Document mBnJXqwR2j2VvnYDpEMdvepRk

FILE NAME: Saranac 7th Symposium (SSY) DATE: 1952 DOC#: SSY023 DOCUMENT DESCRIPTION: Transcript of Presentation by Dr. Vorwald with Discussion *ZM S3 FEQUt FAGS J-M J *>" g ? pCX.^-^ &T9 th&ra artkc ^nastiont.- -ua th ctacsa Qasstlanx (So response?)* If t, tm will paos to tlx last pa&sr, that of our host, Doctor ^vva.M, vlio will diacuas his I .kt&A stu d ies on pulmonary cancer in tha experim ental exposure j to berylliu m * j BY DOCTOR VORWALD{ j Iia so rry to say tha rep o rt I ' m about to g iv e j j emanates from the work of ray co lle a g u e s, p a r t ic u la r ly Doctor P r a t t , and Mr. Darken, Mr. Del&hant and Hr. Urban of the Saranac Laboratory* A lso , the second remark i s th at the | hour i s la ta and as host to th is con ference, I'm sure th at | they w i l l agree w ith ne when I cut roy paper d r a s t i c a l l y , j so th at I w i l l not fcfe - longer than tan minutes, i f th at* j Third, I am not going to bow to those who champion the j human axparim antation versus animal experim entation beceusa j these observations are purely a cc id e n ta l* They varan *t planned* The snimals performed the experiment f o r u s , Rad vie have r e l a t i v e l v l i t t l e to do with i t , except to p lace them in an environment fo r other purposes* B r i e f l y than, tha rep o rt in v o lv e s ,th is p i l o t or te n ta tiv e ro p ert in vo lves an exper* n t wo are a wore o s posing largo groups of white ra ts to in h alatio n of atmos pheres contaminated w ith berylliu m in th form of pure b e rylliu m sixlohate, in one iu s .a n c , and - uno form o f pu. b a ry lliv m oxi - in another* ThoanimalB, the white r a t s , and I c a l l a tte n tio n to that, that these animals are not m ice, were brad in our own stock wad they come o r ig in a lly or are descendants about 193o from the Worcester In stitu te M6*.j and no a tte m p t h as been mads to in b re ed or to s o le c t the s t r a i n and the s t r a i n i s s u b je c t to lym phosarcom a a t a low In c id e n c e r a t e which i s n o t p r e c i s e l y known by u s , b e c a u se la rg e enough groups o f anim als have nevor boen kept in a duration o f l i f e experim ent# A ll r a t s under th is o b se rv atio n were fed ad lib w ith a s t a n d a r d d i e t o f p r e p a r e d dog chow find w a te r. Tha rat', were exposed to pure b e ry lliu m su lp h ate in an atmos pheric concentration o f 0011 m illigram s per cubic fo o t of a ir # The r a t s wore k e p t th e re u nder e x p o su re f o r u s u a lly s i x and a h a l f to se v e n h e a r s d a i l y f o r f it d a y s a week nc .. the an im als which I w ill r e p o rt one, one o f the o b se rv atio n s mads o r tha o b s e r v a tio n s which I w i l l r e p o r t upon a re made j j upon anim als th a t have had th a t exposu re con tin u ou sly fo r j a p p r o x im a te ly t h i r t e e n months# The f i r s t s 1 i >, Jim # And, I w ill, rath er than to show you a l l o f the e p i t h e l i a l ch an ges t h a t have gone on ! in th e bror.-h i a l t r e e o f th e s e w hibe r a t s d u rin g the c o u r s e ; o f th e ir ex p o su re, nam ely, a t one month, a t th ree months, , s ix month3 , n ln ' m onths, ten months and tw elve months, I ; ta k e you lir a e d i. lo l y .> th e fo u r toon month a n im a ls . A t t h a t tin e , th ere were only fo u r w hite r a t s l e f t in the experim ent in th e l a r g o grou p o f - w e l l , i n Ha group o f f i f t e e n f o r ,a le w hite r a t s b e in g exposed to b e r y lliu m su lp h a te in the con- c e n u rstio n s which I have given# A t t h ir t e e n and tnroe q u art 14-67. L J m onths, i t w as o b se rv e d t h a t one an im al v^.a 1 1 1 , and so a s j i s our custom , th a t anim al was s a c r if ic e d ra th o r than to a llo w i t t o d i e , an d we, on k i l l i n g the a n im a l, wo o b se rv e d j a v e r y s t r a n g e l o a i o n which we had mover h e r e t o f o r e o b se rv e ^ in our r a t colony, nd hare i s the g ro ss lung o f th at r a t , j and we s e a t h a t th a r a re p a r o - b r o n c h o la r f o c i o f r e a c t i o n j I to the b e ry lliu m th a t has become b e ry lliu m s u lp h a te , th at J h as become l o c a l i s e d in l' jso a r e a s in the lu n g and in ad -- j d i t i o n , we s e e P.I3 0 r a t h e r c o n s o lid a t o d a r e a s , c:A h a r e i s i ona xnd we can pick c- ne out* Hare i s c a cth o r, and in th is are a h e re , and a ls o t h i s l a r g o turaor m a ss a t t h i s p o i n t * That i s one w?8-* The n e s t s l i d e * And, th e seco n d a n im a l, now, subsequen tly th en, having nado the o b se rv atio n , k ille d m l three rem aining an im als, rem aining in th at p artie u l& r ex p e r im e n t, and I s h a l l now show you th e lu n g s o f th e tn r s e re m a in in g an" m i s an d we have h a re the lu n g o f & r a t a t f o u r t e e n months o f e x p o s u r e , th e g r o s s lu n g * J s e e wt tumor l o c a l i s e d in th e a p e x * We c a n so e the sm a ll x o s io n th o r e . b'o can sea it in the lugn, wo can sea a at.:axx xO>1. at that point. Ja can soe a small las: hare I merely V'l w p e l ns in r .o in t ia g that tlie : mors are multiple within th here is a largeri' tumor w v -'h was one - i one of tho lobes huich is not included in tills section, and we see it - trure JM* a e r i a l s s c l i o n end we s e e the tum or tio n o f that lo b e . T his is the aark ^ the photom icrograph. in the r ^ low est ^ por j * * . l i d . . Th. th ird and * , flw th ! " I B " * M " d 7 m' B l1 f " : ' fw fj f o u r t e e n montha to bt r yJi : .um *aiuu-loLphnaart,eQ, 0on1 1 ja ix llg r a a is p er 1 c u b ic f o o t o f a*'** a. A t tw elve m onths, we do SG9 p ron ou n ced thoae - W * * p l a a * a and I h a v e n 't b o t h a r - d to show -cu fcut * d id n ot t e ilo v o a t t h . tiTM & we b e l i o v e now t h a t t e a t e p i t h e l i a l h y p e r p l a s i a h ad b o e r eic<.rona but a t fo u rte e n months. I t h a s . That ag ain i s | Another g ro ss se c tio n . ' j how 7u cn e c r thB l a r g e r tu m o rs, Horo i s ' a n o th e r tum or im p la n te d on the PJ * r a . H ere l 3 anofcht?r tum or ^ p l a n t e d on :e p l e u r a . r 9 r9 i s th r e e tumors i P i -od on th e p l e u r a an d we q u e s t io n w h eth er t h i s tu ;aor 13 ^ * * * * * * * * * by the trach eo-b ron cM t 1 lymph node which o n d ^raw ti-- ~ d ^ il5r c u p Ao s th e p r o l i f e r a t i o n o f the lo b e a t th io . - i - o i n t . ^ e r a n o t s u r e abo' - 'nv i f. i -* *u. . -it/ j vv -l ya WO D S li-' VO *f U,,,, ' * ' J 8 **?***&. b e c a u se th e re i s no e v id e n c e o f lyr.tph node t i s ^ a Pt +.<. ,, . , , . "J' " S l 'C Wmch ^3 CO^U,.! tO b o th human s u b je c t s and in a n t r a l s u b je c t- ~ -- v jCU w f jio t r i f a r - co.tilc)jQ o f tzlio # 1 " U 1 " C" d b ri8 1 ' ^ *> " t , . raicroco;jia t h U th " " 1S p h , ^ i . o - M 9 . ___ i graph fora the m ajor b ro n c h ia l tr e e , and I c a ll your a tt e n - j tio n to the ep ith eliu m lin in g the m ajor b ro n c h ia l t r e e , calum nary in ty p e, s l i g h t l y h y p e r p la stic and a t some p o in ts the su b lu co se lymphoid t is s u e has ap p aren tly broken throughj w hich may b e a norm al o b s e r v a t io n , ana h e r e we s e e t h a t j lymphoid tis s u e exposed* X w on't d isc u ss th at fu r th e r * j There i s a problem h are which I do n o t th in k p e r t a in s a t th e nor n t , to our io a re d ia te p ro b lem * Tire n e x t s l i d e . And, a s we go f u r t h e r down in t o j the b r o n c h ia l tre e , we ao fin d fo c i where n r o s s - t e e t i o a j o f a r e s p i r a t o r y b r o n c h ia l made up o f e p i t h e l i a l c a l l s , . nick a t the mucosa, ev id en t h y p e rp lasia, but in a ..a itio n , j we a l s o f i n d the a d ja c e n t a l v e o l a r s p a c s s which as* tu.3 tort*j* a d b y* r e a s o n o f th e f i b r o u s t i s s u e o r th e c e l l u l a r r e a c t i o n ;i o f th e a l v e o l a r w a l l s , and we f i n d th o se a l v e o l a r s p a c e s | i ly in g w ith a vary w ell d efin ed ep ith eliu m which in in stan ce;} i s c a lis a n a r , b u t i n m ost i n s t a n c e s i s -f the f l a t c o l l o i d a l ! tJ'P o T h is i s common, a eosjuon f in d in g in th e lu n g , s u b j e c t to chronic diso& 3 e s which g iv e r i s e e s p e c ia lly to f i b r o s i s * i i I t is se e n i n human, in the lu n g s o f human sub- | j s c t s , as wall as i t is s e e n i n the lu n g s of e x p e r Im e n ta l ; animals. Hare is the ty p e o f lesion which we think Siam- ' bates the lesion se e n in human subjects, winch char&oter-- . lacs that lesion due to th e composition of b e r y lliu m * hade: up of large mono-nuclear c o l l s and v a ry e x a c t * I only I ItfO. . p o in t t h a t o u t in p a s s i n g . That i s the l e s i o n w hich wa a re I a tta m p tin g to re p ro d u c e and wa b e l i e v e t h a t we h ave r e p r o duced i t in those anim al s u b je c t s , the r a t s , b u t not in any j o th e r an im al have we p ro d u ced a r e a c t i o n . We have p ro d u ced ; I a re a c tio n a f t e r in .avanoua in je c tic . in the r a b b its# ; D octor Gardner f i r s t showed h is w ith zin c b e ry lliu m su lp h a te , a BeO c o n to n t o f 1 3 .8 p e r c e n t a--d su b se q u e n t t o th a t tim e , j we have c a r r i e d on a l a r g e number o f e x p e rim e n ts w ith van-- j io u s b e r y lliu m com pounds, and we have re p ro d u c e d th e s i m i l a r type o f o stso g a n ic sarcom a w *th m ataotases to the lun gs J w ith I v a r io u s b e r y lliu m compounds# I In p a s s i n g , I m igh t s a y t h a t wo w ereu n s u c c e s s f u l 1 * | in producing th ese le sio n s w ith b ery lliu m s t e r a t e ,w ith j b ery lliu m carbon ate, with - I want to gee the l i s t ao ] b e ry lliu m sb e r a te , b e ry lliu m carbon ate was too to x ic , i t J w a sn 't t o le r a te d by the r a b b it s in tra v e n o u sly . B e ry lliu m j h y d ro x id e and b e r y lliu m m e t a l, we have n o t su c c e e d e d in re ** ; p ro d u c in g t h i s tumor in th e b o n e 3 o f r a b b i t s , b u t we have | done so w ith ain c b e ry lliu m s i l i c a t e , a 13*6 p ercen t BsO, j 18 p e .c e n t BeO, f . 3 p e r c e n t BeO# y e h ave done th e seme j th in g w ith p u re EeQ d e l i v e r e d 5ntr a v e n o u s i y in r a b b i t s , : In lo w er d c s s s , th e lo w e st d ,;e was 650 m illig r a m s # The ; same th in g was acco m p lish ed w ith b e r y lliu m p h o sp h a te , in a dose oX' a H iu n d rei and tw o, 1 0 2 .2 m illig r a m s # I s a y t h a t on ly b e c a u se some o : - ou a re i n t e r e s t e d in th e d o sa g e f a c t o r # I ilT l. So tfc; ii t h i s e p i t h e l i a l h y p e r p l a s i a l i n i n g a l v e o l a r s p a c e s i s a common f i n d i n g , and I air n o t g o in g to e n t e r th e d s b a t a a t the Moment a s t o w h eth er t h i s r e - e p i t h e l i a l i s a t i o n re p re ** s e a t s a hyper, i s i a o f e p i t h e l ia l to ep ith e liu m which n or m ally lin o s the a lv e o la r space o r whether i t re p re se n ts growth o f ep ith eliu m from the a d jo in in g r e sp ir a to r y p a ssa g e w hich we know i s l i n e d w ith e p i t h e l i a # This then i s the s lid e o f the tumors# Now, find i t i s a d e p o s i t o f a l l th3e f o u r a n im a ls , and we f i n d h e re two d i f f e r e n t t y o e s o f tum or, one w h ich i s d i s t i n c t l y &uO-- ; o o id u s in h a and one p a r t o f th e a fine tumor w hich i s tsorc ] "" i a lv e o la r in ty p e, ten d in g to reproduce a t tim es a t the & i- j v a c l a r a r c h i t e c t u r e # W ell# l e t \is go o n , and exam in e some o f those tumors# And we' l l c o n c e n trate , first# upon the ad an e sa- to-as ty p ae o f tu mn oorr, t h a t i s th e a d sn o -c a rc in o ra a se e n in tho se .Lj.*<%...i03 and he: I t dons'Orv5b r ^ to s t h us, a dsney to l y , th e r e aro iz any l a r g e , th oy are hh h y p o ri .L'Oph ie f.i ;pir The n e x t s l i d d , and t a i s ia g y o,i to iiighaz* nificafcio.a because v j attempt here will be to show that this cellular chance, Ihis tuner is, we believe, a fcrueiy m align an t, and i t has been subm itted to o th e r p a th o lo g ists who have rev iew ed the s e c t i o n . A g a in , a h igh & r r t a g n i f i c a - tio n , you ceil see the c e l l s tr u c t u r e . Tne n e x t s l i d e , and s t i l l a h ig h e r mcgn 1f iw a11 cm to show you the d if f e r e n c e s in s i z e an s t a i n i n g c a p a c it y o f th o se c e l l s . Ho r e p r o d u c t io n r e a l l y o f a s p o c i f i c p u l monary t i s s u e grow in g in th e t i s s u e and a l s o p ro d u cin g im p la n ts o r n a t a s t a s s s go to the p le u r a l s u r f a c e ~_ataeta- s e s a lso going to the tran ch oo-'oroneh ial lynph node. The r,ax t s l i d e , a s to th e a l v e o l a r s t r u c t u r e , th e a l v e o l a r ty p e , in d e e d , t h i s h a s b e e n c n llo c i by se a e in c e n t r e s t to the r e sp ir a to r y b ro n e h io -e a rc in ssia , the a lv e o la r ty p e carcin o m a and her we se e a r e p r o d u c t io n o f th e p u l monary s l v o o l s * l i n e d w ith th e m a lig n a n t c a l l s . And h e r e a h ig h e r m a g n if ic a t io n to show y ou th e c h a r a c t e r o f t h a t c e llu la r growth. The n e x t s l i d e , and s t i l l a h ig h o r s i g n i f i c a t i o n o f t h i s a l v e o l a r ty p e ox' s t r u c t u r e and we s e e a ^ a l t i t u d e o f c e lls T h is i a now lin in g an a l v e o l a r s p a c e and h y p a r - tr& u n atie, there i s n ot myotic fig u r e , ex ce p t p o 3 cib ly ta u t may be o n e, I c a n * t remember th p a r t i c u l a r d e t a i l o f s n i s s e c t i o n . Tiia n e x t s l i d e i s a s e c t i o n fro m th e pulm onary im p lan t tumor, end h ere i t is ten din g to rap educe the n a jo r tumor in th e - w ith , a th e pulm onary b r a n c h . The n e x t s lid e , and h ors i s the h ig h powered m a g n ifica tio n o f th a t tumor on th e im p la n t, th e m e g a lo c y tic l e s i o n , and h e re we have obvious m e tastase s go in g on, extrema a c t iv it y . Again note the d iffe re n c e in s iz e and shape of the c e lls and the t hyper trauma t i c ric h o o ss o f the n u c le i, and the la r g e s iz e o f the n u c le o li, a l l o f which i s c h a r a c t e r is t ic fo r a tru e can cer* Tha n ext s l i d e , and t h is then i s the a r e a of the t r a c l oo ~'orone h i a l lyaiph n o d e , t h i s i s th a l a r g e m ass bound a t the tr*ifere-H ti-.n o f th e t r a c h e a and th o s e m e re ly r s p r e - j} s e n t t e r i a l s e c t i o n s b e c a u s e we w ere lo o k in g fo r d i f f e r s c c s 3 in the gorwth of this tumor* Tna next si?. ', shows you now the tumor which has j a p p a r e n tly r e p l a c e d th e x s a ta s t & s e s to o an d r e p l a c e d the an --j t i r e t r a e lio o - b r o n c h ia l lym ph node and h e r e a g a in we se e th e c h a r a c te r o f the c e l l 3 tr u e tu r e rep ro d u cin g the prim ary t'.usiora o c c u r r in g w ith in th a pulm onary t r a c h e a , a n a t h is _ I tumor i s h ig h ly v a s c u l a r i z e d in th a t r a c h e o - b r o n c h ia l l y >'<?& j node* | With that then, we have now with BeO, n a h ave I subjected animals to EeO, yure beryllium oxido exposure* : th a concentration there u -<s approximately 12 iailligr>ucs per ; cubic foot of air and the animals at that experiment were ^ carried along for only alsven and one third months, not uong enough to reproduce the same type of tumor as we have ooserv w ith b ery lliu m su lp h ate# ' I However, a t t h i s tim e , wa saw s i m i l a r e p i t h e l i a l | J h y p e r p la s ia in the b r o n c h i a~ d e m o n stra te d in r a t s v to r j e x p o su re to b e r y lliu m s u l p h a t e , b u t we can p o in t o u t th a t | i n t r a - t r a c h e a l i n j e c t i o n o r b e r y lliu m o x id e , wa havo r o o r o - j duead th e same k in d o f tumor on i n t r a - t r a c h e a l in je c t io n o f j b e r y lliu m o x id e a s wa h ave w ith the b e r y lliu m s u lp h a t e , and | e l so the b e ry lliu m su lp h a te on iiit r a - ir a c h e s l In je c tio n * th o se a n im a ls h av e gon e fo r o n ly e i g h t `j o a u i s , b u t too aniraal k i l l e d a t '.ght months a ls o shows a s im ila r e p it h s l- i s l h*yfcr s a"r o la s ia a d l i n i n g o f th e a l v e o l a r s p a c e s , and we j su sp e c t th a t tlv e an im als w ith lo n g e r p e rio d s o f tim e* they a p p ro a c h th e f o u r t e e n month p e r i o d , w i l l show coL*pi able changes# S o , w ith t h a t th e n , we h o l l a v a t h a t wo h ave p r o duced . a th e w h ite r a t pulm on ary c a n c e r o f th a d e n c - c a r o l - ; noraatous ty p e , w ith m a t a s t a s e s to trie F --vu ral U.vfav3 d, , to th e t r a c h a o - b r o n c h ia l l,-; .sph node# We h ave n o t a s y e t o b se rv ed dir- ta n t m a ta sb a se s# 'T h is, a s I m ontioneu, i s only : p ilo t exporir.ent# The o b se rv a tio n i s only te n tativ e # j I t in vo lv es only four an im als, but a l l four an im als, a ll 1r"a i ' aor\ n in g i n t h a t in i - e la t i o n eap o r irvsnt ] 20 ' <> have s e t up a v e ry l a r . ~s e x p e rim e n t i n o v d e r t o rv ro-^uve and to v a lid a te th ese o b se rv atio n s# e have abandoned tiie s a c r if ic in g p e ri - - so th at the c o n c lu s io n o f tha e x p o s u r e , we w i l l have an ad eq u ate J number o f a n im a ls which, w i l l g iv e v a l i d i t y t o o ur ob >rva-- i tio n s I should lik e to p o in t out here a lso th at th is i s a p i l o t e x p e rim e n t, t h a t t h i s h a s been p ro d u ced in white r a t s * t h a t th is d o e s n o t n aan t h a t b erylliu m w i l l p r o `.'no* | pulsion a ry c a n c e r i n human s u b j e c t s # Thank you# (Applause) Doctor Rhoads has d e leg ates h is a u th o r ity to r , fin d in g i t n ecessary to go back to New York* i t would seem are fa m ilia r , .3id a sp e cie s in which the spontaneous occur* renca o f naopla-iaas seems to be e x c e s s iv e ly r a r e * He nnd h is c o lle a g u e s a re :o be c o n g ra tu la te d f o r t h i s most tia e ly r s p o r t . l-'xy ue h ave some d i s c u s s i o n ? I r e t h e r e n y q u e s tio n s which someone would i l k a to ask ? BY DOCTOR HcCOrrhTCRi j ilould you rap o at a g a in , D octor Vorwald, the ccn- | csntr& tion o f beryllium used? ! iiY DvX/iOH vn;v*Or Zi 0*1 pur cubic m illigram o f air# May I a sk a b o u t th e i n t i - - - t r a c h e a l? The i r t r a - tracheal was an i n j e c t i o n o v e r a p e r i o d of f o u r woaka c o n s i s t i n g totally of 2$ m illig r a m s o r 2 ,5 c.c.'s o f a f i v e p e r c e n t suspension. BY DOCTOR RICSRl Any o t h e r questionsf BY DOCTOR yOFWALDi I w i l l ch eck t h a t . D o c to r B ^ o t j o r , I w~.at to be su r e of t h a t , I h ave i t h a r e * BY DODIOR KID3R: Are th ere fu r th e r q u e stio n sf Yjv T":vP ryv* * Ig n o re a c l i n i c i a n * a ig n c -xtoe f o r a s to ask how o ld in a span' s l i f e a f o u r t e e n month o ld r a t i s , how lo n g do rats liv s? BY. DOCTOH 0 :"- t f-Dr Cur r a t s seld o m l i v e beyon d two y e a r s , s o we b e lie v e th is anim al a t t o u r toon m onths, and th a t m y b a f a c t o r t; i t th e y *r a p p r o a c h in g , t h i s age p e r i o d , when th ey j I m& d e v e lo p pulm onary c a n c e r , i BYTD-0CTQ3 K.vkSY : j I Has tr y in g to t r a n s l a t e i t in to tha xvcjsbsr o f y e a r s th a t hussana hav c a r r i e d a body b u rd en ox' b e r y l l i u m , BY^DOCTCR V v ID ! W ell, I su p pose fo u rte e n months in n r a t , to th a t e x p o s u r e , m ig h t be e q u i v a l e n t to tw on ty-fiv y e a r s in s. human