Document jgKK4kqzYQZOORr17EpZpp2qN

I >t h ;. i c 11 !: \ i rsi M; n i< mm! N',.. W wm V PLAINTIFF'S ! EXHIBIT J A Quest Into The Environmental Causes Of Cancer Of the Lung U: -''-7'int DaiUs .U;.U Uirnrj t\ S. DEPARTMENT <>r IIEAI.T1L EDl'CATIOW and WELFARE US* Public Health Service Public Health Monographs edited and issued by Public Health Reports G. .Sr j pt.KRorr Chief. !)::: : .n Pud.'i-- .Uana^i'i^ l)\reii.,r Mr March's Rosknblim Executive Editor TaftS Pumas Managing Edit r \nh \ I' M-.".' gr-ick Edit'-r BOARD OF EDITORS Edward G. McGwraN. M l) . M P EL. Chairman Chapei Hid Gay loro \V. Anderson. M l) . Dr.P H. Minneapolis Margaret G. Arnstein. R.N.. M.P H. Washington H. Trendley Df.an. D.D.S. Chicane Halbert L. Duns, M.D., Ph.,1). Washington Martha M. Eliot, M.D., Sc.D. Washington Harou> M. Ericksoh, M.D.. M.P.H. f~f " Portland, Oreg. !.F;.>k:o. M I) . Dk.P.H. l)e '.:er \ mimiv G.'MacKeszik It ashmgton Victor H. Haas. M.l>. Retkesda Basil C. MacLean. M.D.. M.P.H. \ete York City Seward E. Miller, M.D. Washington I.eo \V\ Simmons, Ph.DSeze Haven, Conn. U. S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Marion B. Folsom, Secretary PUBLIC HEALTH SERVICE Leonard A. ScheelE, Surgeon Genera! r t A Quest Into the Environmental Causes Of Cancer of the Lung \\ . C. Hueper, M.D. 36Public Health Monograph No. 11 1} The Author I Dr, Hueper is head of the Environmental Cancer Section of the ' Motional Cancer Institute, Public Health Service, chairman of the i Cancer Prevention Committee of the International Union Against i Cancer, and a past president of the American Society for the Study : of Arteriosclerosis. , In his 30 years of clinical, research, and teaching experience, \ Dr. Hueper has become well known both in Europe and in the ; United States as an authority on environmental cancer and an \ arteriosclerosis. He is the author of more than 200 publications in \ these and related fields, including the book "Occupational Tumors and Allied Diseases," published in 19/t2. '** Public Health Service Publication No. 452 (Issued concurrently with the January 1956 issue of Publio Health Reports, Vol. 71, No. 1) Library of Congress Catalog Card No. 55-60064 - Received for publication April 1955 UNITED STATES GOVERNMENT PRINTING OFFICE, WASHINGTON, D. C., 1955 For sale by the Superintendent of Documents, U. S. Government Printing Office Washington 25, D. C. - Price 45 cents ('ontents lilt ri >< {u < t inn .. (irneral cpidetuioloyical cottsiiIn-11 em> . Occupational evidence and r< piralory carcinogen- Kpidemiological data on large indnst rial groups . ()rrupat<mal respiratory cancers and o.-irrmoyms Scope of environmental limy rancor hazards . . Pattern ainl tv pas of respiratory cancer hazard" Occupational respiratory cancer- . Physicochemical state of atmospheric carcinogen- and topograph ical distribut ion of cancers in I In1 respiratory i ra<-t . Specific carcinogens . . ... Inorganic chemicals Nickel _. Chromium Arsenic. Iron .... Beryllium.. Organic chemicals............ ........... .. - ................. 'Combustion and distillation products of coal . Petroleum, shale oil. and natural gas .. . Carbon and silicon polymers . . Asbestos.. Isopropyl oil.. ... . Mustard gas............ ..... Radioactive chemicals. -i.................. - - Comments and conclusions.... ----------- ------------ -- Bibliography------------------- ----------------------- ---------------------- inkc*j**-...' - ifAsy.'. Introduction To be '.h-mitirally acceptable. an\ ihrorv on the etiologv of lumr cancer mu<t reHcrt a critical. balanced. and competent analysis of tin* antin' epidemiological. medical. and ex perimental evidence concerning the typns and environmental distribution of and con tacts with all known or suspected exogenous agents incriminated in respiratory rareioogenesis for rm iroillnflitid. o<T:||)a! HHiai. "I' !!lcdir;i| |V;i-o!,-. It is on I \ i ii rough -^ucti -cm I in v that 'igmlican t and worthwhile mformation mav he ohtaan'd as to tin- relative role which the various indi vidual respiratory carcinogens have played and are playing in the production of lung cancel-. The following facts and observai ions form an im port ant ami integral part of -au-h an assessment. General Epidemiological Consideration* A real, definite, and progressive increase m the frequency of lung cancer started in most industrialized countries around the turn of the century (tables 1-3F that is. at a time when cigarette smoking was still a habit of minor sig nificance [ Probst: Berblinger; Grosze. Kahlau: Fischer: Liekimh '{'his rise was first clearly recognized by pathologists of Central Europe during the early 1920`s through a study of necropsy data collected during the first two decades of the 20th century and was subse quently confirmed and elaborated upon by biostatisticai investigations from America and Europe winch mainly used cancer mortality data (fig. 1). Published records indicate that this develop ment revealed marked variations in the time of onset of lung cancer, in its relative degree of severity, and UK-ita-progression rate for different localities and^untries. In Germany, for in stance, an iiusease in the incidence of lung cancer was 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 cancers in Saxony against 6.0 percent in the rest of Germany. In Denmark, accord ing to Clemmesen, a rise in lung cancer fre quency was still doubtful during the first three decades of the 20th century and only became definite efter i'KiO. Similar observations a> to ;t late appearance of tins increase were made in Italy. There -t ill exist striking differences in tiie lung cancer morialitv rale- of different, countries and different regions of the same country dig. 2u In England, for instance. 2$ percent of all cancers in unties involve ihc lung: the corresponding figure for N'orwav is less titan t> percent. Similar discrepancies exist for lung cancer morbiditv rates for different metropolitan areas in the Gutted States as well as for their relative progression rates (table 4). Another example of the existence of striking regio. =1 variations in lung cancer frequency is presented by the remarkable differences in lung cancer mortality rates between urban-industrialized areas and rural districts. This lias been demonstrated for England and Wales and for the Cnited States, where lung cancer death rates were found to be consistently higher in urban areas than in rural areas (tables o-7, figs. 3 and 4). Such observations have been made in Ohio, New York, and Connecticut (Manctiso. McFar land, and Porterfield: Levin. Kraus, Goldberg, ami Gerhardt) and were reported from England anti Wales by Stocks; Kennaway and Kennaway: Fulton; and Philipps. Storks reported the comparative mortality ratios for males in Public Health Monograph No. 36, 195$ 1  *. -r.. - Table 1. Frequency rates of lung cancers in autopsy material (Probst) * I-ung cancers Per'od Number of Total Absolute 1 r autopsies carcinomas No. Percent : Percent of all ' of all cases i autopsies . . 1852-76 : 1854-85 1 Wolf............................... ............. ______ _________ 1877-84 | Passler........................................ ........... ............... 1 1881-94 ! Wolf............................................ ........................... ; 1885-94 : ... i 1885-97 i Marchesani............................ _______ _______| 1887-96 5 - 1889-99 : Feilchenfeid............................ ........................... 1895-1900: Riechelmann............................ ....................... 1895-1901; Sehrt................................ ........... ................ 1899-1903: Marchesani............................. .. _____ _______. 1886-1906; 8. 716 12, 307 4, 172 .. 9. 246 : 7, 228 !.. 1, 946 L. 5, 022 1 7, 790 ! 1. 741 : 3,337 .. 1852-1900 j 870 i ; sit j 711 ! 159 ! ; 8 . 9 L. 16 31 .. 9 4 .. 10 ... 22 ; 27 1 3> 6 1. 83 1. 27 4. 3 3. 8 1. 88 0. 057 . 065 .21 . 17 . 428 . 10 . 26 . 07 . 24 . 39 . 17 . 18 1900-1925 Redlich........... ............. ............................ Karrenstein.............. .................... ............... Probst........................ ............................ Briese............ .............. ........................... Bejach................................................................ Bejach.............................................................. Rau........... .................. ............. ..................... Berblinger.......................................................... Materna........................ ............................ Probst.............................................................. Materna ................................................ Breckwoldt................. ............... _.......... Ran..................................................................... Berblinger....................................................... Probst................................................ ................ Materna......................................... ............ ..... Berblinger __ ______ ___ Matema ____________ Breckwolrit T38'-?-:... Prnhst. 1900-05 1900-06 1900-07 1900-11 1900-11 1904_0g 1906-10 1907-13 1898-1916 1908-13 1909-12 1906-16 1909-14 1910-14 1912-14 1912-14 1911-15 1914-18 1912-22 1915-17 1914-19 1915-19 1915-19 1916-20 1918-20 1912-23 1916-22 1915-23 1920-21 1919-23 1920-24 1921-23 1920-25 1921-25 1924 2, 002 10, 272 496 934 2, 739 12. 971 6, 808 5, 801 4, 754 4. 816 2, 347 866 3, 448 715 265 1,287 692 586 552 363 48 218 389 1,667 6, 083 5, 518 3, 280 4,989 1,609 3, 336 2, 429 1,049 6, 359 3, 697 749 70 554 530 337 392 94 755 8, 301 287 75 -- 892502 31 32 90 12 20 3 60 33 29 6 15 8' 1 11 13 5 21 27 10 24 5 146 10 38 458 24 6 26 36 6. 3 5. 1 a 42 a8 ai 2. 79 1. 13 6 88 4. 51 4. 8 4. 95 a7 2.2 a os 1. 5 . 67 .31 . 37 ........... .*11 .9 .46 . 45 .5 . 13 . 31 . 34 . 11 a 34 11.23 7. 14 3.7 4.3 a9 6 12 5 31 58 49 54 & 75 8.3 50 a7 7. 17 4. 9 .38 1. 01 . 19 .35 .36 .49 .30 . 59 .31 . 58 .3 . 99 .57 .39 .97 2 Environmental Cim of Cancer of dw LU| 104'>-4h. ;in hi alii witii iifvi;iiioiis from (he i';i 11' '<'t at i 00. as follows: uvenmv 'll'"'::)- .s' i. i j;; > t ::; whh ..wr '.'DO ooo i:nn'i ali i rail"-, for iuug '';iih'it m< >M a h' v of selected -ire> a'tiotu: while males 04 leais of ag'o m uriuia and rurtii enimiie< wotv: 1.11! :t ii > :. lai.-r ll.tm. W -- r ll:im. ('rm lion . . Birmingham. Sini'ttiu irk. \Va!>all. HY-u Bromw ich.... . .. ... M.iiu'ii'"it*r. Salford. Srockport................... Liverpool. Itooilc. Birkenhead. \\ allasey... Leeds. Bradford. Halifax............................. .. I .Vi lot 15'.) 102 132 ' < 'Me i).- 7 . Kurai 7:i . . The standard mortality ratio is < )l>served deaths ,E,xpected. d, eath, s . mo. .. . n on. >i Sheffield. with 12 LOGO occupied dwelling.'. ... \ewca-tle and (iatcshead. with X7.0UI) occupied 135 The type of county is dclincd. according to degree of urbanization, as follows: Metropoli dwelling............. 1U tan county containing cities with popula Aggregate of 6 towns. cadi with 50.000 to S5.0OO occupied dwellings................ .. . ......................... Aggregate of 3 towns, each with 10.000 to 50.000 occupied duvlliues............ .... ... ...................... Aggregate of 12 towns, each with 30,000 to 40.000 occupied dwellings..................................... Aggregate of 13 towns, each with 20.000 to 30.000 occupied dwellings- - . ........................... Aggregate of 20 towns, each with less than 20.000 occupied dwellings. ..................................... tions of 100.000 or more (01 percent urban); Lid urban -containing cities with 19.">() populations 107 of 50.000-100.000 (00.2 percent urban): rural containing communities with 1950 populations 101 below .">(),()00 (41.4 percent urban). (.'nrweti, Ivetmaway. and Kctmaway only I no recently recorded fresh evidence supporting SO earlier observalions. The new evidence indi cated the existence of positive correlations In Ohio, for the years 1947-oi (Matuutso, between population density in England and McFarlane, and Porterfield), the standardized Wales and mortality from cancer of tho lungs Tahle 2. Frequency rates of lung cancers in autopsy material of t.erman patholotrieal institutes, 1906-52 1 Author Citv Period t'ereent age of tuug cancers among all cancers Male Female Fischer-Wasels......... Frankfurt.............................. . ............... Simross.............. . Goettingen............................ Schairer ami Schoe- Jena............. ........ .......... ................. ..................... niger. . Peters......................... Berlin............................... ... ... ____ Koch........................... Dusseldorf.................. . .................. .. ............. ........ Buschbek.................. Dresden.......... ........................ ....................... Dormanns................. Germany............................. ... ......................... Simross.................... .. Goettingen..... ........................ ..................... Peters......................... Berlin........ .............................. _____________ Gerbe......................... Zwickau.,............................... ......................... Koch................ .......... Duesseldorf.......................... ......................... Weber and Knotts^,. Frankfurt................................ . _____ _____ Schairer and SchSB*-' Jena........................... . . .......... .. . .. nger, J: Fischer-5V asels. 227-- Frankfurt................................ Koch______ ___ ___ _ Duesseldorf............................. ... . . ..................... Knorr................... .. Leipzig........ ................... Emminger and Ein- Bavaria........................... . . . .. fait. Koch........................... Duesseldorf... . ............... Fischer......................... Jena............... Koch______ _________ Duesseldorf. _ Weber and Knoll___ Frankfurt___ Kahlau......................... Germany____ 1906 1906-12 1910-14 1913-17 1920-23 1924-27 1924-31 1925-33 1927-31 1927-31 1928-31 1931-40 1932 1932-39 1938 1942-45 194.5-48 1945-48 1946-47 1940--18 1948 1951 1952 2. 59 2. 2 1. C. 0. 1)7 6. 2 ........................................... 3. 61 ......................................... 12.9 ........................................... 19. 79 ................-..................... 13.0 ......................................... 9. 83 ....................... - ............... 15. 4 ! .................. ....... .......... 13.0 ,...... .................................... 12. 28 A........................................ 13.9 ' ............................ -.......... 12. 0 1......................... ................. 12.94 2.38 21. 86 ... ................................ 13.0 ............................................ .............. : 21.4 . 4.8 26. 23 i______ -- '..................... 13.0 ........... ;..................... 35. 53 i..................-....................... 28. 6 : ..... ............. - - - _____ .' 23. 4 5. 4 1 From Kahlau. Public Health Monograph No. 36, 1955 3 Fiiruri* 1. Lorn paraU'v ircnil.- in r<->fnrutir> <'acrr moetaiitv. I i 1 1 4 f i , < of males and females and cancer of the larynx of males, hut not of females. This relation is even apparent when comparing relative lung cancer death rates in the United States and England with the relative population density in these countries. Whereas, in the United States, with a population of 45 persons per square mile, 1 lung cancer death occurs per 6,600 inhabitants, in England these figures stand at 755 persons per square mile and 1 cancer death per 3,500 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 as the observations made in Ohio and in England and Wales. Such an interpretation is suggested Table 3. Lung cancer rates in necropsy material of various German institutes of pathology for the period 1895-1925 Period ; Total cancers j ,i Lung cancers Percent of lung cancers among all cancers Range Average 1895-1905.............................. 1906-15................................... 1916-25_____ _____________ _____________ {?:!?5}10-276 15,431 2sl}398 { 832 5. 2 / 1. 9-6. 2 } 1. 9-6. 2 l 2. 1-5. 0 3. 0-7. 0 Figure 2. Age-adjusted death rates for respiratory cancer per 100,000 white males in the United States, 1950. (Lew) Under 17 17-20 21-24 25 6 Over Public Health Monograph No. 36, 1955 348108--55------- 2 1 Table k Incidence of respiratory cancer, morbidity rates per 100,000 population for 0 metropolitan centers bv sex, 1937 and 1947 Morbiriit c rate' Primarv site and cirv ' 1937 Male Females 1947 Percent increase 1937 1947 Percent increase 1937 Total 1947 Percent increase Bronchus and lung: Atlanta.................... .. New Orleans... . ... Dallas______ _____ ... Birmingham............ .. Denver................. ..A ^an Francisco. .... . ... Chicago____ ...... ... Pittsburgh................ ... Detroit..... ............... ... Larynx: ' Atlanta.................... ... New Orleans............ ...: Dallas......................... .. Birmingham............. ..A Denver................ .... SaQ Francisco. _... ...: Chicago............. Pittsburgh................. Detroit....... ............... -- j o. 0 13. 1 5. 9 4. 5 9.1 15. 6 13.3 9. 7 1 12. 6 . 1.4 11.3 3.2 1.4 2.0 4.5 6. 7 ; 4.4! 3. 5 ; 13. 4 39. 1 29. 0 18. 9 21. 9 34. 3 29. 5 26. 1 32. 0 4. 0 14. 9 5. 3 4. 0 4. 1 8. 8 : 7. 0 ; 8. 0 ' 6. 4 168 198 392 320 141 120 122 169 154 : 186 32 66 186 105 ' 96 4 82 ! 83 j !. 0 2. 8 .5 2. 1 4. 2 3. 9 4. 3 4. 9 2. 3 .3 .4 1. 5 .0 . 0> .4 ! .4 4 i 5. 0 400 4. 2 50 6. 4 1. 180 3. 9 86 8. 1 93 8. 1 108 7. 0 63 o. o 12 5. 7 148 ' 0. 3 i. 0 .4 1. 3 .0 .8 1 .6 .8 .3 ! 150 73 300 50 : 100 -25 : 2. 9 7. 6 3. 1 3. 3 6. 6 9. 8 8. 8 7. 3 7. 6 .9 5. 6 2. 3 .7 .9 2. 4 3. 5 2. 4 2. 0 8. 9 20. 8 17. 2 U. 0 14. 8 20. 8 18. 0 15. 6 19. 0 2. 0 7. 6 2. 7 2. 6 2. 0 4. 6 3. 7 : 4. 4 : 3. 4 ! 207 174 455 233 124 112 105 114 150 122 36 17 271 122 92 6 83 70 * i i by the fact that the white male inhabitants also had. aa abnormally high skin cancer death rate (Patno). This is in agreement with the general experience demonstrating the dual role played by many occupational carcinogens, such as arsenicals, coal tar, petroleum derivatives, and radioactive substances in the production of both cutaneous and respiratory cancers. An additional expression of this urban-rural pattern of lung cancer rates is contained in the recent report of Lew, who found that these rates were 30 to 50 percent higher among indus trial policyholders of the Metropolitan Life Insurance Company than among males holding general policies.: Lew found, on the other hand, that such, tees did not exist for female holders ktypesof policies. He pointed out th policyholders represent, for the m 'urban wage earners and their families lower-income brackets and include a high proportion of men engaged in manufacturing, mechanical industries, mining, transportation, and personal service. In con trast, the general policyholders are drawn mostly from middle- and higher-income groups engaged in nonhazardous occupations. The apparent causal significance of these epidemiological findings has been demonstrated by several investigators. Appreciable amounts of 3,4-benzpyrene have been demonstrated by Waller and Cooper (R. L.) among the air pollut ants of English cities; by Kotin and associates in the particulate phase of these atmospheric constituents in Los Angeles, and in the exhaust fumes of gasoline and diesel engines (tables 8 and 9). It has been estimated from these figures by Blacklock, Kennaway, Lewis, and Urquhart that about 16 mg. of 3,4-benzpyrene Table 5. Cancer of lung and fauysi, England and Vales 1946-49 (Kennaway and Kennaway)- Type of community Lung can Larynx can cer ratio* cer ratio1 Males Fe males Males Fe males Greater London................ 100 100 100 County borough............... 129 137 125 Other urban districts____ 160 156 14$ Rural districts 233 185 170 Number of persons producing 1 death. 100 55 59 42 Environmental Cause* of Gaaeer of the Lang *W. - Table 6. Lung cancer death rates in 25 States of the United States, 1946 and 1948, crude death rates per 100,000 Figure 8. Cancer of the lung in males aged 25 years and over, England, 1921--30. Reproduced by per mission of the British Empire Cancer Campaign. State 1946 1948 Industrialized States Connecticut.................................. ____; Illinois........................-............... - ____ 8. 5 8. 1 11. 1 8, 2 Marvland.........................-.......... Massachusetts...........................- ____ Michigan. ................ ................... 10. 4 : 8. 4 10. 2 7. 1 New Hampshire....................... ____ 7. 4 . 10. 1 New Jersey................................. ____ 9. 7 9. 7 New York..................................... ____ 10. 2 11. 9 ; Ohio................................................ ____j 6. 0 : 7. 3 Pennsylvania......... ............... -- 8. 4 .7 : Rhode Island........................ .. ____ ! 8. 7 1 7. 4 4 i) 1 States with regional industrialization > i 1946 ; 194,8 t . 1 6. S 7. 4 - . . : 6. 5 8. 5 3 i) ' ____ ; 7. 3 ' 9. 4 10. 0 ; 8. 8 5. 7 ; 8. 0 Agricultural States Actual mortality percent of that apetted frathe <fcjtribubo of population byagemddassofdirtrfct t | 1946 I 1948 IMtrTO 7Q - 1$ - <0O- <>S - ISO-HSuo Alabama____________________ ............! 4. 0 ; 5. 1 - Arkansas................................ .. ............; 3. 6 ! 5. 4 Figure 4. Observed and expected lung cancer deaths New Mexico. _ ^....................... North Carolina_____________ ............1 North Dakota........................... 2.6; 3. 1 | 3. 0 4. 0 4. 1 in urban and rural Ohio, 1947-51. (T. F. Mancuso) Oregon...................................... ............ 4.1 ; 4. 4 South Carolina ____________ 3. 7 > Washington................................ ............1 5. 1 4. 2 , Wyoming................................... ............! 4. 9 I 3. 9 The death rates for the year 1046 were taken from ' "The American Cancer Society, Inc., 1949, Cancer Death Hates for each State in the United States by Site," those for the year 1948 were produced by the National Office of Vital Statistics. Table 7. mortality rates, per 1,000 deaths by MK&Ji*. Austria, 1954 (Herbich and Neubold) ------------------------ ------------------------- Community Total Males Fe males Vienna................................... : 32.7 59.0 7.8 Cities 60,000-1,000,000................. 18. 2 31. 6 Cities 20,000-60,000..................... 18. 4 32. 3 Remainder of Austria....; 10. 3 17. 3 5.0 3. 9 3. 7 Lung cancer deaths 8 counties Remainder of Ohio Observed 1,550 728 Expected 1,261 1,017 Public Health Monograph No. 36, 1955 Table 8. Estimated amount1 of aromatic hydro carbons in 1-minute samples of gasoline exhaust with varying engine revolution speeds (Kotin) Revolutions per minute Pyrene Com pound . Benz pyrene Benzpery- le.ne Anthanth- rene :>oo 1.000............. 1.500............. 2.000 2.500 3,000............. 3.500............. 225 439 507 374 346 121 . 48 ! 289 : 325 266 : 142 ; 127 25 i 5' 120 61 . 33 I 40 ! 25; i3 ; 10 i 235 177 , 60 ! 73 : 70 i 85 1 39 ! 153 102 36 27 31 14 15 1 Quantities are expressed in Mgra. at 0 load. may be inhaled and retained in the lungs from these sources during a lifetime and that this quantity represents approximately 40,000 times the dose (0.4 micrograms) capable of producing cancer in mice upon subcutaneous introduction. It should be emphasized in this connection that 3,4-benzpyrene is only one of the several car cinogenic chemicals isolated from atmospheric pollutants and that, therefore, the actual total amount of atmospheric carcinogens reaching the lung is considerably higher (Falk and Steiner; Kotin and associates). The benzpy rene content of the air was increased fourfold during smog days (Waller). It is difficult, if not impossible, to reconcile the obvious causal significance of this factual evidence with the claim that such regional, and especially urban-rural, differences in lung cancer frequency are totally accounted for by differ ences in the cigarette smoking habits of the two population groups or merely reflect local discrepancies in the diagnostic acumen of urban and rural physicians and in the availability of diagnostic medical facilities. Such explanations become even less tenable in view of the fact that the annual age-adjusted increase in frequency of lung cancer deaths was higher in 1914-30 than in 1931--44 (table 10), whereas the markedly increased cigarette con sumption during previous years should have boosted the annual progression rate above that seen during the earlier period. It has been sug gested (Lickint; Hammond) that this paradoxi cal behavior of progression rates is attributable to the fact that many cigarette smokers did not live long enough to develop a lung cancer because of their precocious death from coronary sclerosis, which also is assumed to be elicited in Table 10. Annual age-adjusted increase of fre quency of lung cancer mortality ! Percent increase Sex ii-- -- -- . --. | 1914-30> j 1931-40' j 1938-44' Males........................ ! Females................ _q 1 Dorn. 1 Potter. 10. 5 i 8. 0 '< 8. 5 j 2. 5 , 5. 8 2.0 Table 9. Estimated amount1 of aromatic hydrocarbon in 1-minute samples of diesel exhaust with varying load and engine revolution speed and with fuel-injection inefficiency (Kotin) Revolu tions per minute Load Condition Pyrene Compound X Bena- pyrene Bema- Antban- peryleae threne 1,000 1,200 .. v-v 0 Compression release..................... 4t i&r#- .....do............................................ ____ do.................................... IkrwsI- :____ d_.................................. ____ do..................................... M SHE'.v'O*1' ____ do-.................................. 1, 400 - )S y* _____do............................................. Y< 0 y* X _____ do........................ .................... y* y* __ .do............................................... 137 267 536 1,800 2, 50<ir 208 257 448 888 1,912 188 177 220 734 822 22 76 175 640 --639 0 o 278 488 614 0 56 76 337 346 146 465 772 1,320 876 9 47 437 432 1,706 80 78 1,372 982 1,687 22 42 124 610 1,265 79 40 171 930 976 0 0 368 1,071 944 0 43 223 472 469 4. 3 24 197 320 944 20 16 69 577 666 1 Quantities are expressed in *gm./min. 8 Environmental Causes of faarrr of the Lang. wwaw imi<fwamene the majority of eases by cigarette smoking, according to -natisticai evidence. Such an explanation conveniently disposes of an observation challenging the validity of the Table 11. Sex distribution of lung cancer in the United States and selected foreign countries, 1850-1953 Country Year Author Male* female ratio United States. Mexicans 1.. Norway........... Sweden............ Denmark..... Austria.......... Germanv....... France........... Canada Argentina____ England........... 1953 1951 1947 1950 1946 1951 1941 1951 1949 1941 1935 1953 1953 1925 1947 1931 1945 1953 1953 1850-1899 1900-1919 1920-1929 1930-1939 1940-1949 1952 1948 1947 1949 1949 Dorn........... . 5:1 Moore......... . 6. 6:1 Humphrevs... 7:1 Beeler et al... 11. 5:1 Lindskog....... 4. 5:1 Carlisle et al... 29:1 Halpert...... 14:1 McBurnev et 29:1 al. O'Keefe........ 20:1 Farberow and 13. 5:1 Baslow. Neelv..____ Steiner.. .. 1:1 1:0. 7 Kreyberg......... 4:1 .. .do.................. Henschen...... 1:1 2:1 Clemmesen... __do.............. Denk............ : Gros2e.......... ; ...dO_______ : __dO....... ...... : __ do........... . ...do............. : 5:4 3:1 15:1 6. 6:1 1. 8:1 3. 1:1 3.8:1 3. 8:1 ...do.................. 5. 4:1 Lemoine...........t 10:1 Gagnon: 8:1 Santas.............. ; 50:1 Mason ______ ; 10:1 Fulton..............1 7. 3:1 . 1i 1 Mexicans living in Los Angeles. cigarette theory and may perhaps inomentarilv satisfy the protagonists of this concept, although it cannot he taken seriously by anyone who has any competence in the study of arteriosclerosis (Hueper). It is remarkable, moreover, that after a considerable increase in king cancer frequency in Russia observed during the first decades of this century, this development seems to have come to a halt during recent years, according to Anfilogow (cited by Ihckint). Considering the recorded strikingly irregular epidemiological behavior of lung cancer in diff erent countries, states, provinces, communities, and population groups, it is obvious that this pattern scarcely corresponds with the pattern presented by the degree and spread of the cigarette smoking habit. If the action of en vironmental carcinogens other than those pos sibly contained in cigarette smoke should mainly account for the remarkable increase in lung cancer frequency and for the causation of a major portion of lung cancers, industrial and industry-related carcinogens would well fit this pattern since the growth of industrial establish ments and the use of their products in the economic life of different countries have greatly lacked uniformity in time, type and extent. This concept receives support from a crit ical evaluation of the data on the sex distri bution of lung cancers, the changes in the sex ratio during recent decades, and the probable reasons underlying at least a part of these phe nomena (tables 11 and 12). Considering the remarkable variations which the male-female ratio of lung cancers has shown at different Table 12. Male-female sex ratio of lung cancers in Germany, 188^1927 ml 1940-50 1886-1927 1940-50 City v Author Ratio City Author Wolf................................ Berlin......................... Do.......... ........... Do.. . Do . Koeln........... .............. Wahl................................ Bejach............................. Redlich ..................... Eichengruen and Essen. Bilz................................... 6. 7:1 5. 3:1 2. 5:1 2. 9:1 3. 7:1 2. 3:1 3. 6:1 5. 2:1 4. 7:1 1. 5:1 8.0:1 1. 8:1 __ Berlin.... ...................... Potsdam...................... _____do______________ Berg................................. Hollmann...................... Kautzscb.____________ Frey........................... Ratio 11*1 15*1 7:1 9:1 19:1 21:1 7:1 18:1 24:1 49:0 12:1 Public Health Monograph No. 36* 1955 9 'v J mm times. in iiiflVn-m localities, and in different demoiirapiur croups, it is most unlikely that such discrepancies and changes are attributable to fluctuations in the intensity of one single factor, such as cigarette smoking. Instead, they appear to he due to alterations in the type and extent of the action of a broad spectrum of en vironmental respiratory carcinogens affecting the members of the two sexes to different degrees. The marked and growing predominance of males among lung cancer victims seems to be due largely to the following factors: 1. Males are more extensively employed than females in occupations which produce and use known or suspected atmospheric carcinogens. Also, males work more consistently and over longer periods of their lives in such occupations. 2. Males predominate in outdoor occupa tions, especially in urban areas, where they be come exposed to carcinogenic pollutants in the general atmosphere (effluents of domestic and industrial furnaces, exhaust from gasoline and diesel engines, dust from rubber tires and from asphalted and oiled roads). 3. Males more often than females perforin heavy physical labor requiring deep and fre quent respiratory movements facilitating the penetration of carcinogenic air pollutants into the distal portions of the respiratory tract, thereby increasing the frequency and degree of exposure. 4. Males more often than females work through the entire span of their occupational life within urban areas with proved carcino genic atmospheric pollution, while females stay for larger portions of their lives in the cleaner suburban dormitory communities. These considerations provide substantial sup port to the concept that local differences in general and occupational industrial air pollu tants may more plausibly account for an ap preciable portion of the observed differences in attack rates for the two sexes rather than do local variations in their smoking habits. The doubts as to the unrestricted validity of the cigarette theory are deepened if critical evaluation is made of another dubious link in the chain of claims advanced to bolster this concept. It has been maintained (Graham) that squamous cell carcinomas of the bronchial mucosa are a specific response to cigarette smoking since (a) this histological type of bron chogenic carcinoma was allegedly rare before 1920; (b) it has increased considerably since that date in relative frequency in comparison to other histological types of carcinoma, es pecially adenocarcinoma; and (c) it is more often found in males than in females. The facts are as follows: Bronchiogenic squamous cell carcinoma has commonly been found with all known occupational respiratory cancers (table 13). However, many of these agents have also elicited other types of pul monary carcinomas, such as undifferentiated, round cell carcinomas and adenocarcinomas. Thus, there is no evidence supporting the view that any specific respiratory carcinogen elicits a specific and characteristic type of cancer. A study of lung cancer records of cases observed Table 13. Hutdogieal types of occupational respiratory cancers, according to carcinogenic agent "ff' Organ Squamous cell carci noma with or without cornifica- tion - Hound ceil or oat cell carcinoma Anaplastic or polymor phic carci noma Adenocar cinoma 3 4 2 n2 u9 3 3 i 3 2 7 6 4 2 6 1 1 10 Environmental Causes of Cancer of die Lang Figure 5. Annual tobacco consumption in pounds per capita. Great Britain, Norway, Switzerland. Turkey, and the United States, 1900-50. Public Health Monograph No. 36, 1955 11 bofore 1020. or even, before 1000. readily estab carcinomas among 15 lung cancers; Probst, i lishes the fact that during those years squamous 1927--25 percent squamous cell carcinomas be cell eiircinomas of the bronchi were by no means tween 1905 and 1918; Watsuji, 1903--23 percent rare occurrences (Wolf, 1895--8 squamous cell squamous cell carcinomas between 1892 and j 1S99; Adler. 1912--approximately 40 percent Table 14. Consumption of tobacco in pounds per head-year. New Zealand and United Kingdom. squamous cell carcinomas among 181 lung car 1900-1950 (Eastcott) cinomas collected from the literature with ade quate histological data; Proc. First Nat. Cancer Pounds of tobacco per head-vear Conf., 1949--44 percent squamous cell carci nomas in males; 11 percent in females. a ' vN-ew-*^ Zealand United Kingdom While adenocarcinomas, are more frequent in females than in males, they also are more fre quent in young persons than in old ones (Lind- skog; Proc. First National Cancer Conf., 1949). 1900..................................... 1910...................................... 2. 3 2. 69 I. 95 2. 22 The evidence on hand scarcely supports the i3 1920...................................... 1930...................................... 1940...................................... 3. 59 3. 28 3. 87 2. 99 contention that adenocarcinomas are of endog 3. 31 3. 97 enous causation (Lickint) or that they .have an 1950...................................... 5. 36 4. 22 etiology differing from that of squantous cell ------------------- :------------------------------- carcinomas (KrevBerg). The male-female sex 1 Table 15. Average death rate per year per million persona (male*) from juicer of the3tang, 1932-53, New Zealand compared with England and Wale* (Eaetg&tt) i Age Period Country pgr 35-44 45-54 55-64 65-74 75 and over f i 1932-36 ..................... 13 87 158 204 62 1937-41............................. 1940-41............................. 33 108 235 283 126 424 802 715 213 448 1942-46............................. 1942-46 ......................... 46 168 466 635 132 466 1,072 1,032 326 527 1947-51............................. 1947-51............................. 43 >r 287 732 1,014 166 781 1,682 1,857 735 1,073 1952-53 ....................... 1952-53............................. England and Wales.................................... 61 175 305 1,027 1,450 358 2,171 2,650 l, no 1,688 kb*ii-A `h.db'V. Table 16*-.. Obemd and expected mortality from cancer of the lung according to place of birth, '* ' New Zealand or the United Kingdom (Easteott) Place of birth Observed deaths Expected deaths -Age at entry to United Kingdom Under 30 30 and over Observed deaths Expected Observed deaths . deaths Expected deaths United Kingdom..................... 632 721. 8 369 279. 9 201 229.2 168 139. 8 Note: The significance of the difference between observed and expected deaths in the two countries is p<0.001. 12 Environmental Came* of Cancer of the Lang Figure 6. Trends in selected environmental factors, ( nited States, 1900-53 (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 not support the view that women have any hormonal protection against the action of en vironmental respiratory carcinogens if identical conditions of exposure prevail. The claim that squamous cell carcinoma of the bronchi is in any specific way related to cigarette smoking thus may be laid to rest, since no special histological type of bronchiogenic carcinoma bears any consistent connection with any of the recognized respiratory car cinogens. , Finally, it mentioned that there does not exist &ny^BBUjj|iism between the annual per capita coq&Kpjon of tobacco in different countries andtrorfespective pulmonary cancer death rates (Herbich and Neubold; Gilliam) (fig. 5). It has been calculated that the English lung cancer rate is apparently double that of the United States, although the English smoke 30 percent fewer cigarettes per capita than Americans. This interesting and perhaps sig nificant observation, which fails to support the validity of the cigarette theory, is disposed of by its proponents by assuming that exposure to cigarette tar is less severe for Americans who do not smoke cigarettes to the very end than for English smokers who, for economic reasons, indulge in this questionable habit. Recent epidemiological studies of Eastcott in New Zealand provided the most important data on this point. It was found that the relative consumption of tobacco in pounds phead-year for the population of New Zeala and the United Kingdom revealed an inverse relation to their lung cancer death rates (tables 14 and 15). Eastcott, moreover, found when comparing the observed number of lung cancer deaths with the expected number for native New Zealanders of British.extraction and for immigrants from the United Kingdom that the immigrant group meets with a much higher incidence of broncho genic cancer than would be expected on the basis of equity, suggesting that the immigrant has an increased susceptibility to lung cancer (table 16). The chances of dying of cancer of the lung are 30 percent higher for all United Kingdom Public Health Monograph No. 36, 1955 348108--SO-----S 13 immigrants, but for those who were 30 years of age or more on entering New Zealand, the risk is 75 percent higher, according to Eastcott. Differences in habits of tobacco smoking are unlikely to contribute to this picture, in the opinion of Eastcott. Herbich and Xeubold pointed out that there did not exist any consistent proportional fre quency between cigarette consumption and lung cancer mortality for Upper Austria and Kaernten, on the one side, and for Steiermark and Tyrol, on the other side, although in ail four provinces there prevailed approximately the same per capita consumption of cigarettes. These authors suggested that the high lung cancer mortality among the people living in the marginal regions of the northern slope of the Alps might be related to climatic-atmospheric Figure Rise in annual production or consumption of cancer-related industrial chemicals between 1900 and 1948. PRODUCT - UNIT 1 BITUMINUS COAL -PRODUCTION IN U.S., MILLIONS OF NET TONS 2. FUEL BRIQUETS -TOTAL PRODUCTION. THOUSANOS OF NET TONS 3. CARBON BLACK - PRODUCTION, IN MILLIONS OF POUNDS 4. PETROLEUM - PRODUCTION OF CRUOC PETROLEUM, MLLIONS OF 8ARRELS 5, PETROLEUM, ASPHALT - PRODUCTION OF ASPHALT (FROM PETROLEUM), THOUSAfOS Of SHORT TONS 5. COAL TAR - PRODUCTION,- THOUSANDS OF GALLONS 7. ISOPROPANOL5. AS6CST0S - PRODUCTION- THOUSANOS OF POUNDS APPARENT CONSUMPTION, THOUSANDS Of SHORT TONS,(M.YRBK- 9. ARSENIC 10. CHROMITE - PRODUCTION AND IMPORTS/ THOUSANOS OF SHORT TONS TOTAL SUPPLY, THOUSANDS OF TONS SOURCE-MINERALS YEARBOOK, 1945 1900 1905 mo IMS 1920 1925 1930 1935 1940 1945 1950 li 14 1. Fin iiapnu mil Gnat* of Cianr At Eng % mil if piifcHumni.MaTi'iJii.ijriW ;id conditions anti to the direction of prevailing consumption of cigarettes (fig. 6. Hammond; rk winds, which bring the industrially polluted fig. 7, Huoper) and is similar to the increase in all air of Vienna into the valleys of the northern production of other cancer-related chemicals. Alpine regions. It is apparent from the numerous observa Similar observations on the influence of the tions and facts of general environmental nature ns prevailing winds upon the relative frequency of cited that there exists an impressive amount of ho lung cancers in different areas of the English circumstantial evidence of different character he Midlands were reported by Stocks. Herbich and from various sources which strongly sug vie and Neubold, moreover, found that the lung gests that several, if not many, environmental cancer mortality rates were twice as high in factors acting in varying degrees and combina >00 communities located along main highways, tions cause or contribute to the development of where the atmosphere was polluted with exhaust fumes from gasoline and diesel motors and the pulmonary cancers and are involved in their dust and fumes of asphalted roads, than among recent rise in frequency. Much of the evidence the inhabitants of villages and towns situated on hand, particularly the irregular epidemio remote from such traffic arteries. In fact, the logical pattern of lung cancer, points to an rise in lung cancers follows more closely the important role which industry-related factors increase in consumption of motor fuel and the and the growth of modem industry may have construction of asphalted highways than the assumed in these respects. Occupational Evidence and Respiratory Carcinogens The concept that environmental factors cause or contribute to pulmonary cancers is supported by epidemiological, medical, and experimental evidence obtained from analysis of lung cancer rates of various occupational population groups as well as by studies of lung cancers and their specific and different causal agents present in a number of restricted worker groups and in well-defined industrial operations. striking difference between the rates for agri cultural laborers and for employees in the nonferrous metal industry, with rates for trans portation workers occupying a position directly behind the rates for nonferrous metal workers. It seems to be characteristic of inhabitants of agricultural areas to rank first in death rates from cutaneous cancer and last in rates for pulmonary cancer. This is in accordance with the relationship between solar radiation and Epidenriologjcai Data on. Large Industrial Ggjffipg Table 17. Lung cancer death ratee per 1,000 death* from ail cause* for 7 indu*trial group* in Ohio, 5,309 males, 1947 (Mancuao) EpidemiokiBHStudies on die frequency of lung cancer aaBpgmembers of large industrial groups and nfmftrbtTr brought to light the Industry Death rate existence of marked' variations in the liability of persons engaged in different occupations to cancer of the lung. Tables 17-19 supply striking illustrations of these differences and list some of the factors which may possibly be o responsible for them. Table 17, which lists lung cancer death rates 3.22 2.91 2. 34 2.18 1. 53 . 82 .68 L 76 for seven industrial groups in Ohio, shows a Public Health Monograph No. 36, 1955 15 skin cancer and the relationship between low concentrations of carcinogenic air pollutants and him: cancer. Xonferrous metal workers, on the other hand, often have contact with dust, fumes, and vapors of some carcinogenic metals, such as chromium and nickel, or with arsenieals which are impur ities in many nonferrous metals (copper, zinc, silver). Transportation workers are exposed to the exhaust from gasoline and diesel engines, petroleum lubricants, and dust from asphalted roads. The relatively high death rates of workers employed in the rubber and plastics industry may possibly be attributable to the use of coal tar, petroleum oils, and tars, furnace black, mineral pigments of carcinogenic chemi cals, and aromatic amino-antioxidants used in the production of rubber and plastics. The actual discrepancy in the lung cancer liability between operating and nonoperating railroad workers is even greater than is appar ent from the figures listed in table 18. The employment ratio of operating to nonoperating railroad workers in one of two large railroad companies was 1:4. From this ratio, it appears that, on the basis of the crude, nonstandardized (sex, age) figures presented, about 75 per cent of the lung cancers in railroad employees occurred among the operating group, which supplied only 25 percent of the total number of employees. Operating railroad workers in cluded engineers, firemen, brakemen, conduc tors, switchmen, and roundhouse personnel, that is, workers exposed to the inhalation of coal soot and oil fumes from diesel engines and fuel and lubricating oils, which contain carcinogenic polycyclic hydrocarbons. Dunner and Hicks recently called attention to two additional worker groups, boiler scalers and grain dockers. In the experience of Dunner and Hicks, these workers showed an excessive liability to cancer of the lung. Twen- Table 18. Frequency of lung cancer among operating and nonoperating railroad workers Railroad Period Type of railroad worker Total lung ; Operating cancers 1_______ Nonoperating ; Undetermined _____ Number ; Percent Number Percent Number Percent A.................. ............I 1940-50 B................. ............j 1939-49 29 104 24 ! 59 ; 83 57 17 15 i 14 i 30 i 29 Table 19. Occupational groups with excessive incidence of lung cancer Occupational group Potential respiratory carcinogens Investigator Metal workers, welders, metal grind ers and polishers, wire makers, tool and die makers, foundry workers, metal monkgan;.lathe workers, etc. Cigar mantipggjOerB- and tobacco- Engineers, machinists, plumbera^ttp^'^erators in smelt- Painters, decorators............ ................. Tar workers, road workers, asphalters, paviours, stokers, patent fuel workers, furnace men, foundry laborers, rollers, etc. Metal dust, lubricating oil mist___ Tobacco dust, insecticides, soot___ Metal dust, soot, lubricating oil__ Metal pigments, coal tar dyes, carbon black, asphalt paints, solvents, vehicles (lacquers, res ins, synthetic plastics). Tar and pitch fumes and dust, soot. Kennaway and Kennaway: Turner and Grace; Mailer; Dublin and Vane; Wynder and Graham; Mc Laughlin; Breslow and associates. Seyfarth; Kennaway and Kennaway; Enger; Veraiuys; Brinhmann. BECC1 1944 and 1952; Gillespie; Turner and Grace; Mailer; Wynder and Graham. BECC1 1944; Mailer; Dublin and Vane; Fulton; Wynder and Gra ham. Kennaway and Kennaway; Fulton; BECC1 1952; Registrar-General (1938); McLaughlin. 1 Report of the British Empire Cancer Campaign. 16 Environmental Cansea of Cancer of die Long t iiMire ORE SMELTING CHROME PLATING PIGMENTS, PAINTS INK, PRINTING ABRASIVE ORE REFINING PLATING CHROMATE BUFFING NICKEL CARBONYt CRE M'NlNL SMELTING ARSENiC PESTICIDES PHARMACEUTICALS ASBESTCS(?} MINING ISOPROPYL OIL (?) ASBESTOS PROCESSING ASBESTOS WEAVING TAR FUMES PRODUCTION MANUFACTURING COKE OVEN SERVICING ASPHALT DUST RADIOACTIVE D;. PITCH, TAR HEATING \ SOOT, PITCH,TAR, ASPHALT DUST 1> MINING l; UIMUWUM ORE REFINING _A = minuses LLNG ty-four lung cancer cases were found among 5.000 dock workers at Hull, England, of whom 2,500 were exposed to grain dust. There wore 10 boiler sealers 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. Xo lung can cers were observed among dockers who were not exposed toKgrain dust. It may be possible that boiler sewers sustain a carcinogenic expo sure to chromate-containing scale, if chromates were used as antirusting agents, or that these workers sustain a pulmonary deposition of iron oxide. Whether specific vegetable matter or some carcinogenic contaminant of the grain, such as residues of chemical fungicides or other processing or preserving agents, account for the abnormally high frequency of lung cancer among grain docket's is at present a matter for speculation. Mention also may be made of the recent observation of Faulds on the excessive fre quency of pulmonary cancer among English iron ore workers employed in mining activities at two different locations. Necropsies performed on these miners during 1932-53 showed a lung cancer incidence of 9 percent (192 necropsies with 17 lung cancers), while post-mortem ex aminations done on 2,378 males of comparable age who were not employed in these mines revealed that only 44, or 1.85 percent, had primary lung cancers. It is remarkable that there did not exist any parallelism between the degree of pulmonary fibrosis observed in the iron miners and their liability to lung cancer Public Health Monograph No. 36, 1955 17 .Sir* ~?WCg>jfc" *-*& (degree of fibrosis in cancerous lungs, 1 plus; in tuberculous lungs, 2 plus; in fibrotic lungs without cancer and/or tuberculosis, 3 plus;. The absence of a positive correlation between pulmonary fibrosis and lung cancer was noted when the evidence on lung cancer among the radioactive ore miners of Joachimsthai and Schneeberg was analyzed (Hueper), Although the actual causal factor responsible for the lung cancer among iron ore miners remains to be determined, it may be mentioned that Levin and his co-workers recently recorded a positive statistical correlation between an occupational exposure to iron oxide and heat and cancer of the lung. The studies of Breslow, Hoaglin, Rasmussen, and Abrams on 518 histologically proved cases of lung cancer in California suggested the existence of an increased liability to lung cancer for members of the following occupational groups: welders, sheet metal workers, steamfitters, boilermakers, crane operators, and nonferrous metal smelter workers, that is, individuals who are exposed to metal dusts and fumes; oilers, oil field workers, wipers, and marine engineers, who have contact with oil fumes, mists, and sprays; asbestos workers; construction and maintenance painters, who inhale vapors or various organic solvents, resins, lacquers, plastics, and rubber, as well as finely dispersed inorganic and organic pigments (chromium, nickel, copper and arsenic compounds, carbon black, aniline dyes); and commercial cooks exposed to fumes and mists of overheated vegetable and animal fats and mineral pan greases. A recent study of the causes of death of the members of the International Photoengravers Union raised the suspicion of an excessive lung cancer liability for members of this occupational group. , From d^fiHferent lung cancer death rates listed fof^jlp&arious occupational groups, it is obvious 'v'&njjp'thiB total number of workers possibly exposed to occupational carcinogens of known or still unknown nature is evidently very large and comprises workers employed in basic and processing industries, construction, trans portation, services, trades, laboratories, and pro fessions (fig. 8). It is, on the other hand, equally clear that the quantity and quality of information available on the occupational aspects of lung cancer causation are deplorably defective because of an absence of extensive anil prolonged analyses of lung cancer deaths among various industrial groups for specific causal factors. The evidence on hand nevertheless is adequate for demonstrating that the wide varia tions in lung cancer frequency apparently existing between different industrial population groups are attributable to differences in more or less well-definable occupational exposures and not to differences in cigarette smoking habits. Occupational Respiratory Cancers and Carcinogens Conclusive evidence of the existence of exogenous carcinogens and environmental re spiratory cancer hazards is provided by the epidemiological, medical, and experimental data concerning occupational respiratory cancers. A general view of the occupational respiratory cancer panorama, including causal agents, and organs affected is presented in table 19. Scope of Environmental Lung Cancer Hazards An indiscriminate acceptance of the figures given in table 20 as reflecting the actual scope of these identified and recognized respiratory cancer hazards, however, would be seriously misleading, despite views expressed by several protagonists of the cigarette theory (Ringertz; Wynder and Graham; Levin; and others). Although a definite demonstration of specific occupational lung cancer hazards has so far been made for only relatively restricted worker groups, tbe evidence on hand is not ODly un equivocal but also indicates that other worker groups exposed to the same causal agents or subjected to identical or similar working condi tions are subject to the same hazards. In contrast to the apparently low carcinogenic potency_of the suspected, but unidentified, agent presumably contained in tobacco smoke, the occupational respiratory carcinogens are evidently highly potent, as shown by their 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 EnriroBiMtal Owes of Cnetr of die Xuf i f "41 4 * j respiratory carcinogens occur as industryrelated general atmospheric pollutants, it may justly be assumed that these pollutants repre sent the cause of a significant portion of lung cancers among members of tlie general popula tion, especially those who live and work in highly industrialized areas. The approximate scope of occupational ex posures to the various respiratory carcinogens may be estimated from data supplied by Bloom field and his co-workers. From a survey of 1,503,204 workers employed in all industries of 10 States, it was found that 7,976 were exposed to fumes and dusts of chromium compounds and Table 20. Occupational respiratory carcinogens and cancers recorded during past 75 years, their causes, sites, and numbers Agent Site of cancer Year dis covered Number of recorded cases United .States Other countries Total Arsenic.................... - ____ __ .... Lung.......................................... Asbestos...........................-.. - ....... ............do......................................... Chromates........................... - - . ...............do....................... ................ Nickel......... -.......... -............... Nares and nasal sinus............. Coal tar................. ................. ... 2 Lung. .................................. .. Petroleum oils......................... .Lung and larnvx..................... Isopropvl oil............................ Larvnx................................. ...... : Nasal sinus____ _ . .............. Radioactive chemicals_____ ____ Lung............................................ Nasal sinus............................. ... ... ... ... ... ... ...' .. . 1930 1934 1932 1932 1936 1936 1940 1879 1931 : 1 : 7! <v> 75 i 0i 0: 0 7i 1. 4: 0: 01 3j 125 ' 16 i 74 ! 65 j 34 ; 51 ! 53 j 33 : 0: 01 01 625 0i 1, 001 1 23 96 140 84 51 53 40 1 4 6 625 3 1, 126 Table 21. Respiratory cancer attack rates, by environmental carcinogens Carcinogen Attack rates Incidence in . Sites of cancers population : Percent Rate per 100.000 at risk : of all ; cancer : . ' I deaths i ; Morbidity !; Mortality' Aromatic r *-drocarbons: Coal tar i umes Petroleum oils............. ........ Carbon and silicon polymers: Isopropyl oil .Asbestos............................... Lung...................... 500:100, 000 Lung...................... 2,000:100,000 Paranasal sinuses, 1 , larnyx. Lung____________ 10:100 Metals: Arsenic___ Chromates Nickel Ionizing radiation: Radioactive ores. Lung Lung Nares, paranasal sinuses. Lung...................... 329:100,000 574:100, 000 Lung 45 55 134.5 ( nor mal 6.5). (13.2-20 percent asbestosis autopsied (0.8-2.4 percent normal)). (42X nor mal) 145.7 males (10.9 nor mal.) 140-338 (20X nor mal). (50-80 percent of all deaths). Public Health Monograph No. 36, 1955 19 -M. (-r- 3.356. to fumes and dusts of arsenicals. For and cooling oils have so far totally originated industrial workers of all 48 States, respiratory from Europe, despite the fact that American liealtli hazards existed from the inhalation of industries offer ample opportunities for identical dust, fumes, mists, and vapors for 35.000 indi exposures, that an excessive liability to lung viduals employed in asbestos operations, in cancer has been noted for paraffin prossers em 55.000 having contact with arsenicals, in 240,000 ployed in oil refineries, and that the survey of inhaling various types of metal dust, and in one oil company has shown that there was a 2.500.000 having cutaneous, respiratory, and marked predominance of operating refinery digestive exposures to various combustion and workers among the lung cancer victims of this distillation products of coal tar, pitch, creosote particular organization. oil, soot, and to petroleum fueloils and lubricat Finally, attention may be called to the fact ing oils, greases, and cooling oils, to name a few. that the entire evidence as to the existence of m The highly defective state of knowledge con lung cancer hazards for radioactive-ore miners cerning the actual number ofoccupational respir has come from the observations made in Schnee- atory cancers is, moreover, demonstrated by berg and Joachimsthal. However, mining of the fact that information on the existence and uranium ores has been carried on for 10 to 20 number of such cancers in specific industrial years in the Congo, Canada, and the United operations with recognized respiratory cancer States and extensive milling operations of the hazards is distinctly spotty, not only as to data African ores have been conducted in Belgium available from different countries but also for many years without any official record of concerning those on hand from identical opera similar respiratory complications among the tions of the same country. The following ob workers employed. servations may illustrate this point. Additional incompleteness of the existing rec The existence of an excessive liability to can ords on occupational respiratory cancers may cer of the lung from an inhalation of coal tar be related to the possibility that pulmonary fumes by retort attendants of gas and coke cancers may have their causation from agents oven plants has been established by a few re entering the body by an extrarespiratory route. ports from Japan, Canada, and England. While all known respiratory carcinogens are of Apart from these isolated data, no others are environmental origin and are inhaled as air available for similar operations from these or pollutants, there exists some suggestive occupa any other highly industrialized countries (Ger tional, medicinal, and experimental evidence many, United States, France, Italy, Poland, indicating that agents introduced by other Russia). Likewise, there is no official record routes may be effective in eliciting lung cancers. available concerning the occurrence of respir Several cases of lung cancer are on record which atory cancers '} nong carbon electrode makers developed after an oral administration of ar- and attendant, in aluminum manufacturing senicals and which appeared in individuals with plants, where workers become exposed to dust arsenical dermatoses and skin cancers (Neu- and fumes from the pitch and petroleum asphalt bauer). Lung cancers also have been observed in the electrodes, and where, according to in- in some aniline dye workers suffering from formatawakwlplable from four different countries, primary occupational bladder cancer (Mfiller) 1 < tar cancers of the skin have been following prolonged cutaneous, ingestive, and jh~rrrwMnffin iTgiiit nf mirh contacts. respiratory exposure to dusts and vapors of It isjpfpleover, surprising that data on the certain carcinogenic aromatic amines. The occurrenceof lung cancersamong producers and possible scientific and practical significance of users of arsenical insecticides have been re these findings is suggested by the experimental 1-5 ported almost exclusively from Europe, al observation of lung cancers in 10 percent of though the United States has been for many rats given the potent carcinogen, 2-acetylamino- years the main producer and consumer of these fluorene by an extrarespiratory route (Biel- products. Similarly, reports as to the existence schowsky). A cutaneous as well as parenteral of respiratory cancer hazards from an occupa introduction of coal tar and several polycyclic tional inhalation of mists and fogs of lubricating hydrocarbons as well as of urethane resulted in 20 Environmental Cibim of Cancer of the Lang -m :l pcerooioU' appearance aiui ail increased 11ltn- exists III (lie vicinity ol tiotiferrous nictui -llleli- in ber of pulmonary Manors in mire. ers releasing in their effluents and from then' ill 'lug heaps fumes and dust containing nickel, 1 Pattern and Type* `>f Respiratory Cancer arsenicals, chromium ' omponnds, and berylli a- Hazards um. Similar exposure exists in the viemitv of of If a map of the distribution and relative con carbon black plants, oil refineries, tar distilleries, a centration of the dilferent carcinogenic air pol gas plants, and similar industrial establish lutants were prepared for a given area, it wouhl ments producing large amounts of soot or other us exhibit a sort of crazy quilt pattern to which polycyclic hydrocarbon containing effluents, the general atmospheric pollutants would fur and in tlit> vicinity of radioactive ore mills and rt nish the overall background color, varying in atomic energy plants. of depth between darker urban areas and lighter The individualized type of air pollution con rs rural districts. Other types of carcinogenic nected with the smoking of tobacco, with its atmospheric pollutants having a more circum suspected carcinogenic hazard to the lung in of scribed held of distribution would appear as the special form of cigarette smoking, may be 20 irregularly arranged and variously sized and included in this type of exposure to atmospheric od shaped spots and islands of different colors carcinogens. lie superimposed upon the general background. d. During the last 75 years, an increasing ;m It stands to reason that such locally differing number of specific chemical and physical agents of exposure patterns are bound to exert an im have cither definitely been recognized or are he portant influence upon the epidemiological char strongly suspected of being responsible for the acter and incidence rates of pulmonary cancers appearance of cancers of the nares. paranasal of various regions; each one of the various sinuses, larynx, and lung among members of carcinogens would produce its own epidemi certain occupational groups. These specific ry ological scatter pattern showing a diminishing occupational exposures are associated with the its spread of cancers from multiple carcinogenic inhalation of coal tar and pitch fumes and dusts, te. production foci. mists and fogs of petroleum derivatives, soot, of The following three main types of exposure vapors of isopropyl oil, that is. the crude liquor iir to environmental atmospheric carcinogens may from which isopropyl alcohol is distilled; arsenic, >a- be distinguished: nickel, chromium compounds, asbestos, and ee 1. General environmental atmospheric ex ionizing radiation. Since the available evidence er posures to certain aliphatic and polycyclic establishes such carcinogenic connections with rs. hydrocarbons released into the atmosphere as only some, but not with all, inhalants, such as eh incomplete combustion products of domestic silica or coal dust, it is apparent that carci ir- and industrial and ship fuels, as parts of the nogenic activities are not associated with all th exhaust fumes of gasoline and diesel engines, as atmospheric pollutants. abrasion products of rubber tires-, and as dust li ed from asphalted and oiled roadc^ exposure to Occupational Respiratory Cancers m arsenicals contained in the mineral ash and soot The respiratory cancers of recognized or r) of burned coal and in the effluents of certain strongly suspected occupational origin are im nd metal smelters, and related to the large-scale portant, not only as industrial disease manifes of use of arsenical pesticides; and exposure to tations but also as prototypes of etiologically lie radioactive either naturally released and topographically identical cancers affecting of from the soit9|i|from bodies of water or pollut workers in other, similarly hazardous occupa :al ing the atagHlpSjfe 83 the result of nuclear tions as well as-of those cancers involving an of explosions. indefinite portion of the general population sus iO- 2. Special and locally restricted atmospheric taining for environmental reasons contacts el- exposure to carcinogenic pollutants of the air with the same industry-related carcinogens. 'al lie in n* Public Health Monograph No. 36, 1955 348108-55- -4 21 Physicochemical State <>t Atmospheric Carcin>>- for the cancers of the bronchi. The bronehio- f/f/iv and Typographical Distribution of genie cancers found among chromate manufac t'nncm in the Respiratory Tract turers. asbestos workers, and coke oven and gas In agreement with observations made as to reasons for the topographical distribution of environmental cancers in other duct systems (urogenous and alimentary canal), respiratory cancers of environmental origin are preferably occupying sites where (a) the flow of the inhaled polluted air is interfered with, that is, in the normal narrows of the respiratory tract, such retort workers are representative of this type of exposure. Atmospheric pollutants of gaseous and vapor types not only penetrate into the lungs but also into the nasal sinuses, where they may be deposited by degradation into solids (radioactive gases), by decomposition into solids (nickel carbonyl), or by condensation and poly merization into liquids or solids (aliphatic epox as the region, of the nasal turbinates and the larynx or its bronchial bifurcations, or (b) where ides contained in crude isopropanoi liquor). In assessing the relationship between the *11 the respiratory tract forms dead end saecula- physicochemical status of atmospheric carcino tions, such as the paranasal sinuses and the genic pollutants and the localization of cancers peripheral bronchiolar regions of the lung, in within the various parts of the respiratory tract, which inhaied carcinogenic matter may accu consideration also must be given to the fact that mulate. condense, and precipitate. The traffic gaseous and liquid carcinogens may become ad pattern of air pollutants in the respiratory tract sorbed to the surface of carcinogenicaily inert thus corresponds to the distribution pattern of solid dust particles and behave under such con `t respiratory cancers elicited by atmospheric ditions more like solid particles. Such com Jr carcinogens. binations, for instance, occur in relation to the The second principal factor which determines exposure to radioactive gases adsorbed to rock the localization of an environmental cancer dust in uranium mines as well as concerning the within the different sections of the respiratory inhalation of liquid or solid aliphatic and poly tract is represented by the physicochemical cyclic carcinogenic hydrocarbons adsorbed to status of a particular carcinogen, since this con-, the surface of mineral road and industrial dust dition largely influences the site or sites of chief or of carbon constituting the bulk of soot. exposure to an atmospheric carcinogen. Car The first evidence indicating the existence of cinogenic dusts consisting mainly of coarse causal relations between environmental factors particles are mainly arrested in the nares, where and the development of cancers of the lung was they cause cancers of the turbinates. The recorded in 1879, when Harting and Hesse nasal cancers observed among copper-mokel established the cancerous nature of the lung #k matte refinery workers inhaling the coarse dust diseases prevalent among the radioactive-ore of the roasters illustrate this interrelation. miners in Schneeberg, Saxony. This discovery, The excessive incidence of larynx cancer of historical importance and great present sig among na^^j^onen inhaling carcinogenic nificance, attracted little attention at the time shale il jfppi^ from the revolving spindles because radioactivity was still an unknown fact 4 | likewise p||Sp<& another example of this mech and cfiitcers-oi the lung were comparatively rare anism because it is likely that the relatively before the turn of the century and therefore of i : large droplets of this oil are arrested in the upper little medical interest. 5I portions of the respiratory tract, making the It was not until the third and fourth decades narrows of the larynx the part of main exposure. of this centuiy that additional, well-defined Dusts or mists composed of particles having occupational activities and environmental a diameter below 4 microns, on the other hand, agents were again related to the causation of t ' penetrate into the deeper parts of the respira cancer of the lung and other parts of the respira V, tory system and therefore are mainly responsible tory tract, that is, the nasal cavity, paranasal H- 22 EnvirotuiientaJ Cuuei of Caacerof the Loaf 1 sinusvs, and larynx. Among these additions to the list of environmental respiratory cancers u-e/v the Itmir cunvvrs atno/ig chromate matinfuciuivrs ^ in:5.')i. of asbestos workers (1935). of arsenic workers (1930), and of coke oven opera tors (1936), the cancers of the nasal cavity, para nasal sinuses, and lung among copper-nickel smelter workers (1932). the carcinomas of the nasal sinuses among luminous-dial painters (1931), the cancers of the nasal sinuses, larynx, and lung among isopropanol manufacturers (1946), and cancers of the larynx and lung among workers exposed to lubricating oil sprays or mists (1936, 1949). Specific Carcinogens Inorganic Chemicals NICKEL Nickel, one of the most industrially important metals and principally mined in the Sudbury district of Ontario, Canada, has many uses: alloys (iron, copper, chromium, aluminum, cobalt); molybdenum (employed in the manu facture of stainless steel, heat resisting steels, forgings, casts, wires, sheets, structural shapes, tubing, rods, bars, strips, and so on); electro plating; catalysts; ceramic enamels and colors; pigments in paints and inks; storage batteries, and so on. Exposure to nickel fumes and nickel dust of metallic nickel and its compounds or to nickel carbonyl vapors is, therefore, frequent for indus trial workers of many types and in many opera tions. While skin contact to nickel and nickel salts not infrequently results in the development of an appareqjjjifr allergic type of dermatitis, inhalation ofJa^y&atile nickel carbonyl has been responaMM^^an appreciable number of acute and of3jjg||fatal poisonings. The pul monary manifestations (congestion, desquama tion of alveolar epithelium, fibrinous acellular exudation into alveolar spaces, bronchial mu cosal hemorrhages) are apparently attributable to the toxic action of finely dispersed nickel formed from the disintegration of nickel carbony! upon the pulmonary structures. Krafft suggested that these reactions are the result of a nickel allergy having the lung as its shock organ. The first report concerning the occurrence of an excessive number of cancers of the nasal passages (nasal cavity and paranasal sinuses) and of the lungs among workers of the Clydach plant of the International Nickel Company, located at South Wales, England, was made by Grenfell in 1932, although the first appear ance of these neoplasms among the nickel refinery workers was noticed in 1924 (Baader). Subsequent reports dealing with these cancers were made by Stephens; Amor; Cooper (E. H.); Carozzi; Bridge; and Merewether. From 1923 to 1948 inclusive, there were reported to the Chief Inspector of Factories a total of 47 cases of cancer of the nose and 82 cases of cancer of the lung from the nickel works. By the end of 1948, 46 of the workers with nasal cancer and 72 of those with lung cancer had died. None of the patients with nasal cancer and only 2 of the patients with lung cancer had commenced work in the nickel refinery after 1924, when a recon struction of the plant had been carried out. The average exposure period for the nasal can cer patients was 23 years (range, 3-26 years), and for the lung cancer patients, 25 years (range, 1-33 years). No cases of cancer of the larynx have occurred, and only 1 cancer of the naso pharynx was observed at Clydach. The nasal cancers involved the turbinates, nasal septum, and paranasal sinuses (ethmoids). Of these, the majority were of the undifferc dated cell type (6), some showed a squamow'. cell character (3), while columnar cell carcinomas were uncommon (1). Of the lung cancers, of which histological studies were available in only 4 cases, 3 were of the small cell, pleomorphic type, while 1 was a squamous cell carcinoma. Similar_observations were recently recorded from a Norwegian nickel refinery, where 3 cases of lung cancer were seen (Lpken). In one of these cases a squamous ceil carcinoma was associated with sarcoid lesions. Goldblatt and Wagstaff mentioned that so far cancers of the respiratory traet have not been noted among the workers employed at the German nickel refinery at Ludw^shafen, Public Health Monograph No, 36, 1955 29 i r h;i< 'iii'l'i' i'rrn !i } H >rte< i ;tli Ul:U-U;d f J't - <j11(>n< \ <"jura*:' c;uu,i,r> ;irunn^ .'he uork- <'(- i>t i i<ii*i:r\ nickel ore mine* and -meiler< lii C;im;h!;i. a[I h<ni^h -rverni nl n:i:ii r-uii" I'aiurrs ui'i'r ivcriulr 'fen in mil' ('aiuuitan nickel plant. .Imoi1 pointed mil that the majorin of' indi viduals employed at Clydach will) developed respiratory cancers were not exposed to the inhalation of nickel earbotnl Imt to that of nickel matte dust or dust from the nickel matte roaster (Loketii. Mori* recent data communi cated by Morgan confirmed this observation, although exposure to nickel carbonyl vapors had occurred more frequently among the af fected workers than was apparent from the data previously given hy Amor. The rela tively high incidence of' cancer of the nasal cavity indeed suggests that a rather coarse partieulate dust readily arrested at the region of the turbinates may have been active in the production of cancers at this particular site, while nickel-contahiing vapors or a very small particulate dust most likely account for the cancers of the lung and nasal sinuses. .Vs to the causative agent, various theories have been advanced. Amor favored the con cept that the inhalation from arsenic-containing sulfuric acid used in the refining process was the active carcinogenic agent. It is most unlikely that this is correct because the nickel refinery workers do not suffer from perforated nasal septa and display no evidence of chronic arsenicism such as dermatosis and cutaneous cancers, which almost always have accompanied the occurrence of lung cancer among workers exposed to arsenical dusts or fumes (Hueper). Amor stated that the refined nickel-copper ores are free from radioactive matter. The respiratorycancers observed among nickel refinery workeragtiius are not identical in etiology with those seenin miners employed in the radioactive mines of Schneeberg and Joaehimsthal. Workers employed at the roasters, in the nickel carbonyl operation, and in other parts of the plant, on the other hand, become exposed to the inhalation of dust, fumes, or vapors con taining nickel. Nickel is the common denomi nator for all of them. It thus is most probable that the respiratory carcinomas observed among nn'ki'l !vIi:ht\ u ii'ker> are !v;irt um prodm-;^ in more 11r fi!11 (\ di'piT-rd nickel jiariirjr'. or \ .1 f < U". I" h r n' !' 111 > e\nienee :i v;t [j ;d >|e. hoUWiT. wtiidi l; s J !<-:i! I" 111 ;i I the ! !i f l:i I a ! lo U of nickel iii particulate or vaporized form is ac companied by pulmoiiarv eh;tn>:e' ,,j :l pneumoconiot ic mi l lire. The concept of a nickel etiologv nl respiratory cancers was tested in animals by ('ampbeli. who exposed mice to the inhalation of powdered nickel matte and observed that these animals hud a lung tumor incidence significantly higher than that of the ttnexposed control mice. The recent experiments of Hueper seem to demon strate more conclusively the carcinogenic prop erties of metallic nickel. When pure metallic nickel powder was implanted into the femoral and pleural cavities and >ubeutaneous tissue of I 7'> nits, cancers developed at the site of injec tion ill *>0 of litem. U helher or not nickel assumes a carcinogenic role for cancers of other organs and following exposures bv other routes is uncertain. It may be mentioned, however, that Araki and Mure demonstrated, by spceirographic methods, nickel in human and animal cancers of various types and sites. The nickel content ranged from t>.27-k mg. per kilogram of fresh tumor tissue to 0.2 mg. kg. No assessment of the decree of occupational nickel cancer hazard can be math' 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 respire,- ory cancer hazards for persons having for other reasons contact with dust, fumes and vapors containing nickel or its com pounds. CHROMIUM Chromium as a metal, alloy, or compound is list'd for many purposes in industry. It is for titis reason that a large number and variety of workers have contact with chromium and chro mium coinpoumlsnud that even restricted groups of the general population may possibly be come exposetl to these agents in the form of dust, vapor, fumes, mist, liquids, and solids (Bourne and Rusliin). Workers most likely to be ex posed to chromium and its compounds are acetylene workers, aniline workers, bleachers. 24 Environmental Causes of Cancer of the Lung blueprinted, ebrome.workers, chromium platers, facture of certain chromium pigments (zinc chromate manufacturers, chromite miners, cray chromate, barium chromate, lead chromate). on makers. >lye workers, electropiaters. enamel In these operations, both water-soluble and workers, glass and pottery frosters. glass color insoluble chromium compounds are inhaled by ed. pottery glazers, artificial flower makers, the exposed workers. The chemical nature of battery makers, linoleum workers, paint mak the actual carcinogenic agent which is respon ers. ink makers, painters, photographic work sible for the excessive liability of chromate and ers, photoengravers, polishers, printers, rubber chromium color workers to cancer of the lung workers, steel workers, tannery workers, vui- is still controversial. canizers, waterproofers of textiles and paper, Although all investigators believe that some welders, users of chromate antirust agents in chromium compound or compounds are causally railroad engines, automobiles, steam heat in involved, it has remained uncertain whether stallations, and bitumen and oil refineryworkers. the compounds suspected are hexavalent or An environmental atmospheric contamina trivalent, water soluble or insoluble, mono tion with chromium compounds may result chromates or dichroraates. Water soluble ^ from the release of chromium-containing indus chromium compounds (monochromates, di trial wastes of chromate plants and of oil chromates, and zinc chromate) are most often refineries using a chromium-containing silica incriminated. catalyst for the catalytic cracking of oils. An Mancuso and Hueper recently pointed out environmental spread of chromates may also that it may be more likely that carcinogenic follow the use of such compounds as antirusting effects are elicited by chromium compounds agents in automobiles and for anticorrosive which are either not soluble in water or are coating of airplanes. Since many of the only slightly so, because such chemicals, when industrially used chromium compounds exert inhaled as dust, would be retained and deposited a corrosive action on tissues, skin contact in the lung and thus exert a prolonged effect and/or inhalation of such agents results in the development of chrome ulcers of the skin and upon the pulmonary tissues. Such chromium compounds present in a chromate plant would nasal septum which in turn provide definite be represented by chromite ore and its early proof of an existing health hazard. Com conversion products preceding the formation menting on the appearance of such manifesta of monochromates. These little water-soluble tions among workers in new industries using trivalent chromium compounds occur in the chromium compounds, the Chief Inspector of material present in mixers and roasters and Factories of England and Wales remarked in are contained in the slag which usually is stored his report of 1944 that "the control of old for future use in the yard area of the plants.. hazards in new industries is of interest to others Supporting this concept as to the chemical as well as to the student of industrial health, nature of the carcinogenic chromium compounds for it would seem that in many cases the hazard is the fact that workers as well aa animals ex is not recognized until damage to tissue has posed to the inhalation of chromite ore dust been done, when-old principles have to be have not only a high chromium content of the relearnt and adaglBd' to new uses." lungs but also an excessive blood chromium v This reflectm&pKrration seems to be quite level (Mancuso and Urone). Recent experi appropriate vn^eontemplating the possible ments on rats which inhaled finely powdered , * existence of :)^Kjjjirttbry cancer hazards for individuals enipPjfed in the numerous indus chromite ore dust showed that after 18 months trial operations for which no pertinent pub lished data of any kind exist at the present time. a chromium level of 13.0 and 17.0 gamma, re spectively, in 100 cc. of blood was found in 2 The observation of apparently occupation- rats studied. This finding, moreover, definitely connected cancers of the respiratory organs, establishes the fact that a fraction of the chro especially the lung, has been limited so far mium contained in chromite ore is solubilized to two types of operations, the production of in the pulmonary tissues and discharged into chromates from chromite ore and the manu the blood. PaMk Health Monograph No. 36> 1955 25 Additional support of a rausai role of trivu- !riu compounds may he derived from tin- ob servation that 10 of tiie 20 chromate workers with lung cancer reported on by Alwens and Jonas in 1938 were not employed within the manufacturing buildings or were repair men or maintenance workers (blacksmith, glazier, driver, welder, or manufacturer of sulfuric and hydrochloric acid, produced in a nearby build ing). While all of them probably had some exposure to chromates, it is likely that their contact with chromite ore dust or with dust from the slag heaps containing more or less "insoluble" chromium compounds was much more pronounced (Mancuso; Urone and Anders; Bourne and Yee: Buckell and Harvey). As the result of the retention of "insoluble" chromium compounds in the lung tissues, there develops a blackish spotty pigmentation and a spotty fibrous thickening of the peribronchial and interstitial tissue where the chromium dust particles are deposited. This pneumonconiotic condition called chromitosis was described by Andrievskaya and Mislavskaya in chromite ore miners, and by Lukanin; Letterer, Xeidhardt, and Klett; and Mancuso and Hueper in chro mate manufacturers. It was produced experi mentally in rabbits by Lukanin. Letterer re ported a chrome silicosis in a polisher in an iron foundry who inhaled silica and chromium oxide dust. While the attempts of Gross and Koelsch and of Campbell to produce lung cancer in mice by exposing them to chromate dust were unsuccessful, Schinz and Vollmann, who im planted powdered chromium metal into the femoral cavity of rabbits observed after more than 3 yeacE^ranimal withcancer of the lung, and 1 of the femur. It is definitely surprising that an excessive liability to lung cancer has been established so far only for chromate workers in Germany(Pfcil: Alwens and Jonas: Telekv; Carozzi; Gross and Koelsch; Alwens. Bauke and JonasLehmann; Martineek; Gross; Koelsch; Alwens anl associates; Goldblatt and Wagstaff) and in the Lnited States (Machle and Gregorius; Gregorius: Baetjer: Hueper: Mancuso and Hueper; Impreseia; Division of Occupational Health, U. S. Public Health Service) and in chrome pigment workers in Germany (-Baader; Gross and Koelsch; Letterer, Xeidhardt and Klett). Bidstrup found a single case of lung cancer upon X-ray examination of the chest of 321 chromate manufacturers employed for more than 10 years in English plants, while no data exist on this point in regard to chro mate-producing or -consuming plants in other countries, such as Switzerland, Italy, and France. Apart from the excessive frequency of lung cancers among chromate workers which, ac cording to American observations, ranges from 13 to 31 times the normal frequency of lung cancers among the general male population, an occupational origin of these cancers is strongly suggested by the shift of the age distribution toward younger age groups. This is particularly striking for the lung cancers present among German chrome pigment workers, since 50 per cent of the cancers affected individuals before the age of 40 years, when lung cancers of un known etiology are relatively infrequent (table 22). The quantitative data on the chromium con tent of various organs and blood of persons with chromium lung cancer have been reported by several investigators (Alwens and Jonas; Let- Age distribution of cases of chromium cancers oftheitmg, according to type of worker Type of worker ] 21-30 i American chromate................................... ........ j German chromate....................................... ...........; German chrome pigment......................... 1 10 31-40 8 3 5 Age (years) 41-50 51-60 61-70 71-80 Total 16 10 10 1 , 54- 7 14 12 1 38 3 1 1 ........... 50 26 Environmental Casses of Cancer of the Lang 1 i l I h y r- 54 38 !0 n* u-rcr. Xiedhurdt and Kiett: Miincuso and Hucperb Spannagel recently noted a peculiar behavior of the chromium content of the blood and urine in chromate workers before and after the development of lung cancer. It was found that in chromate workers the normal urinary excretion of chromium ceases with the develop ment of lung cancer while simultaneously the blood chromium level becomes elevated. If confirmed, this observation may have distinct importance in causal, metabolic, and diagnostic respects. With the exception of 2 cases--L cancer of the nares (Newman) and 1 cancer of the maxillary sinus (Goklblatt and Wagstaff)--the lung was the exclusive site of respiratory cancers observed among chromate workers. The total number of these cancers is at present around 125 cases from all sources. None has been reported as originating from nasal septum ulcers. Chromium pneumoconiosis thus seems to accompany the development of cancer of the lung in chromate and chrome pigment manu facturers. It is uncertain, however, whether the pneumonoconiotic process plays an essential or modifying role in the specific cancorization process or whether it is merely a phenomenon of coincidental coexistence. ARSENIC Arsenicals represent a byproduct or waste product of the smelting of many ores (copper, zinc, silver, cobalt, antimony, iron, bismuth, nickel, tin, and lead). Arsenicals are present in the smelter fumes and slag heaps. They are extensively produced and used, especially dur ing past decades, as-insecticides, fungicides, and vermicides (sheep and cattle dip, grasshopper bait, rat poison), as well as a herbicide, especial ly for clearuuS^^ad rights-of-way. Arsenicals are appUed.MHjsi% to orchards and vineyards and are dittfi^fiofi*: airplanes upon cotton, com, soybe^^pQH^potato fields. They are em ployed as wood preservatives, in the manu facture of glass, lead-base alloys, dyestuffs, bronzing and paint pigments, and medicinal and cosmetic preparations (Mote). Arsenic and its compounds constitute, according to "Environment and Health," a health hazard for 35,251 workers employed in American in dustries. This definitely is a very roibcrvauvo estimate of the number of exposed workers, considering the long, although incomplete, list iif different occupations emailing contact with arsenicals sjiven by Chamberlain. The estimate, moreover, does not include the rather consider able number of persons who are exposed to arsenicals for purely environmental reasons by ingesting arsenicals with foodstuffs contami nated with arsenical insecticide residues, by consuming drinking water polluted with arsen icals leached into drinking water supplies from mine and smelter dumps, or by inhaling arsen icals released into the air from industrial establishments or by small- or large-scale dust ing operations of arsenical pesticides. From the published evidence, it appears that environmental and nonoeeupational contacts with arsenicals have been responsible in recent decades for the majority of cases of chronic arsenicism and cutaneous arsenical cancers (Xeubauer; Hueper: Arguello, Tello, Macola and Manzano; Butzengeiger; Baader; Nieberle: Hofmann; Prell; Holmquist; Montgomery and Waisman; Cannon; Arhelger and Kremen; Straube; Bohtienkamp; Hanser and Simon; Gonnet; and many others). While the causal role which arsenic plays in the production of cancers of the skin on the basis of chronic arsenicism of occupational, medicinal, or environmental origin has long since been firmly established, it is rather recently that exposure to arsenicals has seriously been considered as a principal causal agent of cancers of the mucous membranes, such as those of the bronchi, stomach, and bladder. Indeed, today there exists as yet only highly suggestive but not conclusive evidence linking cancer of the lung with an occupational exposure to arsenical dust. However, in almost all cases of lung cancer for which such claims were made, there existed stigmata of chronic arsenicism in the form of arsenic dermatosis with or without skin cancers." -Thejfihalation of arsencial dust and fumes induces rather frequently the develop ment of perforated nasal septa as well as chronic irritative conditions of the bronchi, thereby creating a symptomatic cancerigenic pattern similar to that seen in chromate workers. Under such circumstances, the existence of a causal relationship between cancer of the lung Public Health Monograph No. 36, 1955 27 ' :g-a:. - -' jfs* V- anii chronic arsenirism appears to he a reason able ronclusion. Chest and X-ray examina tions of 40 workers employed in an arsenic smelter revealed a mild degree of pneumoconi osis iSaupe). Although Saupe himself did not discover any evidence of lung cancer among the workers studied--even though they often were afflicted by hyperkeratoses of the skin and perforated nasal septa--he cited the autopsy observations previously made by Schmorl on 2 arsenic smelter workers who died from cancer of the lung (Teleky). Frommel briefly mentioned the occurrence of a eancer of the lung in a taxidermist who used an arsenical powder for dusting the pelts of animals. Four additional cases of lung cancer in sheep dip workers with arsenic dermatosis noted in one of these were reported by Merewether, while Hopkins and Van Studdiford observed in a farmer living near a cotton field sprayed with insecticides, arsenical dermatosis, epitheliomas and cancer of the lung. The occurrence of 5 cases of lung cancer (Merewether; Hopkins and Van Studdi ford) among only 24 individuals suffering from occupational arsenical dermatosis and epitheli omas caused Xeubauer to wonder whether this is mere coincidence, because only 2 cases of lung cancer were observed among 143 cases of medicinal arsenic cancers of the skin (Russell and Klaber), or whether under occupational conditions the irritation of the respiratory tract by arsenical dust was responsible for the phenomenon. Henry, commenting on the occurrence of skin cancers among sheep dip workers (1910-23), recorded 2 additional cases of lung cancers among 10 such workers who had cutaneous cancers. He mentioned, moreover, the pres ence of cancers of the left foot, abdominal wall, and lung in a furaaceman in a sodium arsenite- factory. Analyzing the mortality experienc^^^^feep,di|>; factory, Hill and Faning fo^3B&^.7, or 31.$ percent, of the 22 cancenj^H^pf^death among members of this group wffpl&aited in the respiratory organs, while 3, or 13.6 percent, were situated in the skin. There were, during the period 1910--43 a total of 75 deaths from all causes among workers in this factory. The proportional excess of cancer deaths was mainly attributable to an excessive frequency of cancers of the lung and skin, which were confined to workers in the chemical processes and were absent among members of the general group who would be unlikely to be exposed to any specific hazard. Perry, Bowler, Buckell, Druett, and Schilling concluded from the clinical evidence obtained that, after many years of exposure to arsenicals, these sheep dip workers may develop a squamous cell carcinoma in the bronchus. The most recent addition to epidemiological investigations on arsenic cancer was made by Snegireff and Lombard in studies of cancer deaths among employees of several metallurgi cal plants of unidentified type. Of the total of 109 deaths from all causes recorded during the last 25 years, 12 were due to cancer of all sites, and of these, 6 were located in the lungs. The investigators concluded from this evidence that "there are indications that biologically the human race made the adjustment to arsenic in 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 be capable of upsetting the biological equilib rium"; and further "that the handling of arsenic trioxide 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 the causal relationship to cancer." In view of the fact that 50 percent of all cancer deaths among employees of one plant sur veyed were caused by cancer of the lung, the observations made in fact strongly suggest a carcinogenic action of inhaled arsenic trioxide upon the tissues of the lung of the exposed workers. This interpretation of the data of Snegireff and Lombard is supported by the high incidence of lung cancers among the population of several counties in' Montana where copper smelters and mines were operated for many years, creating an occupational and environmental pollution of the atmosphere and soil with arsenicals. Prolonged inhalation of arsenical dust and fumes appears to produce an increased liability to cancer of the lung (table 23). . However, the existence of such connections 28 Firrimomenta! Cituci l Ctw of the Lai| W: V** ' ** * Table 23. Luna cancer mortality in several Montana counties, 1947--48 (Lull and Wallach)1 County and total population 1940 Major industry Number lung cancers , ______ Total Male Fe male Total Percent lung cancer Annual lung cancer death race/100,000 cancer . deaths . Male Fe male Male 12 Fe male Deer Lodge, 13,627__ - . Copper smelting 3._ Silver Bow, 53,207.........- Copper mining 3................... ' Cascade. 41,499................. : Copper mining, smelting 3,, Gallatin, 18,269............. Agriculture.................................... 1 21 : 27 20 1 0 21 2 29 5 : 25 : 0i 1 98 ; 30. 8 259 , 22. 6 299 i 12. 7 i 81 ; 3. 0 ; 0. 0 145. 7 1. 5 48. 6 : 3. 5 46. 3 ; .0 : 5. 2 0. 0 3. 9 12. 3 .0 1 Personal communication of unpublished data. 2 The estimated crude death rate for lung cancer among white males in the entire United States in 1947 was 10.9 per 100,000 population. 5 The workers employed in copper ore mining and smelting inhale dust and fumes of arsenic contained in the ore and released as a byproduct and waste product during the smelting process. should be acknowledged only when there art and Faulds, 1 case; Dreyfuss, 3 cases in existed at some time clinical and, if possible, watchmakers; Vorwald and Karr, 3 cases in histological and biochemical evidence of chronic hematite miners; Simons, 1 case in a blaster of arsenicism. In view of the absence of any iron casts). It may be mentioned, moreover, such evidence associated with chronic arseni that Kennaway and Kennaway reported a cism among the nickel refinery workers affected 2.25-fold incidence of pulmonary cancer among by cancers of the nasal cavity, paranasal metal grinders and that Turner and Grace as sinuses, and lung, and among excessive tobacco well as Campbell noted an excessive frequency smokers with cancer of the larynx and lung, of lung cancer among metal workers. it is most unlikely that exposure to arsenic The most recent contribution to the problem dust, fumes, and vapors plays any role in the of siderotic cancer of the lung was furnished by production of respiratory cancers in members Faulds, who noted that among 192 iron ore of these population groups. miners coming to necropsy between 1932 and 1953 there were 17 lung cancers (8.85 percent). Ehrbardt and Guthert, on the other hand, The extensive production and use of various noted that red siderosis of the lung does not types of iron and of diverse iron products offers produce a special predisposition to lung cancer. frequent opportunities for the inhalation of The uncertainty existing in this respect is dust and fumes of iron and its various alloys further illustrated by statistical data provided and compounds by iron ore miners, arc welders, by J. W. Brower, Deputy State Registrar, grinders, polishers, silver finishers, and metal Minnesota Department of Health, on the num workers. ber of deaths from lung cancer among iron ore The resulting red or black siderosis caused by miners residing in St. Louis and Itasca Countgb pulmonary retea$(W.f Frf}*or of FejOJIjO, (total number of miners, 13,313) against that respectivelyr>^^^^^dered- an inert form of of residents of Minnesota (population- base, pneumoconia|Kii||ch does not cause disability 2,982,483). There prevails a consistently higher i and which tcf3ESp& part seems to be revers lung cancer death rate for iron ore miners for l ible. The <@pNHsbn of iron oxide particles the 5-year"p5riod than that noted for Minne { does not elicit- in the lungs a progressive and sota residents (table 24). . marked fibrosing reaction unless the inhaled Experimental studies on animals, exposed to dust also contains silica, producing then a iron oxide and hematite, respectively, gave con siderosilicosis. tradictory results as to the production of lung The coexistence of siderosis and cancer of tumors. While Vorwald and Karr, usjng gujhea the lung has occasionally been observed (Stew pigs and rate, failed to obtain lung cancers with Public Health Monograph No. 36, 1955 lamps and neon tubes, atomic energy products, ceramics, refractories, X-ray tube windows, vitreous enamel, radio tubes, textile fibers, gas mantles). It is evidently for this reason that untoward effects in persons exposed to the in halation of dusts and fumes of bervllium and St. LouisItasca County miners its various compounds have been recognized only during the last decade. These manifesta tions were of both acute and chronic nature as far as the respiratory organs were concerned i. 1950........ 1951______ 1952_____ . 1953_____ 1954______ . 328 289 329 : 367 345 5 11.0 4 ; 9. 7 12 ! 11. 0 8 1 12. 3 6 11. 6 37.6 (acute beryllium pneumonitis, chronic pneu- 30. 0 moconiotic granulomatosis, berylliosis). Some 90. 1 60. 1 investigators used the term "sarcoid" in de 60. 1 scribing the histologically peculiar, pulmonary manifestations. It is remarkable moreover, that chronic berylliosis has appeared not only hematite dust. Campbell reported an increase among exposed workers, but also among per in the number of lung tumore in mice exposed to sons living in the neighborhood of fluorescent iron oxide over that of the control series. lamp factories and inhaling their beryllium- When the available evidence is viewed criti cally, it is still uncertain whether an exposure containing effluents (Eisenbud, Berghout and Steadman; Eisenbud, Wanta, Dustan, Stead to iron dust conveys an abnormal liability to man, Harris, and Wolf). lung cancer. Although Warren and Drake Similar observations on occupational beryl recently concluded that the development of liosis were reported from Germany, Italy, primary carcinoma of the liver as a sequela of England, Russia, and Canada. Not infre hemochromatosis apparently depended in part quently, similar granulomatous lesions have on the intracellular deposition of iron, such been observed in other parts of the body after considerations may not necessarily be applicable the usually traumatic introduction of beryllium r.i.- ' to pulmonary siderosis and cancer. dust, especially of beryllium phosphors from I- i!: However, thorough and comprehensive epi broken fluorescent tubes. The skin of the demiological data on the incidence of lung fingers and hands was the most frequent cancer in workers exposed to iron dust are not extrapulraonary location of these reactions. available. Hence, a definite conclusion on this Beryllium granulomas have also been found in problem must be withheld. The availability of the nose and in the anterior ocular structure. conclusive information on this point appears to It is noteworthy that beryllium apparently be urgent, in view of the suggestive evidence once inhaled is retained over a long period of recorded by Faulds and because of the fact that time in the human body, since beryllium has damages have been allowed in the past by court been detected in the urine up to 10 years' after action in dancer of the lung, cessation of exposure (Klemperer, Martin; and in the aggravation of which the Van Riper) and has been demonstrated in the mhalatio^^ei^ust^ was alleged to have lungs of rats 1 year after the inhalation of played a l8|p|fgifrroie. \ beryllium.. ..pride (Dutra, Largent, Cfaolak, BBBYLUttM Hubbard and Roth) as well as in their bones (Stokinger, Steadman and Root; Barnes), Beryllium is a metal which has found signifi where it may replace calcium. The skeleton cant industrial use only since about 1920. It retains the bulk of the beryllium in the body was not until about 1940 that beryllium and its (50-80 percent) if the inhale^ aerosols are compounds were extensively employed for soluble compounds, such as beryllium sulfate numerous purposes and products (beryllium- and beryllium fluoride; the lungB itetaiff* the copper, beryllium-aluminum, and beryllium- bulk of beryllium if the compounds. are in nickel alloys, glass, phosphors in fluorescent soluble, such as. beryllium oxidd. Experiments 39 EnrirocuheuUl Caom* of-Ctarer rf' lfcfr lwiif 79V <*t' Aldridge. Bumes. and Denz, moreover, have diown that beryllium ions react rapidly with certain tissue proteins and form complexes with plasma proteins when introduced into the blood. These omplexes protect the beryllium from being precipitated by phosphate ions. The metabolic peculiarities of beryllium com pounds obtain special importance in view of the fact that Gardner in 1946 reported the produc tion of osteogenic sarcomas in rabbits injected intravenously with insoluble beryllium-contain ing powders (beryllium phosphate., zinc beryl lium silicate). Other investigators subse quently confirmed these results with the same and other beryllium compounds (beryllium oxide, beryllium silicate, metallic beryllium) introduced into rabbits by the intravenous or respiratory routes (Sissons; Barnes, Denz and Sissons; Hoagland, Grier and Hood;Nash;Dutra, Largent, and Roth; Barnes). The preparatory period for the sarcomas was 11-24 months. Commenting on the successful production of osteogenic sarcomas in rabbits after inhalation of beryllium oxide, Dutra, Largent, and Roth noted the fact also that the bones of persons dying with berylliosis contained not inconsider able amounts of beryllium. They came to the following conclusions: "During the last 20 years, considerable numbers of persons have been exposed to dusts of poorly soluble com pounds of beryllium in various industries throughout the United States. Despite the fact that cases of cancer of this type have not been reported, it is possible that the inhalation of poorly soluble compounds of beryllium may eventuate in osteogenic sarcoma in man. Pre sumably, the incubation period of such tumors would be considerably longer in man than in rabbits, and observations may be required over a period of years before it will be known whether persons who have been exposed to beryllium are have such tumors." Barnard als^Mttwted that osteogenic sar coma from ccSeMgaids of beryllium "might possibly be industrial hazard." So far, only rabbits have responded with the devel opment of osteogenic sarcomas following the administration of beryllium compounds. The direct introduction of powdered beryllium metal into the femoral cavity of rats, into the pleural cavity, and into the paranasal sinuses failed to elicit a single neoplastic response at the site of injection in any 1 of the So animals used within an observation period of 2 years (Hueper). When in 1948 Hueper proposed that the sarcoid pulmonary manifestations of berylliosis might be followed by outright malignant lesions in the lungs, this suggestion was received with a great deal of skepticism. The recentlyreported successful production of bronchogenic carcinomas in the lungs of rats which, over periods of more than l year, inhaled dust of soluble and insoluble beryllium compounds (Vorwald), however, makes the appearance of such delayed malignant sequelae in man a distinct possibility, especially as several cases with coexisting berylliosis and cancer of the lung have recently been observed (Kahlau). In view of the established occupational as well as general environmental occurrence of human berylliosis, it may be pointed out that the dis covery and identification of this pneumoconio sis was definitely facilitated by the distinctive and definitive histological features of the dis ease. If these manifestations should be fol lowed by the development of cancers of the bones and lungs, the establishment of causal relations between a previous exposure to beryl lium and the subsequently appearing cancerous reaction would appear to be rather easy. The studies on the toxicity and carcinogenic ity of beryllium compounds indicate that the toxic and cancerous manifestations are to be considered as responses to the action of beryl lium itself and not as the result of the associated anions of its acidic salts (Stokinger, Sprague, and Hall). In considering possible future car cinomatous developments in persons with pre vious exposure to beryllium, some consideration also may be given to the toxic effect exerted by beryllium on the liver leading to the develop ment of cirrhosis and to an impairment of the metabolic and detoxicating function of this organ (Aldridge, Barnes, and Denz; Hoagland, Grier, and Hood). Organic Chemicals COMBUSTION AND DISTILLATION PRODUCTS OP COAL The apparent innocuousness of coal and, possibly, graphite dust as respiratory carcin ogens is not shared by the incomplete combus tion, distillation, and hydrogenation products Public Heahh Monograph No. 36, 1955 31 "if A. rt-- . V if of coal pitch, tar. soot, creosote oiis. anthracene oils, tar oiis. and highly viscous oily and tarry fractions obtained by the direct hydrogenation of coal employed by the Bergius process). The carcinogenic action of these combustion and distillation products of coal on man and experi mental animals has been established beyond any doubt. Although the bulk of the casuistic and epidemiological human evidence of occupa tional coal tar and pitch cancers has come from England and Germany, it cannot justly be assumed that American-made coal tars, tar oils, creosote oiis and pitches differ fundamentally in their carcinogenic properties from those manufactured abroad. The exposures sustained by the numerous types of American workers in a great variety of occupations and operations do not seem to differ from those found for their European colleagues, nor are the carcinogenic effects on the skin of these workers at variance with European observations. However, in addition to skin contact with these products of processed coal, there exists for some groups of workers a considerable exposure to these agents in the form of dust or fumes (tar distilleries, tar paint, shingle, roofing paper, paper conduit, and battery case manufacture, gas works, coke oven operations, road construc tion and repair work, roofing, brickmaking, foundries, furnace attendance, railway engine driving, roundhouse operations, pickling of lumber, chimney sweeping, cork brick manu facture, electrolytic metal production, and so on). Since the high boiling fractions of synthetic oils produced by the direct hydrogenation of coal through' the Bergius process have been shown to be highly carcinogenic to the skin and/or subcutaneous tissue of mice and rats, respective^.certain types of workers manufactur^jBgJj^d^dng sudtproducts and inhaling fumes||Eiitt4 of these carcinogenic petroleum and E^^stitute8 may have a special lung caneManufacturing plants using the Bergjtis process have been operative for some 20 years in Germany and have recently been constructed' by several industrial concerns in the United States. Not only the environmental, but also to a greater degree, the occupational inhalation of dust, soot, and fumes produced by the incom plete combustion of coal results in the develop ment of a "soot lung," called bituminosis, which is characterized by die deposition of finely dispersed carbon particles contaminated with hydrocarbons normally contained in coal tar in the interstitial lung tissue. Roent genological changes may appear in the lungs after many years of exposure to high concen trations of soot in the air inhaled. While the pulmonary deposition of small to moderate amounts of soot in the lungs, such as is com monly found in inhabitants of industrialized regions, does not elicit any appreciable fibrous proliferations, massive storage of soot particles in the lung tissues may finally be associated with an increase of the interstitial connective tissue and with pseudoglandular formations of peribronchial alveoli. The human evidence relating exposure to coal tar and pitch dust and fumes with an increased liability to cancer of the lung is not extensive and is in part controversial. The human evidence relating exposure to coal tar dust and fumes with an increased liability to cancer of the lung is equivocal. Kennaway and Kennaway stated that "coal tar in the atmosphere, whether derived from roads, domes tic chimneys, or any other source, does not cause an exceptionally high incidence of cancer 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 employed in the tar industry and in the construction and maintenance of tarred roads. McLaughlin did not find any lung cancer among 3,059 foundry workers subjected to clinical and X-ray examinations, although there were 3 deaths from lung cancer among 64 deaths from all causes. Mens recently reported that of 93 workers in Swiss gas plants who died during the 1926-46 period. 21, or 22.6 percent, died from cancer of all sites, thereby confirming previous English experience that workers^in tar and pitch operations have an excessive liability to cancer in general. Iso-' lated observations of lung cancer in workers exposed to the inhalation of tar fumes were: made by Koelscb (blacksmith, tar worker), Rodenacker (briquette factory worker), and Mullschitzky (tar worker)'. In an analysis of lung cancer deaths among, members of different occupational groups for the years 1933-38 Kennaway and Kennaway, on Environmental Cibm of Cancer of the fun# !'t. 7r the other hmicl. noted that an abovo-avrra^e an excessive liability to cancer of the respiratory 1100) Urns: --uncer frequency existed for the tract. It is not unlikely that a more thorough fnllowinsr occupations: <rnshouse workers. 129: and competent analysis of the death records of s:as stokers. 284: gas producers. 202: gasworks other workergroups, which have so far been found crane opera tors. 138 ; gasworks superintendents. to lack such tendencies, might extend the types 136: printers. 119: chimney sweeps. 119; and number of tar and pitch workers having an asphalt workers. 164: metal polishers. 174: abnormally high respiratory cancer rate. A painters. 129: tanners. 141: street, cleaners. 169: recent observation of lung cancer in a worker and automoblie drivers. 149. They recorded, exposed to heated pitch and asphalt points to moreover, a ninefold increase of lung cancer another source of occupational pulmonary tar among employees of a Canadian gas plant. cancer of definite practical importance (Patch). Additional supporting information was pro vided by the observations made among Japanese PETROLEUM, SHALE OIL, AND NATURAL GAS generator gas oven workers employed in steel The carcinogenicity of certain high boiling plants and among gashouse retort workers in fractions of petroleum and oil shale, as well as Canada and England (Kawahata; Kuroda and of the combustion products of some of these Kawahata; Cruickshank; Doll). The Japanese petroleum derivatives, such as oil shale and i investigators found, within a 6-vear period, 21 natural gas, have definitely been demonstrated cases of lung cancer among generator oven not only on experimental animals but also on workers who were exposed to the inhalation of workers developing cancers of the skin after hot tar fumes when stoking coal. An excessive prolonged contact with these agents. Known lung cancer rate was absent among workers carcinogenic chemicals, moreover, have been employed in other parts of the steel mills. The isolated from these petroleum derivatives as general incidence of lung cancer among the well as their combustion products (Berenblum generator gas workers was 5 per 1,000 workers and Schoental; Fischer, Priestley, Ebv, Wanless t employed. Seven of these 21 lung cancers and Rehner; Falk, Steiner, Goidfein, Breslow r occurred in workers aged 40 years or younger and Hvkes; Waller; Rehner; Kotin and as (33 percent against 18 percent in cryptogenetic sociates.) \ lung cancers) (Hueper). The exposure time In addition to skin contact with carcinogenic r varied from 9 years to 23 years, the average petroleum derivatives many workers are also 1 being 16.6 years. Similar observations were exposed for occupational reasons to an inhala l recently made among Canadian gashouse work tion of oil mist or fumes (workers in paraffin y ers. Of 14 cases erf cancer among retort house pressing operations, certain groups of oil refinery workers, 6 were due to cancer of the lung, 1 to workers, spinners, metal lathe workers, foundry h cancer of the larynx, and 1 tc, cancer of the workers, metallurgical workers, printers, and ethmoid sinuses (57 percent were- cancers of the so on). In spite of this established occupational upper and lower respiratory tract). respiratory exposure to petroleum and shale s It is likely that similar lung cancer incidence oils, there are on record only three cases of oil 6 rates may exist among American tar workers. pneumonia among such workers, although such Following a a tar distillery where some conditions have rather frequently been observed it 25 skin cancMpitd more than 80 pitch warts after repeated medicinal instillations of mineral n had been otfigfe&d among the 300 workers oil containing nasal drops (oil aspiration pneu during an 8-yiplperiod, there was found 1 case monitis olTparaffinoma of the lung). In fact, !`S of lung cancer^. Subsequent inquiries made by two cases of cancer of the lung apparently e company officials brought the number of lung developing on the basis of a medicinal mineral cancers in this and other tar operations to 6 oil pneumonia have been described (Wood; ), cases of cancer of the lung. d Sante). From the evidence available, it appears that The occupational evidence available or pub the inhalation of tar fumes sustained by workers lished on this aspect of cancer of the lung is of certain operations (coke oven, generator gas rather scanty and in part controversial. Kenie plants, gas plants, tar distilleries) seem to have naway and Kennaway found a relatively high *n >g Public Health Monograph No. 36, 1955 33 - ..*vrf ratio of laryngeal hut not of pulmonary cancer in mulespinners. who inhale a mist of the carcinogenic shale oil lubricating the spindles. Southam noted that mulespitmers occasionally develop multiple primary cancers involving the stomach or the lung in addition to cancers of the skin. Scott, on the other hand, stated that he had not observed a single case of lung cancer among shale oil workers. Huguenin, Fauvet and Bourdin, who ana lyzed a series of 112 lung cancers for possible etiological factors, found that 18, or 16 percent, were metallurgical workers exposed to the inhalation of nebulized lubricating* and cutting oils, 8 were chauffeurs, 5 were mechanics, and 1 was an engineer. Huguenin and his associ ates concluded that their observations indi cated an excessively high frequency of lung cancer among workers exposed to vaporized or nebulized lubricating oil. While the study of Gafafer and Sitgreaves on cancer morbidity and mortality among the male employees of an oil refining company did not reveal any abnormal liability of the members of the occupational group to cancer of the lung, this judgment may have to be revised, at least for certain types of refinery workers, according to more recent and scrutinizing observations. Rosch observed three primary cancers (skin, stomach and lung) in a paraffin worker. Touraine and Bour also attributed the development of pulmonary cancer among certain worker groups to lubri cating oil mists. Such exposure conditions may account also for the excessive lung cancer mortality among male metal grinders observed by Turner and Grace. There is, moreover, some evidence available indicating that the inhalation of mists or fogs of certain ps^cessed petroleum oil fractions also conveys 8teg8jsreased liability to cancer of the lung. Ditgjarafc recent survey on cancer inci dence amoaffipmployees of a large oil refinery, the surprising-' observations were made that there was not only a highly excessive incidence of scrotal cancer among employees of the paraf fin pressing department but that incidence of cancer of the lung was also excessive. Paraffin pressers, who represent about one-tenth of the total employed worker group, furnished 56 percent of the lung cancer observed. Since soot as a waste or commercial product 1ms been found to be carcinogenic and to contain known carcinogenic hydrocarbons, a thorough and competent survey of occupational groups particularly exposed to the inhalation of soot (operating railroad personnel; stokers; carbon black manufacturers; rubber, paint, and ink makers; painters; soot burners; printers; diesel engine drivers; carbon electrode manufacturers and users in aluminum plants; smudge pot operators; phonograph record makers) is an urgent necessity. The negative conclusions reached by Ingalls as the result of a survey of the carbon black industry are based on evidence of dubious merits, because only 79 of the 677 evaluated workers have been employed for 10 years or more in the industry. Since the major ity of known occupational lung cancers have an average latent period of over 10 years, Ingalls' conclusions are actually based on 79 living and active workers. It stands to reason that an analysis of the death records of former carbon black workers may have told a different story, especially if the diagnoses were based on autopsy findings. Such investigations would also add to our knowledge as to the existence, extent, and type of bituminosis which might be expected to exist in workers inhaling finely dispersed soot particles. At the present time, exposure to tar, pitch, asphalt, heavy fuel oils, lubricating and cutting oils, soot from domestic furnaces, incinerators, industrial power plants, oil refineries, steel plants, metal smelters, carbon black factories, oil dumps and smudge pots, as well as exposure to the effluents of diesel and gasoline engines, represents the roost widespread occupational and environmental contact with carcinogenic material. The specific carcinogenic agents con tained in these carbonaceous matters are certain specific aromatic hydrocarbons, which, not in frequently are attached to carbon particles giv ing rise, when inhaled, to bituminosis or anthracosis; or they are constituents of oily matter which, when inhaled and retained in the lungs, cause oil pneumonia or paraffinoma of the lung. Since pure antbracosis is not causally related to cancer of the lung, the pneumoconioses ac companying respiratory carcinogenesis by aro matic hydrocarbons do not play a primary and essential role in this process, although the pneumoconioses may lower the intensity and 34 Environmental Cause* of Cancer of the Ln| prolong tin? duration of tho effect of the specific carcinogenic chemicals on the lung tissues. -Since our civilization and economic life has been built around the production and use of the basic carbonaceous substances and their deriva tives. it does not seem feasible to attain com plete protection against exposure to these carcinogenic chemicals with the preventive and prophylactic engineering and sanitary measures practical and economical at the present time. There is, however, no doubt that a great deal remains to be done in this respect and that we are still rather far removed from having the maximal amount of possible reduction in expo sure to the respiratory cancer producing hydro carbons contained in the various carbonaceous substances mentioned. Carbon and Silicon Polymers Recent studies of English investigators (Hen dry, Homer, Rose, and Walpole; Hendry, Rose, and Walpole; Haddow) have furnished a new and intriguing concept as to possible combinations of carcinogens with tissue proteins through the postulated formation of cross linkages between certain types of carcinogenic chemicals and the macromolecular fibers of chromosomes. This hypothesis was evolved from evidence obtained in the study of carcino genesis by nitrogen-mustards, diepoxides, polyethyleneimines, and related compounds. In view of the fact that one of the 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 mucoproteins of chromosomal origin, by cross linkage with multipoint attachment, and there by cause mitotic aberrations. The initial re action of one ofrthe epoxide groups of mono meric molecule^^aibh the cell component also may start a pre^gpof polymerization by being followed by a^M^eondensation of the free epoxide groupsItaMra polyetheneoxy-etructure. These concepts are important in connection with respiratory carcinogenesis for several reasons. Since Oppenheimer and associates; Druckrey and associates; and Zollinger have shown that a parenteral implantation of various polymerized plastics (cellophane, polyethylene, polyvinyl chloride, polymethyl methacrylate, polyamide, Teflon, and others) into rats and mice are followed by the develop ment of sarcomas at the site of deposition, there exists the possibility that the inhalation of vapors, mists, and dusts of the monomers and polymers of these and related chemicals for occupational reasons may create a respiratory cancer hazard to man. The more immediate importance of these concepts, however, lies in their application to the production of occupational respiratory can cers by a silicon polymer, asbestos, possibly also by a carbon polymer contained in isopropyl oil (polypropylene or propyl epoxide). The probability of such an action mechanism, more over, is supported by observations of lung cancers among Japanese mustard gas manu facturers. ASBESTOS Asbestos differs from the ordinary giant molecular crystalline silicates not only in its chemical and physical properties, but also in the anatomical aspects of the pneumoconiosis produced by it. In contrast to the tridimen sional polymerized silica crystals in which no oxygen atoms are left carrying charges to attract positive ions, asbestos consists of giant fibrous molecules composed of polymerized silico-oxvgen tetrahvdra which are arranged in chains or bands (Parkes). Depending on the origin of asbestos, the fibrils may be short or long. Italian, South African, and Australian asbestos (amphibils) consists of fibrillar or ra diating crystals of calcium-magnesium silicate or sodium 'iron silicate (40 percent iron oxide). Canadian, 'Russian, German, and French as bestos is hydrated magnesium silicate, which contains small amounts of iron oxide (5.75 per cent) . Canada furnishes about 75 percent of the world production of asbestos. Canadian asbestos, because of its long .fibers, is especially suitable for textiles. Depending on its physical characteristics, asbestos finds numerous uses (textiles, filter material, building material, gaskets, insulating material, adsorbants, and so on). Some 35,000 workers in the United States are exposed to asbestos dust. . It is asserted that inhaled asbestos dust pro- PnbUe Health Monograph No. 36, 1955 3* duces asbestosis only if the inhaled fibers are sufficiently long. In the absence of fibrous structure, the dust is said to be inert iWyers: Vonvald. Durkan. and Pratt). Sim-o the larger fibrils are arrested in the bronchioles (Gardner), the granulomatous reactions form peribronchiolar fibrous cuffs with giant cells and asbestos bodies. These have a fibrillar core and an iron staining proteinic or colloidal silicic acid sheath. Whether the iron in the sheaths originates from the asbestos fibers or is derived from blood or tissue elements is still controversial. These two observations de serve special mention because of the apparent dependence of cancerous changes in the lungs of asbestos workers upon the presence of asbestosis and in view of the possibility that the proteins of the lung tissue may specifically interreact with free groups of the filamentary asbestos molecules (Druckrey and associates). The coexistence of asbestosis with cancer of the lung was first reported by Lynch and Smith in 1935 (l case). They later recorded 3 addi tional cases (Lynch and Smith; Lynch). Simi lar observations have subsequently been re corded from this country (Stoll, Bass, and Angrist, 1 case; Holleb and Angrist, 2 cases; and Homburger, 3 cases); from Canada (Desmeules, Rosseau, Gilroux, and Sirois, 2 cases; Cartier, 4 cases; Rousseau, 1 case); from Eng land (Glovne, 17 cases; Harrison, 3 cases; Merewether, 31 cases; Cureton, 1 case; Owen, 1 case), and from Germany (Nordmann, 2 cases; Linzbach and Wedler, 1 case; Homing, 1 case; Welz, 2 cases; Bdhme, 1 case; Domenici, 2 cases; and Baader, 1 case). Thus, there is at present a total of 80 cases of asbestosis cancer of the lung on record. To this numljaj? must perhaps be added the 8 cases of lung complicated by asbestosis which fjB&|iway and Kennaway discovered in an aiuiSHiPNh6 death certificates of males regjstertjPlpweett 1021 and 1938. Eleven additiouttcaies of asbestosis cancer of the lung in workers in two English plants were recently reported by Doll, who felt from his statistical analysis that there exists a definite causal rela tion between these two. conditions (table 25). Merewether noted that the mean age of males with asbestosis cancer of the lung was 55.2 years (range 22-72) and that their mean expo sure time was 20.1 vears (range 6-40), while tiie mean age of female cases was 44.6 years (range 32-71) and their mean exposure time was 7.6 years (range 0.5-48). However, in many cases there elapsed a long exposure-free interval rang ing from several months to 20 vears before the lung cancer became manifest (Wedler; Wyers). The age distribution of asbestosis cancer of the lung was: 25-34........... Age (gears! Cafes of lung cancer 2 35-44...................... 11 45-54................................................... 16 55-64................................................-.............................. 17 65-75................................ -................................... .......... 5 Total............. -....................-............................... 51 Since lung cancer of unknown etiology occurs rather frequently before the age of 40 and since 26 percent of the asbestosis cancers appeared before the age of 44, it seems that there exists a moderate shift toward younger age groups for cancers associated with asbestosis of the lung. The exposure time for asbestosis lung cancer, excluding the series of Merewether, was: Krpotvrt time (gears) Cotes of lung cancer I-3................................................................................ 4 4-10............................................................................. 6 II-20................................................................................. 4 21 and over................................................................. 7 Total................................................................ 21 The exposure time of this series covers a wide range (1-23 years), indicating that type and intensity of exposure to asbestos as well as perhaps an individual susceptibility to asbesto sis play an important role in determining the development of this pneumoconiosis and thereby the possibility of a secondary carcinomatous sequela in the lung. There were 37 males and 15 females among the 52 cases for which information on sex was available! The male:female ratio is thus 2.5:1, which represents a marked shift toward the female side when compared with the usual sex ratio of 5:1 to 10:1 for lung cancers of unknown etiology. Equalization of carcino genic exposure as represented by asbestosis, for the two sexes, thus resulted in a trend toward equalization of liability to lung cancer. It is of importance to note that the mean 36 - Environmental Caues of Cancer of the Ub| .wr^t'safcep'' ;. -PC I 1F1' |HW Tahlp 25 Causes of death among male asbestos workers compared with the mortality experience of all men in England and Wales (Doll) t\ui'C of death Number of deaths Number observed Expected on England and Wales rates Test of significance of difference between observed and expected (value of P.) Lung cancer 1............................................................... - -............. Other respiratory diseases ' and cardiovascular diseases-- With mention of asbestosis-------------------------------------------- Without mention of asbestosis------- - . .................... Neoplasms, other than lung cancer...................................... - All other diseases 13..2.............................................................. ........ All causes 11 : 0. S 14 ____ - -7.-6-;} 6 4 4 U} 39 , 15. 4 ; <0. 000001 <0. 001 >0. 1 <0. 000001 1 Including 1 case with pulmonary tuberculosis, 2 Including pulmonary tuberculosis. 3 Including 2 cases (benign stricture of esophagus and septicaemia) in which asbestosis was present but was not thought to have been a contributory cause of death. age of 128 noncompiicated cases of asbestosis served do not deviate essentially in their l was only 44.2 years (Merewether). One may relative frequency from those seen in cancers of i conclude from this observation that some of unknown etiology. There were 22 squamous r these individuals apparently died from asbes carcinomas, 7 oat cell carcinomas, 4 anaplastic tosis before their lung cancer had a chance to carcinomas, and 6 adenocarcinomas. In view develop (Linzbach and Wedler). of the fact that one of the Norwegian cases of Additional support for a causal relation nickel cancer of the lung was associated with between asbestosis and cancer of the lung is pulmonary sarcoidosis, it may be mentioned derived from the fact that Merewether found, that Skavlem and Ritterhoff reported the l among 266 cases of asbestosis observed during combination of an asbestosis with a sarcoidosis 5 1924-46, 31 cases of coexisting cancer of the of the lung which, however, was not compli t lung (11.65 percent), while there were 91 cases cated by a carcinoma. of lung cancer with an average age of 59.4 Attempts have been made to refute the claim i years among 6,884 cases of silicosis (1.32 per of a causal relation between asbestosis and cent) which came to autopsy. Wedler noted lung cancer by determining the frequency of 0 that asbestosis cancer of the lung occurred in pulmonary cancer among the total worker 1 14 cases, or 15.2 percent of 92 cases of asbestosis population of the asbestos industry (Cartier; on which necropsies were performed, whereas Vorwald). Such a procedure is bound to give the normal rate of lung cancer in autopsy misleading results. It is quite immaterial how e material was estimated to be 2-6 percent. many workers employed in the indus N,y develop v Lanza, Vorwald, Warren, and Cartier are all lung cancer, since an undetermined portion of 5 quite skeptical as to the actual existence of these workers doubtlessly sustains either no an excessive liability of individuals with exposure or only a low intensity exposure and asbestosis to and Cureton and thus does not develop asbestosis of the lung, S Homburger ajflEMMji*ded on this question. which is the prerequisite for the subsequent S Other invest^H^k^^^ favor this con cancerous development. Asbestosis must be d cept or conJHgilfa^ existence of a causal coDsideredlBrthe essential stigma of an effective il relation as htghffi' probable or established exposure. It is, moreover, necessary to know .f (Kennaway; Merewether; Teleky; Nordmann; the sex and age distribution of the worker 1- Hueper; Gross; Lecoeur; Smith; Saita; Wegelin; population studied and evaluated as well as to >r Linzbach and Wedler; Stoll, Bass, and Angrist; know the duration of employment and exposure. d Welz; Doll). A marked labor turnover in the industry is not The histological types of lung cancers ob inducive for obtaining reliable information on n PoUie Health Monograph No* 36* 1955 37 the actual number of lung cancers and asbes tosis cases which may result from effective exposures. For these reasons, no definite conclusions can be drawn from the observation of Cartier, noting S cases of lung cancer among 4,000 workers studied for 10 years, especially as the frequency of asbestosis among effectively exposed workers increases with the duration of exposure (Bohme). Kennaway and Kennawav reported that 8 lung cancers may be found among 4,000 males of the age range 45-64 years. The evidence on hand, at any rate, has con vinced the West German Government to make asbestosis cancer of the lung a compen sable disease (Tabershaw). The experimental approach to the problem has so far given equivocal results. Vonvaid and Karr, using guinea pigs which were exposed to asbestos dust, obtained negative results. Nordmann and Sorge employed mice for this purpose and claimed to have produced bronchiogenic carcinomas with pulmonary fibrosis in two mice. This observation needs to be con firmed before it can be accepted. ISOFBOFYL OIL Through the recent discovery of cancers of the paranasal sinuses, larynx, and lung among isopropanol manufacturers, the occurrence of carbonpolymer cancers has probably been exextended to man. Isopropyl oil--the crude liquid from which isopropyl alcohol is distilled and which is a slightly turbid, viscous liquid, slowly turning, upon standing, into a brownish to blackish tarry material--contains polypropy lene compounds as well as propylene ether, which may be oxidized into propylene peroxide and propyhBgpfeyepoxhle having a tendency to polymerto|^^|4ypropyiene, merchandised as Oppon<^^^^^ed commercially as an oil for WorkenSpIij&ojed in isopropanol manufac ture have been exposed to the inhalation of vapors, mist, and dust of isopropyl oil escaping from leaky pipe connections, defective pumps, and gaskets, or spilled on the floor at the occur rence of breaks in pipelines and during repairs on pipes, pumps, and stills. Weil, Smyth, and Nale reported that, between 1928 and 1950, a total of 7 neoplasms affecting various parts of the respiratory tract (nasal sinuses, 4; larvnx, 2; and lung 1) came to observation among 71 employees, or in S.4 percent of those who worked more than 5 years in the isopropanol plant. Five additional cases were observed in another isopropyl alcohol plant, making a total of 12 cases, 7 of which involved the nasal sinuses, 4 the larynx, and 1 the lung. It was calculated that the incidence rate of cancer of the nasal sinuses and larynx for the second group was 134.5 per 100,000, against a normal rate of 6.3, and that the incidence of these can cers exceeded the expected incidence 21.3 times. From the evidence available it is likely that these cancers as well as those associated with asbestosis belong to the new class of "polymer cancers." MUSTABD GAS The alleged carcinogenic action of war gas poisoning figured prominently in the specula tions as to the cause of the increase in lung cancers observed during the early 1920,s (Kikuth; Brockbank; Klofcz; Derischanoff; Hunermann; Reiche). Residuals of warfare gassing were noted by Matz in 10 out of 138 cases of pulmonary cancer among American World War I veterans. Four out of 64 cases of lung cancer, recorded by Brockbank, were gassed badly during this war. Macklin noted that war gas poisoning occurred in 5 percent of 264 cases of lung cancer among males, while it was present in only 2 percent of soldiers without this disease. Koelsch ceded that a few cases of lung caneer exhibi t a doubtful etiological relation to war gas injury, which was claimed to have caused also two cancers of the larynx (Spamer; Tilley)v No distinction was made at that time as to the particular chemical nature of the various gases used during World War I. These contentions found little acceptance at that time. From a carcinogenic viewpoint, special interest has to be attached to the various arsenic-containing gases, especially Lewisite, and to mustard gas (dichlorethyl sulfide). The arsenical war gases, when, inhaled, theoretically may not only cause nonspecific chemical damage to the respiratory tissues but also may produce there a specific delayed carcinogenic reaction. st Environmental Ceaeea of Caneer oft toe Twj in fe such as Chat seen exceptionally after skin burns with these gases. Cancers of such an origin belong to the group of arsenic cancers. A possible carcinogenic action of mustard gas upon the bronchial mucosa, on the other hand, may be related to its cross-linking and radiomimetic effect, and may be identical with that demonstrated to exist for experimental animals exposed to several sulfur- and nitro- mustards of aliphatic and aromatic nature. According to the mentioned theoretical con cepts, the causative mechanism operative in these cancers resembles in some respects that possibly active in polymer cancers. During the last few years, three cases of bronchiogenic carcinoma and 3 cases of larynx cancer were observed among long-term em ployees of the Japanese Army Poison Gas Manufacturing Plant on Okuno Island, where Lewisite and Yperite were made. One of these workers was 30 years old and a second, 53 years old. Ail three suffered from chronic war gas poisoning due to contact with mustard gas (Yamada, Hirose, and Miyanishi). In view of these observations, the distinct probability of carcinomatous effects upon the lung following exposure to mustard gas or chemically related products deserves serious consideration. While the fundamental concept of "polymer cancers" is a tentative one and needs to be supported by additional evidence, the available data are sufficiently important to require serious attention from both a scientific and a practical viewpoint. The 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 part of the working popu lation into direct contact with chemicals of this type. It seen^tq be advisable, therefore, to study thesft^M^tion- groups during the coming decwSap^fhe occurrence of cancers, particularly vSggp- affecting the respiratory system. . Radioactive Chemicals Up to some 10 years ago, occupational expo sure to radioactive agents was limited to rela tively small groups of industrial and profes sional workers (miners and refiners of radio active ores, industrial and medical consumers of radioactive substances--gas mantle manu facturers, luminous dial painters, radio tube makers, physicists and their assistants, radiolo gists and their assistants). Since the advent of successful atomic fission and the ready produc tion of synthetic radioactive substances, the number and variety of individuals who have occupational contact with radioactive matter have rapidly and greatly increased (uranium and thorium ore miners, smelter and refinery workers, atomic energy plant employees, mili tary personnel, and agricultural, biological, medical, chemical, metallurgic, oil, pharma ceutical, and other industrial research workers employing radioactive isotopes, as well as operators handling directly or indirectly ma terials or technical devices giving off ionizing radiation, such as radioactive static eliminators (Silson; Berman and Ernest; Bryan and Silver man), sewage disposal workers, paper and textile manufacturers, and so on. It is an established fact that cancers of the skin, connective tissue, and bone and blood forming organs have resulted from excessive exposures to radioactive substances affecting the organism or parts of it by various routes. There exists a great deal of highly suggestive, if not conclusive, epidemiological and experi mental evidence relating an occupational in halation of radioactive dust and gases to the development of pulmonary cancers. Although excessive medicinal and occupational exposure to ionizing radiation (radium, X-radiation) alone may produce in man and experimental animals & fibrosis of the lungs (Kalbfleisch; Doenecke; Belt; Bergmann and Graham; Engelstad; Warren and Gates; Leach, Farrow, Foote and Wawro; McIntosh; Warren and Spencer; Widmann; Bauer; Bauer and Schraer; Tonges and Kalbfleisch; IVeid and Goldberg), occupational exposure to radioactive dust and gases has often been complicated by simuL taneous inhalation of dust containing various metals (chromium, nickel, iron, arsenic, cobalt) as well as silica. Pulmonary cancers observed among radioactive-ore miners, therefore, have been complicated in an appreciable number of cases by silicosis of a minor to moderate d^ree. It is for these reasons that the radioactive genesis of the cancers of the lung noted among these miners as well as among uranium-and '-xggt g PabUc Health Monograph No. 36, 1955 39 nulittm retiiu'ry workers has been doubted by some investigators. who felt that one of the various nonradioactive metals or the silicosis represented the main causal or an important contributory ngent (Schinz; Lorenz; Schmorl; Hostoski and Saupe) or that the available evi dence did not provide absolute proof of a radio active genesis (Lacassagne). Several investi gators felt that the lung cancers among the radioactive-ore miners in Schneeberg and Jo- achimsthal were principally attributable to a hereditary predisposition, created by inbreeding of the mining population (Macklin and Macklin; Lorenz; Vesin). The "mala metallorum" causing death at an early age of the miners in the ore mountains of Saxony was first described by Agricola during the early part of the 16th century and was sub sequently mentioned by other investigators (Henckel; Scheffler; Thiele). However, it was not until 1879 that its malignant neoplastic character was correctly recognized (Harting and Hesse). This judgment was, subsequently confirmed by Cohnheim; Aucke; Arnstein; Uhlig; Risel; Schmorl; Beyreuther; Rostoski, Saupe and Schmorl; Lange; Neitzel; Dohnert; Baader; Teleky; Hueck; Rostoski, Saupe, and Schmorl; Thiele; Weber; Koelsch; Linde- mann; Doubrov; Brandt; Brezina. Although the miners of the uranium ore mines in Jo- achimsthal (Czechoslovakia) also were suffering from a fatal lung disease similar to that observed among the cobalt ore miners in Schneeberg, Saxony, it was not until 1926 that the cancerous nature of the pulmonary disease among these miners was recognized (Ldwy). Additional confirming evidence was provided later by Beutel andWaldrich; Ziel; Sikl; Saupe; Peller; Pirchan Baader; Behounek and Fort; yideg^^^^K)rtxng a radioactive origin of the limg|5g|H|among these two groups of miners wiSlIwidded-by the observation of lung cancers among employees of radium refineries and radium laboratories. Ldwy reported the occurrence of two such cases among the workers employed in the laboratories of the Joachimsthal mines, where the ores are refined and the puri fied material is tested. One of the cases had chronic radiodermatitis, leukemia, and lung cancer. A similar observation was recorded by Teleky and bv Xoitzel in a German teelmician of a radium laboratory. The cancerous lune was found to be radioactive. Four cases of lung cancer have recently been observed, according to Baader. among the workers employed in the radium ore processing plant in Belgium, where the occurrence of such complications was pre viously said to be absent (Maisin. citing Deiaet). Perhaps the development of a bilateral alveolar carcinoma of the lung in a woman 16 years after the intravenous injection of 75 cc. of Thorotrast may also supply suggestive evidence that lung cancers may originate from radioactive material used medicinally, when such materials become arrested in the lung. Mention may also be made in this connection of a report of Martland relating the occurrence of cancer in the ethmoid cells in a luminous dial painter, and of two additional cases re ported by Aub, Evans, Hempelmann, and Martland. Dial painters not only ingested radioactive material which became deposited in the bones and produced osteogenic sarcomas, but they also inlialed this matter which, thus, may have produced the carcinoma of the paranasal sinus. The four cases of cancer of the lung recently reported in an industrial population at an atomic pile site, however, are definitely not causally related to any specific radioactive ex posures sustained by the workers concerned. In these cases exposure and latent period were insufficiently long to cause lung cancer (Love). On the other hand, the argument that these workers were, 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 meteorologic conditions were unfavorable for the ready dispersal of radioactive wastes at this particular operation. In favor of an occupational and radioactive origin df~the4ung cancers among the Schneeberg and Joachimsthal miners is, moreover, the fact that the excessive liability to pulmonary neo plasia is limited to the workers employed under ground and is absent among the workers employed aboveground, and among the popula tion at large of Schneeberg and Joachiinsthal, including the employees of the cobalt pigment plantusingthe Schneebergores(Bauer; Schmorl). 46 Environmental Cwm of Ganeev of tfc Lang An excessive lung cancer attack rate, aUo, has not been found among the miners of the nearby Johann Georsrenstailt region, where the mines have a low radioactivity. There is, further more. no valid evidence n record that miners of arsenic-, chromium-, nickel-, and bismuthcontaining ores are affected by lung cancers at a rate even remotely approaching that seen among the two radioactive ore miner groups. The attack rate of lung cancer among the Schneeberg miners has consistently been be tween 75 and 80 percent since 1879, while that of the Joachimsthal miners has been stated to range from 40 to 50 percent. However, this incidence rate may be too low, considering the recent statement of Baader, who noted that during the period 1939-43, a total of 180 cases of lung cancer were acknowledged as compen sable diseases and that in 1929 there were only 323 miners employed at Joachimsthal. Consid ering the fact that the exposure and latent period of lung cancer in Joachimsthal miners ranges from 13 to 23 years, it may justly be as sumed that these lung cancer cases originated in a miner population of approximately 300 to 400 members working at these mines between 1920 and 1930. The exposure and latent period at Schneeberg is stated to vary from 15 to 18 years for the majority of the cases, but occasion ally to be as short as 7 years (Baader; Rajewsky, Schraub, and Kahlau). The total number of Schneeberg miners who died from cancer of the lung between 1879 and 1939, according to available records, stands at approximately 400, while the number of Jo achimsthal miners who fell victim to this disease has reached 225 (1926-43). 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 shiffrtoward younger age groups. * fi ii mi 11niradioactivity of the Schneeberg afiM|||la&tnathal mines have dem onstrated tha^^^^th'plaees, mine air and dust have an excesro^Kdegree of radioactivity sur passing many times the maximal tolerance dose (Joachimsthal 30 times (Peller); Behounek; Behounek and Fort; Tschelnitz; Ludewig and Lorenser; Lange; Rajewsky; Stocklasa). It was suggested that the recent introduction of pneumatic drills into these mining opera tions aggravated the hazard by increasing the production of fine particulate dust containing solid radium. Repeated attempts have been made to pro duce cancers of the respiratory tract in experi mental animals exposed to the inhalation of radium emanation and/or radioactive mine dust (vSchmidtmann; Lowy; Campbell; Dohnert; Kahlau; Rajewsky, Schraub, and Kahlau). vSchmidtmann obtained neither pneumoconiosis nor pulmonary cancer in animals exposed for 2 years to the inhalation of Schneeberg mine dust collected from drill holes. Campbell, on the other hand, reported that mice which inhaled dust of Czechoslovak pitchblende displayed a significantly increased number of pulmonary tumors. In experiments of Dohnert and of Hueck, mice were placed in cages within the mines. Some mice developed moderate chalicosis, while pulmonary and mediastinal tumors (adenomas, round cell sarcomas), in addition to an occasional squamous cell metaplasia of the alveolar epithelium, were seen in an "ab normally" high percentage of the exposed animals. However, the actual number of affected animals was small, and the interpreta tion of the results as to their significance was therefore difficult. Kahlau and Rajewsky, Schraub, and Kahlau subjected mice to the inhalation of radon. Many of the animals developed bronchial lesions characterized by an atypical epithelial lining as well as by pulmonary adenomas (in 7 of 12 mice of the test series, against 1 in the control series). While they concluded from this evidence that the radioactive origin of lung cancers in Schneeberg and Joachimsthal miners was confirmed, it seems to be advisable to con sider the evidence obtained by these investi gators as highly suggestive, but not conclusive, because great variations in the incidence rate of lung tumors occur among different groups of mice belonging to noninbred strains. Additioaalr-miLdly suggestive observations have been reported by Lorenz, Heston, Eschenbrenner, and Deringer as well as by Henshaw, Riley, and Stapleton. Both groups of investi gators found that mice exposed to ionizing whole body radiation revealed, in addition to leukemia and ovarian tumors, some increase in the number of pulmonary neoplasms. Of Public Health Monograph No. 36, 1955 41 greater significance in this connection are the findings of Lisro ami Finkel. who found meta plastic ami neoplastic proliferations of the bronchial epithelium in rats inhaling an aerosol of radioactive cerium. Similar results were obtained with plutonium brought into the lungs of rats. Since uranium ore miners inhale not only radon and radium dust but also uranium, which may be retained in the lungs, Hueper, Zuefle, Link, and Johnson injected metallic uranium powder dispersed in lanolin into the pleural and femoral cavities of rats and obtained sarcomas at the sites of injection in 13, or 24 percent, of the 54 rats surviving the minimal latent period of 6 months. Evidence thus produced shows that focal accumulations of uranium, which is an alpha-radiation emitter, may exert a cancerigenic action upon the surrounding tissues, but it does not discriminate between the influence of metal toxicity per se and radioactivity in the genesis of these lesions. From a critical evaluation of the epidemio logical, clinical, and experimental evidence available, it appears that a prolonged inhalation of radioactive gases and/or dust may elicit pulmonary cancers in man (Martland; Evans). In commenting on the production of lung cancer by atmospheric carcinogens, an editorial {Lancet, 1952) remarked, "radioactivity of Joachimsthal mines is stated to be 30 times the tolerance dose. It is scarcely surprising, there fore, that in the past more than half the miners died of lung cancer," It stands to reason that this effect on the lungs of workers will prevail wherever similar conditions of exposure to radioactive gases and dust exist. The excessive suicide rate observed in the past among the miners in Joachimsthal (Sikl) aptly reflects the human nggory produced if such hazardous working:^jn^ons are permitted to persist. WhiledfiKpthus can be little, if any, doubt of the printnpiFofe of ionizing radiation in the producti^^ Iung cancers among radioactive ore miners and similarly exposed occupational groups, some comments on the possible signi ficance of pneumoconiosis in eliciting or modi fying this effect may be indicated. Reports on the occurrence of pneumoconiosis among the miners in Schneeberg and Joachims thal are contradictory. While Schmorl as well as Rostoski, Saupe, and Schmorl in their early reports (1926, 1928) noted that Schneeberg miners suffer from more or less Intense anthracosilieosis and that this condition was causing or favoring the development of the bronchial cancers. Rostoski and Saupe stated in 1930 that pneumoconiosis was usually not very extensive in cancerous lungs. Because of the relatively slow course of the pulmonary tumors, Rostoski and Saupe felt that pneumoconiosis may slow the intrapulmonary growth of the tumors. Hueck, on the other hand, remarked that silicosis does not represent a precancerous con dition for the Schneeberg lung cancers. Some of the miners had silicosis but not lung cancer, while others had lung cancer but not silicosis. Similar discrepancies seem to prevail con cerning the Joachimsthal miners. Ziel in 1935 reported that marked silicosis among these miners is quite frequent and that ashed lungs contain large amounts of silicon oxide. Pirchan and Sikl, on the other hand, maintained that no pneumoconiosis could be 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 Lowy. Sikl, in his most recent communication on the subject, stated that some degree of fibrosis suggestive of silicotic origin could, of course, be seen in the cancerous lungs, and there were single cases of marked silicosis combined with cancer. On the whole, however, silicosis was not a prominent feature in cases of cancer; on the other hand, the lungs most heavily affected with silicoflbrosis were generally free from malignant growth. Behounek and Fort noted that pneumoconiosis was recorded as the cause of death in only 8.2 percent of 63. miners who came to autopay between 1929 and 1938. This statement contrasts strikingly with the observations made by Saupe during a chest X-ray study of 398 Joachimsthal miners conducted in 1939. He found that 43.4 percent of these~~l&iner8 presented roentgenological evidence of pulmonary silicosis. However, silicosis was of minor degree among the 7 miners who were suspected of having pul monary neoplasms. Although the data are in part contradictory, it seems that silicosis does not play any sig nificant role as a direct or contributory cause of cancer of the lung among the radioactive- 43 Enrifoameatal Cmw of Caaecvoftfce.Ian* m r-T- ore miners in Srlmeebcrg and Joachimsthai. Whether it has an antagonistic effect upon the cancerization process or modifies the course of the established cancer remains problematical. Finally, it may be mentioned that these lung cancers vary a great deal in histological struc ture. Many were squamous cell carcinomas; others, round cell or anaplastic carcinomas; while a few were of adenocarcinomatous type. The radioactive lung cancers, thus, follow in this respect the general pattern set by all other occupational cancers. The rapidly growing production and use of radioactive material and the thereby condi tioned, markedly increased exposure of some limited worker groups as well as the general population to gases, dusts, and mists containing radioactive matter of long half-life doubtlessly represents a potential respiratory cancer hazard of serious proportions. The attack rate of lung cancer from such sources is very high, 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 the continuous and strict supervision concerning the amounts of radio active effluents emitted from such establish ments, are urgently necessary for safeguarding the health of these individuals. Table 26. Latent periods of environmental respira tory cancers, in months (Hueper) Cancer of -- Agent Lung Nares and nasal sinuses Average Range Average Range latent oflatent latent oflatent period period period period Asbestos....................... 18 15-48 :............................ Chromates.................. 15 .5-47 ............i............... Nickel________ ______ 22 ! 6-30 ; 11 j 3-26 Tar fumes__________ 16 : 9-23 !................... ........... Isopropyl oi!................................................ Ionizing radiation__ : 25-35 7-50 i 10 : 6-16 25 ; 19-32 Intensive studies also are needed for deter mining whether, through radioactive fallouts, the inhalation of highly radioactive dust par ticles diffusely settling in the bronchial mucosa and producing there minute foci of high inten sity radiation may elicit delayed cancerous reactions. Since radiation cancers, like other occupational cancers, have a long latent or induction period (table 26), it is essential that all possible precautions be taken against en vironmental contamination with radioactive matter to prevent a possibly permanent con tamination of the human environment with dangerous amounts of radioactive matter. Comments and Conclusions The comprehensive panoramic view and analysis of th*|iB$ie epidemiological, medical, and experimej^fi^^idence available on exog enous respirattBpvfetrcixiom&a and carcinogens leave no doub$3if the fact that not only large occupational population groups but also the general population have definite and prolonged contacts with one or several of these agents. For most of these agents, adequate conclu sive proof of their carcinogenicity is provided by epidemiological, medical, and experimental data. One of several specific carcinogenic chemicals has been isolated from several agents representing variable chemical mixtures (soot, coal tar and pitch, petroleum oils, gasoline and diesel engine, exhaust). Wherever a definite identification of a specific causal agent, such as isopropyl oil, asbestos, and chromates, has not yet been attained, the epidemiological evi dence based on an evaluation of cancer inci dence of relatively small, occupationally cir cumscribed total populations at risk is suffi ciently reliable to prove the presence of an occupational respiratory cancer hazard causally PoUie Health Monograph No. 36 1955 43 related to a specific industrial operation. Epi demiological. medical, and experimental data concernin'' these respiratory carcinogens attest their high carcinogenic potency under occupa tional conditions, particularly when acting on humans. It is therefore reasonable to assume that inhalation of the same agents, in a miti gated form as air pollutants, by the general population is responsible for a considerable portion of the lung cancers attributable to such contacts. If this coherent and logical picture presented by the evidence supporting the various occupa tional respiratory cancers and, especially, the coal tar fume cancer of the lung, is'compared with that available for the cigarette smoke lung cancer, even upon superficial examination, several additional serious defects and inconsis tencies not previously pointed out become apparent. It is surprising to note the absence of positive statistical.associations between lung cancer and cigarette cough, although this latter symptom is clinically characteristic of chronic chain smokers. Despite the fact that the Ups and oral mucosa are constantly bathed in the tarnliquor oozing from the tip of the cigarettes and despite the contact of these parts with the smoke coming from the cigarettes, there is no consistent statistical association with cancer of these parts. The assertion that no tarry material exudes from the cigarette tip is belied by the evident fact that chronic cigarette smokers are observed to have brown-stained fingers. There is, on the other hand, not a single record available of cancer of the fingers attributable to cigarette tar. Such cancers of the fingers would be equivalent to the numerous cases of coal tar cancers of the hands for which records are available. In an attajgpfr to provide an explanation for this discrepinpg^in the carcinogenic behavior between cofpttur and cigarette tar, Lickint resorted to the speculative assumption that cigarette tar possesses a special tissue specificity so that the skin of the first three fingers, although impregnated with cigarette tar, is "immune" to its carcinogenic action. It also would be medically unsound to con clude upon a sort of racially conditioned tissue immunity for explaining the observation of Lipsehiu, who reported in 1931 that the autopsy records of a large Jewish hospital in Warsaw, Poland, showed 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 that Eastern Jews are par ticularly prone to develop thromboangiitis obliterans, which has the best established causal relations to tobacco smoking. The claimed absence of a positive association between lung cancer and the habit of inhaling cigarette smoke also is inconsistent with the rule that the incidence rate of occupational cancers increases with the intensity of exposure to a carcinogen. The medical considerations on cigarette smoke cancer of the lung thus reveal a number of serious and fundamental defects and contradictions. The best that can be said about the experi mental evidence on hand regarding carcinogenic properties of tobacco tar is that it indicates the carcinogenic agents in some cigarette tars tlu-ough the use of hyperreactive animals. There is no evidence that these observations of the skin of a strain of selectively inbred mice have any equivalent in man. Thus the prac tical importance of these observations as to cancer of the human lung is at present uncer tain, especially since Passey, in recent experi ments on mice painted for 16 months with tobacco tar, was unable to elicit a single'cancer of the skin. From these considerations, it is apparent that any final decision concerning the relative role of cigarette smoking in the causation of cancer of the human lung should be kept in abeyance until a great deal of additional and more valid, and especially medically conclusive, evidence becomes available. The data on hand make it unlikely that cigarette smoking repre sents a major factor in the production of lung cancer and in its recent phenomenal rise in frequency.For these reasons, it would be most injudicious mainly to base the future preventive control of lung cancer hazards on a theory of such doubtful scientific merits and to concen trate the immediate epidemiological and experi mental efforts on this apparently overprop agandized concept. The apparent wisdom of such an attitude is readily apparent from the fact that not only a great deal of the circum- 44 Enviromnental Catue* of Cancer of the Long MaM'la! > I < "_r i < a ! \ K !r| ICC lSuill ;l I -m j>r:t>'!. :eaii\ M !IV f; | ( i I lai a Mil >Mrlu-i \ i mm, 'jM'i'ilir ;|||'|" nl' i; u I i <-a 11 -- that ihe-c ,';lMa-T' a-v <' t < ICI-II [)a l mual origin "!' points ;m ;m ins; i-v-tvlaUmI No! <>nl\ j;ir'.rM ocrupational groups Imt also the tnrtnl>ot< of the ir<'tuT;ii population have 'ontaet \\it!i tiic'i' airmts in various forms ami intensity. KinaiK . i n:i \ .mi oaf!'! [O'! Iff* f ;<< point ri:a!. in arn ai a puijuneru aai .ids; n i in a it v 11! ! !((- |i"_ral lii'piitc i''"|!i:rin.' t -:< a-"-. -- <( h- aiulitv for the (it-\"[oiinirMl of a iv^ptra t < > r \ * a n * < r. any evidence inrrimmatmy "pt,,-ific occupational lactor^ -hoidd be uri\eii underem-c over that poS'iblv provided I > V a cigarette sniokiny history. 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O.: Experimentelle Erzeugung maligner Xierenkapseitumoren bei der Ratte durch Druckreia (Plastic-Kapseln). Schweiz. Ztschr. f. Path, u Bact. 15: 666-671 (1952). %- 54 Environmental Causes of Cancer of die Long f 1 Current Titles Public Health Monographs No. 19. Medical service areas and distances traveled for physician care in western Pennsylvania. Antonio Ciocco and Isidore Altman. (Public Health Service Publication No. 248) 1954. 32 pages. Illustrated. 25 cents. [Published concurrently with Public Health Reports 69: (3); see pages 321-322 for summary article.) No. 20. Gamma globulin in the prophylaxis of poliomyelitis. Report of the National Committee for the Evaluation of Gamma Globulin in the Prophylaxis of Poliomyelitis. (Public Health Service Publi cation No. 358) 1954. 178 pages. Illustrated. $1.25. [Published concurrently with Public Health Reports 69: (5); see pages 519-520 summary.) No. 21. Why some sanitary engineers leave the field. Irwin M. Rosenstock and Arthur P. 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[Published . .. concurrently with Public Health Reports 70: (12); see pages 1247 1248 for summary.] "ilPPfe W?)' study of selected home care programs. Alice M. Waterhouse, Eleanor G. Bailey, Jeanne T. Palmer, and- Mary C. Gillis. (Public Health Service Publication No. 447) 1955. 128 pages. 65 cents. (Published concurrently with Public Health Reports 70: (12); see pages 1249-1250 for summary.] No. 36. A quest into the environmental causes of cancer of the lung. W. C. Hueper. (Public Health Service Publication No. 452) 1955. 54 pages. Illustrated. 45 cents. [Published concurrently with Public Health Reports 71: (1); see interpretive article. . s. ovEiKir ni>Tui oFricti ii Public Health Monographs are edited and issued by Public Health Reports under the general direction of the Board of Editors. The monographs present contributions to knowledge in the fields of public health, particularly material that is extensive, detailed, or specialized. 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