Document JK8DXqob0V2GVD7vr71dRqVO

FILE NAME: International Harvester (INTH) DATE: 1953 DOC#: INTH052 DOCUMENT DESCRIPTION: Conference Presentation - Cancer of the Lung-A Critical Presentation %n/] il - Aaericsun -ata *r !-.;iteetings - f-,iscsil,fbevu Jk J. t fo tfj 0 f &r 'tf&w H ; * A n ttc k a n C **cex S o te tf ; Attach*] t yere*$por.dr.&4 `itr, 47 Bravee Street > !` * 3. filler,, -- N ew York 4, M. T , :: education jec/icnj \ Ar.eri.an Csneer Society Annual M eeting - S cien tific Seaaiuir-- ....... ......... .......--- .................. - CANCER OF THE LUNG: A CRITICAL EVALUATION Hotel Commodore New York, N . Y. November 3 - 4, 1953 ffovemb-er 3, 1953 h 18 LUNG CANCER ON THE INCREASE- - EVALtATION? OF PRE5ENT DAT EVXDENCE Ha red F , Dorn N ational InStitsJStea o Befbesda D CU**Oq; Daniel Moni ' A m erican C ncer Suciety, N. Y. L ETIGLOGY: OCCUPATIONAL. AND ENVJRONMENTAk A3PECTS U) The P la c e o i T obacco In Use E tiology o Leng C ncer E rn est L, WyneT ' M emorial Gaacer Genter, N-Y, E, Cuyse HmjieeR A m erican C ncer S ociety, N. Y, Discussion: A lexander Gilliam. National C ancer Institute, Bofiiogda H. B, Parm eie P* LorC lard Comp. ay, J e r se y City (2) The Current Statu* of A ir Pollution Studies in tbe E tiology f Lung Cancer Paul Kotin U n iversity of South.err California . Dos Angeles {3} Tb* E xperim en tal P roduction of Lung Tumor, HmwnCumfitucgt i^i * " . nl irsr^w_^Biw.pr.' T r i S l l e r j j j*__+I>-M.i.i .tr,e.cj*t_*c'*r*,*__*>_*_^_w*iNi-A*tiAnAN*:a t i o n a l Andervoat C an cer Ifnnes^tit?u* te, Betbesda si'"fencfte Sect ion ACS, itw ited le* HisHmer to ( p a rticip a te in a d iscu ssion o f remarks by Sector i nass-sond and kyrster (abova) - dec lin in g le t t e r jM arry B. N , G reen e stisafced, giving uermiasion to be r^! a* 1.1 j Y ale Umve.ru sty, Nei M aven, Cost*;. Kw MjE. 1 of 1 5/25/2007 3:29 PM 0060112077j>2.png (PNG Image, /5UxW -- , D iscu ssio n ; William * N ew York Unhr. V e lie v a M ed icit C t r ., K crm am i Laocd Argonne National Laboratory- - * m} -p o te n tia l O ccu p a tio n a l F a c to r s - New Center, it. Y. D iscu ssion : lal Chromates ibl Arsen.ica.le G oal'lar ' derivatives (c) Beryllium Id) Radioactive dust (e) Aebeet (f) Genetics <*> The O r p h ic Willard Machlo N ation^ fiesearch Council, , ~ B, Awards* MiUr _ c 13. S. Public Health Service, W ash., u W. G. Hueper .. aiijt National Cantor institute, Selheada .Arthur J, V o rw a ld S&ranac Lahe, N.Y. Alerrill Eisembud _ .r t , . S . A tom ic E n ergy C om m isWm N . * . Kenneth Id.' Lynch M edical C o lleg e of -South C a r o l C h arleston W alter B .. H eston n*>+k#ada National Canter in stitu te Bethead* . ,, * , i-am - af Prolilein N ational institutes of H ealth,. B athes i n . CONTROL; Du Ef cTiE&CcTiIiOv N A***S'PECTS ' , , . Dwi,, , t s ,, f the M * (|J Dividend# and D viw its Cancer Survey Method in D etecting L ew is Guise los Angela*, C alif. Lung 1 of 1 VJ 78, (,<* , P.M 1 -2- \Y' "+)7'^0 XkA AA 5/25/2007 3 *0* C A N C E R OF 'IKE LUNG am e v a l u a t io n o f th e p r o b l e m roceedings oi the Scientific S ession Annual M eeting A m eric an C a n c e r Society, Inc. N o v e m b e r 3 - 4, 19 5 o C opyright 1956 . The A m erica n C ancer S ociety, Inc. 521 W est 57 S treet, New York 19, New York L ibrary of C ongress C atalog Card Num ber 55-11610 :ONIENTS A l l' ^d. LiCI iO'<>- L ha rLe 3 S, t a m e r o n , M . D S tJ M G C A N C EL ON 1 HE IN C R EA SE? EVALUA1 ION IF PRESENT -DAY EVIDENCE 1 n I -iiv C a n c e r o n th e i n c r e a s e -----E v a l u a t i o n d Present-D ay Evidence A a i c i d F . 1) a ~n , I hi . D . iTis c us s i o n n D f ii )E < D a rn e l H o r s , Ph. D. I "7 7' :u I C E G G / -----O C G C P A T I O N A L A N D E N V I R O N M E N T A rri ro EGECC'S r u- F i n e of L o b a c t c m th e E t i o l o g y of L u n g C a n c e r b Ij E rn e s: D Wynd.-r, M_D. r <e T: c e of Lob s u r e m t h e E t i o l o g y of L u n g C a n c e r _ Eu/Lor Hanirnond, Sc.D. r? Jr-i ns .on A - l i s d i ' ..Eiiiam, Ed. D. -V 9 s i s : 1 1 io : : i u ' sue t . o o r :: , A i r - P c II.j H o -i S t u d i e s m T i e 'A .- m n - E - C - a . Goi T --PPiEi.uEMGGPKBEG I* S Ip $,* > M * w&: -' iffc-j - t-C'v' T he E x p e r i m e n t i P a , duct ion oi Lae I e rrors H a r r y S, N. CPr e e n o , M . D . 7 1 D iscu ssion W i l l i a m E, S m i t h , M D, 75 P o ten tial O c cu p atio n al F a c to r s in Lung C a n c e r W i l l i a m E. Sm i th , M. D. 77 Discus sion Chromate s S e w a r d E. M i l l e r , M. D. 83 A rsenicals; C oal-T ar Derivatives W. C. H u e p e r , M. D. 89 A d e n o c a r c i n o m a in the L,ung of A lbino R ats E xposed to Com pounds of B e ry lliu m A r t h u r J. V o r w a l d , M. D. 103 Radioactive Dust M erril Eisenbud 111 A sbestos K e n n e t h M. L y n c h , M. D. 115 G enetics in C a n c e r of the Lung W a lte r E. H e s to n , P h. D. 119 G eographic C onsiderations in the L ung-C ancer P ro b le m H a r o l d L. S t e w a r t , M. D. 127 D iscussion from the F loor 129 CONTROL: DETECTION ASPECTS D ividends and D efects of the M ass S urvey M ethod in D etecting Lung C ancer L e w i s W. G u i s s , M. D. 137 L ung-C ancer Yield in U rban M ass X -ray Surveys R, J. A n d e r s o n , M. D. 145 D iscu s sion K a t h e r i n e B o u c o t, M. D. 153 BBS - -,i-t-: J. s o n Auvaus ivy/'iivN ? DIAGNOSIS A l a r m and R e sp o n se in C a n c e r of the Lung 161 R i c h a r d H. O v e r h o lt , M. D. D iscu ssio n W i l l i a m G. C a h a n , M. D. 169 Routine C h e st F ilm s in the D etection of E a rly Lung C ancer with P a rtic u la r A ttention to the Im p o rta n c e of C o m p a ra tiv e Studies 175 L e o G. R i g l e r , M. D. D is c u s s io n 187 M e r r i l l C. S o s m a n , M. D. P o te n tia l A p p lica tio n of S u p erv o ltag e R o en tg en Rays in the D etection of E a r ly P u lm o n a ry L esio n s W i l l i a m J. T u d d e n h a m , M. D. , Jo h n F. Gibbons, M.D. , and Eugene P. Pende rgras s , 191 M. D. P r a c tic a l A pplications of Exfoliative Cytology i n t h e E a r l y D i a g n o s i s of L u n g C a n c e r 197 P e t e r A. H e r b u t, M. D. T h e VaLue of E x p l o r a t o r y T h o r a c o t o m y m t e D iagnosis of Unknown P u lm o n a ry L esio n s W i l l i a m F . R i e n h o f f , J r . , M. D. 201 C a n c e r of th e Lung: One D i s e a s e ? 205 E v a r t s A. G r a h a m , M. D. B io lo g ic a l B e h a v i o r of C a r c i n o m a s of the Lung as Influenced by Their Cellular Structures 209 B e l a H a l p e r t , M. D. M u ltip le F o c i of O rig in of Lung C a n c e r L a u r e n V. A c k e r m a n , M. D. T h e R e l a t io n s m1 p ox- "POut-ilIm-y-nor-vnn aP rryV A.il GfiOm a tO S 1 3 Lo C a n c e r o f t h e L u n g H a n s F , S m e t a n a , M. D. 213 219 TmpC::-* :`c A TV treai meni The O p era tio n to be U n d ertak en 231 E d w a r d D. C h u r c h i l l , M. D. T he R e su lts of R a d ic al P n e u m o n e c to m y m C a n c e r of the Lung 2 39 John L. P o o l, M. D. S u rg ic a l P a llia tiv e T r e a t m e n t of B ro n c h o g e n ic Cancer 249 A lto n O c h s n e r , M. D. N e w e r M odalities of I r r a d ia tio n in the T r e a t m e n t of C a n c e r of the Lung n Sc H u g h F . H a r e , M. D. , J o h n G. 1 ru m p, D. Sc. M a e n u s I. S m e d a l , M. D. 259 N ew er M odalities of Irra d ia tio n in the T r e a t m e n t of C a n c e r of the Lung M i l f o r d D. S c h u lz , M. D. D iscus sion "john^G. T ru m p . D. Sc. D iscussion from the F loor 27 5 27 7 T r e a t m e n t of A d vanced Lung C a n c e r by C hem ical Method S w ,, 279 D avid A. K a r n o fs k y , M. D. 2 89 ILLUSTRATIONS SECTION - h ;L T T L L R I M L N T a l P R O D U C T I O N O P L U N G T U M O R S L a r r y S. N . G r e e n e . M. D. Yale U niversicy School of M edicine Gsw Haven, Connecticut I have s e v e r a l s e r i e s of e x p e r im e n ts c o n c e rn e d w ith the E x p e rim e n ta l p ro d u c tio n of lung c a n c e r to r e p o r t . T h e se ex p erim en ts involve a technique different fro m the stan d ard procedure in as m uch as tran sp lan ts of em bryonic tissue r a th e r than the tissu e of the ad u lt a n im a l is u s e d as a te s t m a teri al The desired tissue or organ is rem oved fro m a h alf-te rm tnous e, im p re g n a te d with the m a te ria l to be tested, and Ira n sp la n te d so m e w h e re in adult individuals. The eye, the b rain , or the subcutaneous space offer adequate sites for inoculation. When this technique is utilized with known carcinogens, such as m ethylcholanthrene o r dibenzanchrene, can cer is produced with g reat rap id ity and in high Incidence. M o re o v er, c a n c e r is p ro d u ced in e m b ry o n ic o rg a n s trait, in their adult state, a p p e a r to be r e s is t a n t to Tie c a r c i n o g e n i c a c ti o n of the s u b s t a n c e . As a c o n tro l, t r a n s p la n ts of e m b ry o n ic m o u s e l u n g w e re o b tained halfw ay through gestatio n and tra n sp la n te d to the s u b c uianeous space of the axilla of adult m ic e . The an im a ls .cere killed two m onths afte r tra n s f e r for m ic ro sc o p ic study, m o tio n s sho w ed n o rm a l lung tis s u e m a d e up of e x p a n d e d liv e oil and b ro n c h i. E p ith e lia liz a tio n of a lev o li, c o m m o n ly r e f e r r e d to a s a p u lm o n a r y a d e n o m a , o c c u r r e d w ith high f r e lii-ency i n a i l t r a n s p l a n t s . YTio.-m c o m i n c n t u m o r p r o d u c e d Ln l u n g t r a n s p l a n t s w i t h m rhylrhe um threne is an epiderm oid carcinom a. Typical i e l d e r ci-.i-u c a r c i n e m a d i f f e r e n t f r o m t h e o r d i n a r y h u m a n n o r c a >>i t h e l u r e 1 i n i t s h i g h d e g r e e of k e r a t i n o c c u r s / i reg u la rly th irty to forty days a fter tra n sfer of em bryonic m ouse lu n g containing a sin gle cry sta l of m eth ylch olan th ren e. S arcom as a lso o ccu r in th ese tra n sp la n ts w ith som e f r e quency. They grow rap id ly and ob literate all norm al lung stru ctu res. M ixed tu m ors, that is , ca rcin o sa rco m es, are also com m on. The tum ors occur in a lm o st 100 p er cent of the tra n sp la n ts and are ap p aren t w ithin th irty to fifty days a fter t ia n s f e r . They are true ca n cers. They grow on tra n sfer, m e ta sta siz e , and are h eterologou sly transplantable. It w ould se e m that th is technique m igh t be of som e value m the testin g of su b sta n ces thought to be carcin ogen ic; and this has b een done. B ecau se of the freq u en t o ccu rren ce of can c e r s in lu n gs that show a s b e s to s is , a sb e sto s w as one of the m aterials tested. F ra g m en ts of em b ryon ic m ou se lung w ere im p reg n a ted with a sb esto s fib ers and tran splan ted to the subcutaneous space of m o re than 150 adult a n im a ls. Sm all groups w ere k ille d at in te r v a ls for h isto lo g ic study, but the m ajority of anim als w ere h eld for as lon g as nine m onths. At the end of th is p eriod the tran sp lan ts w ere a ll exam ined h isto lo g ic a lly . A ll show ed a s b e sto s is but in no in sta n c e w hatsoever w as any indication of can cer found. T yp ically, the tran sp lan t show ed a diffuse fib r o s is quite unlike the fib r o sis that o ccu rs in d egen eratin g lung tissu e . Giant c e lls containing a sb e sto s fib e r s a s w ell as typ ical a s b e sto s is b od ies w ere com m on. It is to be em p h asized again that, d esp ite the fa ct that a ll the tran sp lan ts show ed a sb esto sis, none of them showed cancer. A sim ila r s e r ie s of exp erim en ts w as ca rried out u tilizin g b erylliu m . A gain a la rg e se r ie s of anim als w ere used and again the an im als w ere held as long as nine m onths. T ypi cal b ery lliu m granulom as w ere found in the lungs but in no case w hatsoever was there any indication of n eop lasia. F in ally, a se r ie s of experim ents was carried out utilizing 72 a v a rie ty of tobacco p ro d u c ts . T h e s e in c lu d e d e x tr a c ts of pipe to b icco , cig arette tobacco, cig arette p ap e rs, and ta r from pipes. M ore than three hundred anim als w e re used and the m a jo rity w ere held for as long as a y ear. At the end of that tim e the tra n s p la n ts w e re studied h is to logically and in no instance w h a tso e v er w as th ere any in d ic a tion that the m a te ria ls used w ere carcinogenic. B efore con clu d in g , I should like to m ak e one point w ith r e f e r e n c e to the ex p erim en tal production of can cer in anim als. This co n c ern s the fact that hum an lung can cer is a b io lo g ic al entity, and, before experim ental can cer in anim als can be c o n s id e re d a c o u n te r p a rt of the h u m an d is e a s e , a s im ila r biological c h a ra c te r will have to be d e m o n stra te d . Study of tra n s p la n ts a ls o show s the d iffe ren c e m b io lo g ical behavior betw een hum an lung cancer and hum an carcinom as of s im ila r m o rp h o lo g ic a l type o b tain ed f r o m o th er p a r ts of the body. The co m p ariso n h e re is m ad e on h etero lo g o u s transplan tab ility. H e te ro lo g o u s tra n s p la n ta b ility is a m e a s u r e of the p h a se of d ev e lo p m e n t of the tu m o r co n c ern e d . It m e a n s th a t a tu m o r i s i n a l a t e p h a s e o f d e v e l o p m e n t ----- t h a t i t i s m e t a s t a s i z i n g . The r e s u lt s of t r a n s f e r of a s e r i e s of e p id e r m o id c a r c in o m a s obtained fro m sites other than the lung w ere s im ila r to those with other m a te ria l obtained d irectly fro m the operating room . About half of the tu m o rs w e re tra n s p la n ta b le h ete ro lo g o u sly . a In o th e r w o rd s , ab o u t h alf of the tu m o r s o b ta in e d f r o m the operatin g ro o m a re in a late phase of developm ent and a re m e t a s t a s i z a b le and the o th e r half a r e in an e a r l y stag e oi developm ent and are not m etas tasizable . am o m o u a n c r of c u r fig u re s h a s sh o w n th at tum or was heteroiogously transplantable, w ithin a s n o r t p e r io d of tim e, in c e n t xvas n o t h e te c o io g o u s iy c r a n s p la n f a b an d u i c - r d i . the iiatieat o i f u u i . w h e re v e r the the patient died W-t-"m t h e t u m o r be o p e r a t i o n w a s ,a1 yfa<3 Clfi.A ;n.j C aJ. d isc o v e r y and op eration in ep id erm oid c a r c i n o m a in p a r t s of the body other than the lung, a b o u t h a lf of the t u m o r s a r e in an ea rly phase of d evelop m en t. H ow ever, th ere w as a co m p lete r e v e r s a l of th is p ic tu r e in the c a s e of lu n g c a n c e r . In a s e r i e s stu d ied in o u r la b o r a tory every sin gle one was h eterologously transplantable. I em p h a size again that th is tum or tissu e w as obtained at the tim e of clin ica l d isco v ery and at the tim e of clin ica l d is c o v e r y e v e r y sin g le one of the tu m ors w as tran splantable to alien s p e c ie s , w hich m ean s that ev e r y s in g le one of the tum ors was in a late stage of developm ent and was m eta stasizab le. A cco rd in g ly , we found that a ll of the p atien ts sh o rtly died. I em p h asize again that th ese w ere sm a ll tu m ors, m any of them m uch sm a lle r than the ep id erm oid carcin om as of other region s of the body. A point to be em p h asized h ere is that hum an lung cancer is a b io lo g ica l entity, and it is e sse n tia l that exp erim en tal tu m ors in an im als be shown to p o s s e s s analogous p ro p erties b efore they can be con sid ered counterparts of the human d isease. In c o n c lu sio n , then, tech n iq u es that have p ro d u ced ca n cer in high in cid en ce and w ith great rap id ity with known carcino gens have fa iled to produce can cer w ith a sb e sto s, b e r y l lium , and tobacco. Secondly, the id en tity of the exp erim en tal lung ca n cer p ro duced by m eth ylch olanth ren e with the hum an d ise a se is in doubt in as m uch as th ese tum ors fa il to show the sam e biological character as is m anifested by human lung cancer 74 1 V' . , , ' -Kg 1% ; : ' -' 1 1- ' *' v JV ' * 11 ' " 'h- *~ "*-*______" * i ' DISCUSSION- -The E xperim ental P ro d u ctio n of Lung T u m o rs # i l l i a m E . S m ith , M, D, New York U niversity--B ellevue New York, New York M edical C en ter It s e e m s to m e th at two m a in f a c to r s i m p r e s s one in th in k ing about ex p erim en tal studies d irec ted tow ard lung cancer. One is that we should be studying tu m o rs that are as c o m p a ra b le as p o ssib le to the d ise a se as it is seen in m an. The fact is that the g re a t m a jo rity of studies on lung tu m o rs in anim als, valuable though they have been, have centered aro u n d the study of p u lm o n a ry a d e n o m a s in m ic e . T h e se a d e n o m a s a r e d iffe ren t f r o m the g r e a t m a jo r ity of lung tu m o rs in m an. A second point is that v ery little has been done with in h ala tion techniques. A s we have liste n ed to the s p e a k e rs this m orning, we have h e a rd of a n u m b er of su b sta n c e s that a re thought to have so m eth in g to do w ith c a n c e r of the lung in m an. T hese substances enter the lungs by inhalation. We have induced c a rc in o m a s , h isto lo g ic a lly v e ry s im ila r to c a rc in o m a s seen in hum an lungs, by tran sp lan tin g e m b r y onic m o u se -lu n g tissu e into the leg m u s c le s of adult m ice together with m ethylcholanthrene, dibenzanthracene, or ben zp y ren e. in our ex p e rien ce th ese tu m o rs have grow n with g re a t ra p id ity w hen tra n s p la n te d to new h o sts. The m a j o r i t y of these tu m o r s have b e e n t r a n s i t i o n a l - c e i l carcin o m as but we have also seen frankly keratinizing ep i d erm oid ca rcin o m as. Both these types of tu m o rs p re s e rv e their histolgica, ch aracteristics on transplantation. i chink chat what we have Jearn ed is that the n eo p iastir wiang can supe; vene .n c e lls at d iffe ren t s ta g e s in the c o u r s e of m eiapka jia . One o the n eoplastic .Jiange o c c u rs, the cell Is f e e d m_ i '_c . t a g - ; o f m e t a p l a s i a . u s , t m a d Olil w i t h i j O p i a r t s of p f D u u ' _t f . A i . i j . I D O C C L -i C N O E i. A P A IT m a te r ia ls into the lung has u su ally e lic ite d eith er adenom as or sa r c o m a s. P erh a p s th is d iffere n c e is due to the fact that w hen the tissu e is transplanted its lym phatic and v a s cu lar supply is d istu rb ed , and the ca rcin o g en put w ith it can then rem ain in prolonged contact with the tissu e; w h e re a s, w hen the ca rcin o g en is introduced into the norm al lung, it m ay p a ss through it and be ca rried off som ew heri; e lse so that it la ck s tim e to act on the pulm onary ep ith eliu m . T his fo c u se s our attention on the m anner in w hich te s t m a teria l is p resen ted to the lung. T his m ay be cru cia l in exp erim en ts d esign ed to lea rn w hether som e selec ted m a te r ia l can produce can cer in the lungs. R eference S m ith , W. E . : L u n g c a n c e r w ith s p e c ia l r e f e r e n c e to e x p e r im ental a sp ects. (P roc. C ancer P reven tion C om m ittee. ) A. M. A. A rch. Indust. Hyg. 5:209-217, 1952. 76 P O T E N T I A L OCCUPATIONAL FACTORS IN LUNG CANCER W illia m E. S m ith , M. D. N e w York U niver sity - --Bellevue M edical C enter N ew York, New York I n c o n t r a s t to som e other fo rm s of ca n cer, lung ca n cer is no t a com p lete m y stery . T h ere are som e situ ation s in w h ic h c a u s e s of the d i s e a s e have been recognized. T h e f i r s t i n s t a n c e i n w hich a ca u se of lung ca n cer w as r e c o g n i z e d g o e s back to the e x p erien ce of m en in the G erm an and B ohem ian uranium m in es. F or m any y e a r s can cer of the lu n g had b een o b served w ith strik in g freq u en cy in m in ers in t h e G erm an uranium m in es. In one autopsy s e r ie s , 40 p er c e n t of the m in ers who died, died w ith can cer in th eir lungs. In th e 1930's , m ed ical o ffice rs for the m in es a c r o ss the b o r der in C zech oslovak ia conducted a study to lea rn w hether s u c h a problem ex isted in their m in es. M ore than three hundred of their m in ers w ere exam ined flu oroscop ically. Not one ca se of lung can cer w as d etected . N e v e r th e le ss, in the d ecad e in w hich that study w as m ad e, e ig h ty -th r e e of the C zech m in ers died, and m ore than forty of th em had ca n cer in th eir lu n gs. This experience teaches us two im p o rtan t lesso n s. One is that som e fa c to r in the en v iro n m e n t can e n ter the lungs and there produce cancer. The second is that a radiological su rv ey can fail to detect an occupational lu n g -c a n c e r h azard . T he next in s ta n c e in w h ich a c a u s e of c a n c e r of the h u m a n re sp ira to ry tra c t was recognized cam e fro m the experience of a nickel re fin ery in W ales. The m edical o fficers th ere had r e c o r d e d the o c c u r r e n c e of fifty -tw o c a s e s of c a n c e r of the nasal sinuses in m en in this p a rtic u la r plant and ninety c a s e s of c a n c e r of the lung. T he o c c u r r e n c e of th is l a r g e n u m b e r of c a n c e r c a s e s in the r e s p i r a t o r y s y s te m left no doubt chat som e occupational factor w as involved. When tie j o b s o f t h e m e n w h o h a d t h e s e r e s p i r a t o r y - t r a c t c a n c e r s w ere studied, it w as found that the m a j o r i t y h a d w orked in a part of the plant w here the n ick el o r e s w ere t r e a t e d w ith su lfu ric acid to ex tra ct cop p er. The acid used w a s a g r a d e that contained a rsen ic. The o res th em selv es w ere rich in a rsen ic. Both a rsen ic and n ick el w ere p resen t in the dust in the room w here the ca lcin ers for th is operation w ere lo c a te d . In 1921, the p lan t sh ifted to a grad e of a cid fr e e of a r se n ic and, in 1924, reb u ilt the c a lc in e r s to d e cre a se dust and fu m es. T h ere has b een no ca se of n a sa l-sin u s can cer in that plant in any m an w hose em ploym ent has dated sin ce 1924. H ere we have an in stan ce in w hich an occupational lu n g -ca n cer hazard has b een brought under con trol. And h ere we have a third im portant le sso n , nam ely, that som e form s of can cer m ay be am enable to san ita ry -en g in eerin g m ea su r e s d esign ed to m in im ize exp osu re to hazardous m a te r ia ls . In recen t y ea rs, an occupational lu n g-can cer hazard has b e com e apparent in the ch rom ate in d u stry. D r. M achle w as to be h ere today to d escrib e h is stud ies on th is problem . Since he is unable to be h ere, I should lik e to m ention som e of his findings, w hich w ere published a few y ea rs ago. D r. M achle and D r. G regoriu s conducted th eir study at the req u est of the six m ajor ch rom ate-p rod u cin g plants in the U nited S ta tes. T hey found that th ere had b een a to ta l of 193 deaths in the chrom ate plants they studied; six ty -s ix of th ese w ere due to ca n cer, forty-tw o of them to can cer of the r e spiratory system . F o r a group to c o n tr o l th is e x p e r ie n c e th ey tu rn ed to the r e c o r d s of the M etrop olitan L ife In su ran ce C om pany, finding th a t a m o n g 7 3 3 d e a th s o f in d u s t r ia l- p o li c y h o ld e r s 115 had died of can cer and ten had died of can cer of the resp ira to ry tra ct. T here w as thus a d ifferen ce b etw een the 63. 6 per cent can cer of the resp ira to ry tra ct found in the deaths that had o c c u r r e d in the ch ro m a te p la n ts and the 8. 7 p erce n t in the con trol group. A s they exam ined the exp erien ce in the individual plants, they found that in one th ere had b een fifty -fiv e d eath s, n in e teen of them from cancer. E ighteen of those nineteen cancer 78  , ' sv.V'f-r'" v *7 7 - 7'7'-'-77 . -j: vt; I- 3 v, _.; re e r e ; r o f tiio r e s p ir a t o r y s y s r s m . m o r.oT'tc:' jla r ii d ie r e nad b een t h ir t y - s e v e n d e a th s , te n of _n .'.,,a to '.3rir er t h e r e s p ir a t o r y s y s t e m . L ung c a r e e r a m a prom inent cau se of death in other chrom ate plants m a t m e j 3 ludied. H o w e v e r , th ere was one in terestin g e x c e p - T o i r was. a plant in w hich t h e r e had b een th ir ty -th r e e d eath s. O v e r be y e a r s , p e o p l e in industry die just as people die everyw here else. In that p a rtic u la r plant, th irty -th re e m en ran ac m e tc the end of th e ir liv es, hut not one had c a n c e r in m e re s p ira to ry system . This group stood out as being diiterma. f r o m th e e x p e r i e n c e in th e other p lan ts. A study w as m m m a d e ce l e a r n if t h e r e w a s s o m e t h i n g d i f f e r e n t a b o u t : :ii s pJ a r. t . I t : 3 sandy showed that the plant in w hich th e re was no iango'-meer o r o b l e r n r e c e i v e d th e c h r o m a t e s in s o lu tio n , w h e r e a s t .e p l a n t s thaw h a d a p r o b l e m w e r e t h o s e p r o c e s s i n g th e e r e . a ETcni.icn w a s t h e r e f o r e f o c u s e d o n th is la t t e r p h a se of the e jc T A tio a as p r e s u m a b l y the phase that p resen ted the h a z a r d , h e r e re have a r ex a m p le of an im p o rta n t p rin c ip le in In d u s 3 - .a.' m e d ic in e , n a m e ly th a t o c c u p a t i o n a l h a z a r d s do n ot ai :. , aJd o e r s o iiiv l w ithin a p a r t i c u l a r in d u stry but o n ly t h o s e Inon'/Iduals e n g a g e d m certa in p r o c e s s e s . I d e n tif ic a tio n of i._-cme j _-oc.ess c s p e r m i t s in t e llig e n t d e s ig n of m e th o d s tor m e a m d o f d ie h a z a r d . T h is m a t t e r wiLl b e d i s c u s s e d la t e r octay b y D r. S e w a r d M i l l e r . ' .. .a; c ; r ! no-.- i j a n o t h e r t o p i c . A f e w y e a r s a g o , che C r . i e f j erne, w r ci Ha: uv~Im in G re a t B rita in p u b lish ed fig u re s 1 lw. ;n,ai c i d i r l a s t t w e n t y y e a r s h i s o i f i c e h a d r w m v . - d w o o l ce' : d j 3 L i s e s o f a s b e s t o s i s i n m e n a n d t h a t l u g . - i- g a d h i - ' - n f o u n d I n t w e n t y - t w o o f t h e s e c a s e s . i n , , h a - d t e e n 10? r a a s of a s b e s t o s i s . L u n g wwies r -- - c e i i a m u c h s e n e a p e r c e n t a g e oh t h e c o s . r. -. . .. - n m vet the! e 3s In a p e rc e n ta g e bsa: m m a c m e- e e - euO: l u n g s . - ' 1 - ' i- ; " c, r-;. 7 r - > 7 ;: Y o t 7- h . :7 m _ - j 1 ' 7 rij ii ;?C- s id en tically the sam e as the figure for lung cancer m the general population as calculated from the R egistrar -G ener a l's death certifica tes for England and W ales. T hese data led the Chief Inspector to conclude that there was an occupational lung-cancer hazard among individuals, e s p ecially m ales, who developed a sb esto sis. He attempted to learn whether this im p ressio n m ight have a risen because the people who developed a sb e sto sis had lived longer than the individuals who had developed silic o sis and thus had m ore opportunity to liv e into the "cancer age. " But this w as not true. The individuals w ith a sb e sto sis had died ea rlier than the silico tic s. I visited the Chief Inspector about three y ea rs ago at a tim e when he had records of thirty-one ca ses of coexistent a sb es to s is and lung can cer. At that tim e, I had the opportunity to v isit the m edical o fficers of the plants from which these c a se s had com e, and to v isit Dr. Gloyne at Oxford and the laboratory of Dr. C. V. H arrison in London, the pathologistswho had exam ined th ese lungs. I w as able to find out som ething about twenty of the th irty-one c a se s. The m ajor ity w ere squam ous-call or o a t-cell tum ors. A ll of the twenty c a se s w hose reco rd s I had the opportunity to s e e had b een em p loyed in the in d u stry p r io r to 1932. In 1932, m odern exhaust ventilation equipm ent had been in stalled to reduce dust hazards in the plants in which th ese c a se s had occurred. Ten of the other elev en patients that w ere on record had been em ployed at an even earlier tim e, and I did not attem pt to lo ca te th eir r e c o r d s. In the c a s e s that had appeared, the "latent period" betw een beginning of em ploym ent and appearance of cancer averaged about s ix teen and a half y e a rs. In 1950, eigh teen y e a rs had p a ssed sin ce the ven tilators w ere put in, and only one ca se of lung cancer had been recorded among m en w hose em ploym ent had begun since the installation of ventilators in 1932. T his question of a sb e sto sis and lung cancer w ill be d iscu ssed in detail th is afternoon by Dr. Kenneth Lynch. Quite recen tly , the A rch ives of Industrial H ygiene carried som e in terestin g data published by W eil, Smyth, and Nale. T hese authors review ed the m ed ical record s of a chem ical 80 , . ,.i m a ',a , 1-5 o', i.nr, ' / n o ! s t a t i s t i c s r e p o r t s o f t h e MiL-;d b c a L e s , 1/ j e x p e c t e d a p p r o x i r n a e Ly 13. t> p e r e m i t o t tio h e a t h s to b e d e e lo c a n c e r . A c t u a l l y , o n l y 13. L p e r c e n t c e re due to c a n c e r . N e v e r th e le s s , upon a n a ly sin g the c a n . o r d e a t h s by s ite , i n s t e a d of fin d in g th e e x p e c t e d r a t e of 9. 6 :;er cent a ttrib u te d to c a n c e r of the r e s p i r a t o r y t r a c t, they fo u n d a s u b s t a n t i a l l y h i g h e r f i g u r e , n a m e l y 14. 7 p e r c e n t, i'he e x c e s s w a s t r a c e d to a g ro u p of m e n en g a g ed in the p r o duction of is o p ro p y l alcohol. A m o n g s e v e n ty -o n e m e n e n gaged in this w ork, t h e r e had b e e n t h r e e c a s e s of c a n c e r of vie eth m o id sinus, one of the sp henoid sin u s, one m a lig n a n t m c ilio m a of the vocal cord, one c a s e of b en ig n p a p illo m a ci one v o c a l c o r d , a n d o n e c a s e o f c a n c e r o f t h e l u n g . N ccm this ex p erien ce, it would ap p ear that an occupational um or hazard m ight exist for these m en. But what could the offending m a te ria l b e ? The p u rp o se of the p r o c e s s w as to m anufacture isopropyl alcohol, but m any other m ateria ls w ire handled as starting m aterials, interm ediates, or b y products. These various m a te ria ls w ere studied on anim als vt th e M e l l o n I n s t i t u t e i n P i t t s b u r g h . T u m o r s of t h e l u n g w e r e /re d u c e d in m ice by one of th ese m a te r ia ls , iso p ro p y l oil. iso p ro p y l oil is a c o m p le x m ix tu re , and the ex a ct n a tu re of d' ue a vO nt r e m a i n s t o b e d e f i n e d . environm ental lu n g -can cer h azard s have been indicated in serre ether occupations, for exam ple in situations involving .copesare to co al -tar fu m e s , a s will be d i s c u s s e d to d ay by JT , rib .0 D e l . .. m o m m y : s h o u l d l i k e to n o t e t h a t o c c u p a t i o n a l t u m o r h a z . i t s a v o i r :o ~ ei a t i '/ e l y s m a l l g r o u p s of m e n . T h e y c o u ld mu f . p c i to a c m a i for the larg e n u m b er of lu n g -c a n c e r /i.-i r o c c u r T h e y h a v e , h o w e v e r , a n i m p o r t a n t L e s s e n - '..1. m; in tiia : b u y s h o w t h a t a g e n t s f r o m t h e e x t e r n a l , lz / m m ;c;r.. cure,/' th e r e s p i r a t o r y t r a c t a n d t h e r e o r o ,._m- w z: w ;c ; d U r a u e n m t h u s f o c u s e d o n t h e r e t J t o ' p7t i !V h >Jf operating conditions. R eference S m ith , W. E . : A n e v a lu a tio n of c la im s fo r o ccu p a tio n a l fa cto rs in can cer of the lungs. A cta, Union internal, con tre cancer 9:476-484, 1953. 82 DISCUSSION - - P oten tial O ccupational F a cto rs in Lung C ancel CHROMATES Seward E. M iller, M. D. C hief, D ivision of Special Health S erv ices United States Public H ealth Service, W ashington, D. C. I should lik e to d iscu ss the portion of Dr. Sm ith's paper dealing with chrom ate production with resp ect to lung can cer. Since 1890 there have been occasion al rep orts in the E uro pean litera tu re on lung cancer a sso cia ted with exposure to c h r o m a te s. In th is co u n try D r. W. C. H ueper c a lle d a tte n tion to this and review ed the literatu re in 1942. In 1947 and 1948 D r. W. M achle and D r. F . G reg o riu s w ere em ployed by the chrom ate producers to study the incid en ce of lung cancer am ong w orkers in s e v e n chrom ate-producing plants. They studied the health r ec o r d s of th ese em p lo y ees, which w ere available from num erous so u rces, and went back ten to fifteen years when such reco rd s w ere available. A report of this study was published in Public Health R e ports for August 27, 1948, and showed, among other find in gs, that 2 1 .8 per cent of all deaths in the chrom ate indus try w ere due to cancer of the resp ira to ry sy stem . This is sixteen tim es the expected 1 .3 per cent, w hile the crude death rate for cancer of the lung was tw en ty-five tim es the norm al. In 1948 the ch ro m a te-p ro d u cin g in d u stry r eq u e sted the P u b lic Health Service to undertake a com plete m edical and en vironm ental study of the ind ustry in the U nited S tates. The study follow ed the traditional m ed ical, ep id em iological, en vironm ental, analytical, statistical pattern developed by the P u b lic H ealth S e r v ic e during the p a s t fo r ty y e a r s . In 1953 the Public H ealth Service com pleted and published the report of this com prehensive clinical and environm ental study. 83 My d iscu ssio n of the factors resp on sib le for cancer among chrom ate w ork ers is b ased on this study, I w ill p resen t b r ie fly the m anufacturing p r o c e ss, som e m orb id ity and m o rta lity data, ob servation s on w orking environm ent, and som e rem ark s on a p o ssib le tio lo g ie factor. The M anufacturing P r o c e s s. B riefly , this co n sists of ro a stin g the fin ely ground chrom ite ore with soda ash or w ith a so d a -a sh and lim e m ixtu re, to produce a w atersolu b le chrom ium com pound, sodium chrom ate, which is con verted b y a cid ifica tio n and cry sta lliza tio n into c r y sta l lin e sod iu m b ich ro m a te. Soluble m a te r ia ls other than ch rom ates and b ich rom ates occu r in the chrom ate and b i chrom ate liq u o rs. B y-p rod u cts such as alum ina, sodium su lfate, and sodium vanadate m a y b e reco v ered from these liqu ors. The p r o c e ss m ay be divided into two gen eral p h ases known in in d u stry as the dry end and the w et end. The dry end of the p r o c e ss m a y b e subdivided into segm en ts of op era tion referred to as m illin g, roastin g, and leach in g. The w et end m ay be divided into seg m en ts of operation r e fe r r e d to a s n eu tra lizin g , treatin g, and con cen trating. A l though th ese p r o c e sse s are the sa m e, b a sica lly , through out the in d u stry m any m od ification s are p revalen t. Thus, m ix proportions are different; the ex ten t to w hich resid u e is r e c y c le d v a ries; m ethods of roastin g and leach in g differ; m ethods of concentration vary; and m any d ifferences ex ist in m inor p roced u res. M orb id ity and M ortality D ata. A n alysis of the sick b en e fit--a sso c ia tio n reco rd s in the ch rom ate-p rod u cin g plants show s that the annual num ber o f c a se s of sick n ess and nonindustrial in ju ries per 1000 w hite m a les was 116 for chrom ate w ork ers as com pared with 108 for a large group of other industrial w ork ers. For each sp ecific cau se of illn e s s ex cep t can cer the chrom ate w orker had freq u en cy ra tes that w ere not greatly different from other w ork ers; can cer w ith a rate of 7 .1 per 1000 w hite m ale chrom ate w ork ers com pared w ith 0. 7 for w ork ers in other in d u stries stands out as m ark ed ly in e x c e ss for chrom ate w orkers. dwid. doWFutaw M D uring ;hc n in e;-/ear p erio d fro m 1940 through 1948 the a v e r a g e an n u al death r a te p e r 1 0 0 ,0 0 0 m a l e s , a g e d 15 to 74 y e a r s , for all cau ses w as 1503 for ch ro m a te w o rk e rs a n d 92 8 f o r th e c o r r e s p o n d i n g m a l e p o p u l a t i o n of th e U n i t e d States; for all causes except can cer the death ra te s w ere 924 and 797, resp ectiv ely . F o r c a n c e r the actual n u m b e r of deaths of c h ro m a te w o rk e rs was approxim ately four and a half tim es the num b er that would have been expected had the cancer ra te s for all m ales in the United States prev ailed . W hen ca n cer of the r e s p ir a tory system was observed separately for chrom ate w orkers, there w ere nearly twenty-nine tim es as m any deaths found as w ere expected. '} The r e s p ir a t o r y c a n c e r deaths show ed a ra tio of a c tu a l to e x p e c te d n u m b e r of 14 fo r w h ites and 80 fo r c o lo re d . On the other hand, cancer of all other sites was about what w ould be ex p e cted fo r w h ites; the r a t i o of a c tu a l to ex p e c te d n u m b e r of death s was 1. 14, F o r c o lo r e d the ra tio w as 0 ,6 7 indicating that the deaths w ere actually less frequent than f " expected. ',1 < r The W orking E nvironm ent. The excess m orbidity and m o r - taTit^m in^ rs in ch ro m a te p ro d u c tio n led to an e x am in atio n of the v/orking en v iro n m e n t for p o ssib le etio lo g i cal factors. Such basis operations as crushing, grinding, roasting, leaching, granulating, neutralizing, filtering, concentrating, drying, and packing a r e co m m o n to m a n y in d u stries, and there is no evidence th at these operations a s s u c h in v o lv e d a n y p a i't i c u l a r h e a l t h n a z a r d s . It a p p e a r s re a so n a b le , th e re fo re , to s u rm is e that the high p re v a le n c e of c a n cer m a y be re la te d to ex p o su re to soine su b stan ce o r su b stan ce s c h a ra c te ris tic of this industry. The p r i m a r y ra w m a te r ia ls u tilised in the in d u stry a r e c h ro m ite o re , soda ash, tim e . sulfuric acid, fuel oil, w ater, and a ir, .Except fo r the c h r o m ite o re , all of th e se s u b s ta n c e s a r e e n c o u n t e r e<l m m a n y o t h e r i n d u s t r i e s t h a t , s o f a r a s i s k n o w n , have ro unusual p rev alen ce of lung c a n cer. C onsequently, cue m u s t Cv.mutter c h ro m ite o re and i t s d e riv a tiv e s as y.-iu,: c r i cam \i / r e s p o n s i b l e o r the p a th o lo g ic a l e f fe c t. ,ViiW' , e a ti uo w a m c n i s p / o b u m h a v e r e a d i e d l i l t s a m e o ;>m m m m m i - h e m a p p e a r s t o b e g e n e r a l a g r e e m e n t iliac . . , ^<occ , ,./1th p . , c v m u o f i t s . . o i m p o u n d s i s d efin itely im plies,ted. M achle and G regorius su ggested that the carcin ogen ic co m pounds o f c h ro m iu m w e r e the m o n o c h r o m a te s . In our study we d evelop ed and w ish to introduce for con sid eration a new and hitherto unexplored p ossib ility: th e a cid -so lu b le w aterin s o lu b le d e r iv a t iv e s of c h r o m ite o r e . In the w o rk in g e n viron m en t an a p p reciab le p ortion of the total chrom ium was found to be p resen t in an a c id -so lu b le w a ter-in so lu b le state indicating the p resen ce of a form or fo rm s of chrom ium that a re d is s im ila r to eith er in so lu b le ch rom ite ore or the w a ter-so lu b le, hexavalent chrom ium . T hese a cid -so lu b le com pounds are produced in the roast and rem ain p rin cip a lly in the resid u e. C onsequently they a re p resen t in ap p reciab le am ounts w herever ro a st or r e s i due is encountered, w hich would in clu d e m o st of the dry end of chrom ate production. W here ore is crushed, these a cid -so lu b le com pounds would not be p resen t. H ow ever, w here resid u e is crushed and recircu lated , these acidsoluble w ater-in solu b le com pounds ar e encountered, A sm a ll am ount of the resid u e is suspended in the lea ch l i quor and thus en ters the w et-en d p r o c e s s e s . A dditional resid u e and ro a st reach the w et-en d p o rtio n of the plant as a ir -b o rn e dust. T hese two so u rces together with b a sic chrom ium su lfate, in som e in sta n ces, probably account for su ch a c id -so lu b le w a ter-in so lu b le ch rom iu m as was found in the w ork room a ir in the w et end of the p la n ts. It app ears lik e ly that m o st of the resid u e ca rried over w ith the lea ch liqu or is rem oved w ith the sodium su lfate. A cid-soL uble w ater-in solu b le chrom ium originating from subsequent p ro c essin g is predom inantly b asic chrom ium sulfate. Som e p ertin en t o b serv a tio n s on the etio lo g ica l a sp e c ts of th ese a cid -so lu b le, w ater-in solu b le com pounds are: Suffi cien t w o rk -h isto r y data w ere obtainable in ten can cer c a se s so that they could be c o r r e la te d with th eir w orking en v iro n m ent. Of th ese ten c a se s, seven had work h isto ries in d i catin g p rolon ged exp osu re to a p p recia b le am ounts of the a c id -so lu b le w a ter-in so lu b le form of chrom ium found in the r o a st and resid u e. Two c a se s had w ork h isto r ie s in w hich the so le occupation w as kiln operator or kiln -b u ild ing la b o r e r . B oth of th ese o ccu p a tio n s have to do w ith the ro a stin g . ^ - x '* ; ' . One c a se had a w ork h is to ry that indicated e x p o su re to ch ro m ic acid, sodium b ich ro m a te , a n d the acid -so lu b le w ater-in so lu b le ch ro m iu m but not to ro a st or resid u e . All of the c a n c e r c a s e s w ere exposed to the hex av alen t chrom ium compound, since tnis form is distributed through out the en tire plant. No c a s e s o c c u r r e d a m o n g m e n 'with w o r k h i s t o r i e s sh o w in g p ro lo n g ed ex p o su re to high co n cen tratio n of c h ro m ite ore. Now, in conclusion, although the agent re sp o n sib le for c a n ce r found in this in d u stry was not d eterm in e d by the study, attention was d irec ted to the acid -so lu b le w a te r-in so lu b le ch ro m ium com pounds as of possible etiological im p o rtan ce. R e se a rc h is now being c a rrie d out in at le a st two in stitu tions a tte m p tin g to ev alu ate the c a rc in o g e n ic p r o p e r tie s of this suspect. Pw - i! P a s t o r s in. Lunp A rCS N i C A I jS ; C O A L - T A R D E R I V A T I V E S ',V C . H u e p e r , M . D . Chief, E nvironm ental C ancer Section, In stitu te, N ational In stitu te s of H ealth :3 e clac s d a , M a r y l a n d N atio n al Cancer i A r a l i e i i r i g tine r i s e i n t h e f r e q u e n c y of l u n g c a n c e r s d u r i n g ihe oaet five d ec ad es is the in c re a s e in the n u m b e r of r e sp irato ry carcinogens discovered during the sam e period m d polluting the o ccu p atio n al and g e n e ra l e n v iro n m e n t of -iidu six l a i i z e d m a n k i n d (F ig . 1). S e m e c>i t h e s e a g e n t s h a d p r e v i o u s l y b e e n k n o w n f o r t h e i r carcinogenic action on the skin. O thers, p a rtic u la rly som e j{ the m e t a l s , a p p a r e n t l y e x e r t t h e i r s p e c ific a c tio n on the tis s u e s oi the r e s p ir a t o r y tra c t e x c lu siv e ly . In a g r e e m e n t v u h o b s e r v a tio n s m a d e on the to p o g ra p h ic a l lo c a liz a tio n of c a n c e r s m o th e r d uct s y s t e m s of the body, r e s p i r a t o r y c a n airs, oi env iro n m en tal o rig in a re p re fe ra b ly occupying sites w h e r e e ith e r the flew of the in h aled p o llu te d a i r is i n t e r f e r e d w i t h , i c- , i h e n o r m a l n a r r o w s o f t h e r e s p i r a t o r y t r a c t , s u e la a s t h e r e g i o n s o f t h e n a s a l t u r b i n a t e s a n d t h e l a r y n x ; >i i t s b i f u r c a t i o n s ; ox w lie r e t h e r e s p i r a t o r y t r a c t f o r m s dead-end saccuL ajons in which inhaled carcinogenic m a tte r m i / a-, c u m u i a m caul c o n d e n s e , s u c h a s t h e p a r a n a s a l s i n u s e s a _i d n o . _ x i u o l a r r e g i o n s o f t h e l u n g . T h e t r a f f i c p a n or a oi Hi ;m m a i n s m th e r e s p i r a t o r y t r a c t th u s c o r r e s c o n a s ,h.e n r n b u t i o n p a t t e r n o t r e s p i r a t o r y c a n c e r s d ii y it,o.c / h i n i H . piikoi in c a r c i n o g e n s . f . m i i i i i h m t h e p r o d u c t i o n o f c a n ; !03. a 1d Ol Ci\ l GXrlu ET SGillC ISTii OI OC- Table 1 ENVIRONMENTAL CARCINOGENS PRODUCING CANCERS OF THE RESPIRATORY TRACT AS WELL AS OF THE SKIN C arcinogens A rsenicals Type of contact C u tan eou s A lim entary Chrom ates Chrome pigm ents? N ickel carbonyl? R espiratory R espiratory R espiratory A sbestos ? R adioactive chem icals R espiratory Cutaneous A lim entary R espiratory System ic Organ affected Skin carcinom a (B asal-cell cancer Squam ous-cell cancer) Lung carcinom a Lung carcinom a N asal-sin u s carcinom a Lung carcinom a Lung carcinom a Skin carcinom a and sarcom a Bone sarcom a Lung carcinom a Leukem ia and lym pho sarcom a? in a lm o st a ll c a se s of lung cancer for w hich such cla im s w ere m ade, there w ere p resen t stigm ata of chronic a rsen ic ism in the form of a rsen ic d erm a to sis w ith or without skin cancers. Such association s m ust be considered as etiologi cally significant, because sim ilar relationships exist for can cers of the lung and of the skin attributable to exposures Table 3 LUNG -CANCER--DEATH RATE FOR SEVERAL INDUSTRIAL GROUPS IN OHIO, SHOWING THE HIGHEST RATE FOR NON- FERROUS METAL WORKERS Industry Iron and steel T ra n sp o rta tio n A griculture Rubber and p la stics Stone, clay, glass Nonferr'ous m etal % respiratory 2. 18 2. 91 0. 82 2. 34 0. 66 3. 22 cancer M ining and quarrying T o ta l 1. 53 1. 76 90 1min-unirmi ' /, d-l/ Cancer of fbe Respiratory System >_ 1_ d i c e s p e c t r u m o f t h e K n o w n a n a t h e s u s p e c i e u L-espiracory carcin o g en s, ; ' o h i..-_r c o o t , p e t r o l e u m d c r i v a l i v e s , a n d i a d i o a c i.ive /o s ta n c e s. T h e y m u s s e e m to r e f l e c t a c o m m o n e x p o s u r e l, n m r n co c n y i r c n n . e n h i c a r c i n o g e n s , t h e t a r g e t o r g a n o f vhicn va -ies a i d the p h y sic o c h e m ic a l statu s oi the agent 0 CO 1:. i fi 1 . .i ' CU t i 1O' ' C/Ltti it, 1 c-e c o l e i i O i m b e : o t a t s o n i c l u n g c a n c e r s s h o w i n g t h i s swoop com co m p lect a n d b ein g t h u s r e p r e s e n t a t i v e s oi th e ehc, . o g i c a l ent it", ' 'a r s e n i c c a n c e r " c o m p r i s e s e i g h t c a s e s Table 2 LU NG -C A N CER --M O R TA LITY RATES IN SEV ER AL COUNTIES IN MONTANA WITH AND WITHOUT ENVIRONMENTAL AND OCCUPATIONAL ARSENIC HAZARDS C ounty______ Deer Lodge 13,627 Silver Bow 53, 207 C ascade 4 1 ,9 9 9 G allatin 18, 269 Industry Copper sm elting Copper m ining Copper m ining sm elting A griculture No. lune cancer M ale F em ale T otal 21 0 21 27 2 29 20 5 25 1 0 1 T otal cancer deaths 98 259 299 81 % lung cancer M ale F em ale 30. 8 0. 0 22. 6 1. 5 12. 7 3. 5 3.0 0. 0 L u n g-can c er -d ea th rate per 100,000 M ale F em ale 145. 7 0. 0 48. 6 3. 9 46. 3 12. 3 5. 2 Table 6 LUNG CANCER FREQUENCY AMONG OPERATING AND NONOPERATING RAILROAD WORKERS S H O W IN ^ PREPONDERANCE OF LUNG CANCER FOR THE OPERATING RAILROAD WORKERS EXPOSED TO A N INHALATION OF COAL AND OIL SOOT R ailroad A B ------------------------- T SH I number lung P e r io d ________ c a n c e r 1940-1950 29 1939-1949 104 O perating KK Dung cancer i\onope rating w orkers RR w orkers n u m b er %_____ N um b er % 24 83 59 57 U ndeterm ined RR w orkers Number % 30 29 Table 4 L Li M G - C A N C E R - D E A T H R A T I O S F O R C O K E - O V E N A N D GAS-RETORT WORKERS A uthor K aw ah ata Doll Country Japan England No. cases 21 97 M ortality rates 500 284 (gas sto k e rs, coke oven chargers) 202 (g a s -p ro d u c e r m en) of which five w ere found am ong a s e rie s of tw en ty -fo u r o c cupational a rs e n ic c a n c e rs . T his p ro p o rtio n of lung c a n c e rs is high considering the fact that only two p u lm o n ary c a n c e rs 1 dW '5 O C C U P A T IO N A L Table 5 GROUPS WITH AN EXCESSIVE CANCER INCIDENCE LUNG Occupational group M etal w orkers, w elders, m etal grinders and polishers, w ire m ak ers, tool and die m a k e rs, foundry workers, m etal m oul d ers, lathe w o rk e rs, etc _______ I n v e s t i g a t o r _______ Borst; Kennaway & Kennaway; T urner & G race; M ueller; Dublin & Vane; Wynder & Graham; M cLaughlin C igar m an u factu rers and tobacconists Seyfarth; B orst; K enna way & Kennaway; Enger; V ersluys; Brinkm ann v io i n e e r s 7 m e c h a n i c s ,7 m a chinists, plum bers, etc. B E C C * 1944 & 1952;Gillespie; T urner & Grace; M ueller; Wynder & G ra ham M inters dsccrrcorg B E C O 19 4 4 , M a e l i e r ; D u b lin & Va.ne ; F u l t o n ; W y n d e r L Graham road w orkers ' io ii s , s t c k e r " o r i , fur nac e Kennaway k. Kennaway; Pulton; BECO 1952, f e g si i a r - G e n e r a l 0 9 3 8 ) , i l l C d cl u g n l 1 -1 r>j r c- ' ' r. ne e r ( 1a m p a i g n . a s. w ere found am ong 143 m ed icin a l a r se n ic c a n c er s of the skin. In addition to this m ore or le s s con clu sive evid en ce, there exist a number of observations of circum stantial na tu re, supporting the ex isten ce of arsen ic can cers of the lung. H ill and Faning noted that seven c a se s , or 31. 8 per cent of all cancers occurring among arsen ical sheep-dip m anufacturers, affected the lung. Sn egireff, surveying cancer deaths among copper-sm elter w orkers recorded that in one sm elter six out of tw elve cancer deaths in volved the lung. A lso Schm orl reported the occu rren ce of two. lung c a n cers among a rsen ic sm elter w ork ers. Sim ilar im plications have epidem iological data on lung-cancer m or ta lity in s e v e r a l c o u n ties in M ontana (T able 2; s e e page 92). The annual lu n g-can cer death rate per 100, 000 m ales in D eer Lodge County, w here for m any decades extensive sm elting operations of arsenic-containing copper ores were carried out and considerable amounts of a rsen ical fum es w ere relea sed into the atm osphere, stands at 145.7, w hile it is 5. 2 for the neighboring ag ricu ltu ra l G alatin County and 10. 9 for w hite m a les of the United States. An a rsen ica l background m ay also be resp on sib le for the elevated lungcancer death rate found am ong nonferrous m etal w orkers in Ohio, sin ce a rsen ica l im p u rities are com m only contained in such m eta ls, p articu larly copper, zinc, and tin, and may enter the plant air as fum es and dust (Table 3), The a v a il able evidence indicating the ex isten ce of arsen ic cancer of the lung is thus substantial, although perhaps not en tirely conclusive. A total of som e 35, 000 A m erican w orkers are said to be em ployed in operations with potential a rsen ica l health hazards. Many additional person s of the industrial and general population m ay have effective a rsen ical con ta cts, esp ec ia lly when using a rsen ica l p esticid es and h erb i cid es or handling m aterial w ith in secticid e resid u es or liv ing in a rea s w here a r se n ic a ls are r ele a sed into the air as industrial w aste or for p est control. The potential general scope of this hazard thus m ay be considerable. H owever, the extent to w hich such exp osu res are actually effectiv e in producing cancer of the lung or any other organ is la rg ely undeterm ined. T hese considerations also apply to som e degree to lungcancer hazards related to an environm ental or occupational inhalation of incom plete com bustion products of coal, such as co a l-ta r fu m es, pitch dust, and soot (Table 4). 94 Gbservailony m ade among g a s-re to rt w orkers and coke-oven o p erato rs show raih er conclusively that individuals inhaling e x c e s s iv e a m o u n ts of c o a l - t a r fu m e s a c q u ir e a high lia b ility to c a n c e r of the lung. S im ila r e x p o su re s exist for ta r d i s tillers, coal-tar paint m anufacturers and painters, paper conduit m ak ers, roofers, ro ad -co n stru ctio n an d -rep a ir w orkers, blast-furnace attendants, and carbon-black m an u facturers, p ro c essers, and users. The lung-cancer death ra te of J a p a n e s e g e n e ra to r gas w o r k e r s of a ste e l p lan t stood at 500 p e r 100, 000 e m p lo y e e s , w hile it is 40 p e r 100, 000 A m e r i c a n m a l e s age 25 o r m o r e . C a n a d ia n o b s e r v a t i o n s m a d e a m o n g r e t o r t - h o u s e w o r k e r s i n d i c a t e d t h a t 57 p e r cent of all c a n c e r c a s e s involved the r e s p i r a t o r y t r a c t (six of th e m the lung, one the la ry n x , and one the e th m o id r? sinus). Although no co rre sp o n d in g data a r e available fro m o U nited S ta tes p la n ts, th e re is no sound r e a s o n for a s s u m in g that the identical ex p o su res existing in such estab lish m en ts have not identical re s u lts . T h e re is no b a s is for assu m in g that A m e ric a n coal ta r is not carcinogenic, b ecau se adequate ev id en ce e x is ts as to an e x c e s s iv e in cid en c e of sk in c a n c e r s am o n g w o r k e r s of s e v e r a l p r o c e s s in g and co n su m in g f a c to ries, using g as-house and coke-oven ta rs in this country. A dditional support for an occupational o rig in of lung c a n c e r f r o m in h a la tio n of c o a l - t a r fu m e s and soot is fu r n is h e d by the e x c e ssiv e incidence of th ese c a n c e rs found am ong ta r w orkers, asphaiters, paviours, stokers, patent-fuel w orkers, furnace men, foundry w orkers, rollers, and other occupa tional groups with sim ilar tar and soot contacts, according to E n g l i s h s t a t i s t i c s (T a b le 5). T h a t a p o l l u ti o n of th e a t m o s p h ere with soot fro m industrial and dom estic fu rn ace s m ay c a s u a lly be re la te d to the re g io n a l v a r ia tio n s in l u n g - c a n c e r incidence is suggested by the fact that the highest lu n g -c a n c e r d e a fui r a t e s i n t h e U n i t e d S t a t e s a r e f o u n d i n t h e d e n s e l y populated and industrialized States, while the low est ra te s prevail m the predom inantly ag ric u ltu ral States, State-w ide occupational cancer surveys recently conducted in sev eral d i c t e s al so c o n s i s t e n t l y sh o w d e f in ite ly h i g h e r l u n g - c a n c e r n , ; h f.w.es -v -ri b s "ulaed a n d i n d u s t r i a l i z e d t e g t o n s t h a n t r io s e noted 1 . a m ] s i e a s . S im ila r o b s e r v a tio n s w e re m a d e in U r '--Joui n u ' Sla e c , a n e r e t h e ! u ;j- - c ai c. er d e a t h r a t e i n L o n - f , h ' ' r, c.n j f.'Sii r- m e s t n e i ou uns: t llr e.i ci i s i r j r t a , urn I. ASBESTOS; FIBROUS POLYMERIZED SILICATE o \ /> V CHAIN STRUCTURE - r q / X) ^31 I' x o X ,4 'n BAND STRUCTURE - X 0 o 1 ? 31 / l\ 31 SI ,o/ oI \ o. o/ ol \ o / ,o O O.\ / \ / SI SI / 5I\ o o / \ o o o Xo I . CARBON POLYMERS A. POLYETHYLENE - POLYTHENE (polyethylene film) B. POLYVINYL (polyvinyl film) - ch2-ch- ck,-CH - ch^ch- ch., ch r R r C. POLYPROPYLENE (Isopropyl oil?) - ch.,-ch - ch- ch - ch^-ch - ch- ch ch3 ch^ D. CELLULOSE Cellophane) E. PHENOL- FORMAL DEHYDE RESIN (BA K ELITE) F ig. 4. Structural form ulas of carcinogenic polym erized carbon and silico n com pounds. 96 e f f i o n s t r a u o n o f c u ,"c j n o go m e h y d r o c a r b o / i s , p a r t i c u l a r l y tg 4: - b e Tizpy r e n e > m tr.o s o o t of . A m e r i c a n a n d i i g l i s i i c i t i e s w here coal furnishes the principal fuel provides a rational b asis for these regional differences in lu n g -can cer frequency. T hai soot g e n e ra te d by the incom plete co m b u stio n of p e t r o leum d eriv a tiv e s, such as d iesel oil, lu b ricatin g oil, and in d u stria l and d o m e stic fuel oil. co llec te d fr o m the a t m o s phere of a larg e m etro p o litan a re a also contains ca rc in o g e n ic h y d r o c a r b o n s w a s r e p o r t e d th is m o rn in g . T h is o b s e r v a tion c a r r ie s the s im ila r im p licatio n s as to the ex isten ce of an environm ental lung-cancer hazard for the population liv ing under such conditions. The e x p o su re to th e se c a r c i n o genic atm o sp h eric pollutants is evidently intensified under conditions of sm og. W aller in England noted a fo u r-fo ld in c r e a s e of the b e n z p y re n e content of the a ir d u rin g sm o g day s. The potential occupational im p o rta n c e of th e se observ atio n s' is indicated by recen t studies on the lu n g -can cer frequency am ong operating and nonoperating em p lo y ees of two la rg e r a i l r o a d s o p e r a t i n g m a i n l y w ith d i e s e l e n g i n e s { T a b le 6; s e e p a g e 92 ). It w a s n o t e d t h a t 75 p e r c e n t of t h e l u n g c a n c e r s w e r e fo u n d a m o n g the o p e r a t i n g r a i l r o a d w o r k e r s ; i. e. , rw in e e rs firem en, conductors, brakem en, roundhouse m en and s w itc h m e n who a r e e x p o se d to the in h alatio n of oil sooi and who r e p r e s e n t about 25 p e r cent of the total n u m b e r of ra ilro a d em ployees. The crude death ra te s fro m lung c a n cer for operating and nonoperating railro a d w o rk ers thus show a ratio of lo : I, 'th e r e is, m o r e o v e r , so m e evidence av ailab le indicating tnai m e in h a la tio n of m i s t s of c e r t a i n p r o c e s s e d p e t r o l e u m - o i l fra c tio n s also conveys an in c r e a s e d liab ility to c a n c e r of the tang During a recan t survey on the ca n cer incidence am ong em ployees of a larg e p e tro le u m re fin ery , which w as m ainly : j . c u u c t e hv_ c i c u r l 3, r g 0 r ox]- c o m p u r i i G 3 l o r a s c e r t a i r i - - t h e s c r o c a l - c a n c e r r a c e s a m o n g w o r k e r s e m p9l1o y e d m f n e paraffin p re ssin g operation, the su rp risin g observation wai m I-1h a r t ii o j o ' v o i k e r ^ h a d n o t o r Ly a n i g h i y c i i s : mi rot: c a n c e r c n o { 3 1 2 p e r 1 0 0 , 0 0 0 a g a m a r chc cal 1i -'>i/ j t t h a t xixi a r i c h e r e m a i l g m a p o i w o r t c m c o m' c c rcio 1c rx'ic r t x u r i u s h-. 3 n r .>r Ly a i '4 xj ng If;': ,jfh :f rfrC, population of about 2500, the rate for lung ca n cers in p a r a f fin p r e s s e r s is m an y t im e s the n o rm a l r a te . It is i n t e r e s t ing to note in this connection that the se r ie s of eig h ty -six lung can cers analyzed by M ueller in 1939 for the im p ort ance of cigarette sm oking contained tw enty-one individuals who w ere occupationally exposed to petroleum o ils or their com bustion products. S im ila rly Huguenin et al. noted that e ig h te e n of 112 lung c a n c e r c a s e s stu d ied w e r e su b ject to the inhalation of nebulized lubricating and cutting o ils. This o b se rv a tio n le a v e s no doubt that c e r ta in p r o c e s s e d p e tr o leu m o ils are carcinogenic to m an upon skin contact and in a nebulized form produce lung can cers upon their in tra pulm onary introduction. B rief m ention m ay be m ade in th is connection of the ex p eri m ental dem onstration of carcinogenic p ro p erties in several high boiling fraction s of A m erican shale o ils and in o ils obtained by the B ergiu s p ro cess of d irect hydrogenation of coal as w ell as by the F isch er-T ro p sch p ro cess of second ary hydrogenation of carbon m onoxide form ed from coal. Since so far only the production and consum ption of B ergiu s o ils have found industrial use in th is country during recent y e a r s, no data e x ist on the o ccu rren ce of ca n cers in m an from such sources. During the past decade, ob servations on the e x ce ssiv e in cidence of ca n cers of the nasal sin u se s, laryn x,an d lung w ere made among m anufacturers of isopropyl alcohol p ro duced from certain gaseous by-products of petroleum r e fining (Fig. 2). A total of tw elve such c a se s have so far b een recorded, seven of them involving the nasal sin u ses, four the laryn x, and one the lung (F ig. 3). (For F ig. 3 and F ig s . 5 to 12 s e e p a g e s 300 to 302 . ) It w as c a lc u la te d that the in cid en ce rate of can cer of the n asal sin u ses and larynx for th is occupational group w as 134. 5 per 100, 000 again st a norm al rate of 6. 3 and that the incidence of th ese two c a n c e r s e x c e e d e d the e x p e c te d in c id e n c e 21. 3 tim e s . The causative agent is apparently a volatile constituent of the crude liquor from which the isopropyl alcohol is d is tilled . It see m s to be an im purity contained in the liquor, such as m esitylen e, isopropyl peroxide or epoxide, or polypropylenes. The presence of polym erized propylenes and of isopropyl peroxides and epoxides, which rather read ily form p olym ers in the crude isopropanol liquor, is p ar ticu la rly intriguing b ecau se of the production of can cers in , . ,. I.-, i .(>./in*' t h e i m p l a n t a t i o n o f a n u m b e r 01 - b =. ue o o i y - m e r &, s u c h a s b a k e l i t e , c e l l o p h a n e , p o l y e t n y - ; :' r ,o i j c i y v i n y l c h l o r i d e , p o l y t e t r a f l u o r o e t h y l e n e , p o l y - nexar::ietnylenediam ine ad ip ate , and p o ly s ilic o n e (Fig. 4). V :3 th e re fo re , not unlikely that the c a n c e rs of the lung a s - sorhated with isopropyl-alcohol m anufacture and with ex- c o s m e s to a s b e s to s m a y belong to th is new c la s s of p o ly m e r c a n c e r s e l i c i t e d b y c a r b o n an d s i l i c o n p o l y m e r s (F ig . 5). The o c c u r r e n c e of c a n c e r s of the n a s a l cav ity , n a s a l s in u s e s and inny am ong w o rk e rs em ployed in W ales m the refining of'canadian copper-nickel m atte accounted for forty-seven ,.5 i r ( a .r , c f y a e n o s e a n d e i g h t y - t w o c a n c e r s o f t h e l u n g b y yw.g a c c o rd in g to r e c e n t r e p o r t s f r o m N o rw a y , c a n c e r s Qf t h e Lung h a v e ' a p p e a r e d a l s o a m o n g t h e w o r k e r s o f a N o r - .v e g l .i n n i c k e l r e f i n e r y ( t h r e e c a s e s ) , a n d i t s e e m s t h a t s e v - c a s e s of n a sa l c a n c e r s have r e c e n tly b e e n s e e n a m o n g tee w o r k e r s ol a s im ila r o p e ra tio n lo c a te d on the N o rth A m e ric a n continent. While it w as for m any y e a rs u n ce rtain u h w 'n o - n i c k e l w a s t h e c a u s a l a g e n t i n v o l v e d , t h e r e c e n t snc.-eccful p ro d u c tio n of c a n c e r s in r a ts follow ing the i n t r a o s s e o u s im p la n ta tio n of p o w d e re d n ick el show ed c o n c lu s i v e - The- -HU s a l r o l e o f t h i s m e t a l i n t h e p r o d u c t i o n o f t h e o a u -or, i r.'-. o ; c a n c e r s of t h e r e s p i r a t o r y t r a c t i n m a n . G c c u p a - U cm d expo s u m to nickel in this c o u n try is r a th e r ex ten siv e ri , k gj Tice; u s e o f n i c k e l c a r b o n y l a s a c a t a l y s t m ' nc-bp v o d u c t i o n o f p o l y a c r y l a t e p l a s t i c s r e p r e s e n t s t h e m o s t iT e c u t a d d i t i o n touche long l i s t of o c c u p a t i o n a l e x p o s u r e s to nickel. ! Ll t 1 afidA i-3 \ l Cflw 3 Cf k, i k rear-: :c e s sful p r o d u c tio n of c a n c e r s in e x p e r uckel im p la n ts, this m ethod to y w ld f deposition failed with ch ro m iu m and sup ge stiv e r e s u l t s w e r e o b ta in e d in inhaling a fine p a rtic u la te c h ro m ite r o o n c h s ( Y lg s . 9 , 10)- o r, u a o s o o o u s i n t r o d u c t i o n of n i e c a j l i c rhe ottie;r h a n d w a s fo l l o w e d w 'he r ,-,-oas m -i s i g n l i i c a n t n u m o e r o: ar_- , t hu j expo r l m e u r a i iv iJ e u c .: i I O, liLC i t . o m U e c o s i t s or a r . i f c m o ' . , . . . . i ! rj-r-of 1 T h i s c b o rr ; tjiu hi1 !,'<k tjhfiyl ItiriilAt;? I: i/r .*r of E uropean uranium m in e r s to d evelop ca n cer of the lung. C ancer of the lung am ong m em b ers of this occupational group has accounted for fro m 50 to 75 per cent of all deaths in Schneeberg and J o a ch im sth a l's rad ioactive cobalt and u r a n iu m m i n e s . In the J o a c h im s t h a l a r e a a lo n e , 180 c a s e s of occupational lung cancer w ere com pensated during a p eriod of four y e a r s , 1939 to 1943, although the num ber of m in ers em ployed in 1929 totaled about 330. Since several thousand w orkers are at present em ployed m sim ilar opera tions on the Colorado Plateau, it is n e c e ssa r y for p h y sic i ans to know that in this p articu lar group of m in ers the chief health hazard is rep re se n ted by ca n cers of the lung and not by silic o sis or som e other form of pneum oconiosis. The rapid in c r e a se of in te r e st in and a w a ren ess of en v iro n mental and occupational cancer hazards including those r e lating to the resp iratory sy stem has been encouraging. While we are still in the early stages of their recognition and control, a prom ising beginning has been made m this d irectio n . Of the fifte e n d ifferen t A m e r ic a n in d u stries that have shown an active in terest in the study of occupational cancer hazards during the la st five y ea rs, eleven w ere con cerned with agents producing can cers of the resp iratory tract (coal tar, petroleum , isopropanol, carbon black, chrom ate, arsenic, nickel, beryllium , uranium, asbestos, tobacco). M eetings, such as we have today, are m ost valuable in cla rify in g co n tro v er sia l is s u e s , m adding to defective inform ation, and in dis sem inating com petent knowledge among the various parties concerned with the study and control of an in creasin gly im portant cancer h a z ard. T h e fo llo w in g c o n c l u s io n s ca n be d raw n f r o m the totc.1 e v i dence available: 1. Our m o d e r n in d u s t r ia l e n v ir o n m e n t c o n t a in s a n u m b e r of potent resp iratory carcinogens of w idely differing chem ical nature. 2 Effective exposure to these agents exists not only for lim ited occupational groups, but in part also for the g en er al population. 100 ._.a n E -NOiiBIDITY R A TES FOR EIGHT NINN : T AN AN EAS SHOW IN G T H E M A R K E D ALSE .N ,l r f r e q u e n c y d u r i n g t h e D E C A D E , 19 37 - 1 9 4 7 , tONSlLm E A B L fi V A R IA T IO N S IN R E G I O N A L L U N G ANC ER, M O R B I D I T Y , A N D T H E A P P R E C I A B L E D I F F E R NNi S IN TH E R E G I O N A L R A T E S O F P R O G R E S S I O N -' ----- - ' ~ C T\/ A rl ot c _8 GVV He f LAA_Ab EaLRs d i r n i i r fi iia r.n usAii r u Aa c is C 0 Crac a c 1 '"n t f , b u r g h Male s L9 37 rA I 947 13.4 t3. i 0 .9 39. 1 3 9. 0 4 9 18.9 9A i a. L 21.9 34. 3 j. ) . 3 Q. 7 29 5 6. 1 F ornale s 1937 1947 1. 0 5. 0 2. 8 4. 2 0. 5 6. 4 2. 1 3. 9 4. 2 8. I 3, 9 8 1 4. 3 7. 0 4. 9 5. 5 Total 1937 1947 2. 9 8. 9 ? , 6 20. 8 3 .1 17. 2 3 . 3 I 1. 0 6. 6 i -1 ,, 8 9. 8 20. 8 8. 8 1 8. 0 7 . 3 L5 . . R h o ` e n g - c .: a c a r At t AC. iv t a t e s v a r y i n d:1 f f e r e n t c o p u i a n o n g r e u p s o n h tic 0 c e i a t i ve- p o t e n t : y o the' i n d i v i i u a i a g e m im a Dm i n t e n s i ly at id d u r a t i o n of c o n t a c t w i t h t h e m . T g - - e , e a t n 3 c1 1 n l u n g - c a n e e r f r e q u e n c y s e e m s 20 cm J, vJ _N A a a Til S t A A1. :s t a r t e d t o e n t e r o u r e n v x r o n m e nt s o m e - v, - f i v e y e a r s a g o and th a t s i n c e th en h a v e b e c o m e in- vm, a l r h o u g h t h e e x i s t i n g , m a r k e d v a r i a t i o n s ..armor fr e q u e n c y indicate that the locai e t h o s e: a g e n t s d i f f e r e d a p p a r e n t l y g r e a t l y la 1 o u s m t a t i v o r e s p e c t s ( T a b l e '). 1:- 1 O j Ui'l ..alike, l y c h a t a n y si ngl e: f a c t o r p l a y e d a g<- nn.tiit r o l e m b r i n g i n g a b o u t the: s t a r t l i n g m ; iv. c c l.ro q u e n c y , tike any other type of hum an c a n e m , m e - oat a col lection of d i s e a s e s d ifferin g a ,] u p 10 s o fi l e L x t e n i a l s o i / m p i o f o i a 7. The proper appreciation of th ese facts and their r e la tion sh ips m ay help in stim ulating the exploration of m ore e tio lo g ica lly sp ecific approaches to an effective preven tive, d iagn ostic, and therapeutic control of cancer in man. ? I! J 1 fi c c 102 ad al OccupaUonaJ f a c t o r s in L u n e ASBESTOS K e n n e t h M. L y n c h , M, D, P r e s i d e n t , M e d i c a l C o l l e g e oc South C a r o l i n a Charleston, South C aro lin a : t r u s t that the a p p e a r a n c e of this s u b j e c t and a s p e a k e r to ,,he s u b i e c t w i l l not go too f a r in d i g n i f y i n g the p o s s i b l e p o s i cion of a s b e s t o s or a s b e s t o s i s in the q u e s tio n s that we all n a v e a b o u t the b a c k g r o u n d of c a r c i n o m a of the lung. In the a b y sm a l ign oran ce in which we reside in this im portan t t e r r it o ry , h o w e v e r I a s s u m e that it is ju s t if ie d to k e e p b e f o r e such questions as we m a y justify fo r fu rth e r study until we Learn m o r e of the a n s w e r s . in an a u t o p s y s e n e s that p r o d u c e d for s p e c ia l stu d y i o r t y nine ca se s fr o m w o r k e r s in an a sb e sto s m an u factu rin g plant who w e r e sh ow n to h a v e dem onstrable d e p o s i t s of as - O estes in the lu n g s , t h e re w a s a s s o c i a t e d c a r c i n o m a of the Lung m f o u r i n s t a n c e s . I m m e d i a t e l y , of c o u r s e , it m u s t b e noted that both figures are too sm all for v e r y serious s t a tistical types o calculation; h o w e v e r, this gives an in c id en ce of 8 .2 p e r cent. inc s e r i e s has been partialLy p u b lish ed h e r e t o f o r e and rna y l o w be b r o u g h t up to d ate. To it m a y n o w be a d d e d nine a s e s of a s h e s o s :s that h a v e b e e n g a t h e r e d s in c e the .asi, r e p o r t m 1.947. O n e of t h e s e nin e h a d a s s o c i a t e d b r o n e h o ,i ( . rii C - a r c i n e r t . a . In a d d i t i o n , t h e r e h a s b e e n o n e c a s e or a r c i r o n i r . o i m e l u n g c o n f i r m e d b y a b r o n c h i a l b i o p s y 111 1 P i n e a l c a r . o f a s c e s t o s i s , t h a t i s , o n e d i a g n o s e d c l i n i cmil ,' / a n d s b.o wi n a . s b c s t o s i s P o d i c s i n t h e s p u t u m 'J. >.cCi , Li. . ' ili c j d c n c v Kj c a r c i n o m a or rluk 1 1') ; 0J,'gS bC al' J 1 l 01 S St r e s v/c i ' c I ; rn i Lo d i <) C1G S <; dici o r -.id', a n t e d f i br e . - . : . 4 >he i m p s , e i " d . i n h r n e c , On gc c e i i i i i n c t d e n c - el c a r c i n o m a 1 .5 per cent during the sam e period and in the sam e age range as the c a se s of a s b e sto s is . That is the circum stance that b rin g s this to attention: the d iffere n c e b etw een che a n ticipated and the actual incidence, even though the se r ie s is sm all. On the b a s is of p athological study, th e s e fo rty -n in e c a s e s showing a sb esto s deposits in the lu n g s have been divided into groups, using the degree of lung fib ro sis as the m ain criterion of the stage of the d isea se. All of the lung c a r c i nom as w ere in ca ses of at le a st m oderate and usualLy of ad v a n ced f ib r o s is , show ing the usual c h a r a c t e r is t ic s of the disease asbestosis. Since the fir s t rep ort of the o ccu rren ce of carcin om a of the lung a sso cia ted with a sb e sto sis was made by us in 1934, a number of other reports have been published, some by com pilation, I think. Dr. Smith has c a lle d attention to the B rit ish sta tistics reported by the Chief M edical Inspector, Dr. M erew ether, but I believe that Dr. M erewether gathered together reports that had been made by others as well as h is ow n o b s e r v a t i o n s . In 1 947 h e n o t e d that at l e a s t t h ir t y one in stan ces of carcinom a of the lung had occu rred in 235 c a s e s of a s b e s t o s is , giving an autopsy in cid en ce th ere of 13.2 per cent. H o m b u r g e r r e p o r t e d th at, in h is a u t o p s y s e r v i c e f r o m 1918 to 1938, th ere w ere fo r ty -fiv e c a s e s of ca rcin o m a of the lung, an incidence of 1 .0 8 , which is sim ila r to the general in cid en ce in our s e r v ic e ; th ere w ere eight c a s e s of a s b e s t o sis encountered in that serie s with a sso c ia ted pulmonary c a r c i n o m a in f o u r -----a g a in s u f f i c i e n t to c a l l a tte n tio n to i t self, but again dealing in sm all num bers. Stoll, B a s s , and A n g rist r e fe r r e d to a rep o rt by W yers in 1949 r e c o r d i n g 115 c a s e s of a s b e s t o s i s , a m o n g w h ic h th e r e w ere 14. 8 per cent with a s so c ia te d c a r c in o m a of the lung, this being sim ilar to Dr. M erew ether's figu res. Now, obviously, none of these rep orts nor their sum total, as a m atter of fact, can be accepted as conclusive proof that inhalation of a sb esto s dust or contraction of the pulm on ary d ise a se , a sb e sto sis, p r e d isp o se s to the occurrence of cancer of the lung. H ow ever, the estab lish ed fact that 116 -wop m.nrc c b w o r v v r s w o r k i n g in w i d e l y s e p a r a t e d l o c a - dons hare en c cu n tere d the tw o d i s e a s e s in the sam e in d i yj viduals in such a conspicuous w a y m ain tain s the question as one of im portance and w orthy of our attention and of f u r ther investigation. fJ n f o r t u n a t e l y , t h e p r o b l e m d o e s n o t l e n d i t s e l f w e l l t o e x p erim en tal study. A s yet, ne defini tely analogous c a r c i n o m a o: the lu n g h a s bee n e x p e r i m e n t a l l y p r o d u c e d b y a n y c o m p a r a b l e e x p o s u r e . In fa c t , b r o n c h o g e n i c c a r c i n o m a in man has no reported counterpart m other anim als. a p p a r e n t l y the only c l a i m e d p r o d u c t i o n of c a n c e r of the m u g by e x p o s u r e of e x p e r i m e n t a l a n i m a l s to inhalation o a sb e sto s dust, published b y N o rd m an n and Sorge in G e rm a n y , -- s o s u b j e c t to q u e s t i o n t h a t it c a n h a r d l y b e c r e d i t e d . T h e y reported one instance of e x p e r im e n t a l o c c u r r e n c e of c a r c i n o m a of the lung f r o m e x p o s u r e of s m a ll a n im a ls to a s b e s tos dust The c o r r e c t n e s s of that o b s e r v a t io n is s u b je c t to question, while the m e t a p la s ia of epithelium , w hich they a m o a t t r i b u t e d to the s a m e e x p o s u r e , m a y a l s o b e q u e s tioned as to etiology. W a r o wn e x p e r oriental s t u d i e s , n o w e x t e n d i n g o v e r s e v e r a l y ea rs, with the a s s i s t a n c e of the N a tion al Cancer Institute, have; not r e a c h e d a n y c o n c l u d i n g s t a g e . T h e y h a v e not p r e - c u r e d anything s p e c t a c u la r up to the p r e s e n t tim e, and, as v/e k n e w w n e n v/o s t a r t e d o u t , a l l o f u s a r e m o r e o r L e s s behind the eight ball in setting up an e x p e r i m e n t that m a y provide an analogous situation to th a t f r o m w hich c a r c i n o m a n l o a n m a y c o m e , ! "om an a n a ly s is of the p r o b le m , th en , a s it still stands, in a p p o - a r s t h a t t h e a v a i l a b l e e v i d e n c e ' o n w h e t h e r a s b e s t o s i s an a y p l a v a n e t i o l o g i c a l r o l e i n t h e o c c u r r e n c e o f c a r c i n o m a 0- the l i n g is n o t c o n c l u s i v e b u t t h a t it d o e s s u p p o r t the r u s p i c j . i s a f i n enl.1 y to r e q u i r e c o n t i n u e d i n v e s t i g a l l o n ; , r n-wl, m e a v a i la b l e e v id e n c e r o e s not a l l a y that s u s p ic io n . b n NT yi Uy _- i j p g r La ric l o t a a c h a (\ LIT T>t 1O11 j a n d a s s u m n -LJ ' V wTL . oua r r a a t e dj p e t t d p :s ; ( i h) a i s o n e r i n i s s ; b t .5plhTi i : - TO T o amar e o p p a r e n t ! / p e r ci eu? n t e m g u r n s to t s o t UATlnl T ~ " - J T T T .J 0T T , W Ijnie: AT' vio h a j c k a o vdi e d o .t eu oN}11 ''S\ tk J-# if -! .'`il = r-- c e r ta in c a r c in o g e n ic s u b s ta n c e s , such, as have b een d i s cu sse d h ere today, having such an influence under certain m ore or le ss artificial conditions, there is actually m eager e v i d e n c e th at s u c h f a c t o r s p la y a n y c o n s i d e r a b l e p a r t :.n the nafural o ccu rren ce of m alignant n eo p la stic d isea se in man. In p a s s in g , it m a y be n oted that nothing c o m p a ra b le to a s b esto s, the m aterial a sb esto s, is included among the r e p orted ca u ses of ex p erim en ta l can cer. A lso , while in r e c e n t tim e s we have tended to v e e r away fro m the lon genduring b elief in low -grade chronic d isease of structure and fu n ction -d istu rb in g kind as an etio lo g ica l background for cancer, actually we have not produced sufficient e v i dence to d iscard the old theory. Perhaps it m ay be asked why silico s is has not been d is c u s se d in co m p a riso n to a s b e s to s is in the question of the occu rren ce of carcinom a of the lung. Dr. Smith referred to that, how ever, out of a study also made by Dr. M erew ether, I think, in Great Britain, in which the incidence of carcinom a of the lung in a large s e r ie s of c a se s of s i l i c o s is w as not com parable to that in a s b e s t o s is . The only other study of which I am aw are is that of K lotz who, in a sim ila r num ber of autopsies in his s e r v ic e , found a very sim ila r ratio of carcinom a of the lung in fifty ca ses o s i l i co sis to that which we found in our c a s e s of a sb esto sis. He also had in his serv ice a very sim ilar general incidence of carcinom a of the lung, about 1. 17 per cent. That is ap p a ren tly the only com parable study of s ilic o s is excep t the one m entioned by Dr. Smith this m orning. H ow ever, it would not n e c e s s a r il y b e good to draw clo se com p arison betw een s ilic o s is and a s b e s to s is , for the m a teria ls th em selves are not the sam e either p h ysically or ch em ica lly , and apparently the manner in which they cause damage of the lungs is not the sam e. T herefore, although both of them are chronic fibrous d iseases of the lung, there is not n ecessa rily any reason why they should behave alike in referen ce to carcinom a of the lung. In c o n clu sio n I w ish to m en tion that we have en cou n tered an additional case of bronchogenic carcinom a associa:ed with advanced a sb e sto sis. This will be reported in detail in another paper. 118 wMmMSMSgM ..... IB M ? k .aye -, -A, ' DISCUSSION FROM THE FLOOR Chairman P en d ergrass: This sym posium is now open for discussion. Dr. M artin F riedrich; I should like to call to the attention of the physicians gathered here a very in teresting and v a l u a b le g e o g r a p h ic stu d y that w a s p e r f o r m e d in 1911 b y a m edical student, C. E. Green. He toured p ractically all the cities and ham lets of England, Ireland, Scotland, W ales, parts of F ran ce, and parts of G erm any and v ery definitely established that the incidence of cancer at that tim e, even with their diagnostic m ethods and techniques, ran about one ca se in seven in som e towns and ham lets that w ere in a s e cluded hill or valley or on a knoll or along sharp hills; w hereas, in adjoining towns two, three, or five m iles away, with the people in the sam e types of in d u stries, with the sam e types of food and other habits, the incidence ran from one caise of cancer in forty-four to one in fifty-four. He then traced the habits of these people, the m ethods of heating their h om es, and he found that coal w as the com m on fuel used. He noted a few exceptions, how ever, in valleys where the incidence of cancer was extrem ely low and, as with the people in Iceland, these people burned peat. Again, t h e r e w a s one e x c e p t i o n ----a c i t y , tow n , or h a m le t w h e r e the people w ere burning peat and yet the incidence of lung can cer w as as high as in coal-b u rn in g tow ns. On a n a ly sis the peat in that particular site showed as high a sulfur content as in the coal used in other tow ns. In the p eat-burning v a l leys where cancer was very low, the peat had a very low sulfur content. Dr. C. H arold S teffee, N ational C ancer In stitu te; I should like to add two com m ents on the experim ental asp ects of the relationship of chrom ates to lung cancer. For the past two y ears I have been fortunate in being associated with Dr, Anna Baetjer in her project on the relationship of hexavalent chrom ate dust to bronchogenic carcinom a. A s with a sb esto s, nickel, and v a r i o u s other m eta ls, the project s u f f e r s f r o m the fact that th ere is no reg u la rly producible tum or of a n i m als that can be c o n s i d e r e d analogous to human b r o n c h o g e n i c carcin om a, in m ost of the a x u e r r r n a n t s a m ixed -hTormum t c v i - v f u .-. m a t e r i a l , w h i c h s i m u l a t e d t h e d u s t e x p o s u r e or i i u m c n s in. the ch ro m ate-p ro d u cin g plants, has been em ployed. This co n tain e d the he xs valent and trjv a le n t c h r o m i u m co m pounds that o ccu r in the p ro d u c tio n of sod iu m c h ro m a te fro m c h r o m ite, In o th er e x p e rim e n ts zinc and b a r iu m c h ro m a te s have been used. T h ese m a te r ia ls have been a d m in iste re d to m ice, r a t s , g u in e a pig s, an d r a b b it s b y th e i n t r a t r a c h e a l , intrapleural, in tra v e n o u s, o r in h a la tio n ro u te s . Studies have a lso b e e n m a d e u sin g the e m b ry o -lu n g transplant te c h nique in m ice. In none of t h e s e e x p e r i m e n t s h a v e we s u c ceeded in p ro d u c in g b ro n c h o g e n ic tum ors o r in in c re a s in g the number of alveologenic tum ors in Strain-A m ice. There is one encouraging result th a t should be mentioned. In all of the strain -A m ice and in half of the Sw iss m ice given zinc chrom ate intratr ache ally, we have observed an epithelial investm ent of the alveolar w a lls that is, as nearly as I can tell, com parable to that observed b y D r. Vorwald in his b erylliu m -in h alation exp erim en ts in the rat. Dr, V orwald dem onstrated the beryllium lesion s here this afternoon. We have not seen any tu m ors in the an im als we have studied to date, but these chrom ate experim ents are being repeated and extended. Chairm an P e n d e r g r a ss : Is t h e r e any o t h e r d iscu ssio n or question? V oice: I am wondering w h e th e r D r, S te w a r t could com m ent on the geographical distribution of lu n g cancer in the United States ? Chairman P en d ergrass: Dr. Stewart, will you a n s w e r th at question? Dr, Stewart: The m an that i s m o st capable of d o in g that is D r. Harold Do rn, if he is in the a u d ie n c e . He knows m ore about cancer in the United States than anybody I know. Chairman P en d ergrass: D r. D o rn ? (N o r e s p o n s e . ) Dr. Stewart: I think th e m ain features of th e d if f e r e n c e in the distribution of cancer in th e U n ited S ta te s w e r e b ro u g h t out in Dr. H ueper's paper; that is, A tla n ta is c e r t a i n l y a low area; N ew O r l e a n s is high; S a n F ran cisco is high, I a m 1 3 0 b U i Ui'iHrRi 1 ..LPT: really not capable of com m enting on the variations in other parts of the country, but there are variations. Chairm an P endergrass; that, p lease? Dr. Hueper, w ill you elaborate on jOr< Hu e p e r : If w e go into th e a g r i c u l t u r a l s t a t e s w e end up w ith lu n g - c a n c e r -- m o r ta lity r a te s of a n y w h ere b e tw e e n 35 and 45. There are two interesting exceptions. There is a high lu n g -ca n cer--m ortality rate in C alifornia, which one might explain by industrialization. The outstanding state is Nevada, however, Nevada has a high lu n g -ca n cer--m o rtality rate and I can't think of anything that would cau se that. It is an in te r e s tin g state to study. New O rleans is also an in teresting region to study. I can not think of any industry there that might be resp on sib le for the high lu n g -ca n cer--m o rb id ity rate of 39. 1 per 100, 000. I don't know why it is that way, but such com m unities or such regions should be very profitable to study to find s o m e thing about the environm ental ca u ses of cancer in m an and in the United States particularly. Chairman Pendergrass: m ight account for it? Do you think the O chsner Clinic Dr, Hueper: ients. No. Only resid en ts are counted and not tr a n s Dr. Nandi: I am from Burma. I have been rather in ter ested in the incidence of cancer as shown by Dr. Stewart in the slid es a little w hile ago. The figure of 0. 2 per cent w as put down for Thailand. In the F ar E a st our p a th ological stud ies are v ery in com p lete. The a u to p sies that we do and the clin ica l exam in ations show that our fig u res on can cer oi the lung are by no m eans so high as you w ill find m the United S tates, A ustria, and England. N ow we have to r e m e m b e r one thing. That is tne question o f t o b a c c o . Y o u h e a r d e a r l i e r i n t h e m o r n i n g f r o m D r , '-Vyn der that the tob acco that is sm oked is sm o k ed in a different f a s h i o n than y o u s m o k e in t h is c o u n t r y . it i s not so m u c h in the f o r m of c i g a r e t t e s but t h ro u g h a pip e that g o es through p ip e and w h e t h e r th a t h a s got a n y th in g to do w ith the c.ilution of the tobacco smoke and has any bearing on the c a rc in o genic factor in the lung we do not know. S econdly, there is the question of air pollution. Now air pollution, of c o u r s e , is by no m e a n s so g r e a t as in this country. At the sam e tim e we have to re m e m b e r that in our part, dust is a very, very serious problem , especially in the Middle E a s t and probably in India and B urm a. The question of cooking was m entioned. Most of the wom en spend their tim e cooking and we can't say that our incidence of cancer is so high. At the sam e tim e I m ust apologize, as I said at the v ery beginning, that our pathological studies a re so v e r y in com p lete that it would be rather difficult to draw any con clusion . I do su ggest that it is a study that is worth while and I request that the A m erican Cancer Society d ev ise som e m ean s so that som ething m ay be obtained in that regard. C hairm an P en d erg ra ss: I should like to ask Dr, Stewart whether the longevity of individuals living in Thailand is com parable to that in the United States. Is that an explana tion for the low factor of cancer incidence? Dr. Stewart: I think it is a factor. T hese figu res that I presented are really not based on m orbidity studies as we know them in this country, for exam ple. They are based on a se r ie s of autopsies and su rgical sp ecim en s and clin ically diagnosed cases. Now in Thailand, certainly before 1922, they had very good p a th o lo g ic a l stu d ies. D r. E ll is , who is P r o f e s s o r oi P a thology at J efferson M edical C ollege, went over there and stayed for many, many years. The Dean of the m edical school and P r o fe ss o r of R adiology there was a cla ssm a te of m ine, and I have seen a good deal of him since that tim e and he is quite an up-to-date fellow . He certainly knows cancer of the lung very w ell. R ecently Dr. V ellios spent a year there. He was trained by Bob M oore in St. L ouis, and he published his fig u res on c a n ce r in Thailand in the journal CANCER in th is co u n try . It 132 w as f r o m that s e r ie s that I e x tr a c te d that fig u re of 0. Z per cent. Dr. Paul Law son is probably in the audience here and he has just com e back from Thailand w here he spent a year and he tells m e that the old autopsy record s w ere destroyed dur ing the war. How ever, he confirm s the prevailing opinion that cancer of the lung is con sid erab ly le s s frequent in Thailand than it is in this country and in a good m any other countries. 133 Oj-JOD |Oi O j O O LUO D I O S < e-) O O cr B iO S C lE N C E & MATURAS. R E S . U B fA iW U C B