuvc under sucb con ditions more like solid particles. Such com binations, for instance, occur in relation to the exposure to radioactive gases adsorbed to rockdust in uranium minos os well as concerning the inhulution of liquid or solid aliphatic and poly cyclic carcinogenic hydrocarbons adsorbed to tko surface of mineral road and industrial dust or of carbon constituting the bulk of soot. The first evidence indicating the existence of causal relations between environmental fuelers and the development of cancers of the lung was recorded in 1879, when Hurting and Hesse established the cancerous nature of the lung diseases prevalent among the radioactive-ore miners in Schnooberg, Saxony. This discovery, of historical importance and great present sig nificance, attracted little attention at the time bocause radioactivity was still an unknown fuel and cancers of the lung were comparatively rare before the turn of the contury and therefore of little medical interest. It wus not until the third and fourth decades of this century that additional, well-defined occujmlioiuil activities and environmental agents were again related to the causation of cancer of the lung and other parts of the respira tory tract, that is, the nasal cavity, paranasal 22 EnvirwuMalai Cause* o{ Cancer of the Lunq miiiiim'*. unil larynx. Among these addition* u Llir list of environment*! respiratory cancers were- the lung ouncers among chromate manu facturer* (1935), of uxlx-slos workers Q935), of r nic workers (19:50), and of coke oven operai (1930), the cancer* of the nasul cavity, paranasal sinuses, and lung among copper-nickel smeller worker (19152), the carcinomas of the nasul sinuses among luminous-dial painters (1931), the cancers of tile nasul sinuses, larynx, and lung among iaopropaiiol manufacturers (194(1), mid cancers of the luryiu and lung umong workers exposed to lubricating oil spruvs or mists (1936, 1949). Specific Carcinogens ,, Inorganic Chemical* NICKEL ^ Nickel, one of the most industrially important mctuls und principally mined in the Sudbury district of Ontario, Canada, has many uses: alloys (iron, copper, chromium, aluminum, <-oiwi.lt.); molybdenum (employed in the manu facture of stainless steel, beat resisting steels, forgings, casts, wires, sheets, structural,shapes, tubing, rods, bars, strips, and so on); electro- r1 'ting; catalysts; ceramic enamels and colons; milts in paints and inks; storage butteries, and so on. r 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, inhulution of the volatile nickel carbonyl has boon responsible for an appreciable number of acute and often fatal poisonings. The pul monary manifestations (congestion, desquama tion of ulvcolur epithelium, fibrinous acellular exudation into alveolar spacca, bronchial mu- cosal heinorrhuges) are apparently attributable tu the toxic action of iiuely dispersed nickel formed from the disintegration of nickel car- Ikjmv-1 upon the pulmonary structures. Kraffl suggested that these reactions arc the result of a nickel allergy having tho lung as its shock organ. Tho first rc|K>rt concerning tho occurrence of an excessive number of cancers of the nasal puasuges (nasal cavity and paranasal sinuses) and of the lungs among workers of .he Clydach plant of tlie International Nickel Company, located at South Wales, England, was made by Grenfell in 1932, although tho first appear ance of these neoplasms among the nickel refinery workers was noticed in 1924 (Buadcr). Subsequent reports dealing with theoe cancers wen- made by Stephens; Amor; Cooper (E. H.); Carozzi; Bridge; and Merowotiier. From 1923 to 1948 inclusive, there woro reported to the Chief Inspector of Factories a total of 47 cases of cancer of the nose and 82 esses of cancer of the lung from the nickel works. By tho end of 1948,40 of the workers with nsaal cancer and 72 of those with lung cancer iiad died. None of tiic 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 hud been carried out. The average e.\|H>surc jx'riod for the nasul can cer patients was 23 years (range, 3-26 years), and for the lung cancer patients, 25 years (range, 1-33 years). No cases of cancer of the larynx have occurred, und only 1 cancer of the naso pharynx was observed ul Ciyduch. The nasal cancers involved the turbinates, nasal septum, and paranasal sinuses (cthmoids). Of these, the majority were of the umliiforontiuted cell type (0), 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 tho small cell, ploomorphic type, while 1 was a squamous cell carcinoma. Similar observations were, recently recorded from a Norwegian nickel refinery, where 3 case* of lung cancer were seen (Lsken). In one of these cases a squamous cell carcinoma was associated with sarcoid lesions. Goldhlutl and Wugstafr mentioned that so far cancers of the respiratory tract have not boon noted among the workers omployod at the German nickul refinery at Ludwigthafen, FuUic Health MwiegTmph Ns. *6, 19S5 S3 nor lias there been imported uu unusual fre quency of respiratory canc^i-s among the* work ers of the Sudbury nickel ore mines and smelters in Cunudu, although several cases of nasal sinus cancers were recently seen in one Canadian nickel plant. Amor jminted out that the; majority of indi viduals employed at I'lydach who developed respiratory "cancers were not ex|>osed to the inhalation of nickel carbonyl but to that of nickel matte dust or dust from the nickel matte roualer (l^pken). More recruit data eonununicatod by Morgan confirmed this observation, although exjrosure to nickel earlronyl vu|>ore had occurred more frequently among the af fected workers than was apparent from the data previously given by Ajnor. The rela tively high incidence of cancer of tho nasal cavity indeed suggests tiiut a rather eoarsc par ticulate dust readily arrester! at the region of the turbinates may have been active in the production of cancers at thi6 particular site, while nickel-containing vapors or a very smull particulate dust most 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 lioeauBe the nickel refinery workers do not suffer from perforated nasal septa and display no evidence of chronic arscnicism Such as dermatosis and culanoous cancers, which almost always have accompanied the occurrence of lung cancer among workers exposed to arsenical dusts or fumes (Huoper). 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 thoae seen in miners employed in the radiooctivo mines of Schnoebcrg and Joachimsthal. Workers omployod at the roasters, in tho nickel carbonyl operation, and in other parts of the plant, on tho other hand, bocomo 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 nickel refinery * others arc reaction products to more or loss finely dispersod nickel particles or vapors. There is no evidence available, howover, which indicates that the inhalation of nickel in particulate or vaporized form is ac companied by pulmonary changes of a pneumoconiotic nature. The concept of a nickel etiology of respiratory cancers was tested in animals by 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 unoxposod control mice. The ruecut experiments of Huoper seem to demon strate more conclusively the carcinogenic prop erties of motallic nickel. Wbon pure metallic nickel powder wus implanted into the femoral and pleural cavities and subcutaneous tissue of 172 rats, cancers developed at the site of injec tion in 50 of them. Whether or not nickel assumes u carcinogenic 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 spoctrographic 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 mode from the data available since the number of workers at risk is unknown. likewise, no definite opinion can be expressed as to the possible existence and extent of respiratory cancer hazards for persons having for other reasons contact with dust, fumos and vapors containing nickel or its com pounds. CHBOMIUU Chromium as a metal, alloy, or compound is used for many purposes in industry. It is for this rear >n that a large number and variety of workers liavo contact with chromium and chro mium compoundsand tiiatevcn restricted groups of the gonorul population may possibly be come exposed to these agents in the form of dust. vapor, fumos, mist, liquids, and solids (Bourne and Rushin). Workers most likely to be cxposod to chromium and its compounds are acotyleno workers, aniline workers, blcachci's, S4 ~ EnriroomeauJ Cause* of Cancer of (he Lung l>liicjmiiU.-rs, chrome workers, clirotuium platers, chromate manufacturers, chromite miners, cray on makers, dye workers, electropiatcrs, enamel workers, gloss and pottery froslcrs, glass color< |lottery gloxers, urtifieiol flower makers, L ,ery makers, iinoloum workers, point mak ers. ink makers, painters, photographic work ers. piiotoengravers, polishers, prinlcrs, rubber workers, steel workers, tannery workers, vuicuni/.eis, wau-rproofers of textiles and paper, welders, users of chromate antirust agents in ruilrnml engines, automobiles, steam boat in stallations, and bitumen and oil refineryworkers. An environmental atmospheric contamina tion with cliromium compounds may result from Uie release of chromium-containing indus trial wastes of chromate plants and of oil refineries using u chromium-containing silica catalyst for tho catalytic cracking of oils. An environmental spread of chromates may also follow the use of such com|>ounds as anlirustiug agents in automobiles and for anticorrosive coating of airplanes. Since manvy_ of the industrially used chromium compounds exert a corrosive action on tissues, skin contact and/or inhalation of such agents results in the development of chrome ulcers of the skin and nasal septum whieii hi turn provide definite proof of an existing health hazard. Com menting on the appearance of such manifesta- ; among workers in new industries using onromium com]>ounds, the Chief Inspector of Factories of England and Wales remarked in his report of 1944 that "the control of old hazards in new industries is of interest to others as well as to tiic student of industrial health, for it would seem that in many cases the hazard is not recognized until damage to tissue has been done, when old principles have to be relearnt and adapted to new uses." ^ Tliis reflective observation seems to be quite appropriate when contemplating tho possible existence of respiratory cancer hazards for individuals omployod in tho numerous indus trial operations for which no pertinent pub lished data of any kind exist at the present time. The observation of apparently occupatiouconuoctod cancers of tho respiratory organs, especially the lung, has been limited so far to two types of operations, the production of chromates from ciiroinitc ore and the manu- fitrtuic of ceitum chromium pigments (zuic cliromatc, barium cliromatc, load chromate). In these operations, both water-soluble and insoluble chromium compounds are inhaled by Uie ex|>osed workers. Tho chemical nature of the actual curcinogcnic agent which is respon sible for the excessive liability of cliromatc and cliromium color workers to cancer of the lung is still controversial. Although all investigators believe that some chromium compound or compounds arc causally involved, it has remained uncertain whether the compounds suspected are hcxuvalcut or trivolcnt, water soluble or insoluble, monochromaics or dichromatcs. Water soluble cliromium coiujmuiuIs (moiiochroinulcs, di chromates, and zinc chromate) are most often incriminated. Mancuso and Huopcr recently pointed out that it may be moro likely that carcinogenic effects arc elicited by cliromium 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 hi the lung and thus exert a prolonged effect upon the pulmonary tissues. Such chromium com|>ounds present in a cliromatc plant would be represented by chromite oro and its early conversion products preceding tho formation of monochromatcs. These little water-soluble trivolcnt cliromium compounds o?cur in the material present in mixers and roasters and arc 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 contcut of tho lungs hut also un excessive blood cliromium level (Mancuso and Uronc). Kocent experi ments on rats which inhaled finely powderod chromite ore dust showod that after 18 months a cliromium 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 oontainod in chromite oro is solubilizod in the pulmonary tissues and discharged into tho blood. Haklie IWUh XMapifb No. 16, 195S 25 HUP 1 142047 and chrome uisoiiiiiaiu uppcuis to hi- u icucon- ablc conclusion. Chest and X-ray examina tions of 40 workers employed in an arsenic smelter revealed a mild degree of pneumoconi osis (Saupc). Although Saupc himself did not discover any evidence of lung cancer among the workers studied--even though they often were afllicicd by hyperkeratoses of the skin and perforated nasal septa--he cited the autopsy observations previously made by Schroorl on 2 arsenic wne-Uor workei-s who died from cancer of the lung (Teleky). Fronunol Urielly 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 eases of lung cancer in shocp dip workers with arsenic dermatosis noted in one of these were reported by Merewethcr, while Hopkins and Van Studdiford observed in a farmer living near a cotton field sprayed with insecticides, arsenical dermatosis, epitheliomas und cancer of the lung. The occurrence of 5 cases of lung cancer (Merewethcr; Hopkins and Van Studdi ford) among only 24 individuals suffering from occupational arsenical dermatosis and epitheli omas caused Nouhaucr to wonder whether this is mere coincidence, because only 2 eases of lung cancer were observed among 143 cases of medicinal arsenic cancers of the skin (Husscll and Klaber), or whether under occupational conditions tlir irritation of the respiratory tract by arsenical dust was rusjionsihle for the phenomenon. Ilenry, commenting on the occurrence of skin cancers among sheep dip workers (1610-23), recorded 2 additional cuscs of lung cancers among 10 such workers who had cutaneous cancels, lie mentioned, moreover, the pres ence of cancers of the left foot, abdominal wall, and lung in a furnaccman in a sodium arsenite factory. 'Analyzing the mortality ex perience of a sheep dip factory, Hill and Fail ing found that 7, or 31.8 percent, of the 22 cancers causing death among members of this group were located in the respiratory organs, whilo 3, or 13.C percent, were situated in the skin. There were during the period 1010-43 s total of 75 deaths from all causes among workers in this factory. The proportional excess of cancer deaths was mainly attributable to an excissive frequency of cancels of the lung and skin, which were confined to workers in the chemical processes snd were absent among members of the general group who would be unlikely to be exposed to any specific hazard. Perry, Bowler, Buckell, Druett, and Schilling concluded from the clinical evidence obtained that, after many years of exposure to arsenicals, those sheep dip workers may devolop a squamous cell carcinoma in the bronchus. The most rocont addition to epidemiological investigations on arsenic cancer was made by Isnogireir and Lombard in studies of earner douths among employees of several metallurgi cal plants of unidentified type. Of the total of 106 doaths from all causes recorded during the last 25 years, 12 were due to cancer of all sites, and of these, C wore ioeated in the lungs. The investigators concluded from this evidence that "there arc indications that biologically the human race mode the adjustment to arsenic iu the environment and that only rarely, when associated with other contributing endogenous factors such as systemic disease, or possibly factors such as radiation, it may bo capable of upsetting tho biological equilib rium''; and further "Unit the handling of arsenic trioxidc in the industry studied does not produce a significant change in the cancer mortality of the plant employees; hence other factors in addition to arsenic must be con sidered significant in (he causal relationship to cancer." In view of the fact that 50 percent of all cancer deaths among omployecs of one plant sur veyed were caused by cuuccr of the lung, the observations made in fact strongly suggest a carcinogenic action of inhaled arsenic trioxide upon the tissuos of the lung of the expoaod workers. This interpretation of the data of SnegirefT and Lombard is supi>orted by the high incidouco of lung cancels among the imputation of several counties in Montana where copper smellers and mines were operated for many years, creating on occupational and environmental |x>llulion of tho atmosphero und soil with arsenicals. Prolongod inhalation of arsenical dust and fumes uppouts to produce an increased liability to cancer of the lung (lablo 23). However, the existence of such connections - ss Environmental Cause* of Cancer of die Luos DUP 1142048 ssi vtmmmit^Mlaiiligs Tlilt U. Luim cancer murlmlity iu several MiuiUua counties, 1947-48 (Lull and Wattach) 1 'ounty and total pulalion 1940 Major iudumry 1I 1 Number lung | eenoer* , 1 : Male loi&i Fc- ! male Total e&iiccr deaths Pwoent lu&f OfcQoer Annual lung eaaoer death rate/100.000 j Male Fcmale Male `j Fe male Doer Lodge, 13,627. Silver Bow, 53,207.. CbmcuiIc, 4 !,4Uil. Gallatin, 18,269_________ Copper ainelting 1__ i 21 Copixsr raining, 27 Copiicr uiiuing, smelting ! 20 Agriculture 1 1 ____ __ 0 ! 21 2 29 5 ! 35 0| 1 08 30. 8 250 22 6 200 12 7 81 3.0 a o 145. 7 ! 1.5 48. n | 25 40 3 i .0 0.0 20 12 3 .0 1 Personal communication of unpubliahed data. * The oxtimated crude death rate for lung cancer among white rnalca in the entire United 8tatei in 1947 waa 10.9 |wr 100,000 population. __ 1 The workere employed in oop)>er ore mining and smelting inhale dust and fume* of araenic contained in the ore and rolea*ed aa a byproduct and waate product during the ainelting proocas. should be acknowledged only when there existed at sotno time clinical and, if possiblo, histological and biochemical evidence of chronic ursciiicisin. In view of the absence _of unv such evidence associated with chronic arsenicisin among the nickel refinery workers affected by cancers of the nasal cavity, paranasal amuses, and lung, and among excessive tobacco smokers with cancer of the larynx and lung, it is most unlikely that exposure to arsenic dust, fumes, and vapors plays any role in Lite production of respiratory cancers in members of these population groups. 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 and compounds by iron ore miners, arc welders, grinders, polishers, silver finishers, and metal workers. Tits resulting rod or black tidorotis caused by pulmonary retention of F01O1 or of FeiOiHjO, respectively, is considered an inert form of pneumoconiosis which docs not cause disability and which at least in part a**TM to be revers ible. The deposition of iron oxide particles does not elicit in the lungs a progressive snd markod fibrosing reaction unless the inhalod dust also contains silica, producing then a sidcrosilicosis. The coexistence of aideroeis and cancer of the lung has occasionally boon obsorvod (Stew art and. Faulds, 1 case; Dreyfuaa, 3 cases in watchmakers; Vorwald and Karr, 3 esses in hematite miners; Simons, 1 case in a blaster of iron costs). It may be mentionod, moreover, that Konnaway and Kennaway reported a 2.25-fold incidence of pulmonary cancer among metal grinders and that Turner and Groce as well as Campbell noted an excessive frequency of lung cancer among metal workere. The most recent contribution to the problem of siderotic cancer of the lung was furnished by Faulds, who noted that among 102 iron ore miners coming to necropsy between 1932 and 1953 there wore 17 lung cancers (8.83 percent). Ehrhardt and Giithcrt, on the other hand, noted that rod sidurosis of the lung docs 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 Hoaltli, on the num ber of doatlis from lung cancer among iron ore miners residing in St. Louis snd 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-yoor period than that noted for Minne sota residents (table 24). Experimental studios on animals exposed to iron oxide and hematite, respectively, gave con tradictory results as to tho production of lung tumors. While Vorwald and Karr, using guinea pigs and rats, failod to obtain lung cancers with NMc Health Mooofrspk Na. M, 1955 29 DUP 1142049 'iHt--IfAraiE^HI^ir 'ifi'iHffBi IffiaWMMia; MtlilBito* 24. tie*tl iut i cinct'r of tin* lung gmung iron ore miner* and reddcnu of Minnoeota> (lirower) 1950*54 i ear i Number uf duullm j i 1 uUtrt'wi- denu St. ixmtHIliWU County * mifimt Millin'noIn ruHi- dent* St. Jx)ui*(UiM*n (xniiity miner* 1950.......... 1951 -- 1952.......... 1953.......... 1954........ 3ZK ranfl 320 .367 345 5 i 11. 0 4 9. 7 12 11.0 X 12. 3 (> , 1 11. C 37.11 30. 0 90. 1 no. i 00. 1 hemutite dust, Campbell reported ait increase in Lite number of lung tumors in mice exposed to iron oxide over that of tlie control series. When the available evidence ig 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 purl on the intracellular deposition of iron, such considerations may not necessarily he applicable to pulmonary siderosis and cancer. However, thorough and comprehensive epi demiological data on the incidence of lung cancer in workers cx|*ood to iron dust are not available. Hence, a definite conclusion on this problem must bewithhcld. The availability of conclusive information on ibis point appears to be urgent, in view of the suggestive evidence recorded by Faulds and because of the fact tliut damages have boon allowed in the past by court action in at least one cose 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. BXBTLL1UM Beryllium is a metal which lias found signifi cant industrial use only since about 1620. It was not until about 1040 that beryllium and its compounds were extensively employed for numerous purpose and producu (berylliumcopper, beryllium-aluminum, and berylliumnickel alloys, glass, phosphors in fluorescent. lamps and neon tubes, atomic energy producu, ceramics, refractories, X-ruy tube windows, vitreous enamel, radio tubes, textile fibers, go* mantles). It is evidently for this reason tlmi 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 lost decade. These inaiiifesl.utions were of both acute and chronic nature ufar as the respiratory organs were concerned (acute beryllium pneumonitis, chronic pneumoeoniolic 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 effluonts (Eiscnbud, Bcrgbout and Steadman; Eiscnbud, Wanta, Dustan, Stead man, Harris, and Wolf). Similur 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 brokou fluorescent tubes. The skin of the fingers anil hands was the most frequent cxlrapulmonury location of ihusc reactions. Beryllium granulomas have also been found in the nose and in the anterior ocular structure. It is noteworthy that beryllium apparently onec inhaled is retained over a long period of time in the human body, since beryllium lm* boon detected in the urine up to 10 years after cessation of exposure (Klemperer, Martin, and Von Riper) and has been demonstrated in tinlungs of ruts 1 year after the inhalutiou uf beryllium oxide (Dutra, Largeni, Clioluk. Hubbard and Roth) at well os in their bone* (Stokingnr, Steadman and Root; Barnes;, where it may replace calcium. The skeleton retains tho bulk of the beryllium in the body (60-80 jicrcont) if the inhaled aerosols are soluble compounds, such os beryllium sulfate and beryllium fluoride; tho lungs retain the bulk of beryllium if the compounds arc in soluble, such as beryllium oxide. Experiment- 30 Eavimnienlsi Ciums of Cwecr of liie Luna g.i- of Aldridge, liurnea, uud Duuz, moreover, iiuve shown that beryllium ions react rapidly with certain tissue proteins and form complexes with plasma proteins when introduced into the 1 1. These complexos protect the beryllium fu.,n being preei]iitute<l by phosphate ions. The metabolic peculiarities of beryllium com pounds obtain special importance in view of the fuel (hat Gardner in 194G reported die produc tion of osteogenic suruoinus in rabbits injected intravenously with insoluble beryllium-contain ing |>owders (beryllium phosphate, zinc beryl lium silicutu). Other investigators subse quently confirmed those results with the some and other beryllium compounds (beryllium oxide, beryllium silicate, metallic beryllium) introduced into rabbits by tho intravenous or respiratory routes (Sissons; Barnes, Denz and Sissons; Hooglund, Grier and Hood; Nash; Dutra, Largeul, and Roth; Barnes). The preparatory period fur the sarcomas was 11-24 mouths. Commenting on the successful production of osteogenic sarcomas in rabbits after inhalation of beryllium oxide, Dutra, Largent, and Roth noted tiie fact also that the bones of persons dying with berylliosis contained not inconsider able umounts of beryllium. They came to the folflftring conclusions: "During the last 20 year*, considerable numbers of persons have be-- exposed to dusts of poorly soluble comI ds of beryllium in various industries throughout the United States. Despite the fact that casus of cancer of this type have not boon reported, it is possible that the inhalation of ]>oorly soluble compounds of beryllium may evontuate in osteogenic sarcoma in man. Pre sumably, tho incubation period of such tumors would be considerably longer in man than in rabbits, uud observations inuy be required over a period of yoars before it will bo known whether persons who have been exposed to boryllium are prone to have such tumors.'' Barnard also suggested that osteogenic sar coma from compounds of beryllium "might Ijossibly be another industrial hazard." So far, only rabbits have responded with the developraent of ostoogonic sarcomas following the administration of boryllium compounds. Tho direct introduction of powdered beryllium metal into tiio fomoral cavity of rats, into the pleural cavity, and into the paranasal tinuses failed to elicit a single neoplastic response at the site of injection in any 1 of the 85 animals usod within an observation period of 2 yoars (Hueper). When in 1048 Hueper proposed that the sarcoid pulmonury manifestations of berylliosis might be followed by outright malignant lotions in the lungs, this suggestion was roccivod with u 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, inliolod dust of soluble and insoluble beryllium compounds (Vorwald), however, makes the appearance of such dclayod malignant soquelao in man a distinct possibility, ospocially as soveral cases with coexisting berylliosis and cancer of the lung have recently boon observed (Kahlau). In view of the established occupational as well ss general environmental occurrence of human berylliosis, it may bo pointed out that the dis covery and identification of this pnoumoconiotis was definitely facilitated by the distinctive and definitive histological features of the dis ease. If those 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 bo considered as responses to the action of boryl lium itself and not as the result of the associated anions of its acidic salts (Slokingcr, 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 eifoct exerted by beryllium on the liver leading to the develop ment of cirrhosis and to on impairment of the metabolic and detoxicating function of this organ (Aldridge, Barnes, and Denz; Hooglund, Grier, and Hood). Organic Chemicals COMBUSTION AND DISTILLATION MODUCW Or COAL The apparent innocuousncss of ooal and, possibly, graphite dust ss respiratory carcin ogens is not shored by the incomplete combus tion, distillation, and hydrogonation products Public Health Moootrmph No. M, 1955 _ SI of coul (pitch, tur, soot, orcoeoLu oils, uiilhrucuiii' oils, tar oils, and highly viscous oily and tarry fractions obtained by the direct hydrogenation of coal employed by the Borgius process). The carcinogenic action of these oombustion and distillation products of coal on man and experi mental animals has been established beyond any doubt. Although the bulk of the cusuistic and epidemiological human evidence of occupa tional coal tar and pitch cancers has conic from England and Germany, it cannot justly be assumed that American-made ooal 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 teem to differ from those found for their European colleagues, nor arc the carcinogonie effects on the skin of those workors at vsriunce 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 ease manufacture, gas works, coke oven operations, road construc tion and repair work, roofing, brickmaking, foundries, furnace attendance, railway engine <lriving, 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 hydrogonation of coal through the Bergius process have been shown to be highly carcinogenic to tlio skin and/or subcutaneous tissue of mice and rats, respectively, certain types of workers manu facturing and using such products and inhaling fumes or mists of thoso carcinogenic potrolcum and tar oil substitutes may iiavo a spocial lung cancer hazard. Manufacturing plants using the Bergius process have been operativo for some 20 years in Germany and lutvo recently been constructed by several industrial concerns in the United States. Not only the environmental, but also to a greater degree, too occupational inhalation of dust, toot, and fumes produced by the incom plete combustion^ of coal results in the develop ment of a "soot lung,'' called bituminosis, 32 which u> chunictcmcd by the deposition of finely dispersed carbon particles contaminated with hydrocarbons normally contamcd in coul tar in the interstitial lung tissue. Roent genological changes may appear in the lungs after many yoare of exposure to high concen trations of soot in tbo air inhaled. While the pulmonary dc)>osilion 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, mossivo storage of soot particles in the lung tissues may finally be associated with an increase of the interstitial connective tissue and with paeudoglandular formations of peribronchial alveoli. The human evidence relating exposure to ooal tar and pitch dust and fumes with an increased lirbiiity to cancer of the lung is not extensive sr 1 is in part controversial. The human evidoncc relating exposuro to coul tar dust and fumes with an increased liability to cancer of tlio lung is equivocal. Konnaway and Konnaway stated that "coal tor in the atmosphere, whether derived from roods, domes tic chimneys, or any othor aourcc, does not cause an exceptionally high incidence of cancer of the lung." A similar statement was made by Hugounenq and by Husted and Biilmann in regard to the liability to cancer of the lung for workers employod 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 3 deaths from lung cancer among 64 deaths from all causes. Menz recently reported thot of 93 workors in Swiss gas plants who diod during the 1926--1G period, 21, or 22.G |>ercont. diod 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 oxposod to the inhalation of tar fumes were made by Koelach (blacksmith, tar worker;, Bodanackor (briquette factory worker), and Mullschitzky (tar worker). In an analysis of lung cancer deaths among members of different occupational groups for the years 1933-38 Konnaway and Kennaway, on Eiviroamenul Cmw of Gucer of the Lung DUP 1142052 liii' iilhir liiutil, null'd I lull HU uImivi--uvemgi' (iOO) lung cancer frequency existed for the following occupations: guahomte workers, 129; pas stokers, 2S4; pas predneers, 202; gasworks "one operators, 138; posworks superintendents, .0; primers, 119; chimney swoops, 119; asphalt workers, 1G4; metal polishers, 174; puinieis, 129; tanners, 141; street cleaners, 109; and uutomoblic drivers, 149. They rocordod, moreover, a ninefold increase of lung cancer among employees of a Canadian pas plant. Additional supporting information was pro vided by the observations made among Japanese generator gas oven workers omployod in stool plants and among gashouse retort workors in Couodu and England (Kawalutta; Kurodu and Kawnliata; Cruickshank; Doll). The Japanese investigators found, within u 0-ycar period, 21 cases of lung cancer among generator oven workers who were exposed to the inhalation of hot tar fumes when stoking coal. An excessive lung cancer rate was absent among workers employed in other ports of the steel jnills. The general incidence of lung cancer among the generator gas workers was 5 per 1,000 workers employed. Seven of these 21 lung cancers occurred in workers agod 40 years or younger (33 percent against 18 percent in cryptogenetic lung cancers) (Hueper). The exposure time varied from 9 years to 23 years, the average ing 16.6 years. Similar observations wore . ,-cH'Utly 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 tax' workers. Following a visit to a tar distillery where some 25 skin cancers and more than 80 pitch warts had been observed among the 300 workers during on 8-ycar period, there waa found 1 case of lung cancer. Subsequent inquiriea niado by coinpauy officials brought the number of lung cancers in this and other tar operations to 6 cases of cancer of the lung. From the ovidenoo available, it appears that the inhalation of tor fumes sustained by workers of certain operations (coko oven, generator gas plants, gas plants, tor distillorios) eoom to liavo au cM-iivsive hubiliU to cancer of the respiratory tract. It is not unlikely tliat a more thorough und competent analysis of the death records of o tl iot worker groups, wliicli have so fur boon found to luck such tendencies, might extend the types and numlicr of tar and pitch workers having an abnormally high respiratory cancer rate. A recent observation of lung cancer in a worker exposed to licatod pitch and asphalt points to another source of occupational pulmonary tar cancer of definite practical importance (Patch). FBTSOLKUM, S1ULB OIL, BBS KiTUBLL OSS The carcinogenicity of corlain liigh boiling fractions of petroleum and oil shale, as wall as of the combustion products of some of those petroleum derivatives, such as oil shale and natural gus, liavo definitely boon demonstrated not only on experimental animals but also on workers developing cancers of the skin after prolonged contact with those agonts. Known carcinogenic chomicals, moreover, have been isolated from these petroleum derivatives as well as their combustion products (Berenblum and Schoental; Fischer, Priestley, Eby, Waalees and Rehner; Falk, Steiner, Goldfein, Brealow and Hykcs; Waller; Rohncr; Kotin and as sociates.) In addition to skin contact with carcinogenic petroleum derivatives many workers are also oxposod 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 snd shale oils, there arc on record only three cases of off pneumonia among such workors, 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 tlio basis of a raodicinal minorul oil pneumonia have been dcecribod (Wood; Santo). The occupational evidence avuilablo or pub lished on this aspect of cancer of the lung is rather scanty and in part controversial. Konnaway and Konnaway found a relatively high PaWk Health llwiypt No. It, 1955 55 *** -; fj; miiMilaMiniiir ---------- ratio of laryngeal bul no) of pulmonary cancer in mulcspinncrs, who inhaic a mist of the carcinogenic ahalo oil lubricating the spindles. Southern noted that mulcspimiers occsaionally develop multiple primary conccrB involving the stomach or the lung in addition to cancers of the skin. Scott, on the oilier hand, stated that he hud nol_ol>scrvod a single ease of lung cancer among sliulc oil workers. Huguenin, Fauvel and Bourdin, who ana lyzed s~scrics of 112 lung cancers for possible etiological factors, found that 18, or lf> percent, were metallurgical workers exposed to the inhalation of nebulized lubricating ami 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 exposal to vaporized or nebulized lubricating oil. While the study of Gufufor and Siign-uves on cancer morbidity and mortality among the mule employees of un 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 lx1 revised, at least for certain ly]x>s of refinery workers, according to more recent and scrutinizing observations, lidsch observed throe primary cancers (skin, stomach and lung) in a paraffin worker. Tourainc and Bour also attributed Uic^development of pulmonary cancer among certain worker groups to lubri cating oil mists. Such e.\]>osurc conditions may aecouul also for the excessive lung cancer mortality among male metal grinders observed by Turner ami Grace. There is, moreover, some evidence available indicating that the inhalation of mists or fogs of certain processed petroleum oil fractions also conveys an incivuscd 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 bul that incidence of cancer of the. lung was uiso exclusive. Paraffin pressors, who represent about one-tenth of the total employed worker group, furnished 5G percent of the lung cancer observed. Since soot us a waste or commercial product bus been found to be carcinogenic ami to couUm known carcinogenic hydrocarbons, a thorough and competent survey of occupational groups particularly exposed to the inhalation of soot (operating railroad personnel; stokers; carbon block 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 uu urgent ncc<isily. The negative conclusions reached by Ingalls os the result of a survey of llio carbon block industry urc hosed on evidence of dubious merits, because only 70 of the G77 evaluated workers have been employed for 10 years or more in the industry. Since the major ity of known occupational lung cancers have au avenge latent period of over 10 yeur-., Ingalls' conclusions are actually based on 70 living and active workers. It stunds to reason that an analysis of the death records of former carbon black workers inuy liuve told u diirerent lory, especially if the diagnoses were based on autopsy findings. Such investigations would also add to our knowledge us 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 |xiwer plants, oil refineries, steel plants, met ill smelters, carbon black factories, oil dumps and smudge pots, as well us exposure to the diluents of diesel and gasoline engines, represents the most widespread occupational and cnviroumcmul contact witli carcinogenic material. The specific carcinogenic agents con tained in these carbonaceous matters arc certain iqxt-ifie aromatic hydrocarbons, which not in frequently ure ultaelied to carbon particles giv ing rise, when inlinled, to bituminosis or untliraoosis; or they art1 constituents of oily matter which, when inhaled and retained in the lungs, cause oil pnoumoniu or puruffinomu of the lung. Since pure anlbracotis is not causally related to cancer of the lung, llic pneumoconioses ac companying respiratory carcinogenesis bv aro matic hydrocarbons do not play a primary and essential role in this process, although the pneumoeonioses may lower the intensity and Faili--rnUl Cause* af Cancer of the Lunc DUP I 142054 prolong the duration of the died. of the specific carcinogenic chemicals on iho lung tissues. Since our civilization and economic life has been built around the production and use of the ie carbonaceous substances and their drrivit- .. .cs, it does not seem feasible to attain com plete protection against exposure to these carcinogenic chemicals with the preventive in id prophylactic engineering and sanitary measures pruetieul and economical at the present time. There is, however, no doubt that a great deal remains lo lie done in this n-s|ss'l and that we are still rather far removed from having the muxiinul amount of possible reduction in ex)>o- sure to the respiratory cancer producing hydro carbons contained in the various carbonaceous substances mentioned. -- Carbon and tiilicon Colymtrt Keeenl studies of English investigators (Hen dry, llomer, Rose, and Walpole; Hendry, Rose, and Walpole; Haddow) have furnished a new and intriguing concept as to possible combinations of carcinogens with tissue proteins llirough the jKisLuluteil formation of cross linkages between certain types of carcinogenic chemicals and the macromoleculai^ fibers of chromosomes. This hypothesis was evolved f"om evidence obtained in the study of careino.esis by nilrogcii-iniisUinl*, ilie|>oxi(lcs, |>oly- eihyleneimines, und reluted compounds, in view of the fact tliut one of Lite various means by 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 mucoprotcins of dtromosomsl origin, by cross linkage witli inulLijximt 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 earciitogeiMwis for several reasons. Since Oppeuhoiiuor and associates; Druckroy and associates; and Zollinger have shown that a parenteral implantation of various jralyinerizod plastics (cellophane, polyethylene, polyvinyl chloride, polymeiityl methacrylate, polyamide, Teflon, and others) into rats and mice are followed by the develop ment of sarcomas at the site of deposition, there exists the possibility that the inhalation of vujtors, mists, and dusts of the monomers and polymers of these and related chemieais for occupational reasons may create a respiratory cancer, hazard to mail. The more immediate importance of liicsu concepts, however, lios in their application to the production of occupational respiratory can cers by a silicon polymer, asbestos, possibly also by a curlsm polymer contained in isopropyl oil (polypropylene or propyl opoxido). Tho probability of such an action mechanism, more over, is supported by observations of lung cancers among Japanese mustard gas manu facturers. ASBOTOS 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 pnoumoconiosis produced by it. In contrast to tiic tridimen sional polymerized silica crystals in which no oxygen uloms are left carrying charges to attract positive ions, asbestos consists of giant fibrous molecules composed of poiymorizod silico-oxygen tetruhydrs which are arranged in chains or hands (l'urkes). Depending on the origin of asbestos, the fibrils may l>o 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 asliestos is hydrated magnesium silicate, which contains small amounts of iron oxido (5.75 per cent). Canada furnishes about 75 percent of tho world production of asbestos. Canadian asbestos, because of its long fibers, is especially suilablo for textiles. Dopomling 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 arc exposed to asbestos dust. It is asserted that inhaled asbestos dust pro- Pmkiie H--1th No. M, 19SS 35 lluccb U*l>C*lO*io only if UlU illhuh'd libel1* UIY sufficiently long. In tho absence of fibrous trueLure, Ibe dust is said to be inert (Wyors; Vorwnld, Durkun, and J'rutt). Since the larger fibrils arc arrested in the bronchioles (Gardner), the granulomatous reactions form peribronchiolar fibrous cuffs with giuni cells and anbeslos bodies. These liave a fibrillar core and an iron staining proteinic or colloidal silicic, ucid should. Whether the iron in the heaths originates from the asbestos fibers or is derived front blood or tissue elements is still controversial. These two observations de serve special mention because of tbo apparent dependence of cancerous changes in tbo lungs of asbestos workers upon tbo presence of ssbostosis and in viow of the possibility that tho proteins of the lung tissue may specifically interreact with free grou|>s of the filamentary asbestos molecules (Druckrcy and associates). The coexistence of ashestoais with cancer of the lung was first reported by Lynch and Smith in 1931) (1 caso). They later recorded 3 addi tional cases (Lynch and Smith; Lynch). Simi lar observations have subsequently been re corded from this country (Stoll, Boss, and Angrist, 1 case; Holleb and Angrisl, 2 cases; and Homburger, 3 cases); from Canada (Dosmeulcs, Rosscau, Gilroux, and Sirois, 2 eases; Cartier, 4 cases; Rousseau, 1 case); from Eng land (Gloyne, 17 coses; Harrison, 3 cases; Merewether, 3] eases; Cureton, 1 esse; Owen, 1 ease), and from Germany (Nordmanu, 2 cases; Linzbach and WcdJcr, 1 case; Horning, 1 ease; Wolz, 2 eases; B6hmc, 1 cose; Domcnici, 2 coses; and Baadcr, 1 ease). .Thus, there is at pruaent a total of 80 eases of asbestotis cancer of the lung on record. To tins numlmr must perilops he added tho 8 cases of cancer of the lung complicated by ashestosis which Kennaway and Kennawny discovered in an analysis of the death certificates of males registered betwoen 1921 and 1938. Eleven additional cases of asbestotis cancer of the lung in workers in two English plants wore recently reported by Doll, who felt from his statistical analysis tiiat thoro exists a definite causal rela tion between those two conditions (table 25). Merewether noted tiiat the moan age of moles with aabeatoais cancer of the lung wes 55.2 years (rango 22-72) and that their mean expo- sure tune was 20.1 years (range 0-40), while the mean age of female eases was 44.6 years (range 32-71) and their mean exposure lime was 7.C years (range 0.5-48). However, in many cases there clapsod a long exposure-free interval rang ing from several months to 20 years before the lung cancer became manifest (Wcdler; Wyors,. The age distribution of asbestusis cancer of the lung was: Am (fun) ( asrt u! Immv tnur 25-34........................................................................... 2 35-44........................................................................... il 46-54........................................................................... 65-64........................................................................... 1C IT 65-76........................................................................... 5 Toul................................................................ 51 Since lung cancer of unknown etiology occurs rather frequently before tho age of 40 and since 26 percent of the ssbc*tosis cancers appeared before the age of 44, it seems that there exists a moderate shift toward youugor ago groups for cancers associated with asbestotis of the lung. The exposure time for osbeetosis lung c&nccr, excluding the series of Merewether, was: Cm ef Ewpmuittf* if--rt) m%crr I- 3............................................................................. 4 4-10.............................................................. 6 II- 20........................................................................ 4 21 sod over......... ....................... 7 Total............................................................... 21 Tho exposure time of this series covers a wide range (1-23 years), indicating that type and intounity of exposure to asbestos as well os perhaps an individual auaceptibility to asbeeto sis play an important role in determining the development of this pneumoconiosis and thereby tho possibility of a secondary carcinomatous sequoia in tho lung. There woro 37 males and 15 females among the 52 cases for which information on sex was available. Tho male: fomalo ratio is thus 2.5:1, which represents s marked ahift toward the female aide when compared with the usual sex ratio of 5:1 to 10:1 for lung cancers of unknown oliology. Equalization of carcino genic exposure os represented by ashestosis, for tbo two sexes, thus resulted in s trend toward equalization of liability to lung cancer. It is of importance to note that the mean 36 Environwtl Cause* of Caacer of the Lun{ 'aid'' 2.1. (jtiiMi'K of <l*u(li iiulr aKlonitiw wtHirrn iimi|niml with Iiif morlmII y ri|N*rH iia' uf all mi'll iii Kiigliuiti ami Walaa (Uull) Cauxc of (loath N umber of deaths Number observed KxfXxU'd on | England and Wales rales Test of significance of dilTercnoc bolwiun olwervod and expected (value of P.; Hinn cancer 1------- ... . ------- .____ Xher respiratory diseases * and cardiovascular rlismtftr-- Mt'illi mention of asbestosis___________ _____ ____________ . _ TWiUiout mention of ................... ......... r;......... Neoplasms, other than lung esnoer....................... ............. ...1 til other diacaaea *.................................................... _............. ...1 All Muses_____________ __________________ ...! u 14 fi 4 4 3u Uh 7. 0 } 2.3 4. 7 } 15.4 <t 000001 <a ooi >0. 1 <a oooooi 1 Including 1 eaae with pulmonary- tuberculous. * Including pulmonary tuberculosis. __ * Including 2 caaoa (benign stricture of esophagus and septicaemia) in which asbestosis vu present but wai ot thought to have been a oontributory eauae of death. ge of 128 noncomplicated cases of asbestosis /as only 44.2 years (Mcrcwcthcr). One may onchulc from this observation that some of boao individuals apparently died from ssbesosis before tlicir lung cancer had a chance to evelop (Linzbach and Wedler). Additional support for a causal relation etween aabestosis and cancer of the lung is crivcd from the fact that Mcrowcthcr found, mong 26C cases of aabestosis observed during 924-46, 31 cases of coexisting cancer of the mg (11.65 percent), while there were 91 cases f b - cancer with an average age of 59.4 cm .nong 6,884 cases of silicosis (1.32 per mit) which came to autopsy. Wodlcr noted hat aabestosis cancer of the lung occurred in 4 cases, or 15.2 percent of 92 cases of asbostoais n which necropsies were performed, whereas Ue normal rate of lung cancer in autopsy tateri&l was estimated to be 2-6 percent. Jianza, Vorwald, Warren, and Cartier arc all uitc skeptical as to the actual existence of n excessive liability of individuals with sbeetosis to lung cancer, and Cureton and lomburgor arc undocidod on this question, illicr investigators, however, favor this conopt or considor the existence of a causal oialiou as highly probable or established Konnuway; Morowetbor; Toleky; Nordmann; lueper; Gross; iioooour; Smith; Saita; WegoEn; in/.bach and Wixller; Stoll, Baaa, and Angrist; /olx; Doll). The histological types of lung cancers ob served do not deviate essentially in their rclativo frequency from llioao soon 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 tiiat one of the Norwegian cases of nickel cancer of the lung was associated with pulmonary sarcoidosis, it may be mentioned that Skavlcm and RittcrhofT reported the combination of an asbestosis with a sarcoidosis of the lung which, however, wss not compli cated by a carcinoma. Attempts have been made to refute the claim of a causal relation bclwouu 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 bow many workers employed in the industry develop lung cancer, sinco an undetermined portion of these workers doubtlessly sustains either no ex|H>Huro or only a low intensity exposure and thus does not develop aabestosis of the lung, which is tiio prerequisite for tho subsequent cancerous development. Asbestosis must be considered as tho eMontial stigma of an effective exposure. It is, moreover, nocesaary to know the sex and ago distribution of Uio workor population studiod and evaluated as well as to know the duration of employment and exposure. A markod labor turnover in the industry is not inducivo for obtaining reliable information on ahlie Health Hoaofrcpfa No. SC, 1955 57 DUP 1 M2057 Llie uctual number of lung cuiicits unit ukIhs-- losis coses which may result from effective exposures. For these reasons, no definite conclusions cotijbp drawn from the observation of Cartier, noting 8 cast's of lung cancer among 4,000 workers studied for 10 years, especially as tiic frequency of asbestosis among effectively ex I nrus I workers increases with the duration of cx|)osurc (Bohmo). Kennaway and Kcunawuy reported that 8 lung cancers may he found--among T,000 males of the age range 45-04 yeurs. ___ The evidence on hand, at any rate, has con* vinccd the Weat Gorman Government to mako ssbcstosii cancer of the lung a compen sable disease (Tabcrahaw). The experimental approach to the problem has so far given equivocal results. Vorwald and Karr, using guinea pigs which were exposod to asbestos dust, obtained negative rueults. Nordmann and Sorgo omployod 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. on.___ isofsoptl Through the recent discovery of cancers of the paranasal sinuses, larynx, and lung among isopropanol manufacturers, the occurrence of carbonpolymcr cancers has probably been c.\oxtended to man. Isopropyl oil--the crude liquid from which isopropyl alcohol is distilled and which is S~ilighUy 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 propyleno c|>oxidc having a tendonev to polymerize. Polypropylene, merchandised as Opi>onol K, is used commercially as an oil for cable filling. ~ Worker* omployod in isopropanol manufac ture have been expoeod to tho inhalation of vapors, mist, and dust of isopropyl oil escaping from loaky pipe oounoctious, defective pumps, and gaakets, or spillod on the floor at tho occur rence of breaks in pipelines and during repairs on pipes, pumps, and stills. Weil, Smyth, and Nalo reported that, botwocn 1928 and 1050, a total of 7 neoplasms affecting various parts of tin' respiratory tract (iiiu-ji] sinuses, 4; larynx, 2; and lung 1) came to observation among 71 employees, or in 8.4 percent of those who worked more than 5 years in the isopropanol plant. Five additional coses were observed in another isopropyl alcohol plum, making u total of 12 cuses, 7 of w'liich involved the nasal sinuses, 4 the larynx, and 1 the lung. It wus calculated that the incidence rate of cancer of tiic nasal sinuses and larynx for the second group was 134.5 per 100,000, against a normal rate of G.3, and that the incidence of these can cer* exceodod tho expected incidence 21.3 times. From the evidence available it is likely that those cancer* as well as those associated with asbestosis belong to tho new class of "polymer cancers." kostzeo exi Tlie 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; Hunermann; Reiche). Residuals of warfare gaasing were noted by Matz in 10 out of 138 cases of pulmonary cancer among American World War I veterans. Four out of 64 cases of lung cancer, recorded by Brockbank, were gassed badly during this war. Mocklin noted that war gus poisoning occurred in 5 percent of 164 cases of lung cancer among moles, while it was present in only 2 percent of soldiers without this disease. Koelsch con ceded that a few cases of lung cancer exhibited a doubtful etiological relation to war gas injury, which was claimed to have caused also two cancers of the larynx (Spamor; Tilley). No distinction wus made at that time as to the particular chemical naturo of the various gases used during World War I. *- These contentions found little acceptance at that tim<. From a carcinogenic viewpoint, special interest has to be attached to the various arsonic-oontaining gases, especially Jjowisilc, and to mustard gas (dichlorethyl sulfide). The arsenical war gases, when inhaled, theoretically may not only cause nonspecific chemical damage to tho respiratory tissues but also may produce there a specific delayed carcinogenic reaction, U EaTiromratil Comet of Coaeer of the Lung -.m il ut> that aeon exceptional!,) ufU-i' akin burns willi these gases. Cancers of such an origin belong to the group of arsenic cancers. A possible carcinogenic action of mustard 'us upon the bronchial mucosa, on the other .mini, may be related to its cross-linking and rudtoinimciic eirect, and may be identical with llml ilrnionslrnlcd In exist for experimental animals exposed to several sulfur^and nitro- muslards of aliphuLic and oromutic nature. According to the mentioned theoretical con cepts, the causativc morTTanism operative in those cancers resembles in some respects that jHjssibly active in polymer cancers. During the last few years, liiroe eases of bronchiogcnic carcinoma and 3 eases of larynx cancer were observed among long-term em ployees of the Japanese Army Poison Gas Manufacturing Plant on Okuno Island, where Lewisite and Yperite were mude. One of these workers was 30 years old and a second, 53 years old. All three suffered from chronic war gus jKiisoning due to contact with mustard gas (Yamada, Hiro6c, and Mivanishi). In view of these observations, the distinct probability of carcinomatous effects upon the lung following exposure to mustard gus or chemically related products deserves serious consideration. While the fundamental concept of_"polymer cancers'' is a tentative one and needs to be iip|>orlcd by additional evidence, the available data arc suflicionlly important to require serious attention from l>olh a scientific and, a practical viewpoint. The rapidly 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 pari 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. -- Uadiouetwe Chemical* Up to some 10 years sgo, occupational expo sure to radioactive agents wss limited to rela tively small groups of industrial sad profes sional workers (miners and refiners of radio active ores, industrial and medical consumers of ruduiucUvc substances go- man lie 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, tlio number und variety of individuals who have occupational contact with radioactive mutter have rapidly and greatly incroagod (uranium and thorium ore miners, smelter and refinery workers, atomic energy plant employees, mili tary personnel, and agricultural, biological, medical, chemical, molaliurgic, oil, pharma ceutical, and other industrial research workers employing radioactive isotopes, as well ss operators handling directly or indirectly ma terials or teclinical devices giving off ionizing radiation, such os ndiosetive static eliminators (Silson; Berman and Ernest; Bryan and Silverman), sewage disposal workers, paper and textile manufacturers, and so on. It is an established fact that cancers of the skin, connective tissue, and bone and bloodforming organs Lave resulted from excessive exposures to radioactive substances affecting the organism or parts of it by various routes. There exists a groat deal of highly suggoetivc, 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 occupt tional exposure to ionizing radiulion (radium, X-radiation) alone may produce in man and experimental animals a fibrosis of the lungs (Kolbfioisch; Doeneckc; Belt; Bergmnnn and Graham; En gelstad; Warren and Gatos; Leach, Farrow, Foote and Wawro; McIntosh; Warren and Spencer; Widmuuu; Buuor; Buuor and Scliracr; Tfinges and Kalofloisch; Freid and Goldberg), occupational exposure to radiouctivu dust and gases has often been complicated by simul taneous inhalation of dust containing various motals (chromium, nickel, iron, arsenic, cobalt) as well us silica. Pulmonary cancers observed among radiouctive-ore miners, therefore, have boon complicated in an appreciable number of eauu* by silicosis of a minor to modorato dograo. It is for these reasons that the radioactive genesis of the cancer* of the lung noted among these miners os well as among uranium and PaUic Health Moaocnph No. 36, 1955 39 ruiJiuin refinery workeis liu been doubled by tami' investigators, who felt that one of the various nonrodioactivc mo Luis or the silicosis represented the^ main causal or an important contributory agent (Schinz; Ixirenz; Selunorl; Rostoski and Saupe) or that the uvuilahie evi dence did not provide absolute proof of a radio active genesis Several investi gators felt that the lung cancers among the radioactive-ore miners hi Schneclicrg and Jo- achimsthol were principally attributable to a hereditary predis|x>sition created by inbrooding of the mining population (Mocklin and Mueklin; Lorenz; Vosin). The "mala metaliorum'' causing death at an oarly age of the miners in the oro mountains of Saxony was first described by Agricola during the early part of the lOlii century and was sub sequently mentioned by other invoatigutore (Ilcnckel; Schcfller; Tliiele). Howovor, it was not until 1879^tliat its malignant neoplastic ciiaracter was correctly recognized (Hurting and Hesse). This judgment was, subsequently confirmed by Cohnheim; Aucke; Arnstein; Uhlig; Risel; Scbmorl; Beyreuther; Rostoski, Saupe and Schmorl; I^ange; Ncitzcl; Ddhncrt; Bonder; Teleky; Hucck; Rostoski, Saupe, and Schmorl; Thiele; Weber; Koeiscli; Linde- mann; Doubrov; Brandt; Brczina, Although the miners of the uranium ore mines in Jo- achimstiuil (Czechoslovakia) also wore suffering from a fatal lung disease similar to that obeervod among the cobalt ore minors in Schnccbcrg, Saxony, it was not until 192G that the cancerous nature of the pulmonary disease among thoso miners was recognized (Ldwy). Additional confirming evidence was provided later by Bcutcl and Waldrich; Zicl; Sikl; Saupe; Poller; Pircban and Sikl; Boeder; Bcbounck and Port; 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 employoos of radium refinorios and radium laboratories. L6wy reported the occurrence of twojuch cusos among the workers employed in the laboratories of the Joochimslliol mines, whore the ores arc refined and the puri fied material is lusted. One of the oases had chronic rmdiodennatitis, loukemia, and lung cancer. A similar observation wus recorded by Tuicky and by Ncitzcl m u German technician of a radium laboratory. The car.rorous lung was found to be radioactive. Four cases of lung cancer have recently been observed, according to Baadcr, among the workers employed in the 1 radium oro processing plant in Belgium, where the occurrence of such complications was pre viously said tobo absont (Muisin, citing Deloeu. Perhaps the development of a bilateral alveolar carcinoma of the lung in a woman 1G years after the intravenous injection of 75 cc. ofThorotrast may also supply suggestive evidence tlmi lung cancers may originate from radioactive material used modicinally, whon such materials become arrested in the lung. Mention may also be modo in Uus connection of a report of Martland relating tho occurrence of cancer in tho etlunoid colls in a luminous dial painter, and of two additional cases rejmrUxi by Aub, Evans, Hompclmumi, and Martland. Dial painters not only ingested radioactive material which bocamo deposited in tho bones and produced osteogenic sarcomas, but they also inhaled this matter which, thus, may have produced the carcinoma of the paranasal sinus. Tho four cases of cancer of tho lung recently reported in an industrial population at an atomic pile site, however, are definitely not causally related to any specific radioactive ex posures sustained by tho workers ooncernod. In those cases oxposurc and latent poriod were insufficiently long to cause lung cancer (Love). On tho other hand, the argument that theso workors wore, in part, not directly concerned with radioactive material carries little weight. Doubtlessly, they had at times environ mental contact with such a material when the metoorologic conditions were unfavorable for tlio ready dispersal of radioactive wastes at this particular operation. In favor of an occupational and radioactive origin of the lung canoort among the Schneeberg and Joacbimsthal minors is, moreover, tho fact that tho excessive liability to pulmonary neo plasia is limited to Lite workors employed under ground and is absent among tbc workers omployod aboveground, and among tho popula tion at largo of Schnooborg and Joaciiimsthal, including the employees of the cobalt pigment plontuaingtheSchnoebcrgoros(Bauer; Sdunorl). 40 Eniw--ill! Csbms ot Cancer of the Lane An excessive lung cancer attack rale, kino, bus not been found among the miners of the nearby Johann Goorgensladt region, where jthe mines have a low radioactivity. There is, further- v, no valid evidence on rooord that miners ^rscnic-, chromium-, nickel-, and_ bismuth- containing ores are affected by lung cancers at n rate even remotely approaching Unit hooii umong Liie two radioactive ore miner groups. The attack rate of lung cancer ulfTong Uxc Jichnooberg miners has consistently been be tween 75 and 80 permit since 1879, while that of Lho Joacltiiiislhul miners has boen stated to range from 40 to 50 percent. However, this incidence rate may be too low. considering the recent statement of Boodcr, who notod that during the period 1939--43, a total of 180 coses of lung cancer were acknowledged as compen sable diseases and that in 1929 there were only 323 miners employed at Joachimsthol. Consid ering the fact that the exposure and latent period of lung cancer in Joachimsthol 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 Sehneeberg is stated to vary from 15 to 18 years for the majority of the coses, but occasion ally to bo as short as 7 years (Baadcr; Rajewsky, ' aub, and Kahlou) -- , he total number of Sehneeberg miners who tied 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 (1926-43). 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 youngor age groups. Measurements of the radioactivity'of the Sehneeberg and Joochimsthal 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 (Joncbimsthal 30 times (Fdler); Bchounck; Buhounok and Fort; Tschubiitx; Ludowig and Loreuser; Lange; Rajewsky; Stocklasa). It was suggested that the recant introduction of pneumatic drills into these mining opera- tioim aggravated the hazard by increasing the production of fine particulate dust containing solid radium. Repented attempts have been made to pro duce cancers of the respiratory tract in experi mental animals exposed to tho inhalation of radium emanation and/or radioactive mine dust (Hdiiiiiduimnn; Ikiwy; Cumpbcl'; Dolmen; Kolilau; Rajewsky, Schraub, and Kohiau). Schmidlmuiin obtained neither pneumoconiosis nor pulmonary cancer in animals exposed for 2 years to the inhalation of Schnoelx'rg mine dust collected from drill holes. Campbell, on the other hand, reported that mice which inlialod dust of Czechoslovak pitchblende displayed a significantly incrcasod number of pulmonary tumors. In experiments of Dfilincrt snd of Hueck, mice were placed in cages within the mines. Some mice dovolopod modorate chalicosis, while pulmonary and mediastinal tumors (adenomas, round cell sarcomas), in addition to an occasional squamous cell metaplasia of tiic alveolar epithelium, wore 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 thoir significance was therefore difficult. Kohiau and Rajewsky, Schraub, and Kolilau subjected mice to tho 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 tho control scries). While they concluded from this evidence that the radioactive origin of lung cancers in Sehneeberg and Joachimsthol miners wss confirmed, it seems to be advisable to con sider tho evidence obtainod by these investi gators as highly suggestive, hut not conclusive, because great variations in the incidence rate of lung tumors occur among different groups of mice belonging to noninbrod strains. Additional, mildly suggestive observations have been reported by Lorenz, Heston, Eschcnbrenner, and Doringor os well as by Heuahaw, Riley, and Stapleton. Both groups of investi gators found tliat mice ex|>osod to ionizing whole body radiation rovoaied, in addition to leukemia and ovarian tumors, some increase in the number of pulmonary neoplasms. Of Pmfciie Hssllh Monograph No. 36, 1955 41 greater significance m tins connection arc the findings of Lisco and Finkcl, who found mctaplasiic and neoplastic proliferations of the bronchial epithelium in rats inhaling an aerosol of radioactive cerium. Similur results were obtained with plutonium brought into the lungs of rats. Since uranium ore miners inhale not only radon and radium dust hut also uranium, which may be retained in the lungs, Hueper, Zuelle, Link, and Johnson injoctod metallic uranium powder dispersed in lanolin into the plcurul and femoral cavities of rats and obtained aurcomua at tiie sites of injoctiou in 13, or 24 percent, of llie 54 rats surviving Uic minimal latent period of 6 months. Evidence thus producod allows that focal accumulations of uranium, which is an ulplia-radialion emitter, may exert a~ c&ncerigonic action upon the surrounding tissues, but it does not discriminate between the influence of metal toxicity per sc 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 (Mortland; Evans). In commenting on the production of lung cancer by atmospheric carcinogens, an editorial CLancet, 1052) remarked, "radioactivity of Joachimstbal mints is stated to be 30 tunes the tolerance dose. It is scarcely surprising, there fore, that in the pusl more than half the miners diod of lung cancer." It stands to reason that this effect on the lungs of workers will prevail wherever similar conditions of exposure to radioactive gooes and dust exist. The excessive suicide rate observed in the post among the miners in Joachimsthal (Sikl) aptly reflects the human misery produced if such hazardous working conditions arc 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 rodioactivo ore miners and similarly exposed occupational groups, some comments on the possible signi ficance of pneumoconiosis in eliciting or modi fying this effectjuy bo indicated. Koports on the occurrence of pneumoconiosis among the minors in Schnocbcrg and Joachimsthal are contradictory. While Schmorl us well as Rostoski, Saupo, and Schmorl in their early reports (1920, 1928) noted that Selmeeberg miners suffer from more or less intense antiiraooailicosis and that this condition was causing or favoring the development of the bronchia! cancers, Rostoski and Suupc stated in JO.jQ iliai pneumoconiosis was usually not very extensive in cancerous lungs. Because of the relatively alow course of the pulmonary tumors. Rostoski and Saupc foit that pneumoconiosis may slow the intrapulmonary growth of the minors. Huock, on the other hand, remarked that silicosis docs lint represent a precancerous eondilion for the Scimoebcrg lung cancers, dome of Iho miners had silicosis but not lung cancer, while other* had lung cancer but not silicosis. Similar discrepancies seem to prevail con cerning tho Joachimsthal miners. Zicl in 1935 reported that markod silicosis among these miners is quite froquont and that ashed lungs contain large amounts of silicon oxide, l'irchan and Sikl, on the other hand, maintained that no pneumoconiosis could he found, in spite of an abundance of pneumatic drilling, and that pneumoconiosis has no role in the production of the lung cancers. This opinion was shared by l.ibwy. Sikl, in his most roccnt communication on tho subject, stated that some degree of fibrosis suggestive of silicotic origin could, of course, be seen in the cancerous lungs, and there were single casts of marked silicosis combined with cancer. On the whole, however, silicosis wus not u prominent feature in cases of cancer; on tlic other hand, tlio lungs most heavily affected with siheofibrosis were generally free from malignant growth. Bchounck and Fort noted that pneumoconiosis was rccordod as tho 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 Saupc during a cliost X-ray study of 398 Joaeliimstlial miners conducted in 1939. He found that 43.4 percent of those miners proscnuxl roentgenological evidence of pulmonary silicosis. However, ilicosis was of minor dogroo among the 7 miners who were suspected of having pul monary nooplasms. Although the data arc in port contradictory, it seems that silicosis does not play any sig nificant role as a diroct or contributory cause of cancer of the lung among the radioactive- 42 Eariroumul Giuw Cancer of the Lung OUP 1142062 ore miners in Sclun-cbi-rg and Joachmisthal. Whether it lias an antagonistic effect upon tbe canccrizutiorf process or modifies lire course of tbe established cancer remains problematical. '' ully. it may be mentioned lluit these lung ca s van- a great deal in liistological^ struc ture. Many were squamous cell carcinomas; otln-i-s. round cell or imupliistic cmvifiomus; wiiile a few were of adenocarcinomatout, type. The rodiouctivr lung cancers, thus, follow in this respect the general pattern set by all other occupational cancers. The rapidly growing production and use of radioactive mutcriui and the thereby condi tioned, markedly increased exposure of some lhuited worker groups as well os tbe general population to gases, dusts, and mists containing radioactive matter of long half-life doubtlessly rcpivsoiiLs a ]>oicniial respiratory cancer hazard of serious proportions. The attack rate of lung cancer from such sources is very liigh, according to past experience with miners of radioactive ores. Therefore, a competent assessment of the degree of exposure to atmospheric radio active contaminants for worker groups^ and neighborhood populations of radioactive plants and operations, and tile continuous and strict supervision concerning the amounts of radio active effluents emitted from such establish ments, are urgently necessary for safeguarding tli altli of these individuals. Tm14c 16. Latent iwriwlj uf ciivinmmciilul rai{Hnitary esneerm, in months (Hueper) Agent Cancer of -- Lung I j N'sres and , nasal sutures lAvcrugc: ItuiiK'- -Average' House latent loflatent: latent ioflatent : |>eriod | period j |ierio<l , period 18 C 'jirum* _____ .-.-t IS Nickel 22 Tsr fumes 1C Isopropyl oil_______ Ionising radiation__ 25-36 1 l.WR 1 5-47 L 0-30 ! 9-23 i. 1 7-50 j , ____ 11 11 3-26 io ; 6-16 25 | 19-32 Intensive studios also arc needed for deter mining whether, through radioactive fallouts, tho inhalation of liighly radioactive dust par ticles diffusely settling in the brouchiol inuousu and producing there minute foci of high inten sity radiation may olicit deluyod cancerous reactions. Since radiation cancers, like other occupational cancers, have a long latent or induction period (table 26), it is essential that all possible prucuutions bo 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 rcspinilory carcinomas and carcinogens leave no doubt of the fact that not only large occii|>utiomil population groups but also the general population have definite and prolonged contacts with one or several of those 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 lias 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, usbostos, and cliromatos, has not yet been attained, the epidemiological evi dence based on un evaluation of cancer inci dence of relatively small, occupationally cir cumscribed total populations at risk is suffi ciently reliable to prove the presence of on occupational respiratory cancer hazard causally PaUic Smith Monograph No. K, 1955 43 DUP 1142063 ruiuU-d Ui u sjiecilic industrial olH;rut.ioii. JCpidemiological, modicai, and experimental data concerning those respiratory cureinogens attest their high carcinogenic potency tinder occupa tional conditions, particularly when ucling on humans. It is therefore reasonable to mwiune that inhalation of the same agents, in a mitigahnl form us air pollutants, l>y the. general population is responsible for a considerable |M>rtion of the lung cancers attributable to kiicIi contacts. If this colierent iuuI logical picture preHcated by the evidence supporting the various occupa tional respiratory cancers anti, osjieciully, the coal tar fume cancer of the lung, is comparod with tliat available for the ciguretU smoke lung cancer, oven upon superficial examination, several additional serious defects and inconsis tencies not previously pointed out booomc apparent. ~ It is surprising to note the ubsenco of positive statistical associations between lung cancer untl cigarette cough, although this latter symptom is clinically characteristic of uiironic ebuin smokers. Despite the fact that the lips and oral mucosa arc constantly bathed in the tuny liquor oozing from the tip of the cigarettes and despite the contuct of these parts with the smoke coming'from the cigarettes, there is no consistent statistical association with cancer of these parts. Thu assertion tliat no tarry material exudes from the cigarette tip is ln'lied by the evident fact tliat chronic cigurctte smokers are observed to liuvc brown-stained Angers. 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 niunerous 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 beluivior between coal tar and cigarette tar, Lickint ruoortod to the speculative assumption tliat cigarette tar poeseases a special tissue specificity so that the akin of the first throe, fingers, although impregnated with cigarette tar, is "immune'' to its corcinogunic action. It also would bo medically unsound to con clude upon a sort of racially conditioned tissue immunity for explaining the observation of hipschtu, who reported m 1931 tliat the uutopv records of a large Jewish hospital in Warsaw, Poland, sliowed a lung cancer frequency of 8.9 percent of all cancers for Jews against a fre quency of 15.3 percent for non-Jews, especially in view of the fact tliat Kasteni Jews arc par ticularly prone to develop thromboangiitis oblitenniH, which has the lest established causul relations to tobacco smoking. The churned uImcucc of u |xisitivc as&ocu.l ion between lung cancer and the habit of inhaling cigarette smoke also is inconsistent with the rule tliat the incidence rate of occupational cunconi incrousos with the intensity of exposure to a carcinogen. The modicai considerations on cigurctte smoke cancer of the lung thus reveal a number of serious and fundamental dofocts and contradictions. The boat that can be said about the cx|>crimentul ovidcnce on hand regarding carcinogenic properties of tobacco tar is tliat it indicates the carcinogenic agents in somo cigarette tars llirough the use of hyperreactive animals. There is no evidence tliat those observations of the skin of u strain of selectively inbred mica have uny oquivalont in man. Thus the prac tical im|>ortuncc of those observations as to cuuecr of the human lung is at present uncer tain, especially since Passey, in recent experi ments on mice painted for 16 montiis with tobacco tar, was unable to olicit a single cancer of the skin. From lltuso considerations, it is apparent that any final decision concerning the relative role of cigurottc smoking in the causation of cuuccr of tho human lung should be kept in abeyance until a great deal of additional and more valid, and (specially medically conclusive, evidence becomes available. The data on hand make it uulikuty that cigarette smoking repre sents a major factor in the production of-iung cancer and iu its roccut phenomenal rise iu frequency. For those reasons, it would be most injudicious mainly to base tho future preventive control of lung cancer hazards on a theory of such doubtful scientific merits and to concen trate the immediate cpidumiologicul and experi mental afforts on this apparently ovorpropaguudized concept. Tho apparent wisdom of aucli an attitudo is readily apparent from the fact tliat not only a groat deal of the circum- EavirauMBial Csasss of Caacar of tho Lane kluiiiiul epidemiological evidence Liu l also practically tiie entire factual and conclusive evidence uvudablc on specific exogenuous causes of respiratory cancers indicates that those ca 5 urc either of occupational origin or |)Oi, ... to iiulustry-rcjutod factors. Not only large occupational groups but also the members of I lie general imputation liuve eonlnel with these agents in various forms and intensity. Finally, it may be noted that tin- evidence on liand justifies the viewpoint tliat, in arriving at a judgment (liuuder; Liekint) 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 llml |kwmiIiIv provided by a cigarette smoking history. fsUic Health Monograph No. U, Bibliography Adler, I.: Primary malignant growths of tin.' lungs and bronchi. Longmans, Green & Co.. 1012, p. 30. London. Aldridge, W., Barnes, J., and Deux, K. A.: Kx|K:riincului beryllium poisoning. Brit. J. Kxper. Pathl. 30: 375380 (1!M0). " Alwens, W.: Per Chromatlungcnkrebs. Proc.. 8th Internal. Kongr. t. Unfallmcd. u. Berufskrankh., Budapest, 1038. Lcipxig, Georg Thieme, 1030, p. 973-982. Alwens, W., Baukc, E. K., and Jonas, W.: AufTallciidc Hiufung roe Broncbialkrebs bei Arbeitern der ehcmischcn loduKtric. Arch. f. Gcwerbcpath. 7: CO84 (1936). 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(Published concurrently with Public Health Jieporu 69: (3); see pages 321-322 for summary article.} No. 20. Gamma globulin in the prophylaxis of poliomyelitis. Report of the National Committee for the Evaluation of Gamma Globulin in the Prophylaxis of Poliomyelitis. (Public Health Service Publi. cation No. 358) 1954. 178 page*. Illustrated. $1.25. (Publiabed concurrently with Public Health Repotu 69: (5); see pages 519-520 summary.] No. 21. Why some sanitsry engineers leave the Held. Irwin M. Rosenstock and Arthur P. Miller. (Pubbc Health Service Publication No. 359) 1954. 16 pages. Illustrated. 20 cents. [Published concurrently with Public Health Reporu 69: (9); sec pages 865-866 for summary article.] No. 22. The Dcthesda-Ballcrup group of parucolon bacilli. Mary G. West and Philip R. Edwards. (Public Health Service Publication No. 362) 1954. 35 pages. 30 cents. [Published concurrently with Public Health Reporu 69: (10); see pages 1012-1013 for summary.] No. 23. Biological factors m the transmission of American arthropod-borne virus encephalitides. Frederick F. Ferguson. (Pubbc Healtl Service Publication No. 372) 1954. 37 pages. 30 cents. [Publiahed concurrently with Public Health Reporu 69: (11); see pages 1095-1096 for summary.] No. 24. Appraiaing the clinical resources in small hospitals. Faye G. Abdellab and Eugene Levine. (Pubbc Health Service Publication No. 389) 1954. 39 pagea. 30 cents. [Published concurrently with Public Health Reporu 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. (Pubbc Health Service Publication No. 390) 1955. 96 pagea. Illustrated. 50 cents. [Published concurrently with Public Health Reporu 70: (1); see pages 81-82 for summary.] No. 26. A history of plague in the United Slates. Vernon B. Link. (Pubbc Health Service Fubhcation No. 392) 1955. 120 pages. Illustrated. 60 cents. (Published concurrently with Public Health Reporu 70: (3); see pages 335-336 for summary article.] No. 27. Hoof rut |Kipuialiuu in koultlMcsl Georgtu. Dean 11. Leku. il'ublic Health Service Publication No. 373) 1955. 18 page*. Illustrated. 20 cent*. [Published concurrently with Public Health Reports 70: (4); see pages 413-414 for summary.] No. 28. Tularemia in sheep and in sheep industry workers. William L. Jettison 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 aix 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); tee page 857 for summary.] No. 31. Illness and mortality among infants in the first year of life. Selwyn D. Collins, Katharine S. Trantham, and J :aephine L. Lehmann. (Public Health Service Publication No. 449) 1955. 20 pages. Illustrated. 15 cents. [Published concurrently with Public Health Reports 70: (10); see page 1028 for summary.] No. 32. Disposition of first admissions to a State mental hospital. Morton Kramer, llyman Goldstein, Robert H. Israel, and Nelson A. Johnson. (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. II. F. Scboof. (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 bousing laws. Ralph J. Johnson and Roy O. McCaldin. (Public Health Service Publication No. 451) 1955. 34 pages. Illustrated. 30 cents. [Published concurrently with Public Heulth Reports 70: (12); see page* 12471248 for summary.] No. 35. A study of selected borne care programs. Alice M. Waterhouse, Eleanor C. Bailey, Jeanne T. Palmer, and Mary C. Gillit. (Public Health Service Publication No. 447) 1955. 128 pages. 65 cent*. [Publiahed concurrently with Public Health Reports 70: (12); tee page* 1249-1250 for summary.] No. 36. A quest into the environmental causes of cancer of the lung. W. C. llueper. (Public Health Service Publication No. 452) 1955. 54 pages. Illustrated. 45 cents. [Published concurrently with Public Health Reports 71: (1); tee interpretive article. I. IttfUHIT HIITIM Until llll