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FILE NAME: Smoking (SMOK) DATE: 1955 DOC#: SMOKOIO DOCUMENT DESCRIPTION: Book Excerpt -A Quest into The Environmental Causes of Cancer of the Lung ) 'i i t ' l l ) i ! w i'll ,\ 111 \ i m -; i i 'i j . \ i > . r 1' . ' ' * j >' 1 i: ; /i L /' > \ A Quest Into The Environmental Causes Of Cancer Of the Limy; 'i `Kzjttfx- ....... I . S. D E P A R T M E N T - i HEALTH. M )l CATION, a m . W ELFARE J i I C o n lrn is Inirnductioii l iclicl'dl epiiIdilloli.'alea I i`<Hi-u |iTil Ii<<lls (Vclipa Imini I evidence and respiratory rarclllou'eii.- Kpidrmiolcyical (Ini,-i on Ia rye indu>i ri.-iI y m u p s ( Icclipill it Mill I n "-pin 11(II V c;l IICCI'S ;l 11(1 cn rci lioyei is Scopi' cl en v i r on me nt al luii"' cancer ha/siids I'allcrn mill type" cl respiratory ciiiiccr liu/ard- ( Jcciipalional re--p ira t o ry c ;i i i c (t s . _ I'hysicoclieinical "l a ic of a 1iuo-pherie carcinoyeii" and ical (list ril mi Iicn cf cancers in Ilie re-pi ra Icry Ir a d "|,i. ilic i 'yens Iiioryamc clicmieals Nickel ( 'liromimn Arsenic t ron . I'cryllium ( Iryauic chemicals , . . . . . . . __ ( 'cmlmsi ion and distillation p r c du c is cl' coal I'drclciim. shale oil. and na tur al "as ( 'arccn and silicon polymers V-hcstos I -cprcpyl oil Mustard yus Kailicadive chemical" '.incut-- and conclusions "_'l apiiv Inpoyra pli- ..... . ..... . _ I nlr<)<lu(`lion Si'ielllilicalL accept a hie. :l 11\ theory ,.|iol<)iry of liniiT cancer must rcllcrl ;i balanced. Mini r<till|)rl rllI analysis of iii' opi(i<`init>1<>u'i<"i1. 11umIi< i. Mini cxlill evidence cnuccrnilio 111( Ivpes Mini iiiriilMi ilisi rilmi ion of Mini c ont act s knnUll ol' suspected cxom'lions an'clits ulcil ill ms!>iI'M11tr\ mi r c i n o p 'iiesis for <mi i r o n i i i i *i i I:i I . orrii|)M l iolinl. o r m ed ical reasons. 11 is o n ly l liroiio'li sm-li s c r u tin y I lull- significant Mini w o rth w h ile inforiiiM l ion m ny In' o b tain e d ms in ilic ri'lMl i\ ( ruin w h ich tin* v a rio u s imli- \ 11111mI r c s p ir a in rv c a rcin o e e n s Iim vc [>hi\`<mI Mini m ic |>I:i\ i 11;_r in i lie p ro d u ctio n o f lim e can cer. T h e follow iiirr la d s Mini o h s c rv a i ions form mi imItorlM iil Mini in lc o ra l p ari of such Mil Mssessment. O n oral 1 ^ | i <I ( ' 111 i o l o i i i o a l ( i o n s i i l o r a l i o n s dclimlc. Mini progressive increase in , of 11111o- cancer slMrled in mosi .mi/.,-il countries around the turn of the nililrs 1-d). Ilull is. Ml m lime when -iiinkinn was slid a hahil of minor sin- I'm h s i : Berltliiiirer: (iros/.e, Kalilau: l.;,kin|,. 'I'liis rise was firsl clearly ; !i\ pathologists of ( Y n l r a l Kitropc early Ih'JD's throne'll a s t u d y of Mala cnlleeled durillir t h e lil'Sl two ' die 'Jilt11 century and was sulisc- cilirnied and elaborated upon by :i investiiralious from America and ' ah mainly used cancer mortality "i records indicate that lliis developibnI marked variations in the time ' i'iic: cancer, in ils relative decree of : '> m its progression rate for dillcrenl t oi.initrics. In (i ert nany. for in'c'l'cii-c In the incidence of linin' '"*' noted in Saxony and ( Ynlr al ' ' A> late as IT i l . I*'isclier re- 'i,n cancer represented I 1.:! per* I* in saxony a<ruinsl (i.ii percent 1"'iiiiany. In De nma rk, accord' ' '''I', a rise in luno cancer I'reii doiihiful durinsr the first three -`"ill c ini ury and only became delimit' after ITill. Similar observations as to a late appearance of this increase were made in Italy. There still exist slrikinn' dillYrenccs in l he limn' cancer mo r ta li t y rales of different, countries ami different repious of (he same c ou n tr y din;. i. In Fnydand. for instance. 'J.~> percent of all cancers in males involve the luntr: the corresponding fijiiire for Norway is hss t Inin if per t - f i l l . Similar discrepancies exist for luno cancer morbidity rales for different metropolitan areas in the I 'n i lc d St a le s as well as for their relative progression rales l iable -D. A n o t h e r exampl e of Ilie existence of slrikinn- rcn'ional variations in limn' cancer freipicncy is presented by the remarkable differences in luiie cancer mortality rates between iirbaii-iudiistriali/.ed areas and rural districts. This lias been demonstrated for Filmland and Wales ami for the I 'nilcd States, where limn; cancer d e a t h r at es were found to be consistently hijiher in urban areas than in rural areas (tables n-7. liji's. i! a nd 4). Such observations have been made in Ohio. New York, and ('omicclicul (Mancuso. M cFar land. and Porterfield: Levin. Kraus, (ioldberir. and ( ie rh ar dt i and were reported from Filmland and Wales by Slocks; Kennawav and Kcnnawav: Fulton: anil Fhilip|is. Stocks re|)ortcd llie comparative mortality ratios for males in *<!,I, \| "imcriipli N,,. 1955 1 TaMo 1. l*'mnM ,n< y raIrs o f cancers in autopsy m aterial (IVobst) Author Period I.ung cancers *1 : X nm ber of T olal : Absolute j : autopsies ;carcinom as! Xo. j Percent of all Percents of all ` a u topsiefl 1852-1900 R cinhard.. . P u c lis.. W olf_______ P assler___ _ _ W olf........... . Peril t z __ .. Marchesani _ K ik u th __ . . Feilchenfeld - - M archesanL 1852-70 1854-85 1877-84 1881-94 1885-94 1885-97 1887-90 1889-99 1895-1900 1895-1901 1899-1908 1880-1900 8, 710 12, 307 4, 172 9, 240 7, 228 870 ................... 1.940 _________ 5, 022 511 7, 790 711 1, 741 159 3. 337 5 a 8 9 10 1. 83 31 9 1. 27 4 10 22 4. 3 27 3. 8 3 1. 88 0 1900-1925 R cd lich_____ S e v fa lirt____ K arrenstein.. K iknt.h_____ Staehelin. _ . B ejach _____ P ro b s t___ . S e v fa h rl____ B ricse______ B ejach _____ B ejach _____ M archesanL. R a n ________ B erblinger__ M a te rn a ____ S taeh elin __ _ P ro b s t______ S e v fa lirt____ A ssm ann___ M a te rn a ____ Breekwoldt. _ R a u ________ B erblinger__ Probst.. ___ _ M a te rn a ____ K ik u lli_____ M archesanL. Staehelin.. _ L ubarsch.. . S ev fa lirt____ B erblinger__ M a te rn a ____ Breckw oldt.. P ro b s t______ S taeh elin ___ 1900-05 1900-00 1900-07 1900-11 1900-11 1904-08 1900-10 1907-1.3 1898-1910 1908-13 1909-12 1906-10 1909-14 1910-14 1912-14 1912 14 1911-15 1914-18 1912-22 1915-17 1914-19 1915-19 1915-19 1910-20 1918-20 1912-23 1910-22 1915-23 1920 21 1919-23 1920-24 1921-23 1920-25 1921-25 1924 2, 002 10, 272 2, 739 12, 971 0, 808 5, 801 4, 754 4, 810 2, 347 800 3, 448 . 1, 007 0, 083 5, 518 3, 280 4, 989 1, 009 3, 330 2, 429 1, 049 0, 359 3, 097 749 490 934 500 715 205 1, 287 092 586 552 303 48 218 389 70 554 580 337 392 94 755 8, 301 287 75 892 502 31 6.3 l. 5. 1 32 3. 42 90 3. 8 12 2. 1 20 2. 79 3 1. 13 0. 88 00 4. 51 33 4. 8 29 4. 95 0 15 2. 7 8 2. 2 1 2.08 11 5. 0 13 3. 34 11. 23 u 5 7. 14 21 3. 7 27 4. 8 # 10 2. 9 24 0. 12 5 5. 31 140 5. 8 10 ] 38 4. 9 458 5. 4 8. 75 24 8. 3 ,1 6 8.0 26 2. 7 *i 36 7. 17 .] 5 4. 9 i spbbt prafpjr**! C*!TP Environm ental Causes o f Cancer o f the " 1r *y"f*e m , jjl6-49, witli deviations from I ho average rate sal al 100. as follows: of adjacent tow ns with over 200.000 ocoupird dwellings. Loudon, Fast HiOti. B e s t Ilttin. C ro y d o n .. loti Birmingham. S m e t h w i c k , B 'a ls a ll, Wes t Bromwich.------------------ 13-1 Manchester, Salford. Stockport. ____________ l.y.) Liverpool, Bootle, B irkenhead. W a lla se y ... 152 Leeds. Bradford. H alifax____ . . . . . _______ 132 jijgcld. with 124,000 occupied dw ellings. ....... 1 3 ."> tfartlc and Gateshead, w ith 87,000 ocenpicd ,<*cllin*is----------------------------. . . ------------ . . . I l l WTtf:iu: of l>towns, each w ith 50,000 to 85,000 .xvupicd dwellings.................... 113 j^ u a te o f 3 towns, each with 10,000 to 50.0011 occupied dwellings--------------------------------------- 107 lipnialc of 12 towns, each w ith 30.000 to pl.OOtt occupied dwellings---------------------- ------ 101 mrecatc of 13 towns, each w ith 20.000 to 10,0110occupied d w ellin g s..__ ______________ 100 iKtvuatc. of 20 towns, each w ith less th an )m*) occupied dwellings. ______ . . . . ______ 30 la Ohio, for th e y e a r s 1 9 4 7 --51 ( M a n c u s o , .jUFarlnne, a n d P o rte rfie ld '), th e s t a n d a r d i z e d mor la lilv ratios for Inns; cancer lnorialiLv of selected sites anions; white males 25-1)4 year s of ittre in urban ami rural enmities were: M etropolitan comities (Si t'rh a n counties t") .......... Unrai eoimties (73) ___ The standard mortality ratio is Observed deaths Expected deaths loo. The type of comity is defined, according to degree of urbanization, as follows: Metropoli tan county- containing cities with 1950 popula tions of 1()(),()()() or more (91 percent urban); urban --"containing eilies with 1950 populations of 50,000-100,000 (1)0.2 percent urban); rural-- containing communities with 1950 populations below 50,000 (41.4 percent urban). Curwen, Kennaway, and Kennawav only recently recorded fresh evidence supporting earlier observations. The new evidence indi cated the existence of positive correlations between population density in England and Wales and mortality from cancer of the lungs bUr 2. Frequency rates o f lu n g cancers in au top sy m aterial o f G erm an p ath ological in s titu te s, 1906--52 1 Author Cit v Period Percentage of lung cancers amonjr all cancers Sex M ale Female fkirr-Wascts____ : F r a n k f u rt.. Hsnwt........ ........ | G oettingen, .Idairer and Schoe- t J e n a ______ ........ and Knoll__ R itori f nd Sehoe- B erlin___ Pusscldorf. . Zwickau... . D resden....... G e r m a n y __ Goettingen - B erlin_____ Z w ic k a u _____ D u e s s e ld o rf__ F ra n k fu rt----J e n a ________ S#*ff-W ast.k____ * ................._....... .. and Kin- F ra n k fu rt. . D uesseldorf. Leipzig____ B av aria___ ar.il Knoll___ Duesseldorf. Je n a _______ Duesseldorf. F ra n k fu rt. . G erm any__ 'from Kahlau. 1000 1906-12 1910-14 1913-17 1920-23 1924-27 1924- 31 1925- 33 1927-31 1927-31 192S-31 1931- 40 1932 1932- 39 1938 1942-45 1945-48 1945- 48 1946- 47 1940-48 1948 1951 1952 2 50 2. 2 (). 2 3. 61 12. 9 19. 79 13. 0 9. 83 15. 4 13. 0 12. 28 13. 9 12. 0 21. 80 13. 0 26. 23 13. 0 35. 53 28. 6 1. 6 0. 97 - ---------- -- -- 12. 94 21. 4 2. 38 4. 8 23. 4 5. 4 ' i l f * * ' HTM''h Monograph No. 36, 1955 i,.s illlil h 'ln a l r - Mini r a i i r e r til l l i r I;tl \ 11\ iiill IH'I "I fr lllillr -. T i l l ' Iv ImIMII I- |i|i;ii*i*i11 " I n 'l l ro n i|i! in iiir r e l a ti v e h im : ili.'illll rale-. III lilt* l llllt 'il > lM lr- Mini ...,llil w i ll l I I l f re in l i v e J >1| 11;i I io n t l r l l s i l v r n iiiil Hi'-*. W h e r e a s , i i i tin* l i i i l r d w illi ;i p o p n l a i in n o f -1.1 p e r s o n s p e r m ile. I 111l i e e,Hirer t l e i l l l l o e e lir s p e r iiill:! i >i I :i 111 III K ll i r h l l ld I lle s e l i u l i r r s -i m i ii I mi 7.1.1 persons per M p u irr m ile Mini I eMiieer ili'M ili per :;.:;dii inliM liiiM ins. Il Inis reeenlK been observeil IIiill llir lum: enneer dralli rule lor while iiim Ics livimr in llir ilowiiiown nreii of 1'il Islnireli is excessively liijrli Iu ice Ilie rale lor mules livin': elsewhere In l lie ei Iy . Il is s o m e " lui I imeertnin whet her this ohsem mi ion r juries the sjune iJ111 >1it*uIion as llie observations made in Ohio and in Kurland Mini Wales. >iicli an inierprel at ion is .suggested 5 l.m u: <*am-er r a t ' * ' in t i c e m p s t in alt* rial n f t a rititis i i c r t n a i i i n s ! i I t i le s o f p a ! l i n i n g to r tile pt-riutl 1110.7-102.7 IVi inti I'm al camTi's 1.Util! i`i i i nT r > I V ro u ji il hum nitiriT' amoiu! all cancer.' lianue Aventge r/. 'w? -!)!t in. i.V i:ii ; 2s h i !i,s s:{_> i l l . . . i 1. 0 0. 2 :i. s i ' * ' i 2 . 1 .7. 0 ) :i. 0 7. o I. !) li. 2 r e s p i r a l o r \ I'tiiin r per 1110.111111 h i t r mul<`* in 1lie l. n i lc tl (l.e ) **'"' ileallli Momijiraplt No. 30. I9.7.7 5 Ml t 1 % r. h' i- ? 1/. \ ` , c , h- . ' i , . . ' \k ;. i*i *` ' 'jf- .*' l i i * .1 . , Mi T a b le I. I n c i d e n c e o f i T - | i i i a l u i \ c a n c e l'. m o r b i d i 1\ r a l e s p e r 100.000 p o p u l a t i o n l o r 9 m c l r o p u l i I a ll cc In sex . 19.47 m i.I 1917 I'l'iiutti'i -in- aiul nl s Hi t*nc}ni> ;i h'i 1tl im: \W t h'ltRIll' i Hiriiiiimfh'rii 1Il'IlVt'!' S;tn Im'.-hicmli ( 'hir.iuo I'ii i'huriili i U'\mil L:ir\ n \ : \ l la hi ;i New niicau*Dallas Uinniimliam )rit\ it >an l-'ni lcim*. <'tiirau;o Pii t<l>nn:h )<! mil M iirlm III \ r;iIo- Male- 'emails 1u:>7 1n 17 I'hlTnril iinTra>r mar III 17 IVrront increase Tuial III 17 IV inc 7. o 1 1 1't.S l. (i .'). 0 too X s. '.1 i :t. t :vx i '.IS s 1. 'I .7(1 7. li 21). S a. '.1 ii 'AW> . e. i 1. ISO :i. i 17. 2 1. .'i is. '.I :vs\) j. i a. a Sli :i. :> 11. 0 U. 1 Jl. \i 1 II t. J N. 1 '.IS li. (1 11. s 17, li 1. l_MI :i. a S. 1 Ills '.1. s 20. s Id. o j v ; 1 i. a 7. tl r.a s. s IS. II '.1. 7 jii. i 1 WM i. a . 1. o 12 7. :{ 17. li 12 I'. :iJ ii 1.71 j. a o. 7 1 IS 7. <i t'.t. (1 1. 1 l. (i 1mi a ii. a . 2. (1 11. :t t 1. ;>*j . t 1. 0 1711 7. ii 7. 'i :t. J A Mi i. ."i i 7S i. :i 2. 7 1 1 1 o 1 S*i a i, a . 7 2. ti J 0 1 1 Ul.'i a . ti . \) 2. 1) 1. .-1 V s `Mi t s atm 1. 1 1. it a. 7 7. i) 1 i . ii 7(1 : a. 7 1 1 S (1 SJ i . s mu z. l t. 1 a n 1 i . a 27 J. 0 a. t 11\ i lie InrI IImi IIn' \vliit< mnIo inhabit mil s ;iho liml mi a b m i r n u d h hipli ' k i n cancer ilfiiili rsii (l'niiiiii. Thi s h in aprconient with the tionorid experience 11min iis i rn i ii|o li,,. dual rule played by ma ny <>cr111a1ional earemopetis. such ns arsenical'. coal tar. |n'U'<>lriim derivatives, mid mi Iit mi' l ive s ubs t ances in (Im prod net inn nl' Imili cntaiic<11is mu! rcsj>ica11i\ r m i r i 'rs. An mlililional expression of this u r ban- rur al | ni i i r n i nf lime e nnr er rates i ' ouniainoil in the roeeiii report nf la*\v. who luiiiul Ihat those r a i l s won-ill) in .V) jxtcia 11 hiirln-r a m on p i n d us trial ]a i| ii\ holders nl tin' M nl n i|inli Ia ii Life I ii'iiraiiiv Co mp mi y llimi a nu n i e males Imldinp pouoral | nil ions. how fnuml. mi Iho nl her limn I. dial 'iioli ilill'orouoos (|id uni exhl Inr I'oinalo Iii i|i Iors n I Iho Iwu 1y pcs 111 | ml ions. 11o | mini oil nut liml industrial policyholders r o | ) r i s o m , fur llio mii'i purl, iirluiii wapo earners and llioir fmniliis in llio Inwor-iiionmo liraokols ami include a hipli proportion nl inon oiiiraped in nninulaet urmp. moeluinioal imliistrios. minitip, Irmi'puri a Iinn, ami poisumil service. In eontrasi. llio peiienil policyholders aro drawn mostly from middle*- ami Idplter-iiioouti' primps enpnpod in miulia/.ardiiU' oi'oiipal inns. Tho apparoiil causal siptiifiemice of tl epidominlnpienl findings lias Iiooil domoustra by sovoral investipalors. Appreciable anion nf d.-l-lion/.pyrono Imvo Ihm'ii demonstrated W aller ami ( 'oopor ( R. h .) amonp t lie air poll mils uf F.nplish cities; by Kotin and assoeia in tlic particulate phase of those alinospla i(aistitiicnts in Los Anpclcs. and in the exha fumes of pasoline and diesel enpincs (table: and !ti. it lias been oslimaled from tie lipures by Blaekloek. Keiiiiaway. Lewis, a 1 ripibart that about Hi nip. of i!.4-lien/,pvri T n lilc 7. C a n c e r ill* tuner a n d l a r y n x . K u r l a n d a W a le s 1916--19 ( K e n n a i v a y a n d K em taxvay) 'l l |ie nl' mliiniuiill y I.nnir can- I.arvnx ca: cor ra tio 1 ecr ratio1 Mates inl'aol-es Males mFaeil ( iiva t<t \,uin inn . mu 100 100 ( 'minty humm'h 12!) IS7 127 l )t )n*r ur)),,m (list ricts . IfiO 1711 14S Hnral districts.................. . 2SS ts.7 170 1 X a in b o r nl persons pruiliiciiiK 1 doalli. luivirim m eiilal Causes o f C.aiteer of the Lull r,blo6. i i i i r c r <bat !i r;ito-, in 25 S i n t *- o f l In* |0 H> ;im l 19 III. r r m lc la \ ii i ;i t r% j m*i- Tnitol >!- 100.WO Sl all' 1 111i IO |s 1iiH u n n a l i / f ! S i a l i c ;.:iiria 'U t. ' ii .aland-ij',.snTin=L't l> \! 'Ilis-'llll - - Ilam|)slni'' . ..Jersey.... York - - - .. .vKanin . i,' M a u d .. x ' s ! , 11 in ] 2' ' ' '' ' 111 r. n 11 ^ s T 11 i s- S } in. 2 10. 1 II 7 1 1. H 7. 7, N. 1 7. 1 l i n n r r 5. ( n n n T o l tin* I u n y in m a l e s a jre il 2.) \ e a r s a m i <>\ r. I n ^ l a m l . 1921-50. IU 'p r n < lt ir r (l b y p erm i - in n o l t b r I b i t i - h h m p i r e O a n n - r ( .a m p a i l ' l l . S i a l i c w illi t' iii'11:i 1 im l w>l n.-i li/:i 1n Hi . lit .ona. I II Hi m is 0. s >. III. 0 " 7. 1 s. 5 <i t s, s v n \ lii'MMii111r;i 1 S t a le - IHIH III Is - :! .1Mia .. . _ .. . . ' . t 'arnlimi . * . Ilakota . .. . . 7.1 '.inilina . i l'M!l!l"ll - - i. n V 1 5. 0 7i. 1 2. 0 o l I. n V n 1. 1 5. n i 1. 2 i. it 5. 0 i<;i 1h rM i 's for th e y e a r 10 lit w e re la U e n fro m Ami'iii an C a n c e r S o c ia l v. In i 10 10. ( 'a ii r e r Kales for each S t a t e in tin- { n i f n i S t a ll.- i n ' ' ll'i^r for th e y e a r l ! H s u e r r ] m Hlu re d b\ lire f : -::tl n/Iicc dC V it a l S ta tis tic - ' Actual mortality per cent of that expected from the distribution of population by gc and class of district OMer 70 70 - 85 - 0O- 115 - ISO- H?up rijitm* I. O bserw al am i c x p c r t n l lu n ^ c a n c e r <lculbs in u r b a n a m i r u r a l O h i o , 1917- 51. (T . I**. M u n c n s u ) ___ .x / ^, | C co I ; . r |i i a ' -- n 'ON < i' *I*U* 7. la m n r a n c o r m o r l a l i l \ r a t e * . p r r 1.000 i ir.nliw liy sex. in V u s l r i a . 19aI ( l l c r b i r h a m i ^Mlliolll) t nm iniinilv Tniai Males 000 -1.000.000 ' - 2'UM0 f,0,000 f Austria .. 22. 7 IN. 2 IV 1 in. TH. 0 :il. Ii 22. 2 1 7. 2 ,. N 5. n 5. 0 .> 7 U e iiK iiiiilr r nl ( Ihici iUl" itol I. 2C.I 72S I, HIT IIf-iildi Monograph No. SO. l*)o.> i I a l d r 11. I.-I m in i tr<i . m i o i m l ol a r o i l a I i r li\ d r o riirlM im - in l- m i m i lr s i m p l o o f im > o lin r cxltau.sl " i l l i \ ;i i'\ i i i * ( 'H a l in ' r r t o i i i l i o t i <*prrds ( k o t i u ) ....... t i111| I r ( 'mill ^ r l. .1."........1.......I,M. 41 \ . , 1M" / * i\ r iiM 1 I'll'll/T 1' M1It Anil in1111 i fin a<ii > i ono 21,,Ano0n0 .'.Ann :;.non. a.aou 225 JS!) 121> 2.2A 154 IIV.l ;V2A til 177 102 5117 _(n; n> fill 40 47 1 1 12 m 72 >7 ui 127 * 70 41 121 2 A i:t sA 1 1 IS A m 20 15 1 <>nJin111 ir** an* r \ ) n v > ' n I iii im m , ai H load. in.-iy lie inhaled Mini retained iii Ilie lung's from ilirsr sources tinrinir ;i lifclimc Mini lluil lliis <Hi:imii\ represents a ppr oxi ma te ly III.(Kill limes I he dose <0.4 miemvrnmis) <:i|);iI>le of producing eniieer in mice upon sulieniiuieoiis iniroiliietion. II should lie ciuplutsi/.cd in I his eonneel ion lluil II.-l-licli/.pyTelle is null one of Ilie sevel'ill eareinngoiiie ehemicMls isohiled IVoin ;Iinosplierie |)o||iilMlUs Mild Ilull, ihend'ore. Ilie mcI iimI IoImI .iinouni of iilinosplierie carcinogens rea eh dig Ilie lung is consider!!Idy higher ( l*':iIU Mini Sieiner: lvolin Mild nssoeiulesi. T he lieii/.pyrene eonlclll of Ilie nir \v:ls inereMsed I'ourlold during smog days |\Y;dler). Il is difficult. if mil impossible, in reconcile Ilie obvious cmusmI significance of ibis factual evidence wi t h the elniin lluil such regional. iind especially urliMii-riirid. (liU'erenees in lung eiineer frequency arc totally imemmled for by differ cnees in Ilie cigarette smokin': h abi t s of th iwo p o p 11l:i 1ion groups or merely rellcet locai 11isi'i'epMueies in the diagnostie Meiimeii of urbar ii lid rurnI physicians Mild in IIn* availability ol diagnost ie mi'dieiil facilities. Sueii explanations become even less tenablf in view of Ihe fuel Ibill Ilie Mimunl age-adjusted inerense in frequency of lung cancer deaths was higher in 1'.II4 dll llum in I(K51-44 (table 10), whereas ilie markedly increased cigarette eon* sumption during previous years should have boosted Ilie animal progression rate above that seen during the earlier period. It lias been sug* geslcd lU rkiul; Hammond) lluil this paradq*. eid behavior of progression rates is attributable in (lie fuel tluil many cigarette 'smokers did not live long enough to develop a lung canee^ because of their precocious death from coronarjr sclerosis, which also is assumed to he elicited id i T a h i r 10. A n n u a l u ^ c - u d j t i s l r d i n c r e a s e o f fn q itn ir y of lun^r c a n c e r m o rta lity lV m * n l increeaase 1 I9M 40 1 1941-40 1 1933-44V M ales l-'eiuides 1 I lorn. ' I 'n ttcv. 10.5 S. 5 5.: S. 0 2 .5 24 J'a ld e d. K.-I im u lct a m o im l 1 o f n ro m u lir h x d ro c a rh o n in l m im itc sa m n l *s o f diesel e x h a u st u i 1li varying* load a n d cn i:im ' re s o lu tio n *pccd a n d w ith find i n j r r l ion incH ieiciiey (K o tin ) I.V w ilili il It'* ))IT 111i mi i r 1.1will (' tin ii i n hi l.llllll 1, 2011 1. mo 0 ( nin|irr>>inii rrlrax* 1 1 .do 1 do ' l In 1 1 4m 0 (In b . .(In ! . ` In ` 1 (In. b .(In. o (In b . . . (In . 1 (In. . ....In. . . .do 1IJiinn! il ie> are expressed in ^ m , min. a n t i)ll1|)OU!l<l X --- " 147 22 207 70 540 175 1. SOI) 040 2. 500 040 20N 0 257 0 MS 27S SN.X ISS 1. 012 ON ISS 0 177 50 220 7(> 744 447 s22 440 Benzpyrene NO 105 772 1. 420 N70 o 47 447 142 1. 700 SO 7S 1. 372 !)S2 1. 087 Benzpcrylone A n th an -^ threne | -- --------- 1 22 42 124 010 1. 265 79 10 171 !)30 971) 0 0 308 1. 071 944 ! 0 J 43 1 223 I 472 '# 469 i 4. S | 24 $ 197 1 320 1 944 j 20 * 16 i 69 5 iii 7 } 666 ; J 1 j environm ental Causes of o in ilj01" ' "* , ''I'-.'ii''l1' 'M in k in a . fOl'lliUr ' lil11" ` rx " ' ,-1" <llcH Mil v |>I;111:11'n ;i n i i i u ' i i i n i l lx <is-1n>-i- ,111 observa1.idii i'Ii;111<i;L'':11*_r 11i>` \ alidil \ nl' IIn' ,1,1c 11. >r \ ili- l riIm 1ii *(' 1(111" | ilfl <-v in 1In* I'niUMl M lie s iiiu l - rlc *lrl (m in i r ii"*. rounU'y 1 ..'ll' Am imr Malt I'nm I.i ;i 1jt' if.il .NllO- Mexican- : \ r*vay vnark \ .*' rio . -r'liauy. v -- .vina. - 1<).'>> 1I )') 1 1917 1ll.'il) in in p.i.'ii mu 1! i.'i 1 mm mu m;i.'. m.'i.'i i 192.1 1917 m :u 1917. 19.V) 19.'.:; 1S.'il) IS99 1990 1919 1921) 1929 mini man 1910 19 19 197.2 19 is 19 17 1919 1919 ) 'urn Mm ri I i imj)Inv\ * I '.crlc r nl ;) <`;Tjj>Jn h :l ll;:I,H -n MnHiinmv -i ..M. i. O K, l Atl'l N'j nw ;!) i*1 R -lo n . \ *'!`1V SlfilH T K mv! mth do 111`1(-r hi !l 1It'lllllll'M 'll .1.) 1>rliiv ( irns,:.' in in In in I .mil' 'ilm <i;! UUni i S;* lil M :-nn I 'llll mi *i ii. 0 i 7i i i i Ai j'.i i 1i i jo i '_'0 : 1 i:;. A: I 1i 1 o. 7 11 11 ) 1 1 1 1A 1 '*. li 1 i. S 1 ;7 1 1 ^1 s1 :> 1 1 M1 s1 All 1 10 1 7. 1 livinu in l.n> A imlrs . i'2ii I'.'l 11 11u 'nl'V m i l m a \ {i ' r l i a p s i m . i m l i l a n l s - a 1l-l \ 1 ir 11 i i . 1a 2 i m i ' i - i *1 1I d " <m< <-p i , a l t (h nijj' h 11 m m i n . l.o 1a ki h - o r i i m - 1 \ 1. \ a 11 \ .. m w Im. I n n ;i II \ r< 0 n | >'( m i c e m l I m ' I m \ nl a r l n n . ' l e n . ' i - 1i lli'J.ri l i n r o m a r k a l Io. l i n . r e u s e . i l i a l a f l . T a o. Illsll lot a i d e m o r e . n o in I1 1 1 1 2 n i l m T l r i<111<11 \ III l i l ' . ' i a i . l . ' o r s n l d u r u m ' t h e lil'sl 11'';n 11" ill' 1}11- oi III III} . 1Ills d i ' \ e l n | . m e l i l s c o u r ' 111 IlilVl' Ol.lllo 1 > a n a i l d Uri112 I' ooel 11 \ r ; i l ". a c i ' i i n 111 2 1ii A II l i l n m " ' i.' i 11al l . v I d e k i n l ). ( ' m i s i l e r i n y 11 o r e e l . r d e d ' i n k i i m l . ) ii m r u l i i r <| i1 1<*iisi<. 1<>l; i.:! 1 l . r h a v i n r i.l l m i '2 e a i i e e r i n d i l l - 1`IVIll I'll III! l i e - . '1 a 1os . | i r i. v H i r e s , r u m m i l l l i l i e s . a m i | ><.| i l i a I i n n _;t <1111)<, il ' u h v i m i s ll a l l i n - p a l I n n >e;i r e e l \ r u l T r s p i Hu ' Wi l l i 1In' m l I n n p l ' Os el l l 1 ,1 I n ll r i l c u r n i ' a n d s p i v a i l nl' l In- I ' l i r ar i ' l Ii ' '1111.ki l l f 11io a e l ((ill i >! n i - \ Iri.imii nlal o an mnu'oils nllior llian liaise |m>- - i l i l \ I ' l . i i l a i n r i l ii e i y a r e i i o ' m o k e ' I m o l d m a i n l y a r i a . H i l l I n r 1110 r o m a r k a l . e i i i e r e a s e ill l u l l " raill'I'l' roi 11 lone a n d I n r 1 lie c a u s a l i n n nl a m a j n r | >1 >ri u n i n i l i m y o a i l e e r s , m d i i s l i ; a 1 a n d 111(111-1 r \ - r o l a 1oi 1 I l l l r l l l l i o o l l ' w n u i d w e l l lil l l i i ' | . a l l n il ' l i n r 1In 2 l n \ \ ill u f i n d i l ' l r i a l e s a l i l i s h - m o i i l s im i l 1111 Us e u f l i n a r p m d u e i s ill l l i e o . ' . . i n . l i n e l i fe o f l il l ' or e i i t o m m i r i o s h a v e 2 i'" a l l \ l a c k e d im i I'n m i l l y i n l i m e . 1 \ p e a n d r. \ n i l . T h i s (nl|oo|.l ioal ova liialinii receives s ippnrl I'm m il 1h e d a l ; i . n 1l i e a i'1'ildisl ri- lull urn nl lull"' . alieers. lin eliaim es in llie sex l a l III d l i n t i 2 ' I ' m III d o r a d o -. a n d l l i e p m l . a l i l e i v ; i >n l !* m i d o r U iiiu' a i l e a s t a p a r i n l 1In 'SO | ) l | 0 - I i u m o i u i M a l . l o ' I I a n d 12 l niisidei ill2 llie r e m a r k : l.lo v a n a l i u i i ' w in eli ill" m a h - f e m a l e r a i i o im 111112 o m e n ' s l i a s s l i i . w n a l i i Il'l'I'CI 11 T n l.lr 12. Mai '- li'iiia lr -os i* 11io of lu n l l l l ' IT. if. 1i r i i n a i i N . 11111(^1927 a m i 1910-7.0 I SSli 1927 I '.MO Ail <'ii v Am In a' l; 0 in 1 'i \ A II I m liaiin . . W n lf I'.; .a' Srvl'al'tli .). a i'" . Seim 2. ."i 'ii.iiHrii-e 2. W.-ilil a.; ' Hoj ari i 2. a i i i mr ' Keillicli KiciioMcri i<n :i in I I ."<11 I. . I'lli'li- I. 7. Hil/. Ml Kikut li I. x 1ll'l.'ill'll 1.1' 11./.iu 'In /.i\ irkaa I'.ri lin I'i .i ~i la in l\...'lh M Uehi'lirli ill. .1.. Ii-iia 11a m i ni r n 1. i r kinl K nun* M.-rkrl ( Inr!m' I '. n r u ( 1nilliiM hi i l'm\ nr Aiianknr KilUl / >n 11 Kivy Kuni/.nii 17.: 1 11:1 17i; 1 7: 1 9: 1 19: 1 21 : 1 7: 1 IS.'I 21: 1 19:0 12:1 i'ublir llcalili Monograph No. 3(>. I97>7> 9 limes, in ilill'ereul lucidities. and in dill'ereiil demographic {groups, il is most unlikely (lull >ueli disere|>;meies ;ind changes :m' nl trihutahlo lo lliielualious in (lie intensity of one single factor, such its cignrol le smoking. Instead, they appear in l)i> due to alterations in (lie type and extent of the action of a broad specirum of en vironmental respiratory carcinogens ali'octing the momhers of the two sexes to different degrees. The marked and growing ])redominitnee of males itnions; lung eaneer victims seems to be due largely to the following factors: 1. Males are more extensively employed than females in occupations which produce and use known or suspected atmospheric carcinogens. Also, males work more consistently and over longer periods of their lives in such occupations. 2. Males predominate in outdoor occupa tions, especially in urban areas, where they be come exposed to carcinogenic pollutants in the general atmosphere (effluents of domestic and industrial furnaces, exhaust from gasoline and diesel engines, dust, from rubber tires and from asphalted and oiled roads). 3. Males more often than females perform heavy physical labor requiring deep and fre quent respiratory movements facilitating the penetration of carcinogenic air pollutants into the distal portions of the. respiratory tract, thereby increasing the frequency and degree of exposure. 4. Mali's more often than females work through the entire span of their occupational life within urban areas with proved carcino genic atmospheric pollution, while, females st for larger portions of their lives in the clear suburban dormitory communities. These considerations provide substantial su port to the concept that local differences general and occupational industrial air poll Iants may more plausibly account for an a preciable portion of the observed differences attack rates for the two sexes rather than c. local variations in their smoking habits. The doubts as to the unrestricted validit of the cigarette theory are deepened if critid evaluation is made of another dubious link| the chain of claims advanced to bolster U| concept. It has been maintained (Grahar that squamous cell carcinomas of the bronc mucosa are a specific response to ciga smoking since () this histological type of br chogenic carcinoma was allegedly rare 1920; (b) it has increased considerably sh that date in relative frequency in compa~ to other histological types of carcinoma, peeially adenocarcinoma; and (c) it is more of found in males than in females. The facts are as follows: Bronchioge squamous cell carcinoma has commonly b found with all known occupational respira cancers (table 13). However, many of agents have also elicited other types of p monarv carcinomas, such as undifferentia round cell carcinomas and adenocarcino Thus, there is no evidence supporting the that any specific respiratory carcinogen eli a specific and characteristic type of cancer, studv of lung eaneer records of cases obse Tattle 13. Itislo lo g ica l Iy o f o c r i i pa I innal respiratory can cers, according lo carcin ogen ic agent Agent Organ hqiuunoiis cell carci noma with or w ithout eornifica- lion R ound cell or o a t cell carcinom a A naplastic or polym or phic carci noma Adeno cinom*' T a r fu m es____________ . . . . . . L u n g ___ 3 i___ . ___ N ickel____ _______ _______ __ . .d o . Ch r o mi u m. . . _ _________ . . _do. 1 :____________ 3 : > A sb c sto s.. . . ____ . . . . . . __ d o . 111 2 2 R ad io activ e gases an d d u s t. _j . .d o __ ________ ______ 14 ; t) 7 3 i ____________ 6 R adioactive gases a n d d u s t . . __ . . d o . . __________ _____ - 3 1 Isopropyl o il_____ _____ . . 1_____do... _________ _____ 4 10 Environm ental Causes o f Cancer o f the before 1920. or even before 1900, readily e s t a b lishes (lie fact llml during those years squamous cell carcinomas of the bronchi were by no means rare* occurrences (Wolf, ISO.1) --S s q u a m o u s cell Table 11. ('.otisiiiuplim i o f tobacco in pm m ds |*er licail-vear. New Zealand and l oiled Kingdom . 1900-1930 (Easternl) Year i non _ 1 <>1 0 _ J 920. 1930. 1940. 1950. Pounds of l obacco per head-vear Xew Zealand I'n ile d Kingdom 2. 3 2. 09 3. 59 : 3. 28 3. 87 1 5. 30 1. 95 2. 22 2. 99 3. 31 3. 97 4. 22 carcinomas among 15 lung cancers- p 1927 -25 percent squamous cell carcinomas'll tween 1905 and 1918; Watsuji, 1903--23pfr( squamous cell carcinomas between 1Q2 1899; Adler, 1912--approximately 40 p0f J squamous coll carcinomas among 181 lu iu r 'j cinemas collected from the literature with ** quale histological data; Froc. First Nat Ca l Conf., 1949--44 percent squamous cell nomas in males; 11 percent in females. * Wliile adenocarcinomas arc more frequent' i females than in males, they also are more fayl qnent in young persons than in old ones (Ijni,J skog; Froc. First National Cancer Conf., 194}t t The evidence on hand scarcely supports t | contention that adenocarcinomas are of ciuWl enons causation (Lichiut) or that they have**! tioloirv differing from that of squamous carcinomas (Krcyherg). The male-female a*| Tahir 15. Average d eath rate per year per m illio n persons (m a les) from cancer o f ih e lung, 19JJ^ 1 ] New Zealand com pared w ith England and Wales (Euslcntt) 50C 40C 30C 0C IOC Age Period C o u n try i ; 35-44 45--54 1932-30. ____________ J X ew Z ea la n d ................... __________ . . ; i 1937-41. ____________ J ____ d o .......... ........................ ................... . . i 1940-41______________ . E ngland a n d W a le s.___ _______ ; 1 13 j 87 33 ! 108 120 | 424 ( 55-04 05-74 : 1 I : ov 'M | i-- --- * 2 ratio 1 158 | 204 : living 235 1 283 802 | 715 a i l 2.5:1 M tl not si 1942-40___________. . . . __________ 1942-40______________ -i E ngland an d W ales__ . 40 108 406 i 035 ! s i bornn 132 i 400 1, 072 i 1,032 1 9 ] Ttroni 1947-51___ . ....... ......... _j X'ew Z e a la n d ____ ............... . . . 1947-51______________ . 1 E ngland an d Wales . . . _____ _______ 43 287 732 ! 1,014 s ] condii 100 l 781 1, 082 | 1,857 j 7 Tin 1952-53____ _________ .; Xew Z ea la n d _____ __ _____________ 1952-53____ __________ E ngland an d W a le s ... _. . . ________ 01 ! 305 1, 027 1 1, 450 i i. dm ; the b 175 858 2, 171 2, 050 ; ` | . cigarc f tincc [' genic T able 16. Observed and e\peetel m ortality from cancer of the lung according New Zealand or tin *lu lle d Kingdom (K asteott) to place of Urtlkt] 1 *ith nttogi Age at entry to U nited Kingdom Fin not e Place of b irth Observed Expected 1 deaths | deaths U nder 30 30 and over per c; count Observed : Expected deaths deaths Observed j Expected j death deaths death* (fig. 5 lung Xew Z ea la n d ____ U nited Kingdom _ 032 : 309 ; 721. 8 _ 279. 9 i 201 ! 229. 2 the l' 1G8 'i * j JO p X ote: T h e significance of 1hc difference betw een observed a n d expected d e a th s in th e tw o countries is pCO.OOL j .A Amei nifico 12 Environm ental Ciiuses o f Cancer of the L *t. NUI. / T - ': -?;J 'vv. t Figure (> Trem ls in m'UcUm! em irom n eiiln l factors, C n ileil S la te s. IWJO-- (llaim iH im l). of lung cancer (1:0.7) among Mexicans ; in Los Angeles, as well as the ratio of for asbestosis cancers (Merewethor), do upport. the. view that women have any onal protection against the action of onmental respiratory carcinogens if identical itions of exposure prevail. ie claim that squamous cell carcinoma of tfonchi is in any specific way related to ette smoking thus may be laid to rest, no special histological type of bronehioicarcinoma bears any consistent connection any of the recognized respiratory car gos. nidly, it may be mentioned that there does m at any parallelism between the annual capita consumption of tobacco in different ttriesand their respective pulmonary cancer li,rates (Iicrbich and Neubold; Gilliam) 5). It has been calculated that the English Ifdanccr rate is apparently double that of Doited States, although the English smoke Pcent fewer cigarettes per capita than **Cans. This interesting and perhaps sig|0t observation, which fails to support the validity of the cigarette theory, is disposed of by its proponents hv assuming that exposure to cigarette tar is less severe for Americans who do not smoko cigarettes to the very end than for English smokers who, for economic reasons, indulge in this questionable habit. Recent epidemiological studies of Eastcott in New Zealand provided the most important data on this point. It was found that the relative consumption of tobacco in pounds per head-year for the population of New Zealand and the United Kingdom revealed an inverse relation to their lung cancer deatli 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 arc 30 percent higher for all United Kingdom fc Heahh Monograph No. 36, 1955 13 ^ 8 1 0 8 --55-----3 immigrants, hut for those who were 30 years of aye or more on entering New Zealand, the risk i' To percent higher, according to Easteott. Ditl'erenees in hahits of tohaeco smoking are unlikely lo contribute to this picture, in the opinion of Easteott. Ilerhich and Noubold pointed out that there did not exist any consistent proportional fre quency between cigarette consumption and lung cancer mortality for Upper Austria Kacrnten, on the one side, and for Steien and Tyrol, on the other side, although i four provinces there prevailed approxims the same per capita consumption of cigare These authors suggested that the high cancer mortality among the people living ir marginal regions of the northern slope of Alps might be related to climatic-atmospl figure Kim* in a n n u a l prod u ction or c o n su m p tio n o f can cer-related in d u stria l ch em ica ls between and 1948. PRODUCT UNIT l. B ITU M IN U S C O A L - P R O D U C T IO N IN U .S ., 2. F U E L M ILLIO NS OF NET TONS B R IQ U E T S - T O T A L PRODUCTION. THOUSANDS OF N ET TONS 3. C A R B O N B L A C K - PRO DUCTIO N . IN M ILLIO N S OF POUNDS 4. PET R O LEU M - PRODUCTION O F CRUD E M ILLIO NS O F B A R R E L S PETROLEUM , 5. P E T R O L E U M , A S P H A L T - P R O D U C T IO N OF A S P H A L T (FROM P E T R O L E U M ), THOUSANDS OF SHORT TO N S U,lsL.r ia ^ te io rrn ,,^ ouBh in aft f cig ar..|,^ . W gli l.,,,r l v ' n o in ih. loPc of i|,,, itmosp|1(.ri. letw cen |.*,, Jitions and to tin* (lin'dion of prevailing ^ which bring the industrially polluted ^ 0[ Vienna into the valleys of tin' northern Vfpiiic regions. ` ^i,uilar observations on the inllnenee of the ^vailing winds upon the relative frequency of yj11(r cancel's in different areas of the English ; glands were reported by Stocks. Herbich ifid Xoubold, moreover, found that the lung ,,(.t,r mortality rates were twice as high in ,>miiuinifies located along main highways, ,vre the atmosphere was polluted with exhaust from gasoline and diesel motors and the ,.,i( and fumes of asphalted roads, than among inhabitants of villages and towns situated M,10io from such traffic arteries. In fact, (he , in lung cancers follows more closely the remise in consumption of motor fuel and the | miction of asphalted highways than tin' consumption of cigarettes (fig. 0, Hammond; fig. 7, Hneper) and is similar to the increase in production of other cancer-related chemicals. It is apparent from the numerous observa tions and facts of general environmental nature cited that there exists an impressive amount of circumstantial evidence of different character and from various sources which strongly sug gests that several, if not many, environmental factors acting in varying degrees and combina tions cause or contribute to the development of pulmonary cancers and are involved in their recent rise in frequency. Much of the evidence on hand, particularly the irregular epidemio logical pattern of lung cancer, points to an important role which industry-related factors and the growth of modern industry may have assumed in these respects. Occupational Evidence and Respiratory Carcinogens Theconcept that environmental factors cause '(contribute to pulmonary cancers is supported w qiideniiological. medical, and experimental oili'iicc obtained from analysis of lung cancer mesof various occupational population groups a well ns by studies of lung cancers and their <$*filie and different causal agents present in a ranker of restricted worker groups and in 'il-delined industrial operations. {.fwdfiniological D ata on Large Wustrial Groups kpidemiological studies on the frequency of ***cancer among members of large industrial pwjps and trades have brought to light the wetice of marked variations in the liability ** Persons engaged in different occupations to aceer of t|ic lung. Tables 17-19 supply r-ia)g illustrations of these differences and ** *oine of the factors which may possibly bo i '"Twisihle for them. I Tdilo 17, which lists lung cancer death rates noveii industrial groups in Ohio, shows a ,,r iin I*** N4Cr Hrwhli Monograph No. 36, 1955 striking difference between the rates for agri cultural laborers and for employees in the nonferrous metal industry, with rates for trans portation workers occupying a position directly behind the rates for nonferrous metal workers. It seems to be characteristic of inhabitants of agricultural areas to rank first in death rates from cutaneous cancer and last in rates for pulmonary cancer. This is in accordance with the relationship between solar radiation and Tabic 17. Lung cancer death rates per 1,000 deaths from all causes for 7 industrial groups in Ohio, 5,309 m a les, 1917 (M ancuso) Industry D eath rate N onferrous m e ta l_____________ - - _______ T ra n s p o rta tio n __ __ _________ - _________ R ubber a n d p la s tic s________________________ Iron an d s t e e l __________________________ M ining a n d q u a rry in g ............................................j A g ricu ltu re________________________________ j Slone, clay, glass___________________________j T o ta l-------------- --------------------------------- 1 I 3. 22 2. 91 2. 34 2. 18 I. 53 .8 2 . 66 1. 76 15 skin ouncer and IIn' rolat ionsliip between low concent rat ions of mrcinogenic air poll 111an Is and lunjx cancer. Xonferrous metal workers, on the oilier hand, often have eon tael with dust, fumes, and vapors of some carcinogenic metals, such as chromium and nickel, or with arsenieals which arc 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. ' employment ratio of operating to nonoperai railroad workers in one of two large railr companies was 1:4. From this ratio, it app< that, on the basis of flic crude, nonstands ized (sex, age) figures presented, about 75 j cent of the lung cancers in railroad employ occurred among the operating group, wh supplied only 25 percent of the total numbei employees. Operating railroad workers eluded engineers, firemen, brakemen, cond tors, switchmen, and roundhouse persom that is, workers exposed to the inhalation of c soot and oil fumes from diesel engines and fi and lubricating oils, which contain carcinogei polycyclic hydrocarbons. Dunncr and Hicks recently called attenti to two additional worker groups, boiler mvli and grain dockers. In the experience Dunncr and ITicks, these workers showed i excessive liability to cancer of the lung. Twe la b le ltt. 1 rcqtirney o f lu n g cancer a m o n g op eratin g and n on op eratin g railroad workers j Railroad A. Period i Total lung cancers T ype of railroad worker i O p eratin g Num ber l Percent N o n o p eratin g ' ... ' _ Number Percent U ndeterm ined- i ii N um ber | - i 1010-50 I 29 24 ' 83 5 1939-49 | 104 50 57 15 Table 19. O ccupational groups w ith excessive in cid en ce o f lu n g cancer Occupational group Potential respiratory carcinogens Investigator M eta! workers, welders, m etal grind ers and polishers, wire m akers, tool and die m akers, foundry workers, m etal moulders, lathe workers, etc. Cigar m anufacturers and tobacco nists. Engineers, mechanics, machinists, plum bers, crane operators in sm elt ers, etc. P ain ters, d e c o ra to rs__________ ______ T ar workers, road workers, asphalters, pavionrs, stokers, patent fuel workers, furnace men, foundry laborers, rollers, etc. M etal d u st, lu b ricatin g oil m ist___ Tobacco d u st, insecticides, so o t___ M etal d u st, soot, lu b ricatin g o il__ M etal pigments, coal ta r dyes, carbon black, asphalt paints, solvents, vehicles (lacquers, res ins, synthetic plastics). Tar and pitch fumes and dust, soot. Kennaway and Kennaway; Tu and Grace; M uller; Dublin Vane; W ynder and Graham; L aughlin; Breslow a n d associa Seyfarth; Kennaway and Kcnna Enger; Vcrsluvs; Brinkmann. B E C C 1 1944 an d 1952; Gille T u rn e r and G race; M uller; Wj~ and Graham. BEC C 1 1944; M iiller; Dublin Vane; Fulton; W ynder and ham. Kennaway and Kennaway; Ful B E C C 1 1952; Registrar-Ge~ (1938); M cLaughlin. 1 Report of the British Em pire Cancer Campaign. 16 Environmental Causes o f Cancer o f the Figure II. ORE SMELTING CHROME PLATING PIGMENTS, PAINTS INK, PRIN TIN G A B R A S IV E ORE REFINING PLATING CHROMATE BUFFING NICKEL CARBONYL " SMELTING 'M IN IN G ARSEN IC PESTICIDES ph a r m a c eu t ic a ls ASBESTOS (?) MINING ISO PRO PYL OIL ( ? ) ASBESTOS PROCESSING ASBESTOS WEAVING TAR FUM ES PRODUCTION MANUFACTURING COKE OVEN SER V IC IN G ASPHALT DUST RADIOACTIVE DUS1 PITCH, TAR HEATING ; SOOT; PITC H ,TA R, A SPH A LT OUST M IN IN G ' . NASAL SIN USES LARYNX LUNG'i m m & kL tv-four luii"; cancer cases were found among VM dock workers at Mull, Mugland, of whom yOOwere exposed to grain dust. There were ti Itoiler sealers with lung cancer. Willi the oerption of I boiler sealer, none had any :ttdiological evidence of pneumoconiosis and |h` 5 had a slight degree of pneumoconiosis Jpnn histological examination. Xo lung cantn were observed among dockers who were W exposed to grain dust. It may he possible 4*1 boiler scalers sustain a carcinogenic expo| Wv io chromate-containing scale, if chromates I used as autirusting agents, or that these | *wkers sustain a pulmonary deposition of oxide. Whether specific vegetable matter , *me carcinogenic contaminant of the grain, ; as residues of chemical fungicides or other , f^'ssing or preserving agents, account for the abnormally high fiequcncv of lung cancer among grain dockers is at present a m atter for speculation. Mention also may he made of the recent observation of Fatilds on the excessive fre quency of pulmonary cancer among English iron ore workers employed in mining activities at two different locations. Xecropsics 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 , Hrahh Monograph No. 36, 1955 17 m tuberculous limps, 2 plus; in librolic, lungs willioul cancer and/or tuberculosis. 2 plus). The absence of a. positive correlation but ween pulmonary fibrosis and lung rancor wiis noted whim tin' t'vidi'iiri' on lung riinriT among tin* rmliosii'livi' on* mini'rs of .loarbimstbill and Soluii'i'biTg was analyzed (Ilui'pi'r). Although tin* actual causal factor responsible for the lung cancer among iron ore miners remains (o be determined, if may be mentioned (lull Levin and his co-worker's recently recorded a positive statistical correlation between an occupational exposure to iron oxide and beat, and cancer of the. lung. The studies of Tin-slow, lloaglin, Rasmussen, and Abramson ;>1S histologically proved eases of lung cancer in California suggested (he existence of an increased liability to lung cancer for members of the following occupational groups: welders, sheet metal workers, steam lit tors, boilermakers, crime operators, and nonferrous metal smelter workers, that is, individuals who are exposed to metal dusts and fumes; oilers, oil held 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 Pholoengravers Union raised the suspicion of an excessive lung cancel-liability for member's of (his occupational group. From the different lung cancer death rates listed for the various occupational groups, it is obvious that the total number' of workers possibly exposed to occupational carcinogens of known or still unknown nature is evidently very large and comprises workers employed in basic and processing industries, construction, trans portation, services, tr ades, laboratories, and pro fessions (fig. 8). It is, on the other hand, equally clear that the quantity and quality of imui iiiai.iun available oil the occupy aspects of lung cancer causation are depl0 J k p ira to ry r a t e d gene. defective because of an absence of extendy prolonged analyses of lung cancer deaths various industrial groups for specific E l y 1,c m i r t [i,e eau l p ' ainoi factors. The evidence on hand neverthd, f e . *pec> adequate for demonstrating that the wide v * (ions in lung cancer frequency appIln!^ existing between different industrial popnja, ' Oc groups are attributable to differences in n ,,,^ less well-definable occupational exposures * not to differences in cigarette smoking |,ahiu * O ccupational Respiratory Cancers and Carcinogens Conclusive evidence of the existciic,. ,( exogenous carcinogens and environmental r spirat-ory cancer hazards is provided by ^ epidemiological, medical, and experimental dm concerning occupational respiratory cam** A general view of the occupational respirat,*, cancer panorama, including causal agents. organs affected is presented in table 10, Scope of luiriroinneiital L u ix j Cancer I la An indiscriminate acceptance of tlugiven in table 20 as reflecting the actual scop?# these identified and recognized respiraum cancel' hazards, however, would be serioudi misleading, despite views expressed by seven* protagonists of the cigarette theory (Kingrri; Wynder and (iiaham; Levin; and other* Although a definite demonstration of sp-m, occupational lung cancer hazards has so Ut been made for only relatively restricted work* groups, tin1 evidence on hand is not only usequivocal but also indicates that other work* groups exposed lo the same causal agents >r subjected to identical or similar working coinilions are subject to the same hazards, h contrast to the apparently knv carcinogen* potency of the suspected, but unidcntiW agent presumably contained hi tobacco siuoh. the occupational respiratory carcinogens vt evidently highly potent, as shown by their lust respiratory cancer attack rates (table 21). Since environmental carcinogens have shown to produce cancers w'herever tlu-yopr* in adequate intensity and duration, and e*sidering the fact that many of the occupation* ..man's- ..I .,.Irillll oils, oil- eliv c cle for i ll .. Carci * -ui:ilie liydrc i .>:) tar ftuni I', iroli tim oii i >rWin ami sili !-..|iro|>yl oil \.l.~tos M-i.U V- i 1romates. - N:.-k. t Imimnc radiati Radioactive i Environm ental Causes o f Cancer of the k * Hrallh :Vy' lirtttiOi'V carcinogens occur us industryiJ ted general atmospheric pollutants, it may be assumed tlml these pollutants repreTM the cause of a significant |)orliou of lung ijcers among members of the general popula te^ especially fliose who live1 and work in j^lJy industrialized areas. 'Phe approximate scope of occupational ex posures (o (he various respiratory carcinogens may he estimated from data supplied by Bloomlield and his co-workers. From a survey of 1,50.3,204 workers employed in till industries of 10 Slates, it wtis found that 7,970 were exposed to fumes and dusts of chromium compounds and _ 20. O c c u p a t i o n a l r e s p i r a t o r y c a r c i n o g e n s a n d c a n c e r s r e c o r d e d d u r i n g p a s t 75 y e a r s , t l i e i r c a u s e s , s i t e s , **** and numbers Agent Site of cancer Numlx' r of rocurdod vUSO.S Veardis- covered I'nih'd St;i t<*s Other eniiulrie.s Total :Jr*lllC----Wwstos....... ftromates-- Sittrl-------Call Ur----fetroleiim oils, Jgipropyl o il.. .lniioactive chemicals. Total---- ----- h u n g ------ ___ d o __ . . . ___ d o .......... . . . d o . _____ . Xaros and nasal sinus . h ung---- ----- ----- hang ami larnvx. . h u n g . . ___ _ . harvn x.............................. Xasal siini.s. _ . h a n g------ . . . . . .Xasal sinus. .............. 1930 1934 1932 1932 1930 1930 1940 1S79 1931 7 ! 22 i 75 : o ! o 0 1 7 i i 4 i (i i 0 , 3 l 125 i oo ! ! 10 | 74 ! 05 . s4 : 51 53 33 0 0 ' 0 025 0 ; 23 90 140 S4 51 53 40 1 4 r, 025 3 1, 120 Table 21. llespirulory oaneer a tla ek rales, by environm ental carcinogens Carcinogen .Sites of cancers Incidenee in population at risk Attack rates Percent of all cancer deaths H ate per 100.000 _____________________________ M orbidity M ortality ' Aromatic hydrocarbons: Coal tar fumes__________ : Petroleum oils___________ Carbon and silicon polym ers: :yjw, propyl, o.i.l--------------- Anbestos______________ h a n g ____ L a n g ------ | IPianrra,,nyaxs.al l,ung. sinuses, 500:100. 000 `.>.000:100. 000 /1 10:100 45 154.5 ( nor mal 0.5). Uftal.s: Arsenic. : eliminates. foiling radiation: 2; Radioactive ores _ hung. Lung. sinuses. 1Lunin------------ - ; __ . 1 . ! (42 X n or! mill) j 574:100,000 _______ 1 i I ; (20 X nor mal). (13.2-20 percent asbestosis autopsied (0.S-2.4 p ercen t norm al)). 145.7 males (10.9 normat.) I40-33S (50-.N0 percen t of all deaths). M*lir Health Monograph No. 36, 1955 19 3,r?j"G, lo fumes mid dusts of arsenicals. For industrial workers of all 18 Steles. respiratory health hazards existed from the inhalation of dust, fumes, mists, and vapors for 45,000 indi viduals employed in asbestos operations, in 33.000 having contact with arsenieals, in 240,000 inhaling various types of metal dust,, and in 2 .500.000 liavmj' eut-iineous, respiratory, and investive exposures t,o various combustion and distillation products of coal far, pitch, creosote oil, soot, and to petroleum fuel oils and lubricat ing oils, greases, and cooling oils, to name a few. The highly defective state of knowledge con cerning the actual number of occupational respir atory cancers is, moreover, demonstrated by the fact (hat information on the existence and number of such cancers in specific industrial operations with recognized respiratory cancer hazards is distinctly spotty, not only as to data available from different countries but, also concerning (hose on hand from identical opera tions of the same country. The following ob servations may illustrate this point. The existence of an excessive liability to can cer of the lung from an inhalation of coal tar fumes by retort attendants of gas and coke oven plants has been established by a few re ports from Japan, Canada, and England. Apart from these isolated data, no others are available for similar operations from these or any other highly industrialized countries (Ger many, United States, France, Italy, Poland, Kussia). Likewise*, there is no official record available concerning tin* occurrence of respir atory cancers among carbon electrode makers and attendants in aluminum manufacturing plants, where workers become exposed to dust and fumes from the pitch and petroleum asphalt in the electrodes, and where, according to in formation available from four different countries, tar and asphalt cancers of the skin have been observed as the result of such contacts. It is, moreover, surprising that data on the occurrence of lung cancers among producers and users of arsenical insecticides have been re ported almost exclusively from Europe, al though the United States has been for many years the main producer and consumer of these products. Similarly, reports as to the existence of respiratory cancer hazards from an occupa tional inhalation of mists and fogs of lubricating and cooling oils have so far totally origir from Europe, despite the fact that Amertl industries offer ample opportunities for ideal exposures, that an excessive liability to cancer has been noted for paraffin pressers i ployed in oil refineries, and that the survey one oil company has shown that there wa marked predominance of operating refinl workers among the lung cancer victims of particular organization. Finally, attention may be called to the that the entire evidence, as to the existence! lung cancer hazards for radioactive-ore has come from the observations made inSch berg and Joaehimsthal. However, mining^ uranium ores has been carried on for 10 tof years in the Congo, Canada, and the Unii| States and extensive milling operations of African ores have been conducted in for many years without any official recordl similar respiratory complications among workers employed. Additional incompleteness of the existing! ords on occupational respiratory cancers be related to the possibility that pulmon cancers may have their causation from ages entering the body by an extrarespiratory rouj While, all known respiratory eareinogens area environmental origin and are inhaled as .1 pollutants, there exists some suggestive occuj tional, medicinal, and experimental evide indicating that agents introduced by oti routes may be effective in eliciting lung cano Several eases of lung cancer are on record whij developed after an oral administration ofsonieals and which appeared in individuals' arsenical dermatoses and skin cancers (Nd baucr). Lung cancers also have been obser in some aniline dye workers suffering fn primary occupational bladder cancer (Mulla following prolonged cutaneous, digestive, respiratory exposure to dusts and vapors certain carcinogenic aromatic amines, possible scientific and practical significance;^ these findings is suggested by the experiment observation of lung cancers in 10 percent rats given the potent carcinogen, 2-acetylan fluorene by an extrarespiratory route schowsky). A cutaneous as well as parent introduction of coal tar and several polycyc hydrocarbons as well as of urethane resulted i 20 Environm ental Causes o f Cancer o f the 'riK>nai,^ 5precocious appoiinmoo uud on increased nmn0f pulmmuiry tumors in mioo. jr-Hj ' ,0 )miK ssers survey ,,| ,pp ;s ``fiinrr s of 11,:. Pattern and Tppcs of Rispiratanj ( 'linear I hi -arils If a map of Ilie distribution and rolativo oon.iiiralion of Ibo difl'oronl carcinogenic air polluianfs wore proparod for a given area, it would vliibit a sort of crazy cpiilt jiatt-orn to which ,|lt. vcnoral atmospheric pollutants would fur- > tlu. fl., , istciuv r(> iiiiin.f, n ScIiik .. llillillg lt! 10 in _>i, uhh the overall background color, varying in j.ptii between darker urban areas and lighter -iral districts. Other types of carcinogenic aiaospheric poll uIant s having a more eircum^rilicd field of distribution would appear as rc'ularly arranged and variously sized and ' I'liii..,; ns of i|,, -hiiped spots and islands of different, colors .ripi'iimposed upon the general background. Kt'lfriiiin I'econl ,,f i: moulds to reason that such locally differing ,\|Kisure patterns arc bound to exert an im- long if. vrtnnt influence upon the epidemiological charyirr and incidence rates of pulmonary cancers isI.iiijr ,f various ngions, i one of the various K'CrS 111;i\ ulinoiiiir. 'HI !lgCl!>. rarriuogens would produce its own epideini.ilidcal scatter pattern showing a diminishing .pread of cancers from multiple carcinogenic jry rim!, ns iiiv `d ns ii.r xmliietion foci. The following three main types of exposure environmental atmospheric carcinogens may OCCIIp.v v distinguished: oviilcin, !. General environmental atmospheric ex- by mli..* S' CIUHvi- Mires to certain aliphatic and polyi-vclic hydrocarbons released into the atmosphere as ord win, i, .vmnpletc combustion products of domestic on of nr I aid industrial and ship finds, as parts of the Inals uni, | -\limist fumes of gasoline and diesel engines, as t s ( \ , ii- ( thrasion products of rubber tin's, and as dust obscnvU | fi,,m asphalted and oiled mads; exposure to ill}' frm.'i I irwninils contained in the mineral ash and soot (Mull, r ! d burned coal and in the ellluenls of certain live, Hin! I metal smelters, and related to the large-scale vapors | of arsenical pesticides; and exposure to ios. Til- | radioactive material either naturally released ficninv f fromthe soil and from bodies of water or pollut- crimen ini I ifc' die atmosphere as (he result of nuclear credit ' y ^plosions. (yjn inin.* I -'special and locally restricted atmospheric iti* (lh> i- 'posure to carcinogenic, pollutants of the air mrciU'i-'1 polycy, (*Sll 11<<I - exists in the vicinity of nonferrous metal smelt ers releasing in their ellluenls and from their slag heaps fumes and dust containing nickel, arscnicals. chromium compounds, and berylli um. Similar exposure exists in the vicinity of carbon black plants, oil refineries, tar distilleries, gas plants, and similar industrial establish ments producing large amounts of soot or other polycyclic hydrocarbon containing effluents, and in the vicinity of radioactive ore mills and atomic energy plants. Tlu* individualized type of air pollution con nected with tin' smoking of tobacco, with its suspected carcinogenic hazard to the lung in the special form of cigarette smoking, may be included in this type of exposure to atmospheric carcinogens. 3. During the last 75 years, an increasing number of specific chemical and physical agents have either definitely been recognized or are strongly suspected of being responsible for the appearance of cancers of the mires, paranasal sinu.,es, larynx, and lung among members of certain occupational groups. These specific occupational exposures arc associated with the inhalation of coal tar and pitch fumes and dusts, mists and fogs of petroleum derivatives, soot, vapors of isopropyl oil. that is. the crude, liquor from which isopropyl alcohol is distilled; arsenic, nickel, chromium compounds, asbestos, and ionizing radiation. Since the available evidence establishes such carcinogenic connections with only some, hut not with all, inhalants, such as silica or coal dust, it is apparent that carci nogenic activities arc not associated with all atmospheric pollutants. Occupational R<spiriitorij Cancers The res]liratorv cancers of recognized or strongly suspected occupational origin are im portant. not only as industrial disease manifes tations but also as prototypes of oliologiealij' and topographically identical cancers affecting workers in other, similarly hazardous occupa tions as well as of those cancers involving an indefinite portion of the general population sus taining for environmental reasons contacts with the same industry-related carcinogens. the I nn* f "Mic Health Monograph > o. 3 6 , 1955 21 :usi<is--55----- 4 f 'hysicnrli/ m in t I Stale o f A lm o s jiln ric I'a rc ia o - <l<-ns a m i I '< ijio < ira )> h ic< il D i x t r i b i i l i o n o f Cancers in /hi' H e s p ira to ry T ra ci In agreement with observations made ns lo reasons for the topographical dislnbulion of environmental enneers in oilier duet, systems (nrogenous and alimentary canal), respiratory cancers of environmental origin are preferably occupying sites where (a) the How of the inhaled polluted air is interfered with, that, is, in the normal narrows of the respiratory tract, stieli as (he region of the nasal turbinates and the larynx or its bronchial bifurcations, or (b ) where the respiratory tract, forms dead end sacculations, such as the paranasal sinuses and the peripheral bronchiolar regions of the lung, in which inhaled carcinogenic matter may accu mulate, condense, and precipitate. The traflic pattern of air pollutants in the respiratory tract thus corresponds to the distribution pattern of respiratory cancers elicited by atmospheric carcinogens. The second principal factor which determines the localization of an environmental cancer within the different sections of the respiratory tract is represented by the physicochemical status of a particular carcinogen, since this con dition largely influences the site or sites of chief exposure to an atmospheric carcinogen. Car cinogenic dusts consisting mainly of coarse particles arc mainly arrested in the nares, where they cause cancers of the turbinates. The nasal cancers observed among copper-nickel matte refinery workers inhaling the coarse dust of the roasters illustrate Ibis interrelation. The excessive incidence of larynx cancer among mule spinners inhaling carcinogenic shale oil sprayed from the revolving spindles likewise provides another example of this mech anism because it is likely that the relatively large droplets of this oil are arrested in the upper portions of the respiratory tract, making the narrows of the larynx the part of main exposure. Dusts or mists composed of particles having a diameter below 4 microns, on the other hand, penetrate into the deeper parts of the respira tory system and therefore are mainly responsible for the cancers of the bronchi. The bronc genic cancers found among chromate manuf t-urers, asbestos workers, and coke oven and i retort workers are represent,alive of this type exposure. Atmospheric pollutants of gaseo* and vapor types not only penetrate into lungs but also into the nasal sinuses, where may be deposited by degradation into soli (radioactive gases), by decomposition into soli' (nickel carbonyl), or by condensation and memation into liquids or solids (aliphatic epoj ides contained in crude isopropanol liquor). In assessing the, relationship between physicochemical status of atmospheric earcingenic pollutants and the localization of cancetr within (he various parts of the respiratory tract, <on.sidera.tion also must be given lo the fact th gaseous and liquid carcinogens may become ad sorbed to the surface of careinogcnically inert solid dust particles and behave under such con-' ditions more like solid particles. Such com binations, for instance, occur in relation to exposure to radioactive gases adsorbed to ro dust in uranium mines as well as concerning thd inhalation of liquid or solid aliphatic and poly, cyclic carcinogenic hydrocarbons adsorbed the surface of mineral road and industrial dust' or of carbon constituting the bulk of soot. Tlie first evidence indicating the existence < causal relations between environmental factor1 and the development of cancers of the lung watrecorded in 1879, when Harting and Hesse established the cancerous nature of the lung diseases prevalent among the radioactive-orr miners in Schnccbcrg, Saxony. This discovciy,' of historical importance and great present sig nificance, attracted little attention at the because radioactivity was still an unknown fact and cancers of the lung were comparatively t before the turn of the century and therefore < little medical interest. It was not until the third and fourth decade* of this century that additional, well-defined occupational activities and environmental agents were, again related to the causation of cancer of the lung and other parts of the respira-* tory tract, that is, the nasal cavity, paranasal;' 22 Environm ental Causes o f Cancer o f the Lunf ''mouses, :ini larynx. Aimmj; these additions to list of environmental respiratory ennrers tlie lung cancers among chromate nianu- jicturcrs (19.55). of asbestos workers (19:55), of 'tjrsoiiic workers (19)50), and of coke oven opera^rs (1936), (he cancel's of the nasal cavity, parayjtsal sinuses, and lung among copper-nickel ^joeller workers (19:52). the carcinomas of the 5jsal sinuses among luminous-dial painters '(1931). the cancers of the nasal sinuses, larynx, Sgnd lung among isopropanol manufacturers '(1946). and cancers of the larynx and lung imong workers exposed to lubricating oil k:*vs or mists (19:5(5. 1949). &Specific Carcinogens Inorgan ic Ch<mteals kv Nickel, one of the most industrially important, yjietals and principally mined in the. .Sudbury net of Ontario, Canada, has many uses: Iflloys (iron, copper, chromium, aluminum, molybdenum (employed in the inanullltlure of stainless steel, heat resisting steels, (tfergings, casts, wires, sheets, structural shapes, ' -labing, rods, bars, strips, and so on); eleetro|j^ting; catalysts; ceramic enamels and colors; Dements in paints and inks; storage batteries, so on. ^Exposure to nickel fumes and nickel dust of "iic nickel and its compounds or to nickel nvl vapors is, therefore, frequent for indus!|jal workers of many types and in many operu- While skin contact to nickel and nickel [fjptxnot infrequently results in the development I 'M apparently allergic type of dermatitis, iation of the volatile nickel carbonyl has responsible for an appreciable number of and often fatal poisonings. The puly manifestations (congestion, desquama- ||W. of alveolar epithelium, fibrinous acellular into alveolar spaces, bronchial mu- M*l.hemorrhages) are apparently attributable lo-'ie action of finely dispersed nickel from the disintegration of nickel car- piyl ii|H)n the pulmonary struetures. Krall't 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 n u m b er ol c a n c e ls of the nasal passages (nasal cavity and paranasal sinuses) and of the lungs among workers of the Clydacb plant of the International Nickel Company, located at South Wales, England, was made by Grenfell in 1932, all bough the. first appear ance of these neoplasms among the nickel refinery workers was noticed in 1924 (Biuider). Subsequent reports dealing with these cancers were made, by Stephens; Amor; Cooper (E. II.); Garozzi; Bridge; and Merewetber. 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 ease's of cancer of the lung from the nickel works. By the end of 1948, 4(5 of (lie 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, 3-20 years), and for the lung cancer patients, 25 years (range, 1-33 years). No eases of cancer of the larynx have occurred, and only 1 cancer of the naso pharynx was observed at Clydacb. The nasal cancers involved the turbinates, nasal septum, and paranasal sinuses (olhmoids). Of these, the majority were of the undifferentiated cell type (0), some showed a squamous cell character (3), while columnar cell carcinomas were uncommon (1). Of the lung cancers, of which histological studies were available in only 4 cases, 3 were of the small cell, pleomorphic type, while 1 was a squamous cell carcinoma. Similar observations were recently recorded from a Norwegian nickel refinery, where 3 cases of lung cancer were seen (L0ken). In one of these eases a squamous cell carcinoma was associated with sarcoid lesions, Goldblall and WagstafF mentioned that so far cancers of the respiratory tract have not been noted among the workers employed at the German nickel refinery at Ludwigshafcn, Health Monograph No. 36, 1955 23 nor lias then' been reported an iiniisinii fre quency of respiratory cancers among Iho workors of i ho Sudbury niokol oro minos ami smelters in Canada, although several oases of nasal sinus cancers wore, recently soon in ono Canadian niokol plan). Amor pointed out that the majority of indi viduals employed at. Clydach who developed respiratory eaneors wore not exposed to the inhalation of nickel carbonyl hut to that of nickel matte dust or dust from the nickel matte roaster (Lpken). More recent data communi cated by Morgan confirmed this observation, although exposure to nickel carbonyl vapors had occurred more frequently among the af fected workers than was apparent from the data previously given by Amor. The rela tively high incidence of cancer of the nasal cavity indeed suggests that, a rather coarse par ticulate dust readily arrested at the region of the turbinates may have been active in the production of cancers at this particular site, while nickel-containing vapors or a very small particulate dust most likely account for the cancers of the lung and nasal sinuses. As to the causative agent, various theories have been advanced. Amor favored the con cept that, the inhalation from arsenic-containing sulfuric acid used in the refining process was the active carcinogenic agent. I t is most unlikely that this is correct because the nickel refinery workers do not sulfer 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 (ITui'per). Amor staled that the refined nickel-copper ores are free from radioactive matter. The res piratory cancers observed among nickel refinery workers thus arc not identical in etiology with those seen in miners employed in the radioactive, mines of Sehneoberg and Joachimsthal. Workers employed at the roasters, in the nickel carbonyl operation, and in other parts of the plant, on the other hand, become exposed to the inhalation of dust, fumes, or vapors con taining nickel. Nickel is the common denomi nator for all of them. It thus is most probable that the respiratory carcinomas observed among nickel refinery workers are reaction products more or less finely dispersed nickel particles vapors. There is no evidence available, ho ever, which indicates that the inhalation; nickel in particulate, or vaporized form ls companied by pulmonary changes of a pneu eoniolie nature. The concept of a nickel etiology of respira cancers was tested in animals by Campbell, ` exposed mice to the inhalation of powd nickel matte and observed that these a had a lung tumor incidence significantly ] (ban that of the unexposed control mice, recent experiments of Hueper seem to dem sIrate more conclusively the carcinogenic p erties of metallic nickel. When pure me" nickel powder was implanted into the femo and pleural cavities and subcutaneous tissue' 175 rats, cancers developed at the site of inj tion in 50 of them. Whether or not nickel assumes a carcinoge role for cancers of other organs and follow exposures hv other routes is uncertain. It lie mentioned, however, that Araki and demonstrated, by spectrographic metlr nickel in human and animal cancers of vari types and sites. The nickel content ranged I 0.273 mg. per kilogram of fresh tumor tissue 0.2 ing./kg. No assessment of the degree of occupatio nickel cancer hazard can be made from the available since the number of workers at i unknown. Likewise, no definite opinion be expressed as to the possible existence extent of respiratory cancer hazards for pe" having for other reasons contact with fumes and vapors containing nickel or its pounds. CHROMIUM Chromium as a metal, alloy, or compound used for many purposes in industry. It is, this reason that a large number and variety workers have contact with chromium and i inium compounds and th at even restricted \ of tlic general population may possibly come exposed to these agents in the form of d vapor, fumes, mist, liquids, and solids (Bo and Rushin). Workers most likely to be posed to chromium and its compounds acetylene workers, aniline workers, bleac 24 Environm ental Causes o f Cancer o f the r d u c l s to articles 0r dde, l10u._ Nation of ,rTM is i pnouino- spiralon- 'bell, \v|1(( po\vcloi(.,| ! aninmi, ly hitrli,.r ice. Tl,,. > demii. nic pro|i. motalla femoral tissue of of inje. - inogeiii.ollowiirj It may id Mur" llOtllod* various, led from iissue io piUioiml lie duu l risk i* ion ciii. ice hiii) person* li dust. Is coin- mini i* t is f"f iety of ,| dine group* ly 1"*- >f dime fonrm lie e\- Is anidler* lilu('printers, dirome workers, rliromium platers, rhroniate manufacturers, chromite miners, cray on makers, dye workers, eleetroplafers, enamel workers, glass ami pottery frosters. glass eolor^ pottery glazers, artificial (lower makers, Ellery makers, linoleum workers, paint mak(r?, ink makers, painters, photographic workfri, pliotocngravers, polishers, printers, rubber workers, steel workers, tannery workers, vulfanizers, waterproofers of textiles and paper, folders, users of chromate antirust agents in : -ailroad engines, automobiles, steam heat inaallations, and bitumen and oil refinery workers. _\n environmental atmospheric eontamimi, Pon with chromium compounds may result, [foin the release, of chromium-containing indus trial wastes of chromate plants and of oil totmeries using a chromium-containing silica .-atalyst for the catalytic cracking of oils. An c'.vironmcntal spread of chromates may also followthe use of such compounds as antirusting tiri'iits in automob" "nd for anticorrosive mating of airplanes. Since many of the industrially used chromium compounds exert i corrosive action on tissues, skin contact ind'or inhalation of such agents results in the development of chrome ulcers of the. skin and nasal septum which in turn provide definite proof of an existing health hazard. Com menting on the appearance of such manifesta tions among workers in new industries using rkromium compounds, the. Chief Inspector of Factories of England and Wales remarked in ; bis report of 1944 that " the control of old Lizards in new industries is of interest to others u well as to the student of industrial health, hr it would seem that in many eases the hazard a not recognized until damage to tissue has !rn done, when old principles have to be ' rebamt and adapted to new uses." This reflective observation seems to be quite fpropriale when contemplating the possible rxHtonee of respiratory cancer hazards for individuals employed in the numerous indus*n*l Operations for which no pertinent pubkdieddata of any kind exist at the present, time. The observation of apparently occupationwnnectcd cancers of the respiratory organs, specially the lung, has been limited so far ta two types of operations, the production of | dimmntes from chromite ore and the manu facture of certain chromium pigments (zinc, chromate, barium chromate, load chromate). In these, operations, both water-soluble and insoluble eluoiniiun compounds are inhaled by the exposed workers. The chemical nature of (lie actual carcinogenic agent which is respon sible for the excessive liability of chromate and chromium color workers to cancer of the lung is st ill controversial. Although all investigators believe that some chromium compound or compounds arc causally involved, it has remained uncertain whether the compounds suspected arc hexavalent or (rivaleut, wilier soluble or insoluble, monoehromnles or dichromates. Water soluble chromium compounds (monochromatcs, dieliromales. and zinc chromate) are most often incriminated. Manenso and Ilueper recently pointed out that it may he. more likely that carcinogenic effects arc elicited by chromium compounds which are either not soluble in water or are only slightly so, because such chemicals, when inhaled as dust, would be retained and deposited in the lung and thus exert a prolonged effect upon the pulmonary tissues. Such chromium compounds present in a chromate plant would be represented by chromite, ore and its early conversion products preceding the formation of monoeliromales. These little water-soluble Irivaleut chromium compounds occur in the material present in mixers and roasters and are contained in the slag which usually is stored for future use in the yard area of the plants. Supporting this concept as to the chemical nature of the carcinogenic, chromium compounds is tin' fact (hat workers as well as animals ex posed to the inhalation of chromite ore dust have not only a high chromium content of the lungs but also an excessive blood chromium level (Mancuso and Urone). Recent experi ments on rats which inhaled finely powdered chromite ore dust showed that after 18 months a chromium level of 13.0 and 17.0 gamma, re spectively, in 100 cc. of blood was found in 2 rats studied. This finding, moreover, definitely establishes the fact that a fraction of the chro mium contained in chromite ore is solubilized in the pulmonary tissues and discharged into the blood. t.un* Health Monograph No. 36, 1955 25 ...... .... n u p p u rt u i a causal rule of triva- lent compounds may he derived from (lie ob servation that 10 of (he 20 chromate workers with lung cancer reported on by Alwens and Jonas in HITS 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 llu* slag heaps containing more or less "insoluble" chromium compounds was much more pronounced (Mancuso; Urone and Anders: Bourne and Yee; Bucked 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 pneumoneoniotie condition called chromitosis was described by Andrievskaya and Mislavskava in chromite ore miners, and by Lukanin; Lelterer, Xcidhardt, and Ivlett; and Mancuso and llueper 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 wen1 unsuccessful, Schinz and Vollmann, who im planted powdered chromium metal into the femoral cavity of rabbits observed after more than 3 years, 1 animal with cancer of the. lung, and 1 with cancer of tin' femur. It is definitely surprising that, an exci liability to lung cancer has been established far only for chromate workers in Gerrni (Pfeil; Alwens and Jonas; Teleky; Caro; Gross and Koelsch; Alwens, Bauke and Jon^l Lehmann; Marlincck; Gross; Koelsch; Alwi and associates; Goldblatf and Wagstaff) ai^ in (lie United States (Machle and Grogoriug. Gregorius; Baefjer; llueper; Mancuso at llueper; Imprescia; Division of Occupatioi Health, U. S. Public Health Service) and chrome pigment, workers in Germany (Baadi Gross and Koelsch; Letterer, Neidhardt ai Klett). Bidstrup found ft single case of 1 cancer upon X-ray examination of the chi of 321 chromate manufacturers employed for more than 10 years in English plants, whilj no data exist on this point in regard to mate-producing or -consuming plants in countries, such as Switzerland, Italy, and France. Apart from the excessive frequency of cancers among chromate workers which cording to American observations, ranges l.'i to 21 times the normal frequency of lung; cancers among the general male population, occupational origin of these cancers is strong^ suggested by the, shift of the age distribute toward younger age groups. This is particular! striking for the lung cancers present among; German chrome pigment workers, since 50 per cent of the cancers affected individuals befoneA the age of 40 years, when lung cancers of up?| known etiology arc relatively infrequent (laMe'i ' . I The quantitative data on the chromium coit*| tent of various organs and blood of persons witS| chromium lung cancer have been reported bjt several investigators (Alwens and Jonas; Let*) T able 22. Age d istrib u tio n o f eases o f ch ro m iu m cancers o f th e lu n g , according to type o f worker Type of worker 21-30 Age (years) j ! 31-40 j 41-50 J 51-00 01-70 71-80 Total : American c h ro m a te _____ G erm an c h ro m a te ______ Gorman chrome pigm ent. S 1 10 ' 19 10 1 3 , 7 14 12 1 5 | 3 1 1 1 26 Environmental Causes o f Cancer o f the j^f.JJiedhardl nnd Kiel l ; Mancuso and ^ cr). Spannagol recently noted a peculiar ehavii' of the c hr omi um conleni of t he blood ^ urine in ehroiitiitc workers hel'ore tmd after bedevelopmi'Mt of limy cancer. It was found ht in chromate workers the normal urinary jcrctiou of c hromi um reuses with the developof loots rancor while si mul t aneousl y the jjjpod chromium level heroines elevated. If ^ g ^ e d , this observation may have distinct importance in causal, metabolic, and diagnostic Aspects. With the exception of 2 e a s e s c a n c e r of tjjC nares (Newman) and I caneer of the auxiliary sinus (Cioldblatt and WagstaH') -the juBgwas the exclusive site of respiratory cancers ifogerveh among chromate workers. The total junibcr of these cancers is at present around [25 cases from all sources. None Inis been sported as originalinjr from nasal septum slews. Chromium pneumoconiosis thus seems to ^company the development of cancer of the in chromate and chrome pigment mannj^cturers. It is uncertain, however, whether ! ihepneiimonoeoniotie process plays tut essential 5% modifying role in the specific- eaneerization ?pcwcss or whether it is merely a phenomenon ' coincidental coexistence. AHSKNH' Arsenicals represent a byproduct or waste rjroduct of the smelting of many ores (copper, line, silver, cobalt, antimony, iron, bismuth. Cteckcl, tin, and lead). Arsenicals art* present Niathc smelter fumes and slag heaps. They are S:talcnsively produced and used, especially dur* impost decades, as insecticides, fungicides, and Vyrnnicidcs (sheep and cattle dip, grasshopper ; kit, rat poison), as well as a herbicide, especial\ It for clearing railroad righls-of-wav. Arsenicals applied as sprays to orchards and vineyards . md are dusted from airplanes upon cotton. . ton, soybean, and potato fields. They are em- jJotihI as wood preservatives, in the mantifacttire of glass, lead-base alloys, dyest nil's. Wonr.ing and paint pigments, and medicinal and cosmetic preparations (Mote). Arsenic tad its compounds constitute, according to i - "Environment and Health," a health hazard t: fer 35,251 workers employed in American in- iluslnos. i in& ttt'muu . estimate of th<> number of exposed workers, considering the long, although incomplete, list of dill'ci'cnl occupations entailing contact with arsenicals given by ( 'hamberlain. The estinuile. moreover, does not. include the milter consider able number of persons who are exposed to arsenicals for purely environmental reasons by ingesting oi'Kdtieids with foods!tills contami nated with arsenical insecticide residues, by consuming drinking water polluted with arseniea-ls leached into drinking water supplies from mine nnd smelter dumps, or by inhaling arsenieals released into the air from industrial establishments or bv small- or large-scale dust ing operations of arsenical pesticides. From the published evidence, it appears that environmental and nonoccuputional 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, Mneola and Manzano; Butzengeiger; Bander; Xieberle; Hofmann; Broil: Holinquisl: Montgomery and Waisman; Cannon; Arhelgor and Ivremen; Straube; Bohnonkamp; Hauser ami Simon; (unm et; and many others). While the causal rob1 which arsenic plays in the production of cancers of (lie 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 fur which such claims were made, there existed stigmata of chronic, arsenicism in the form of arsenic dermatosis with or without skin cancers. The inhalation of arseneiul 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 canccrigenic pattern similar to that seen in chromate workers. Under such circumstances, the existence of a causal relationship between cancer of the lung | f*Uic Health Monograph No. 36, 1955 27 .`ind chronic arsenicism appeal's to he a reason able conclusion. C'liest, and X-ray examina(ions oC 40 workers employed in an arsenic smeller revealed a mild decree ol' pneumoconi osis (Suupe). Although Saupe himself did no!- discover any evidence of lung cancer among the workers studied--even though they often were, alllicled by hyperkeratoses of the skin and perforated nasal septa--lie cited the autopsy observations previously made hv Sellmorl on 2 arsenic smelter workers who died from cancer of the lung (Teleky). Frommol briefly mentioned the occurrence of a cancer of the lung in a taxidermist who used an arsenical powder for dusting the pells of animals. Four additional cases of lung cancer in slice]) dip workers with arsenic dermatosis noted in one of these, were reported by Merewether, while Ilopkins 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 eases of lung cancer were observed among 142 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 slice]) dip workers (1910-22), recorded 2 additional eases 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 furnneeman in a sodium arsenite factory. Analyzing the mortality ex perience of a sheep dip factory, Hill and Fail ing found that 7, or 21.S percent, of the 22 cancel's causing death among members of this group were located in the respiratory organs, while 2, or 12.0 percent, were situated in the skin. There were during the period 1910-42 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 lung and skin, which were, eontined to worka in the chemical processes and were ab among members of the general group who wonjjjL be unlikely to be exposed to any specific hazard# Ferry, Howler, Buckcll, Druett, and SeliiH^M concluded from the. clinical evidence obtain^ th at, after many years of exposure to arsenic*^ these sheep dip workers may develop a squamo^ cell carcinoma in the bronchus. 'Pile most recent addition to epidemiologic^' investigations on arsenic cancer was made In Sncgircfi' and Lombard in studies of canc^ deaths among employees of several metallurgy eal plants of unidentified type. Of the to(4 of 109 deaths from all causes recorded durin the last 25 years, 12 were due to cancer of t | sites, and of these, 0 were located in the lung*. The investigators concluded from this evidenci) that " (here are indications that biological^ the human race made the adjustment t arsenic in the environment and that onlr-= rarely, when associated with other contributing] endogenous factors such as systemic disease,,or possibly factors such as radiation, it m I be capable of upsetting the biological cquilit*. i rium" ; and further " that the handling of? arsenic trioxide in the industry studied doe** not produce a significant change in the cancer i mortality of the plant employees; hence other/ factors in addition to arsenic must be con- j sidered significant in the causal relationship to cancer." In view of the fact that 50 percent of cancer deaths among employees of one plant sur-\ veyed were caused by cancer of the lung, the observations made in fact strongly suggests carcinogenic action of inhaled arsenic trioxid* upon the tissues of the lung of the exposed workers. 'Phis interpretation of the data of SnegirclF 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 andej 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 22). However, the existence of such connection* 28 Table 2.1. Litiipc cancer m ortality in several M ontana co u n tie s. 1917--Ml (L ull and W allacli) 1 County and total population 1940 Major industry r w f L o d g e , 13,027__ __ C opper sm elting 3_ Sjer Bow', 53,20<-------- : C opper m ining 3------------fLgde, 41,499........ ........ C opper m ining, sm e ltin g 11 CJUtin, 18,209------------- A griculture------------------- Num ber luun cancers M ale mI-acl-e 21 0 27 2 20 1 i) 1 0 , 1T o ta l ; I 21 29 25 ; l T o ta l i cancer deaths 1 1 98 i 259 : 299 ; 81 l'orcont Iiiiik ! cancer ! i 1 Mule j i M 1- j male 1 ; 30. 8 ; 0. 0 ! 22. (i ' 1. 5 1 12. 7 : 3. 5 | 3. 0 , . 0 t ' Annual lung | cancer death ra te /100,000 i M ale -'i inl ' aC l- c j j 145. 7 48. (i 1 4<>. 3 1 5. 2 | 1 0. 0 3. 9 12. 3 . 0 i personal com m unication of unpublished d a ta . The estimated crude death rate for lung canci ainonif white mules in the en tire I'n ite 1 S lates in 1947 was per 100,000 population. ** ifh e workers em ployed in copper ore m ining a (1 sniclti nu; inli .lie dust uul fuim s of arseM l i c CA m taincri in the tnd released as a b y p ro d u ct and w aste product during th e sm elting process. jboultl be acknowledged only when there firistftl at some lime clinical and, if possible, listolopcal and biochemical evidence of chronic mcnicisni- In view of the absence of any mcli evidence associated with chronic arseni(jjra among the nickel refinery workers affected Jr cancers of the nasal cavity, paranasal (inuses, and lung, and among excessive tobacco : mokers with cancer of the larynx and lung, ''t is most unlikely that exposure to arsenic |#t, fumes, and vapors plays any role in the i production of respiratory cancers in members of these population groups. IRON The extensive production ami use of various typesof iron and of diverse iron products offers Inqucnt opportunities for the inhalation of /'nut and fumes of iron and its various alloys compounds by iron ore miners, arc welders, '/finders, polishers, silver finishers, and metal Quarters. t The resulting red or black siderosis caused by Ijfdbnonary retention of Fe20 3 or of FcsOJTO. Kpiptctively, is considered an inert form of ^pneumoconiosis which does not cause, disability jh'irf which it least in part seems to be revers|pi. The deposition of iron oxide particles *S*" not elicit in the lungs a progressive and fplirked fibrosing reaction unless the inhaled also contains silica, producing then a fejdkosilicosis. -iThc coexistence of siderosis and cancer of 'ias occasionally been observed (Slew- art and Faulds, 1 case; Dreyfuss, 3 cases in watchmakers; Vorwald and Karr, 3 cases in hematite miners; Simons, 1 case in a blaster of iron casts). I t may be mentioned, moreover, that Kennaway and Kcnnaway reported a 2.25-fold incidence of pulmonary cancer among metal grinders and that Turner and Grace as well as Campbell noted an excessive frequency of lung cancer among metal workers. The most recent contribution to the problem of siderotic cancer of the lung was furnished by Faulds, who noted that among 192 iron ore miners coming to necropsy between 1932 and 1953 there were 17 lung cancers (8.85 percent). Ehrhardt and Giithert, on the other hand, noted that red siderosis of the lung does not produce a special predisposition to lung cancer. The uncertainly existing in this respect is further illustrated by statistical data provided by J. W. Brower, Deputy State Registrar, Minnesota Department of Health, on the num ber of deaths from lung cancer among iron ore miners residing in St. Louis and Itasca County (total number of miners, 13,313) against that of residents of Minnesota (population base, 2,982,483). 'There prevails a consistently higher lung cancer death rate for iron ore miners for the 5-year period than that noted for Minne sota residents (table 24). Experimental studies on animals exposed to iron oxide and hematite, respectively, gave con tradictory results as to the production of lung tumors. While Vorwald and Karr, using guinea pigs and rats, failed to obtain lung cancers witn Health Monograph No. 36, 1955 29 T a b le 21. D e a th s <lue to e a n e e r o f th e lu n g a m o iifi iron ore m iners am i residents of M innesota, (lirow er) 1950-51 V( ar Number of deaths Death rale per 100,000 i | Minnei sot,a resii (touts j St.. Lowis-i Minne Itasca j sota resi Cmoimneirtsy i! dents St. EonisItasca County miners 1950. ____ j 32,S 1951 . 2S9 1952 . . _ . , 329 1953, ____ 3<i7 1954. 315 5 ! 11. 0 4 i 9. 7 12 ; 11. 0 S i 12. 3 <) 11. (I 37. (i 30. 0 90. 1 HO. 1 (i0. 1 hematite dust, (hunpbcll reported ail increase, in the number of lung tumors in mice exposed to iron oxide over that of the control series. When the available evidence is viewed criti cally, it is still uncertain whether an exposure to iron dust conveys an abnormal liability to lung cancer. Although Warren and Drake recently concluded that the development of primary carcinoma of the liver as a sequela of hemochromatosis apparently depended in part on the intracellular deposition of iron, such considerations may not necessarily be applicable to pulmonary siderosis and eaneer. However, thorough and comprehensive epi demiological data on the incidence of lung cancer in workers exposed to iron dust are not available. Hence, a definite conclusion on this problem must be withheld. The availability of conclusive information on this point appears to be urgent, in view of the suggestive evidence recorded hv Faulds and because of the fact that damages have been allowed in the past by court action in at least one case of cancer of the lung, in the production or aggravation of which the inhalation of steel dust was alleged to have played a significant role. BKRYLMUM Beryllium is a metal which has found signifi cant industrial use only since about 1920. It was not until about 1940 that beryllium and its compounds were extensively employed for numerous purposes and products (berylliumcopper, beryllium-aluminum, and berylliumnickel alloys, glass, phosphors in fluorescent lamps and noon tubes, atomic energy pro(|,lrt4 t Aldrkte (('ramies, refractories. X-ray tube 'vin(j D.l pda'll th: vitreous enamel, radio tubes, textile fibers ^ ta in mantles'). It is evidently for this reason il! ! P untoward ('(feels in persons exposed to ihe - * halation of dusts and fumes of beryllium ^ bfee*1- ? {com bein its various compounds have been reeogni^ Tlic me only during (lie last decade. These manifest*.I- pounds ol lions were of both acute and chronic nature (*ct that far as the respiratory organs were concern^ jk>ii nf t)s (acute beryllium pneumonitis, chronic pnPB- jntraveno inoconiotic granulomatosis, berylliosis). Sor> mg l,0'v<1' investigators used the term "sarcoid" itl ^ jium sili> scribing the histologically peculiar, pulnioiurt qUi'Utly C manifestations. I t is remarkable moreor* *nd othc that chronic berylliosis has appeared not onlr oxide, he among exposed workers, blit also among jHT. introduce' sons living in the neighborhood of fluorescent : rrspirator lamp factories and inhaling their beryllium Sissons; B containing effluents (Eisenbud, Berghout and U rg en t, : Steadman; Eisenbud, Wanta, Dustan, Stead- period for man, Harris, and Wolf). CmmiK Similar observations on occupational hervh ostoogeni' liosis wore reported from Germany, Italv of herylli England, Russia, and Canada. Not info, noted tin qucntly, similar granulomatous lesions hart dying ""if been observed in other parts of the body after , tide ainoi the. usually traumatic introduction of beryllium r following dust, especially of beryllium phosphors from years, CO broken fluorescent tubes. The skin of the W u exp1 fingers and hands was the most frequent, pounds extrapulmonary location of these reaction!.. Uirougho' Beryllium granulomas have also been found in fact th a t the nose and in the anterior ocular structure. Wen repc It is noteworthy that beryllium apparently : of poorly once inhaled is retained over a long period of "ev en tu ati time in the human body, since beryllium has jum ably, been detected in the urine up to 10 years afl would lx cessation of exposure (Klemperer, Martin, and rabbits, Van Riper) and has been demonstrated in the over a p( lungs of rats 1 year after the inhalation of whether beryllium oxide (Dutra, Largent, Cliolak. berylliun Hubbard and Roth) as well as in their bone* Barnai (Stokinger, Steadman and Root; Barnes), coma fri where it may replace calcium. The skeleton possibly retains the bulk of the beryllium in the body far, only (nO-SO percent) if the inhaled aerosols are opm ent soluble compounds, such as beryllium sulfait adm inist and beryllium fluoride; the lungs retain tl* direct int bulk of beryllium if the compounds are in imo th e soluble, such as beryllium oxide. Experiment* cavity, a 30 Environm ental Causes o f Cancer of the U<1 PMic H f e :. go, Barnes, ami Denz, moreover, have that beryllium ions react rapidly with jttain tissue proteins and form complexes will) a proteins when introduced into the r <j. These complexes protect the, beryllium being precipitated by phosphate ions. Themetabolic, peculiarities of beryllium comylpindaobtain special importance in view of the r that Gardner in 1940 reported the producijjnof osteogenic sarcomas in rabbits injected Ravenously with insoluble beryllium-containpowders (beryllium phosphate, zinc, beryljRi silicate). Other investigators subseyntlv confirmed these results with the same other beryllium compounds (beryllium rB*le. )cryllium silicate, metallic beryllium) into rabbits by the intravenous or lipiraloiy routes (Sissons; Barnes, Denz and ,|Roqs;Hoagland, Grier and Hood;Nash; Dutra, Ijirgent. and Roth; Barnes). The preparatory for the sarcomas was 11-24 months. ['Commenting on the successful production of cnic sarcomas in rabbits after inhalation IbtrylliuM oxide, Hu Ira, Lurgent, and Roth the fact also that the hones of persons with berylliosis contained not inconsidcr- imounts of beryllium. They came to the ing conclusions: "During the last 20 considerable numbers of persons have exposed to dusts of poorly soluble com- of beryllium in various industries out the United States. Despite, the that cases of cancer of this type have not reported, it is possible that the inhalation iy soluble compounds of beryllium may te in osteogenic sarcoma in man. Prcy, the incubation period of such tumors be considerably longer in man than in and observations may be required period of years before it will be known persons who have been exposed to arc prone to have such tumors.'' also suggested that osteogenic sarfrom compounds of beryllium "might ly be another industrial hazard." So i.vrabbits have responded with the develBt of osteogenic sarcomas following the tion of beryllium compounds. The introduction of powdered beryllium metal femoral cavity of rats, into the pleural flhtnd 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 (Hucper). When in 1948 11neper proposed that the sarcoid pulmonary manifestations of berylliosis might he followed by outright malignant lesions in the lungs, this suggestion was received with a great, deal of skepticism. The recently reported successful production of bronchogenic carcinomas in the lungs of rats which, over periods of more than 1 year, inhaled (lust 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 he 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 tiie 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 (o 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 OF 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 * H*hh Monograph No. 36, 1955 31 ` '-i:.!'- A 1: ' i r of coal (pitch, lar, sool, creosote oils, anthracene oils, tar oils, and highly viscous oily and tarry fractions obtained by (be direct- hydrogenation of coal employed by (he 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 casuisticand epidemiological human evidence of occupa tional coal tar and pitch cancers has come, from England and Germany, it cannot- justly he assumed that Ameriean-inade coal tars, tar oils, creosote oils and pitches differ fundamentally in their carcinogenic properties from those manufactured abroad. The exposures sustained by the numerous types of American workers in a great variety of occupations and operations do not seem to differ from those found for their European colleagues, nor arc 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 Bcrgius process have been shown to lie highly carcinogenic to the skin and/or subcutaneous tissue of mice and rats, respectively, certain types of workers manu facturing and using such products and inhaling fumes or mists of these carcinogenic petroleum and tar oil substitutes may have a special lung cancer hazard. Manufacturing plants using the Bergius process have- been operative for some 20 years in Germany and have recently been constructed by several industrial concerns in the United States. Not only the environmental, but also to a greater degree, (tic occupational inhalation of dust, sool, and fumes produced by the incom plete combustion of coal results in the develop ment of a "soot lung," called bituminosis, 32 which is characterized by the deposition ^ finely dispersed carbon particles contaminate with hydrocarbons normally contained in COt| tar in the interstitial lung tissue. genological changes may appear in the lUn* after many years of exposure to high conc<^ (rations of soot in the air inhaled. Wiii]o t|* pulmonary deposition of small to moderai, amounts of soot in the lungs, such as is con, monly found in inhabitants of industrialize regions, does not elicit any appreciable fibron, proliferations, massive storage of soot particle in the lung tissues may finally be associate with an increase of the interstitial connect^ tissue and with pseucloglandular formations of peribronchial alveoli. The human evidence relating exposure t0 the other (100) luu following jriis stoke crane ope t ; pro asphalt ' painters, and auto, moreover among er Additii vided by u,monitor plants ai Canada i Kawnhat coal tar and pitcli dust and fumes with aa investiga increased liability to cancer of the lung is not extensive and is in part controversial. cases of workers ' The human evidence relating exposure to ro*l tar dust and fumes with an increased liahilitr to cancer of the lung is equivocal. Kennawu and Ivemiaway slated that "coal tar in iht atmosphere, whether derived from roads, dome*, t tic chimneys, or any other source, does noi hot tar h lung can einployet general i gcneratoi employee cause an exceptionally high incidence of canctr occurred of tlie lung." A similar statement was made (33 porct by Hugouncnq and by Hustcd and Biiimani J. lung car in regard to the liability to cancer of the lung varied fi for workers employed in the tar industry and being 1C in the construction and maintenance of tarred recently roads. McLaughlin did not find any lung cancer among 3,059 foundry workers subjected I to clinical and X-ray examinations, although there were 3 deaths from lung cancer among 04 deaths from all causes. Mcnz recently reported that of 93 workers in Swiss gas plant* who died during the 1926-46 period, 21, or 22.4 percent, died from cancer of all sites, thereby i confirming previous English experience that workers in tar and pitch operations have u> excessive liability to cancer in general. Iso lated observations of lung cancer in worker* exposed to the inhalation of tar fumes were t made by Koelsch (blacksmith, tar worker). Rodenackcr (briquette factory worker), and Miillschitzky (tar worker). / In an analysis of lung cancer deaths among members of different occupational groups forthe i ers. Of workers, cancer o etlunoid upper ar. It is li rales mi Followir 25 skin had bei during a of lung compau cancers cases of From the inhn of eerta plants,; years 1933-38 Kennaway and Kennaway, on Environm ental Causes o f Cancer o f the | Public I JjOother liiind. null'd llint an above-average (100) lung `"incur frequency existed for (lie following occupations: gashonse workers. 129; ^ stokers, ->s l ; pie p ro .ln ...P O P : gasworks ganc operators. 13S; gasworks superintendents, 136; printers, 119; chimney sweeps. 119; jsphftit workers. 104; metal polishers, 174; painters, 120: tanners. 141; street, cleaners, 109; jjjd automobile drivers. 149. They recorded, poreover, a ninefold increase of lung cancer among employees of a Canadian gas plant. ^Additional supporting information was proStiied bv the observations made among Japanese ^aerator gas oven workers employed in steel 1;?pUnts and among gashonse retort workers in [ Ouiatln ami England (Kawahata; Ktiroda and I'juvahata; Cruiekslumk; Doll). The Japanese j-'ferestigators found, within a G-yeur period, 21 ftfes of lung cancer among generator oven iWkers who were exposed to the inhalation of Mot tar fumes when stoking eoal. An excessive cancer rate was absent among workers t/goploycil in other parts of the steel mills. The ipaitfal incidence of lung cancer among the, rpnerator gas workers was 5 per 1,000 workers s deployed. Seven of these 21 lung cancers incurred in workers aged 40 years or younger vf{3percent against 18 percent in eryptogenetic ijang cancers) (Hueper). The exposure time ijnrietl from 9 years to 2.4 years, the average 1G.6 years. Similar observations were vJKWitlymade among Canadian gashonse work.vib. Of 14 cases of cancer among retort house /.Writers, Gwere due to cancer of the lung, 1 to tttcer of the larynx, anti 1 to cancer of the ^ittmoid sinuses (57 percent were cancers of the Zipper and lower respiratory trac t). : It is likely that similar lung cancer incidence ;?W* may exist among American tar workers. Jdlowing a visit to a tar distillery where some MS*kin cancers and more than 80 pitch warts been bserved among the 300 workers loingan 8-year period, there was found 1 case lung cancer. Subsequent inquiries made by yJBBjpanv officials brought the number of lung ytSfcttrs in this and other tar operations to G > f cancer of the lung. Irom the evidence available, it appears that . inhalation of tar fumes sustained by workers , tffwtain operations (coke o v en , generator gas . rants, gas plants, tar distilleries) seem to have an excessive liability to cancer of the respiratory tract. It is not unlikely that a more thorough and competent analysis of the death records of other workergroups, which have so far been found to lack such tendencies, might extend the typos and number of tar and pilch workers having an abnormally high respiratory cancer rate. A recent observation of lung cancer in a worker exposed to heated pitch and asphalt points to another source of occupational pulmonary' tar cancer of definite practical importance (Patch). l'KTROLEUM, KHALK OIL, AND NAT URA L GAS The carcinogenicity of certain high boiling fractions of petroleum and oil shale, as well as of the combustion products of some of these petroleum derivatives, such as oil shale and natural gas, have definitely been demonstrated not only on experimental animals but also on workers developing cancers of the skin after prolonged contact with these agents. Known carcinogenic chemicals, moreover, have been isolated from these petroleum derivatives as well as (heir combustion products (Bercnblum and Seiioental; Fischer, Priestley, Ebv, Wanless and Kehner; Falk, Steiner, Goldfcin, Breslow and Ilvkes; Waller; Kehner; Kotin and as sociates.) In addition to skin contact with carcinogenic petroleum derivatives many' workers are also exposed for occupational reasons to an inhala tion of oil mist or fumes (workers in paraffin pressing operations, certain groups of oil refinery' workers, spinners, inetal lathe workers, foundry' workers, metallurgical workers, printers, and so on). In spite of this established occupational respiratory exposure to petroleum and shale oils, there are on record only' tlirce cases of oil pneumonia among such workers, although such conditions have rather frequently been observed after repeated medicinal instillations of mineral oil containing nasal drops (oil aspiration pneu monitis or paraffinoma of the lung). In fact, two cases of cancer of the lung apparently' developing on the. basis of a medicinal mineral oil pneumonia have been described (Wood; Sante). The occupational evidence available or pub lished on this aspect of cancer of the lung is rather scanty and in part controversial. Kcnnaway and Kennaway found a relatively high Health Monograph No. 36, 1955 33 ratio of laryngeal I>111 not of pulmonary cancer in imdespinncrs, who inhale a mis( of the carcinogenic shale oil lubricating tlx1 spindles. Sou11min nolod tImt imdespinncrs occasionally develop multiple primary cancers involving Ilie stomach or the lung in addition lo cancers of die skin. .Scott, on the other hand, staled that he had not observed a single case of lung cancer among shale oil workers. Huguenin, Fan vet, and Bourdin, who ana lyzed a series of 112 lung cancers for possible etiological factors, found that IS, or 16 percent, were metallurgical workers exposed to the inhalation of nebulized lubricating and cutting oils, S were chauffeurs. f> were mechanics, and 1 was an engineer, Ilngucnin 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 Sit greaves 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 lo 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 processed petroleum oil fractions also conveys an increased liability to cancer of the lung. During a recent survey on cancer inci dence among employee's 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 ine'idene'e of cancer of the lung was also excessive. Paraffin pressers, who represent about one-tenth of the1 total employe'd worker group, furnishe'd 56 percent of the lung cancer observed. Since soot as a waste or comnu'rcial product has bi'en found to be carcinogenic and to conti known carcinogenic hydrocarbons, a thoro- and competent survey of occupational groups particularly exposed to the* inhalation of (operating railroad personnel; stokers; carhop black manufacturers; rubber, paint, and makers; painters; soot burners; printers; d engine drivers; carbon electrode manufacture!! and users in aluminum plants; smudge poj operators; phonograph record makers) is urgent necessity. The negative conclusion^ reached by Ingalls as the result of a survey the carbon black industry are based on evideni of dubious merits, because only 79 of the f evaluated workers have been employed for years or more in the industry. Since the major, ily of known occupational lung cancers havi an average latent period of over 10 yeartf Ingalls' conclusions are actually based on living and active workers. It stands to reason1 that an analysis of the death records of fortni carbon black workers may have told a different? story, especially if the diagnoses were based autopsy findings. Such investigations woi also add to our knowledge as to the existence-* extent, and type of bituminosis which might b* expected to exist in workers inhaling fine! dispersed soot particles. * At the present time, exposure to tar, asphalt, heavy fuel oils, lubricating and cutting oils, soot from domestic furnaces, incineratoi * industrial power plants, oil refineries, $j plants, metal smelters, carbon black factoric*! oil dumps and smudge pots, as well as exposure, to the diluents of diesel and gasoline engines^ represents the most widespread occupational; and environmental contact with carcinogenic; material. The specific carcinogenic agents con-; tained in these carbonaceous matters arc certain, specific aromatic hydrocarbons, which not in frequently are attached to carbon particles gife ing rise, when inhaled, to bituminosis or authi*| cosis; or they arc constituents of oily math*- which, when inhaled and retained in the lung^ cause oil pneumonia or paraffinoma of the lung*- Since pure anthracosis is not causally rela to cancer of the lung, the pneumoconioses coinpanying respiratory carcinogenesis by matie hydrocarbons do not play a primary essential role in this process, although pneumoconioses may lower the intensity 34 Environm ental Causes o f Cancer o f the a -s > ; r-,. IS # /' prolong tlxt' duration o! (In* ellVct of tin' specific ^rcinogomV chemicals oil (lie lung tissues. Since our civilization and economic, life lias been.built- around llie production and use of the linsie carbonaceous substances and their deriva tives, it docs not seem feasible to attain com plete protection against, exposure1 to these carcinogenic chemicals with (In 1preventive 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 wo sre still rather far removed from having (lie maximal amount of possible reduction in expo sure to the respiratory cancer producing hydrocuihons contained in the various carbonaceous iijbstnnees mentioned. Carbon and Silicon Polymers Keccnt studies of English investigators (Hen dry. Homer, Rose, and Walpole; Ilendrv, Rose, and Walpole; Haddow) have furnished i 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 dii'micals and the nmcromoleeular fillers of chromosomes. This hypothesis was evolved fromevidence obtained in the study of carcino genesis by nitrogen-mustards, diepoxides, polvctliyleiieimines, and related compounds. In viewof the fact that one of the various imams by which these substances may exert, their specific action in tin* cells is through polymeri zation, it is assumed that polymerized epoxide chains might interreact with proteins or mueoproteins of chromosomal origin, by cross linkage with multipoint attachment, and there by cause mitotic aberrations. The initial re action of one of the epoxide groups of mono meric molecules with the cell component also may start a process of polymerization by being followed by a self-condensation of the free epoxide groups into a polyethencoxy-structure. These concepts are important in connection with respiratory carcinogenesis for several reasons. Since Oppenlieimer and associates; Oruekrcy and associates; and Zollinger have *kowii that a parenteral implantation of various polymerized plastics (cellophane, polyethylene, polyvinyl chloride, polymethyl methacrylate, polyamide. Teflon, and others; into rats and mice arc followed by the develop ment of sarcomas at lhe 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 tin* ordinary giant molecular crystalline silicate's 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 polymerizeel silica crystals in which no oxygen atoms are le'ft carrying charges to attract positive1 ions, asbestos consists of giant fibrous molecules composoel of polymerized silico-oxygcn tefrahydra which arc arranged in chains or hands (Rarkes). Depending on the origin of asbestos, the fibrils may he short or long. Italian, South African, and Australian asbestos (amplubils) consists of fibrillar or ra diating crystals of calcium-magnesium silicate or soeiium iron silicate (40 percent iron oxide). Canadian, Russian, German, and French ashi'stos is hydrated magnesium silicate, which contains small amounts of iron oxide (5.75 per cent). Canada furnishes about 75 percent of tlie 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- Public Health Monograph No. 3 6 , 1955 35 tUit-i'- :i-4 >e-l i >-i ~ m i l s il l l i r i t; 11; 1 11i i l i b e r - : 1 1 V " >iS111111111\ hum In l i e :11>~t11<i nl lihroiis -Irueiure. 11ir du-l I- '.-ml In lie mrrl ( Wy e r s ; \ m u ;i lI . I ) u r k : m . :l l nl l Y u l i e Since 111< l.-liv'cr l i l i l ' i U :II'|` . ' i l ' l v- l . -d i n i l l . ' l.i'.MK-liinli-' ( liinlnri'i. ilii1 gr anul oma mils reactions form peri Io ouel ii<>I;11' librous cmli's willi giant cells and aslicsios bodies. 'Flics, have ;i lilil'ill.'ir core .-uni .-in iron st ai ni ng | >r<><ci n i,- or <-<>1i<>i<hi I silicic acid sheath. Whether ilic iron in die st ic:i 11is originates (mm die asbestos libers nr is deriv ed from lilond or Iissue elemeiils is s| ill eoid mversial. Th es e 1\\ o obs er vat i ons d e serve special ment i on liecause ol die ap p a re nt dependence of eaneerous changes in die limes of aslicsios workers upon die presence of asliesInsis and in view of die possibility dial die proleins ol die lung Iissue ma y specifically inlerreael willi free gr oups of die lilaiueiilary aslicsios molecules (l)ruekrev ami assoeialesi. 1lie eoexisleilee ol asltesiosis willi cancer of die lime was lirsi reported by Lynch and Smidi in I'.Kb'i (1 easel. T h e y later recorded 4 a d d i tional eases (Lynch and Smith: Lviieln. Simi lar observations have subsequently been re corded from this country (Stoll, Ibiss, and Angrist. I ease; Holleb and Angrist, eases: and 1Iombiirger. 4 easesi; from C a n a d a (Deslneiiles. Kosseau. (lilroii.v, and Sirois, 2 eases: ('artier. 4 eases: Rousseau. I ease); from K u r land ((iloyne. 17 cases: Ifarrison. 4 eases; Me re we the r, 41 eases; C u r c lo u . 1 ease: Owen. 1 easel, and from (lenmmy (Nordmann. 2 cases; Lin/,bach and Weller. 1 case; Horning, 1 c a s e ; W el/., 2 eases; Hdhme. I ease: l^omeniei. 2 eases; and Hander. I case). Th u s , there is at present a total of SO eases of nshestosis cancer of the lime on record. To this number must perhaps be added the S eases of cancer of the lung complicated by asbestosis which Ivennaway and Kennawav discovered in an analysis of the death certificates of males registered between 11121 and IDUS. Eleven additional eases of asbestosis cancer of the lime in workers in two English plants were recently reported by Doll, who felt from his statistical analysis that there exists a delinile e.-msal rela tion between these two conditions (table 25). Mer owol her noted that the mean a ire of males with asbestosis cancer of the lung was no.2 years (range 22-72) and that their mean expo- -ure time w;i> 21).I years (range li 40). while t mean aye of female eases was 44.(i years (ran 42 71 i and their mean exposure time was < years (ranire 0.5 IN). However, in iiiniiv cag i h e re elapsed a lung exposure-free ml erval ran imr from several months to 2(1 years before t| Imnr cancer became manifest (Wedler; Wyers 'Flic aye distribution of asbestosis cancer, the limy was; Cant ]>/>('par*: claunen*f :tl M.Y-1 I ] t."> -:> i } .Vl -it I rr -7" .................... I Since limy cancer of unknown etiology occur rather frequently before the aye of 40 and sine 2(i percent of ilie asbestosis cancers appearc, before i he aye of 44. it seems that (here existsi moderate shift toward younger aye groups 16) cancers associated with asbestosis of the lun| The exposure lime for asbestosis lung cancer, excluding the series of Merowolher. was: * Ilxposnrt lim e (years) Casts. lailf canon i - : t ____ ________ _____________ ______ _ ______________ i-in ........................... ............. ............ ........ I1-2U . . . _____ 2 1 and over...... .. . ________________________ T o t a l _____ ____________ 2, 'Flic exposure time of this series covers a wid range (1-24 years), indicating that type an, intensity of exposure to asbestos as well ai perhaps an individual susceptibility to asbestop sis play an important role in determining the development of this pneumoconiosis and thereby th,' possibility of a secondary carcinomatou sequela in the lung. There were 47 males and 15 females amon the 52 cases for which information on sex wa available. 'Flic male: female ratio is thu 2.5:1. which represents a marked shift towa the female ide when compared with the usua sex ratio ol 5:1 to 10:1 for lung cancers ol unknown etiology. Equalization of carcino genic exposure as represented by asbestosis, foi the two sexes, thus resulted in a trend towart equalization of liability to lung cancer. It is of importance to note that the mea 36 Environm ental Causes o f Caneer o f the Lu . Caiios f <l*-alh anion): m ale aslicsliis workers eoui|mre<i w illi Ilie m o rta lity experienee o f all m en in Kiigtuinl am i W ales (D oll) ( 'ause of ileal h Number of deal Iis Number observed I'.xpecleil on Kimland and Wales rales Tesl of sicnilicance of diirerence belween observi'd and exported ivalue of I',i espiratory diseases - and cardiovascular diseases-- mention of asbestosis. . . ......... .......... out mention of asbestosis........... sms, other than ltitiK c a n c e r... r diseases 3----------- --------- - . ......... All cau ses................... - .............- --------- ------------------- 11 0. s <0. 01)01)01 It < 0. 001 4 4 : 7 7 l} >0. t . :w 15. 4 ' < 0. 000001 Deluding 1 case with pulm onary tuberculosis. Deluding pulmonary tuberculosis. Deluding 2 eases (benign stricture of esophagus and sept icaemia) in which asbestosis was present b u t wa3 night to have been a contributory cause of death. [ 128 noncomplicaled cases of asbestosis ,nly 44.2 years (Mercwether). One may ide from this observation that some of individuals apparently died from asbesbefore their lung cancer had a chance to up (Linzbach and Wedler). ditional support for a causal relation jen asbestosis and cancer of the lung is ed from the fact that Mercwether found, ig 266 cases of asbestosis observed during 46, 31 cases of coexisting cancer of the ((1.65 percent), while there were 91 cases ing cancer with an average age of 59.4 i among 6,884 cases of silicosis (1.32 peri-.which came to autopsy. Wcdlcr noted wbestosis cancer of the lung occurred in net, or 15.2 percent of 92 cases of asbestosis riuch necropsies were performed, whereas normal rate of lung cancer in autopsy tUI was estimated to be 2-6 percent. Ota, Vo: aid, Warren, and Cartier are all lAdceptical as to the actual existence of ttcessive liability of individuals with to lung cancer, and Cureton and $4 ;cr are undecided on this question, finvestigators, however, favor this eonjjjjr.' consider the existence of a causal ife ' as highly probable or established |j|w ay; Mercwether; Telekv; Xordmann; m Gross; Lecoeur; Smith; Saita; Wcgelin; Ijchand Wedler; Stoll, Bass, and Angrist; oU). pbistological types of lung cancers ob- served do not deviate essentially in their relative frequency from those Siam in cancers of unknown etiology. Then* were 22 squamous carcinomas, 7 oat cell carcinomas, 4 anaplastic carcinomas, and 6 adenocarcinomas. In view of the fact that one of the .Norwegian eases of nickel cancer of the lung was associated with pulmonary sarcoidosis, it may be mentioned that Skavlcin and KitterhoU' reported the combination of an asbestosis with a sarcoidosis of the lung which, however, was not compli cated by a carcinoma. Attempts have been made to refute the claim of a causal relation between asbestosis and lung cancer by determining the frequency of pulmonary cancer among the total worker population of the asbestos industry (Cartier; Yorwald). Such a procedure is bound to give misleading results. It is quite immaterial how many workers employed in the industry develop lung cancer, since an undetermined portion of these workers doubtlessly sustains either no exposure or only a low intensity exposure and thus does not develop asbestosis of the lung, which is the prerequisite for the subsequent cancerous development. Asbestosis must be considered as the essential stigma of an elective exposure. It is, moreover, neccenjry to know the sex and age distribution of the worker population studied and evaluated as well as to know the duration of employment and exposure. A marked labor turnover in the industry is not inducivc for obtaining reliable information on lth Monograph No. 36, 1955 37 llio iicliiii! number of hmj; cancers and asbestosis cases which may result from effective exposures. For these reasons, no definite conclusions ran bo drawn from the observation of Cartier, noting 8 eases of hmg 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 (Bolnne). Ivennaway and Ivcnuaway re|)orted that. 8 lung cancers may be found among 4,000 males of (lie age range, 45-64 years. The evidence on hand, at any rale, has con vinced the West Gorman Government- to make asbestosis cancer of the lung a compen sable disease (Tabershaw). The experimental approach to Ihe problem has so far given equivocal results. Vorwald and Karr, using guinea pigs which were exposed to asbestos dust, obtained negative results. Xordmann and Sorge employed mice for this purpose and claimed (o have produced brouchiogenic carcinomas with pulmonary fibrosis in two mice. This observation needs to be con firmed before if can be accepted. isopROryL on. 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, xiscous liquid, slowly turning, upon standing, into a brownish to blackish tarry material --contains polypropy lene compounds as well as propylene ether, which may be oxidized into propylene peroxide and propylene epoxide having a tendency to polymerize. Polypropylene, merchandised as Opponol K, is used commercially as an oil for cable filling. Workers employed in isopropanol manufac ture have been exposed to the inhalation of vapors, mist, and dust of isopropyl oil escaping from leaky pipe connections, defective, pumps, and gaskets, or spilled on the floor at the occur rence of breaks in pipelines and during repairs on pipes, pumps, and stills. Weil, Smyth, and Xale reported that, between H)2S and 1950, a total of 7 neoplasms affecting various parts of 38 tin* respiratory tract (nasal sinuses, 4; lai 2; and lung I) came to observation among employees, or in 8.4 percent of those w| worked more than 5 years in the isopropa^ plant. Five additional cases were observed ^ another isopropyl alcohol plant, making a total of 12 eases, 7 of which involved the nasip sinuses, 4 the larynx, and 1 the lung. It 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 nonay rate of 0.3, and that the incidence of these can. eers exceeded the expected incidence 21.3 times. From the evidence available it is likely thy these cancers as well as those associated with asbestosis belong to the new class of "polym^ cancers." MUSTARD QAS The alleged carcinogenic action of war gy: poisoning figured prominently in the specula, lions as to the cause of the increase in lungcancers observed during the early 1920i (Kikulh; Brockbank; Klotz; Derischanofb Hiinermann; Reiche). Residuals of warfare gassing were noted by Matz in 10 out of 13g cases of pulmonary cancer among Americas! World War I veterans. Four out of 64 casesof lung cancer, recorded by Brockbank, were gassed badly during this war. Macklin noted that war gas poisoning occurred in 5 percent of 164 eases of lung cancer among male*,' while it was present in only 2 percent of soldiers without this disease. Ivoelsch con* ceded that a few cases of lung cancer exhibited a doubtful etiological relation to war gas injury,' which was claimed to have caused also two cancers of the larynx (Spamer; Tilley). No distinction was made at that time as to the particular chemical nature of the various gasa used during World War I. These contentions found little acceptance si that time. From a carcinogenic viewpoint, special interest has to be attached to the various arsenic-containing gases, especially Lewisite, and to mustard gas (dichlorcthvl sulfide). The arsenic../"`vr gases, when inhaled, theoretically may not only cause nonspecific chemical damsgt to the respiratory tissues but also may product there a specific delayed carcinogenic reaction, P li ra lli an ni At o'l tie |H> hr< cm plo M Lt" wo i old poi (Y. thecan exp proi V cam supj date atte view prod untu and ruhb briit} latio type stud; coini parti systc Up sure tivch siona, activ. Environm ental Causes o f Cancer o f the LoM1 Public 5*55 jji i' : as that scon exceptionally after skin hums ri'jjj these pises. Cancers of such an origin belong to1' group of arsenic cancers. ' VA possible carcinogenic action of mustard upon the bronchial mucosa, on the other bwl, may be related to its cross-linking and jjdioinknctie eU'eet. and may be identical with 'that demonstrated to exist for experimental %imals exposed to several sulfur- and nilrolaustards of aliphatic and aromatic nature. According to the inonlioned theoretical con;p*s' the causative mechanism operative in these cancers resembles in some respects that Possibly active in polymer cancers. During the last few years, three eases of \ Jconchiogenic carcinoma ami 3 eases of larynx ;<jnccr were observed among long-term cm- ; plovees of the Japanese Army Poison Gas Manufacturing Plant on Okuno Island, where 'lewisite and Yperite were made. One of these 'workers was 30 years old and a second, f>3 years <id. All three suffered from chronic war gas ^poisoning due to contact with mustard gas Jr{fcmada, Ilirose, and Miyanishi). In view of observations, the distinct probability of frtreinomatous effects upon the lung following yWposure to imistard gas or chemically related `^products deserves serious consideration. While the fundamental concept of " polymer Queers" is a tentative one and needs to be. itiwpported by additional evidence, the available arc sufficiently important to require serious ^attention from both a scientific and a practical i'ffiewpoint. The rapidly expanding industrial ^production and industrial and general use of Sutural and synthetic polymerized substances ^ind cross-linking chemicals in plastics, films, jabbers, rosins, adhesives, textiles, and so on. /brings a considerable part of the working popuvhtion into direct contact with chemicals of this it seems to be advisable, therefore, to AKody these population groups during the .Lcoining decades for the occurrence of cancers, /`.particularly those affecting the respiratory yfcWkcm. y:- Radioactive Chemicals v ' Up to some 10 years ago, occupational expo- Avflfcre to radioactive agents was limited to rela- liwely small groups of industrial and profeswwial 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 (heir 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, metallurgie, 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 Silverman), sewage disposal workers, paper and textile manufacturers, and so on. It is an established fact that cancers of the skin, connective tissue, and bone and bloodforming organs have resulted from excessive 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 annuals a fibrosis of the lungs (Kalbfleisch; Doenecke; Belt; Bcrgmann and Graham; Engclstad; Warren and Gates; Leach, Farrow, Foote and Wawro; McIntosh; Warren and Spencer; Widmanu; Bauer; Bauer and Schraer; Tonges and Kalbfleisch; Freid and Goldberg), occupational exposure to radioactive dust and gases has often been complicated by simul taneous inhalation of dust containing various metals (chromium, nickel, iron, arsenic, cobalt) as well as silica. Pulmonary cancers observed among radioactive-ore miners, therefore, have V.e i complicated in an appreciable number of cases by silicosis of a minor to moderate degree. It is for these reasons that the radioactive genesis of the cancers of the lung noted among these miners as well as among uranium and .. .ffeUie Health Monograph No. 3 6 , 1955 39 radium rclmerv workers h:is been doubled by some investigators. who fell that. one of the various nonradionetive metals or the silieosis represented the main causal or an important, contributory assent (Schinz; Lorenz; Selunorl; Kosloski and Saupe) o r t h a t th e 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 Sehneeherg and Joaehimsthal were principally attributable to a hereditary predisposition created by inbreeding of the mining population (Macklin and Maeklin; Lorenz; Vesin). The "mala metallonun" 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 10th century and was sub sequently mentioned by other investigators (Hcnckel; Schedlcr; Thiele). However, it was not until 1870 that its malignant neoplastic, character was correctly recognized (Hailing and Hesse). This judgment was, subsequently confirmed by Cohnheim; Aueko; Arnstein; Ulilig; Risel; Selunorl; Beyreuther: Rostoski, Saupe and Selunorl; Lange; Neitzel; Dolmert; Baader; Teleky; Hueck; Rostoski, Saupe, and Selunorl; Thiele; Weber; Ivoelsch; Lindemann; Doubrov; Brandt; Brezina. Although the miners of the uranium ore mines in Joachimsthal (Czechoslovakia) also were suffering from a fatal lung disease similar to that observed among the cobalt ore miners in Schneeberg, Saxony, it was not until 1020 that the cancerous nature of the pulmonary disease among these miners was recognized (Lowv). Additional confirming evidence was provided later by Beutel and Waldrich; Ziel; Sikl; Saupe; Feller; Pircban and Sikl; Baader; Behounek and Fort; and Teleky. Evidence supporting a radioactive origin of the lung cancers among these two groups of miners was provided by the observation of lung cancers among employees of radium refineries and radium laboratories. Lowy reported the occurrence of two such cases among the workers employed in the laboratories of the Joachiinsthal 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 bv Teleky and bv Neitzel in a German technii of a radium laboratory. The cancerous lw was found to be radioactive. Four cases of 1 ^ cancer have recently been observed, accordii to Baader, among the workers employed in tb*,radium ore processing plant in Belgium, a the. occurrence of such complications was p^/ viously said to be absent (Maisin, citingDelaet):Perhaps the development of a bilateral alveoli carcinoma of the lung in a woman 16 years aft*t the, intravenous injection of 75 ce. ofThoroti may also supply suggestive evidence that W ; cancers may originate from radioactive matoritl used medicinally, when such materials become arrested in the lung. Mention may also be made in this connections of a report of M artland relating the occurrence of cancer in the ethmoid cells in a luminous dial painter, and of two additional cases t*.. ported by Aub, Evans, Ilempelmann, and' Martland. Dial painters not only ingested radioactive material which became deposited in the hones and produced osteogenic sarcomas,' hut they also inhaled this m atter which, thus;: may have produced the carcinoma of the paranasal sinus. An c not I ; Jo h a have niorc of ^ ? conti a ra ; anioi . T1 Seim i twee ; (if tl' rang incid rocci durii of hi Nthh .12:11 ering peril rang' gunu in a 400 ! The four cases of cancer of the lung recently? 1920 reported in an industrial population at a# r. at S< atomic pile site, however, are definitely noG vean causally related to any specific radioactive ex ally t posurcs sustained by the workers concerned.:; Sclir; In these cases exposure and latent period went T1 iOnnsuftfhiecieontthlyerlohnagndto, ctahuesearlguunmg ecnant ctehra(tLothveen). ? l d1i9e3d9 workers were, in part, not directly concerned,' appr with radioactive material carries little weight; achit Doubtlessly, they had at times environ has mental contact with such a material when th* nuini meteorologic conditions were unfavorable for at a the ready dispersal of radioactive wastes alj data this particular operation. M the ( In favor of an occupational and radioactive M origin of the lung cancers among the Schnceberj Selin and Joachiinsthal miners is, moreover, the fact; onsti that the excessive liability to pulmonary noo*| have plasia is limited to the workers employed under*,) pass: ground and is absent among the workert3 (Joa> employed aboveground, and among the popula-y Bela tion at large of Schneeberg and Joachimsthd,! Lori including the employees of the cobalt pigment- It w plantusingthe Schneeberg ores (Bauer; Sclimor!).: of p 40 Environmental Causes o f Cancer o f the h a l PU '^excessive lung cancer attack rale, also, has pot been found among tIn* miners of Urn nearby Jobs'111 Georgenstadl region, where the mini's fevc a low radioactivity. There is, further- re, no valid evidence on record that miners of arsenic-, chromium-, nickel-, and bismuth, (oiitainmg ores are affected hv lung cancers at ! rate even remotely approaching that, seen uiiong the two radioactive ore miner groups. The attack rate, of lung cancer among the vlineeberg miners has consistently been be- ; ,*pen 75 and 80 percent since 1S79, while that of the Joachimsthul miners has been stated to ^ re from 40 to f>0 percent. However, this incidence rate may he too low. considering the rfcoiit statement of Bander, who noted that during the period 1909-40, a total of ISO cases of lung cancer were acknowledged as compell able diseases and that in 1929 there were only 323miners employed at Joaohinisthal. Consid ering the fact that the exposure and latent period of lung cancer in Joachimsthal miners ; fliers from 10 to 20 years, it may justly be as sumed that these lung cancer eases originated a a miner population of approximately 000 to J(H) members working at these mines between 1920and 1900. The exposure and latent period tt Sdmccbcrg is stated to vary from 15 to 18 rears for the majority of the eases, hut occasionillvto he as short as 7 years (Bander; Rajewsky. sdiraub, and Kahlau). The total number of Sehneeberg miners who died from cancer of the lung between 1879 and 1930, according to available records, stands at approximately 400, while the number of Joadiitrsthal miner's who fell victim to this disease has reached 225 (1920-43). 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 10), which shows the definite shift toward younger age groups. Measurements of the radioactivity of the Sdmeeberg and Joachimsthal mines have dein; *trated that, in both places, mine air and dust i bare an excessive degree of radioactivity sur g in g many times the maximal tolerance dose j.-(Joachimsthal 30 times (Poller); Behounek; t Behounek and Fort; Tschelnitz; Ludewig and , Lorensor; Lange; R ajew sky; Stoeklasa). , ^ w*ts suggested that the recent introduction *f pneumatic drills into these mining opera- lions aggravated the hazard by increasing the product ion of fine particulate dust containing solid radium. Repealed 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 radioartive mine dust (Sehmidtmann; Lowv; Campbell; Dohnert; Kahlau; Rajewsky, Sehraub, and Kaldau). Sehmidtmaim obtained neither pneumoconiosis nor pulmonary cancer in animals exposed for 2 years to the inhalation of .Sehneeberg 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, lu experiments of Dohnert and of Ilucek, mice wen* placed in cages within the mines. Some mice developed moderate chalicosis, while pulmonary and mediastinal tumors (adenomas, round roll 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 afreeted animals was small, and the interpreta tion of the results us to their significance; was therefore difficult. Kahlau and Rajewsky, Sehraub, 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 cont rol series). While they concluded from this evidence that the radioactive origin of lung cancers in Sehneeberg and Joachimsthal miners was confirmed, it seems to be advisable to con sider the evidence obtained by these invest/* gators as highly suggestive, hut not conclusive,'< because groat variations in the, incidence rate of lung tumors occur among different groups of mice belonging to noninbrod strains. Additional, mildly suggestive observations have been reported by Lorenz, Heston, Eselicnbreimer, 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 hU it Health Monograph No. 36, 1955 41 greater significance in this connection arc the thuliums of hisco and Finkel. who found lnetnplaslic and nco|>lastic proliferations of the. bronchial epithelium in rats inhaling an aerosol of radioactive cerium. Similar results were obtained with plutonium bronchi into the lungs of rats. Since- uranium ore miners inhale not only radon and radium dust, hut also uranium, which may he retained in the lungs, llueper, 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 (i months. Evidence tints produced shows (hat focal accumulations of uranium, which is an alpha-radiation emitter, may exert a cancerigenic action upon the surrounding tissues, hut it docs not.-discriminate between the influence of metal toxicity per se ami 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 (Mart-land; Evans). In commenting on the production of lung cancer by atmospheric carcinogens, an editorial (Lancet, 1952) remarked, "radioactivity of Joaehimsthal mines is stated to he JO 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 Joaehimsthal (Sikl) aptly reflects the human misery produced if such hazardous working conditions are permitted to persist. While there thus can he little, if any, doubt of the principal role of ionizing radiation in the production of lung cancers among radioactive ore miners and similarly exposed occupational groups, some comments on the possible signi ficance of pneumoconiosis in eliciting or modi fying this effect may be indicated. Reports on the occurrence of pneumoconiosis among the miners in Sclmeeberg and Joachiinsthal arc contradictory. While Schmorl as well as Rostoski, Saupe, and Schmorl in their early reports (19211, 1928) noted that Schnee miners suffer from more or less intense anf cosilicosis and that this condition was eau, or favoring the development of the brone] cancers, Rostoski and Saupe stated in 1930 pneumoconiosis was usually not very extenj^ in cancerous lungs. Because of the reli slow course of the pulmonary tumors, Rost- and Saupe felt that pneumoconiosis may sloj) the intrnpulmonary growth of the tumo| liueck, on the other hand, remarked p silicosis does not represent, a precancerous ( dition for the Sclmeeberg lung cancers. Son of the miners had silicosis but not lung . while others had lung cancer b u t not silicosis Similar discrepancies seein to prevail co*, corning Ilie Joaehimsthal miners. Ziel in 18jj reported that marked silicosis among miners is quite frequent and that, ashed lung contain large amounts of silicon oxide. Pirchg and Sikh on the other hand, maintained thato pneumoconiosis could he found, in spite of u abundance of pneumatic drilling, and that pneumoconiosis 1ms no role in the production^ the lung cancers. This opinion was shared by Lowy. Sikl. in his most recent communieatio* on the subject, stated that some degree fibrosis suggestive of silicotic origin could, 4 course, be seen in the cancerous lungs, and that wore single cases of marked silicosis combing with cancer. On the whole, however, silicon^ was not a prominent feature in cases of cancer, on the other hand, the lungs most affected with silicofibrosis were generally fr from malignant growth. Behounek and Fort noted that pneumoconiosis was recorded u the cause of death in only 8.2 percent of 6S miners who came to autopsy between 1929 ani 1938. This statement contrasts strikingly witk the observations made by Saupe during a, chest X-ray study ef 398 Joaehimsthal minai conducted in 1939. Ko found that 43.4 percent of these miners presented roentgenological, evidence of pulmonary silicosis. However,, silicosis was of minor degree among the 1 miners who were suspected of having pub 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 caused cancer of the lung among the radioactive- 42 Environm ental Causes o f Cancer of the L*1! piiiicrs in Sclmoeborg ,-md Joncliimsllial. r. loiPthcr it i'ns !U1 antagonistic olIVcl upon (lie '"t rization process or modifies (lie course of reestablished cancer remains problematical. finally- it may be mentioned that, these Inns: peel's vary a {Treat deal in histological strucs M f l i l V w o r t ' s c j u a m o u s roll c a r c m o m a s ; ^rs, round cell or anaplastic, carcinomas; j^jle a few were of adenoeurcinomatous type, radioactive lung cancers, thus, follow in respect the general pattern set by all jdK-r occupational cancers. The rapidly growing production and use of ^active material and the thereby conditiooni, markedly increased exposure of some jpited worker groups as well as the, general `^illation to gases, dusts, and mists containing jjdioartive matter of long half-life doubtlessly presents a potential respiratory cancer hazard serious proportions. The attack rate of Jung rtno-r from such sources is very high, according v past experience with minors of radioactive jffs. Therefore, a competent assessment of &e degree of exposure to atmospheric radioUtivc contaminants for worker groups and yjgkborhood populations of radioactive plants i*l operations, and the continuous and strict jupervision concerning the amounts of radio active effluents emitted from such establish ments, are urgently necessary for safeguarding health of these individuals. Table 2f>. I.alen l periods o f en v iro n m en ta l respira tory eaneers, in m onths (Ilueper) t'ancer of -- Agent Xares and nasal sinuses ; i Average | Range -Average: Range i latent joflatciitl latent ioflatent period period period period C hrom ates ................ N ic k e l.____________ 'Par fu m es___ . ..... Isopropyl o il. _ ___ Ionizing radiation. .. 18 15 22 10 25-35 15-48 5-47 0-30 0 23 7-50 11 3-2(5 10 0-10 25 10-32 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 2(5), 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. >n Comments and Conclusions -.d :h i The comprehensive panoramic view and r* "tttlysis of the total epidemiological, medical, -lit tad experimental evidence available on exog.-il ous respiratory carcinomas and carcinogens r. We uo doubt of the fact that not only large tmpational population groups hut also the il- pneral population have definite and prolonged fltotarls with one or several of these agents. rv. r For most of these agents, adequate conelui- vt proof of their carcinogenicity is provided if to epidemiological, medical, and experimental 0m> of several specific carcinogenic chemicals has been isolated from several agents representing variable chemical mixturesyfsoot, 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, luis 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 inward causally .n| Health Monograph No. 36, 1955 43 t V lit t CVl to 0|S\ V tot. demiological. medical, and experimental data concerning these respiratory carcinogens attest their hirh carcinogenic ])oteney muh'r 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, ('specially, the coal far fume cancer of the lung, is compared with that available for the cigarette smoke lung cancer, even upon superficial examination, several additional serious defects and inconsis tencies not previously pointed out become' apparent. It is surprising to note the absence of positive statistical associations between lung cancer and cigarette cough, although this latter symptom is clinically characteristic of chronic, chain smokers. Despite the fact that the lips and oral mucosa arc constantly bathed in the tarry liquor oozing from the tip of the cigarettes and despite the contact of these parts with the smoke coming from the cigarettes, there' is no consistent statistical association with cancer of these parts. The assertion that no tarry material exudes from the cigarette tip is belied by the evident fact that chronic cigarette, smokers arc observed to have brown-stained lingers. There is, on the other hand, not a single record available of cancer of the fingers attributable to cigarette tar. Such cancers of the, fingers would be equivalent to the numerous cases of coal tar cancers of the hands for which records are available. In an attempt to provide an explanation for this discrepancy in the carcinogenic, behavior between coal tar and cigarette far, 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 immunitv for explaining the observation of *pov.J l tA'Ll ill ii/OA IliU-bbUUH records of a large Jewish hospital in w Poland, showed a. lung cancer frequency percent of all cancers for Jews against a qucncy of 1o..'i percent for non-Jews, esp in view of the fact that Eastern Jews are tieulurly prone, to develop thromboa obliterans, which has the best cstab' causal relations to tobacco smoking. The. claimed absence of a positive associ" between lung cancer and the habit of cigarette smoke also is inconsistent ride that the incidence rate of occupa cancers increases with the intensity of ex to a carcinogen. The medical considers! on cigarette smoke cancer of the lung ' reveal a number of serious and fundam defects and contradictions. The best that can be said about the e mental evidence on hand regarding carcino propert ies of tobacco tar is that it indicates carcinogenic agents in some cigarette . through the use of hyperreactive aj ` There' is no evidence that these observatio the skin of a strain of selectively inbred have any equivalent in man. Thus the lical importance of these observations as cancer of the human lung is at present u tain, especially since Passey, in recent e menls on mice painted for 16 months tobacco tar, was unable to elicit a single of the. skin. Prom these considerations, it is appa that any final decision concerning the rela role of cigarette smoking in the causatio cancer of the human lung should be kep abeyance until a great deal of additional more valid, and especially medically concl evidence becomes available. The data on make, it unlikely that cigarette smoking re sents a major factor in the production of cancer and in its recent phenomenal frequency. For these reasons, it would be injudicious mainly to base the future preven control of lung cancer hazards on a theo such doubtful scientific merits and to con trato, the immediate epidemiological and e: mental efforts on this apparently overp agandized concept. The apparent wisdo such an attitude is readily apparent from fact that not only a great deal of the cir 44 Environm ental Causes o f Cancer o f the 10autojw ^lifti epidemiological e<>vviidence lint also ' ' Vn"s*. ^tically tho i'iitin* facltunal and conclusive "cy of ^piice available on specific exogeneous causes "st a f^ Respiratory rancors indicates thill these '`spei-ialjT ce,-s are either of occupational origin or * are ^ n(3 to industry-reluled factors. Not only ,0aiis:iiu PLoccupational groups hut also the members s,a*)lisli^ j (he general population have contact with ipje agents in various forms and intensity. *soeir.||(), f "tlialir., with I ' "Palin* CX| ) ( M |, Klcrati,,, ung m damnme >e exp.-. euiogi-i,,., cates *tte i.,ri aniiiii,;. nt ion- ,,| red iu:, f the pi,,,. ns as iy, it un. ,f. t C.\|)ITr tlis Wlti; le cniiiv ippatv:; relate, uition ..f kept mill a';; uchtsii. on hai 'i g ivp:<of Iiii.i: rise in he iiif'i ventm leory eoiirrl:1 exprr.crpn>|>alotn " om t!" cirrimi- Finally, it may he noted that the evidence on hand justifies the viewpoint that, in arriving at a judgment (Bander; Liekinl) in any medico legal dispute rei|iiiring the assessment, of li ability for the development of a respiratory eancer, any evidence incriminating specific occupational factors should lie given preference over that possibly provided by a cigarette smoking history. lie I.uM PWir Health Monograph No. 36, 1V55 45 Bibliography Adler, I.: P rim ary malignant, grow ths of tin* lungs and bronchi. 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