Document nVkZd7LOZEN3J1kp6M11o1j1

(Article by P. belore a n d Borgomano: French; J. Ned Lyon 'J= 227- 233, 1928) 0 Benzene con i n d u r c oppou1t.e a c t i o n s on l e u k o p o i e s i s d e p e n d i n g on i t s dose. H n r e o v e r , s e n s i t i v i t y t c t h e benzene compounds v a r i e s g r e a t l y among i n d i v i d u a l s . These two facts w y e x p l a i n t h e p a r o d o x n l d e v e l o p m e n t of a c u t e l e u k e m i a i n d u c e d by .I compound t h a t is u s e d i n t h e t r e a t m e n t of cert a i n forms of leukemia. Our c t i n i c a L case r e p o r t , u h t c h may seem u n i q u e u n c i 1 now, gives. US . L l w o p p o r t u n i t y t o disvuss t h e rcl.ic i o ~ i s h l p sh e t s w n 1eiikcrnl.t and s e v e r e a n e m i a a n d also the t o x i c etiology of c e r t a i n , ? c u t e l e u k e m i a s . I n sddit L o n t o the f a c t chat b e n z e n e , a coal t a r d e r i v a t i v e , my p r o d u c e a c u t e leukemia, a nev q u e s t ion atlses r e g a r d i n g t h e r e l a t i o n s h i p between c e r t a i n forms o f . a c u t c leukemia and sari o m i t o s c s . -1- ._ . -.,.-I- \ .,- . REVIEU OF CLASSICAL STUDIES I. Chemical s t u d i e s . Benzene, b e n z i n e and b e n z o l . A3-cbrdins C C I KOIIN-AUREST, ttic o n l y disc i n c t I i m amnp; /jIlgst? t h r e e c n e m i c a i names. 19 a d l f f e r ~ n c cin p u r t t v . Benzene 1s d C 11 h y d r o - carbon, t h e nosc simple compound o f t h e a r o n 7 t i c hydrocarDon S e i i e S am! au,-,c~;i:j- t r r - f i t r 4 from t h e llghc p o r t i o n of coal t a r . L'-LYiZ> --- - _ - s?.c--c ` w w r e r n m m e r c ia I o e n z c n e . - _ -ed. n n n r c c t r r I C D~ ~ I I L A I I ~ S . ;*rear L-?.;:~:.u~ ,::&, ;::--:!-* *v*. R-nzn! fs real -_- --- -m i -;* -,. -'- - I_' -*- * * s - ( n o r h r toxicology. f o l l o v i n g the i n h a 1 a c : o n 0 : befize?le v a p o r s . tlic dlncinccion b r t u e e n b e n z o l , purc b e n z i n e and unrefiiled b m z i n c or b e n z o l should b e made v h e n ve a r e rrfetring t o nrassive doses. However, such a d i s t l n c r i o n is of no c o n r e r n when ve a r e referring t o an atmospherc t h a t 1s weakly o r e v e n m o d e r a t e l y c h a r f f r d v i t h b e n z i n e . In such cases, ve h n v t l e a r n e d from e x p e r i e n c e t h a t t h e e f f e c t s of t h e benz i n e f n p u r t t l e s a r c af a s e c o n d a r y n a t u r e . Thus. in d i s c u s s i n g t h e t o x l c l y of benzin&, wc s h a l l r e f e r effectvcly t o t h e t o x i c i t y of t h e p u r e C'H` compound v i t h o t l t taking i n t o c o n s i d e r a t i o n t h e e f f e c t of any OC t h e Impurities t h a t arc found in b e n z o l s (KOII!I-A[IRF.ST Ref . . 2 ) . Thcreforc, benzine, h t * n z c n e , and h e n z o l h n v c v c r v s f m l l a r c h e m i c a l .wid t o x f c o 1 o ) ; f c n l p r o p c - r t ICs. Yany a u t h o r s c o n s t a n t l v confuse a l l three cvmpounds. Thc casts o f p o i s i i n i n p a r c ~ l v o v sc-nosed b y b e n z e n e . S l n c e SELGINC, the clinicians h a v e uronL:ly l a b e l e d t h e p r o d u c t t h a t t h e y use for t h e t r e a t m n t of I c t ~ k r m i a s.IS b e n z o l . Tile p h . i r m i c I s t supplies b e n z e n e , and i t is wrong to c a l l t h i s compuund by a n y other n a m (CRLYIFU). I t . Expcrimcnt2LStudles. The fmportnnce of- t h e d o s e . h c h e x p t r f r n c n t a l t c s r a r c h h a s s t u d i e d t h e c f f c e t of b e n m n e on t h e blood. . I n 1907, 1AW;LOIS m d IESUOUIS ( R e f . 3 ) rc.portc.d tlinc animals e x p o s e d t o benzol v a p o r s developed s e v e r e b u t t r a n s l c n t h v p e r g l o b u l i a . The same pear, PA.IAlID ( R c f . 6 ) i i r s t u d y i i i r . slow a n d c h r o n i c t o x i c i t y , o h s c r v e d t h e following symptoms: m c m l n , `3 r c d u c t i o n L t i t h e t i r m q l o b i n * I n a d d i t Ion t o hivizcwc.. twiizi>l r o n t a f i i a 3 I . t r g e riumbcr nf fnpurtics such as t o l u e n e , x y l r n e , . a n d a small amount of c a r b o n s u l f u r . e t e . -2- '. 0 l e v e l , p l y n u c l e o a i a , and normobl.tscs In the blood. I n 1911, SE1.LIHc; ( R e f . 5 ) l n r r p l r r d h y tlic c f l n t c a 1 o b w f v * t i o n a r e p o r t e d hv Barker, a d m l n t s t e r e d s u b c u t a n e o u s i n f e c t i a r of bm-1 to r a b b i t s (mlxed w i t h an equal amount of o l i v e o i l ) in a duse of 1 m i prr kilogram of weight. The a u t h o r o b s e r v e d conrldcrahlc t o x i c effect8 rn ' leukopo I C s LA. P,lPFE!!tlEIH ( R e f . 4 ) ohs.arvcd that L f f a i r l y tau d m e s of b r n t o l are u s e d ,then p r i m i r v lt.ukclrycttst'+ develops. U s l n e e v e n l w r r dorrcn, t h e l e u k o c y t o s e s is no longrr f o l loved b y I c u k i , p r n f a a n d PAPPEHHZLH c m c l u d r d t h . 7 ~ benzol, when g l v r r l In 'lov doses, s t l n u l a t e s h e m a t o p o i e s i s d I n !i:!gt? dnse5, p t o d u c c s ~ p l a n i a . MASATOSHL TAilARA ( R e f . 7 ) i n j e c t e d r a b h l t s e v e r y d a v w i t h 0 . 7 5 mi Of prtrc b e n z i n e p e r k l l o g r a n of u e l g h t . The a u t h o r o b a e w c d a decrease in L ' . ~ r c 2 blood c e l l c o u n t , an t n c r e a s e in t h e number nf w h i t e - b l o o d c e l b , -a n d thcn a p c o z r c s s t v e d e c r c a s c I n t h e number of l e u k o c y t e s . j z - f . B! ? ? d ! X ! i * d cxpcrtmental scudics uticre b e n z o l was i n j e c t e d Subc u t 3 n x v ~ s l vand f o u n d t h a t the compound p r o d u c e s marked stimulacfon O f t k c bnne mirtciv and , i f f c ~ t st h c p r o d u c t i o n of t h r o m b o c y t e s 3nd l e u k o c v t e s h a v i n g poivawrplicrus nuclei. However, i n h i g h e r d o s e s , benzol i n h i b i t s t h e bone marrow. Based o n ttic n-scarcii t h a t h a s been c o n d u c t e d , i t sccmmst h a t t h e c f f r c t o f cxperirnentnl h v n r e n e poisoning d e p e n d s o n t h e dose of t h e t o x i n a d m i n i s t e r e d . I f t h e dose is h i f i h t h c n t h e r c Is a c o n s i d e r a b l e and r a p i d decrcnse In t h r number o f rcd blood c c l l s : I f t h e dose is mmlcrate then p r i m a r y 1eukocytosc.s nritl Gecondiiry l e u k o p e n t a d e v e l o p , a n d i f t h e dose 1s lov t h e n only l e u k o c y t o s e s occurs. ' Ct.nera1 Ly. n u t h o r s siic-h as SELLING,. i n e x p k r i n r n t a l l v d e n o n s t r a t f n ~ t h e t o x i c c f f w t s o f ht-nzol 011 l c u k o p o i v s i s , havc a d m i n i s t e r e d w h a t seem t o b e r n n s i d c * r n h l c * ~ I I S C ' tSo animals. Thts " l c i i k o t i i x i c " actiorl WAS ' u t i 1 i z r d in tho trc*;rtnu*nt o f chronic- lcuki*mi.is. floutwrr. w e s h o u l d note t h a t lov d o s c s p r m l i i r c i . i m p l p t c . I y opposi c c r c s u l t s , n o t o n l y I n r e g a r d s t o t h e w t i l t c blood c c l l s hrit a l s o red blood r-t*Lls. In l * f f c c t , b e n z o l i n high d a w s tends t o d r s t r o v c r y t h r u c y t w , w h i I v i n I I W J dns6.s. i t s t i m u l a t e s t h e i r f o r m a t ivri (SELLIN(;, IXiCLOtS. a n d I)*ISUI'L'IC). 111 clic.rapy, w e f i n d a m y examples o f p h y s i c a l . , C e n t s o r t o x i n s t h a t havv d i f f e r e n t e f f e c t s , d e p e n d i n g e n t i r c l y on tlicir Jc*sc*. This rnnt*i.pt s l ~ i i c i l dalways h e k v p t I n mtnd when t n t c r p r c * t i n c ttir scc.mingly rcmtr;itllctorv hr-m.itologicai f i n d t n R s o f c e r t a i n i n v v s t i g n t o r s . AIso, t l t c i m p n r t n n r r o f t h c d o s e is a c o n c e p t t h a t s h a l l b c uscad f n 6 - x p l n i r i i n g tlw hc*nzcnc* c t i < t l o g y o f t h e JCutC l c u k e m f a o b s e r v e d i n our patient who vas exposed t o bvnzincb v a p o r s f o r m m y years. 111. T h r r n p c u t i c F i i i d i i i g s . .. I n t h e f i c l d r p f t h e r a p e u t i c s , w e f i n d many t1x;irnpIes o f hcw a r m p n u n d ' r . a c t loo d i f f v r u da-fwnditiy: i v i i tht. dt1<1*, Fear c*x.impli-, i n n r d v r f o r hr*nz.ol t o have ;I l e u k o l y t i r actioii i n t h e t r e a t m e n t nf lrukcmia. i t must be g i v e n i n . -3- 3 ai 1 i 8 .. 0 -LV. Cllnlcal studlcs o e n s c n e p p l s o n l n g . - Ut. shall o n l y m c n t t o n t h e most t y p i c -a 1 exnmplea of bencrnr poisonhg. One s h a l l f i n d t h a t t h e c f f e c t s are t h e same * e t h e r the poiurning 1s . , caused b y benz i n c o r b e n z o l . b A c r t d c n t s r c * u i t l n p from c-xposrire t o b e n z i n e a n d b e n z o l have be- reportcd for n long ttw i n workshops with poor v e n t i l a t i o n ranufacturin$ t h e s e compounds, and t n c n t e r p r 1 s c . s vtrcre t h e s o l v e n t s are used for c l c m ing grease and .ISs o t v e n t s f o r r u b b e r . I n 1897, SANTESSOY r r p c i t t c d n i n e case+ o f c h r o n i c orcupational pol-i n g . F o u r o f tiiv c a ~ t ' sw r e f a t a l . The m.1 jor symptom I n c l u d e d aneda, hemorrhaging in t h e fitnglva. and v a r l o u s v i s c e r a . A t t h e same. t i m , LE W I R a n d CLAUDE ( R e f . 10) r e p B r t c d t h e case of n w o r k e r p o i s o n e d w i t h b e n z i n e v a p o r s . Thts w o r k e r d c v e i o p e d h e w r r t w g i c p u r p u r a a n d arittc- nnc3mia. The p a t i c n t d i e d . A u t o p s y ~ x i ~ o m i n ~ t froenvealed a - v e r y large numbcr of l r u k o c y t c s f I I 1inp. t h e h e p a t l c i n t e r - t r a b e c u l a r cap1 I Inrics, nit. i e u k n c y t i - s ; i p p c a r e d t r r b c more nhrrndant t h J n t h e r e d b l o o d cclls. C a r c f u t c x r t m i n n t i o n o f t h e b l u o d was n o t made, b u t v l t h a u t .c o u n t i n g . it vas e v l d c n t t h a t t h e w h i t e b l o o d c e l l s were a l s o more nraero- i n t h e blood t h a n t h e r r y t h r o c y t e r . I n 1910, BARKER pub1 ishcbd the c l i n i c a l h i s t o r i e s o f t h r e e y o m i P L f l J , t w o of whom d i e d a f t e r h a v i n g s u f f e r e d from p u r p u r a nnd signs o f aplastic .ancmia for o n e month. These vnung g i r l s h a d vorkltd i n 1. shop where b e n z o l was u s e d as a s.o l v r.n c .' In 1916, JULIEN .ind BONN ( R e f . 1 2 ) r e p o r t e d tiir c l l n i r a l h l s t a r v of a worker cmplvycd fcir tuci ncinths i n ;1 f;ictory w h c r c h e s p r e a d a r u h b e t solution dissolved in bcwzinc onto canvils. Mic uorkcr dcvclopcd purpura w i t h b u c c a l h e M r r h a g i n g a n d g i n g i v i t i s . llc d i e d a f t e r wcvernl days. SOC(]L'ET, KI.INT., a n d ICOtlN-,\BREST hnvc describrd r a s e s o f f a t a l p r i s o n - .Inf; ulit.rc the rot I l w i n f i sigiis c l c v c l o p r d : f v v r r , a n c m i a , p u r p u r a , j a u n d i c e , a n d gas t rot n t c s t i I t i t 1 d i s o r d c b r s . I n 1922, Fl,,t'lD[Y a n d RORERTI ( R e f . I h ) r v p n r t c d thc o b s e r v a t i o n of a yomiin uiio d l e d o f nc'utt- licmirrhay.ir p u r p u r a a n d hifih f e v e r a r c o m p a n f e d a . I v u k o p r i r i n . a n d the n e a r y cwnp 1Pt c * d isnppc.1ranc-e o I Is. i n f ; i c t . 1 I i i n was thc octrtti c.iw o f p o i s o n i n g t h a t -4- i o c c u r r e d i n e . v n r k s h o p h e r e b e n z i n e vapors vere b e i n g pemamntly discharged. I n a S a i n t - E t i e n n e f a c t o r y , CIIX,%OVET (Ref. 1 5 ) found a l x w e n who h a d d e v e l o p e d a syndromi. c h a r . i c t c r i z e d bv s e v e r r anemia and u c e r i n e h e m r h a g i n g . T h e i r g t n g t v a h a d the appearance of 5CiiF-::?. In t h e o b s e r v n t f o n s p u b l f s h e d oy t t L i " i i i i X X : 2 s T . ! 5 ! .md a l s o b y FAWE-REAL'LIEU nnd LEVY-BRUHL (Ref. 1 7 ) . i;;=n_ :f * - v p r p anemia w i t h purpur.1 a n d l e u k o p e n i a were r e p o r t e d . F[n;i[ l y , one <if the most r e c = e n t C.tITt.> ,! ;:*:->i-l; ! . . i5~2 ~ : :rc-rrpci by CRF2lTEU. Tht- rase VGIS p u h l l s h r d [ n this juurn,,i : Z !?1'. '!%e worker. o h s e r v t - d b y CRE31El2, had been cmpl..tycd i n cnc k?;t-r! srnrked m&r t h e same c - o n d l t i o o ? r as o u r uun p a t i r n t . Y o r e o v e r . t h e p a t l e n t ' s c i i n i c a ? c o u r s e involved ;rcutc* ancmta w i t h purpura. i l i s clfnlcnl c o u r s e vas v e r y atmilar t o the cotirse of ;icutc I c u k c m i a r r - p r t e d i n o u r p n t l e n t . Because of t h e s e r e a s o n s , w e b e l t e v e t h a t i t would be w o r t h v h i l e t o b r i c f l y r e v i e w t h e c l i n i c a l history r e p o r t e d . by CREFIIEU. Thus. w c s h a l l b e t t e r u n d e r s t a n d t h e m a t t e r when d t s c u s s i n g t h e r e l a t i o n s h i p s between leukemia and anemia. On F e b r u a r y 7 , 1923, a young 2 5 w a r o l d man was Adnitted t o Professor Roqtrc's c l i n i c . F o r h a l f n day t h e r a t f c n t hnd p r o f u s e e p l s t a x i a , r e f r a c t o r y t o t r c a t n h n t . The p t i c n t h a d the a p p e a r a n c e of J b l e e d i n g , p a l e man utio W;IS clcisc t o d e a t h . L .. ._. .- The p a t i e n t prruenLed a b L w d d v r r c r a s l a . The R o u r c e o f t h l . pol- i n g vas b e i n g souyht amnp; the c h c m l c a l s u b q t a n c c q t h a c were used for d r y i n g t h e pyramidon. b%;h.7tvere these s u b a t a n c e q ? A c c o r d l n r ? t o C h c i n f o r m i i t i o n suppLLed b v t h e p a t i e n t and s u h v e q w n t l y completed by 8 - d i a l l e g a l q u e s t l o n n a i r c . p r e s e n t e d b y Dr. H a z e l . t h e o p e c a t i a i n q u s t consisted of ttlltng a " c c n t r i f u q n l d r i e r " 3 1 t h a scat-liquld mixture of pvramtdon a n d b e n r i n r . l i i s lob was t o s t a r t t h e d r l e r , v a t i t s O p C c a t i m . and then empty ft. During t h l r o p e r a t i o n , b e n z i n e vapors were rr?lcrscd strongly b u r i n m d e r a t c anounts. I n c o n t r a s t . d u r i n g t h e c l e m l n g o f the rql-tipnent, t h e worker h a d t o remove t h e Lid of the d r i e r a n d s c r a p o f f the paste t h a t adhered to t h e walls or about 15 minutes. During Chls owrr t i s n . he i n h a l e d b e n z i n e v a p o r s in l a r g e a b u n d a n c e , a n d s l n c e t h i s t a s k had t o b c r e p e a t e d f o u r t i m c s d u r i n g t h e d a y . he vas in a 1 1 e x p o s e d for #.;IS hcur t g massive discharges of b e n z i n e vapors. Thus, t h i s was a case o f b e n z i n e p o i s o n i n E . E m a i n a t f o n of t h e p o t l e n t ' s b l o o d r e v e a l e d t h e f o l l o v i n g v a t u e s : H e m t o l o g i c a l examination: .Red blood cells UhCte b l o o d cells . . . .IIemoql ob i n .G l o b u l a r value .... .... .... .... .... .... .... ........ 190.(100 1,200 18f 1 . . . . . . . . . . .Lcukocytc d l f f c r r n t IaL: Poiynriclcar . . . . . . . . . . .Lymphocytcs . . . . . . . .. . . . . . .Large mononuc 1e:irs hveraqc .monon u c l c a f s 27x 65% 3I 5z So myelocytes. No r c t i c u l o c y t e s . No n u c l e a t e d r e d b l o o d cells. The p a t i c n c d i e d o n F e b r u i r y 14 having r e t a i n e d C o n s c L o u s n e s s until the end. n u s , the vfctfns ( J f t h e s e obscrvnctons underwcnt o c c u p a t i o n a t poisoni n g w i t h b e n z i n e or b e n z o l . After ;I morP or Less l o n g d e a l y . they d e v e l o p e d a n acute a n e m i c syndromr., p u r p u r a , a r c o m p a n l e d b y Ieukopcnla v l t h o f t e n a f a t a l outsomc. FAURE-BEAUI.lEU (Ref. 17) hove d i f f e r v n t f a c e d b e t w e e n t w o forms of b e n z e n e i n d u c e d ;inemfa: a m i l d form c h a r a c t e r i z e d b y a n a n e m i c s v n d t o m c and t h e a p p e a r a n c e o f scurvy a n d a n o t h e r more s c v e t e form c h a r a c t e r i z e d by a s e v e r e a n c m l c syndrome a n d h e m o r r h a g i c p u r p u r a * . An e x t r a o r d i n a r y f a c t is t h a t n e a r l y a l l of the o b s r r v a t l o n s mention g l n g i v a l hcmorrhastlng w i t h s c o r b u c l c c h a n g e s I n t h e gingiva. W e know t h a t t h i s p s e u d o - s c o r b u t i s s t o m i t L t i s i s v e r y common i n cases of a c u t e leukemia --- *We a r e r e f e r r t n g t o s e v p t e case9 of anemia a n d p u r p u r a of an a r s e n l c benzol etloloqy. . and ue shall scr I.itc-r on t h a t t h l s evmptorn wnq o f prfmrry InpOrtanC. In our p a t i c n t ' 9 c i i n t c n l p t c l u r c . TIW ful1twinK I S our p n t i c n t ' s c l i n l c o l h 1story: A case o f a c u t e t : i p i c n l Icukcpr_i.1 d u r i n q z h r o n t c bTzTz;e polsonlnq. ..H. a 4 1 w a r o l d male, V.IY a d m i t t e d on J i t l v 1 4 . 1927, to R . LEPISE'S d e p a r t m e n t v l t h ;I syndrome o f Iicmorrhngic p u r p u r a , whLch h e h i m e l f sWnt a n e o u s i y a t t r i h u t r d t o .? poisnnin~a r q u l r c d d u r i n g h i e empio:rnent i n a p h a m a c c u t i c a l company I n t h e Lvon .1rc.1 where h e VJS e m p l o y e d . Tbe p a t i e n t d i d nnt b a v e nny r e m r k a b l c p r r v i o r ~ sm e d i c a l hfsCOrv. He was s i n g l e a n d ilthou$h h e d L d n o t s p e c i f y , he was a h e a v y drinker ( t w o l i t e r s of wine d a i l y ) . Frrr t h e p n k t : 5 y c n r s , h e was camploycd i n t h e same c h e m i c a l c o a p a n y . For t h c p a s t f i v i - :;i*.irs, h v ' h a s h e e n cri~nx:cd i n a d r p . i r r n = n t v l w r r pyramlddn was d r i c d v i t l l benzine. T h c work toc*k p1.ic.r undcr c o n d i t i o n s i d e n t i c a l t u tliohc d r s c r i h e d p r e v i o u s l y r y CROtLEU's p n t t e n t . GC s h a l l not r c t t c r a t c t h e w o r k i n g c o n d i t i o n s . Our p a t i e n t a d d e d t h a t t h e work i n . t h i s departmc-nt waq c o n s i d c r c d t o IC d a n g e r o u s . i l k c o l l e a g u e s n e v e r s p e n t more t h a n one month on t h i s job. A p p a r e n t l v i n g u ~ dh e a l t h , t h e p a t i e n t c x p e r i c n c c d some epiaastric p a i n a b o u t otic month 390. !le a l s o had p a i n in t h e r i g h t h y p o c h o n d r i m a n d s o w b!oodv v o m i t . On J u l v 1, h e d e v v l o p c d s t n m a t f t i s and b e g a n t o h a v e a b l i w d v c o u ~ t i . On J u l y 5, s u b c u t a n e o u s h c r n o r r h a g r u a p p e a r e d . on J u l y 7, the p a t i e n t became ill. Upon a d m i s s i o n , t h c p n t f e n t was v e r y paLt-, d c p r e s s c d ; h e h a d d y s p n e a . a n d 3 v e r y c x t e n s l v e p u r p u r i c svndrome. Tlic skin w a s c o v e r c d by v e r y many p e t e c h i a e a n d c~c:hymoscu. In a d d i t i o n . he h a d scime hernntom2s. e s p v c f a l l y on t h e l e f t f o r e a r m and i n f i l t r a t i n g t h e subcut:iiicclus t i s s w s . Hfs f a c e vas p u f f y a n d h i s c h i n c o v e r c d b j c c r h v m o s c s . the cippvr p c ? r c i o n n f h i s . neck was d e f o r m e d w i t h a very largc s u b - a n g u l o - n u x i l l n r y a d e n o p a t h y . His mouth s h o w r d s e w r e hwnorrh;ijics a n d u l c c r a t ivc- s t o n . ? t i t is. The lower g i n g i v a uc-rc. s u c , l l c n . fungnrts u l c c t n t c d and h l o o d y . Thc ~ U C V U R memb r a n e s o f t h e c h e c k and p a l a t i n e area verc c c c h y m t t i r . The p a t l e n t c o n s t a n t l y e x p e c t o r a t e d 3 b l o o d y s p u t u m . His b r e a t h V;IS v e r y f e t i d . The lungs and h c . i r t wcrc n o r m i l . Tlic p u l s e r a t c was r a p i d a t 108 , b e a t s a n d r e g u l a r . Thc b l o o d pressure vas 11/8. The* l i v e r c x c e c d c d th* costal cajie by t h r c r f i n g e r w i d t h s a n d was very p a i n f u l . The lower poly o f t h e sp1rt.n c o u l d h e p a l p a t e d . n c p a t l e n t vas v e r y d c p r r s s e d nnd f a t i p c i c d . Itc cnmpl;~lnc.d of 3 s l i g h t Iicadachr.; hc. h a d no s t l f f n c s s o f t h e iiect b u t a slfpchL Kernig's s i g n . nit. tcn&n a n d cutiirwnus r c f l e x r s were n o r m a l . -7- .. . e E x a m i n a t i o n of tht* ganglia riqvratcd nirmrrocts ndmapathlc. in L h . E o n of -11 hard, p a i n l e s s R n n g l i a vlthouc a n y prrladcnitlra for t h e past t h r e e d a y s , t h e patient's v t s i o n vas tmpafred. Hi# p u p i l l a r y reactions vere i n t a c t . The large j o i n t s vere s l f g h t l y p d l n f u l . The urine was r e d u c c d i n volume and v e r y bloody. 111s temperature vas 37'. . _ _H e m t o l o g i c a l tests (Dr. VlNCENll . Y L - . I ~ ~uvIlc as o o e s i b l e t o d i a g n o s e t h e e t i o l o g y of the p u r p u r a s u n d r c z z . -- ..:.;P The blood c l o t t i n g time was delayed (20 minutesl. Ylie cloc r o u l d n o t be rccractca, ,IU --_------..A :<-.:-- - -26 hours a f t e r drawing t h e blood. Henoglobin l e v e l 70%. BLood c o u n t : . . . . .Red b l o o d cells ( p e r m3 ), . . . .White blood c e l l s ( p e r mm ) . 3,1b7,000 542,500 h u k o r y t e d f f f c r c n t 1a I : . . .Lynphobl.lsts . . . . . . . . . . . .N e u t r o p h i l i c nvelocytcs . . .F n s l n o p h t l i s myclnrvtes . . . . . . .. &?sophilic myelocytes . . . . . .Po1ynucItlar n e u t r o p h l l s . . . . . . . . . . . .Lymphocytes .. .. .. . 807 a= 2x I: hi. 3'i: ?lorevvet. ttierc IJcte s c v c r a l n u c c a t e d a r y t l ~ r o c y t c st h a t vere mostly normoblasts. - Albumin: 0.20 - Cytology: 60 w h i t e c l e m r . n t s p c r hand of h j y o t t e ' s cells. Blood culture: n e g a t i v e (Dr. VINCENT). On the n e x t day, t h r p n t l r n t ' s c c r n d l t i o l l w a s c n n s t d c r n b l y exacerbated. fhe p u r p u r i c e r u p t i o n became more a c c e n t u a t e d , t h e c c c h v n o r e s nore numerous, and larger. On the Lnncr s u r f a c e of the right arm. the e c c h y m o s e s -8- The c o n d i t i o n of t h e p a t i e n t ' s mouth YJS s h o c k i n g . The gingiva vere fungous and h e m o r r h a g i c , c o n t a f n i n x some foci Of s p h a c e l w . Thc tarf of t h e p a l a t e was v t o l c t i n co1or a n d c o n t a i n e d necroclr u l c e r a t i o n s . T k base of t h e u v u l a w a s c o v e r e d by a zone of s p h a c P 1 m . The breath was fetid. ' The urine was the c o l o r nf p r u n e j u l c c . Trle h e m a t u r i a vas nearly complete. The o l i g u r i a was 800 mi. The p a t i e n t d i e d tin ttiv morntnp, of J u l y 17: h i s f e v e r had r i 3 e n to .'93 A u t o p s y . Thc Irings werc v c r v c o n g e s t e d ; t h e r p were no s i g n s of t u b e r c u l o s i s . Tile h c n r t was i i n r r m i r k n b l e e x c e p t f a r numerous p u n c t t f o m ' h e m o r r h a g r a under tlic p c r i c a r d i n l v i s c e r a . Tlie i n n e r v a l l o f t h e aorta vas e c c h y m o t i c .is a r e s u l t of endarterial suffusions.. S l i g h t peritoneal h e m o r r h a g i c cf f u s i o n s . The I l v c r was cn1nrl:c.d nnd hnd t h e a p p e a r a n c e of a I lvt-r a f f e c t e d bg t o x i n s and i t i f c c t i c m s . I L was s l a t e colored, t h c c o n s i s t e n r v of sand: a f l n g c r c o u l d bt. i m p r e s s e d w i t h o u t a n y dlfficulty. Upon s e c t f o n l n g , . the parenchyma U.IS d i s r n l a r r d and clear yellow. T h i s d c g c n c r a t * - d l i v e r c o n c a f n c d numerous n r r r t i t i c focl. 'The visceral p c r L t o r w u m was congvsted. The t n t r s t incs v c r c scimevitnt f l a t u l e n t . The k l d n v v u v e r r l a r g p , w h i t i s h , and c*dr*m.icnup. fltcy d c c n p s u l a t e d easily. Upon s e r t l o n i n g . the m i d d l e was u n i f o r m ytiloulsh color. I t vas 'dlfftculr to rwognlze t h c pvrnmids. The r e n a l p e l v i s w a s f i l l e d w i t h blood. Upon o p e n i n g r h o rranium, t h c p i a m.itrr vas v e r y c o n R e s t c d . Ihc l e f t f r o n t a t labc vil+ t t w site o f 3 I w n o r r h ; i g c t h e s l t c of a n cgg and shoved h e m o r r h a p [ c s o f t r n t n q . Thc r i g h t o r c - l p l t a l Iohc c o n t a i n e d s o f t e n i n g o f nrr3 y c . l l u w l . i h rcrlnr. rcm:tininE t w o h t ~ 1 1 ~ ~ i i ci to -nrt a~i ~n r~d v e r y numerous dissr.mtnattd Iimorrhngic f v c t invaIvinK hotti ttw grey and thc white matter. kge verc t t i c r l n r o f .I tiazct i i u t , t i t h e r 5 t l w siie o f a w a l n u t . --9 D ISCUSS lo11 B e c a u s e of its e t i o l o g y , t h i s case v u e o v e r y ~ r u o u 0 1 01w aud prfh a p s e v e n u n i q u e . We h a v e , i n e f f e c t , n o t b e e n a b l e t o f l n d l n t h literature any o t h e r case o f a c u t e l e u k e m i a r e s u l t i n g hubl L W sur@. One may well .Irp,uc t h 3 t t h e a c u t e leukemia d e v e l o p d I n our p a t i m t , i n d e p c n d c n t l y of h i s formcr b e n z e n e p o i s o n i n g . a n d t h a t t h e r e 18 Iw) e t t o i o g i c a l r r l a t i o n s h l p bctucen t h e b e n z e n e e x p o s u r e and t h e s u b . s g M t leukemia. However. t h e r e a r c numerous a r g u m e n t s i n f a v o r Of Such 1 caaae and e f f e c c rch:?v11sh?p. Sccii:: :!a: sever..! . ~ c c L d e n t sh a d a l r e a d y h a p p e n c d I n t h e s h o p where : Z L ,.:L :jA:::;::rxc::: *%.e ( * f his colleagues h a d r e p e a t e d s e v e r e e p i s t a x i s . -Aiiuthe;. - .C Z ! ~ Z ~ ~rlJfr-d frvm a s e v v r e a n e m i c s y n d r o m e v f t h h e m r r h a g f c p u r p u r a . iiie d . i : - c t O : * ~ L U F C f n h a i a t i o n vas v e l l - k n m i n t h i s shop, ana the u o r k t * r s uho v e r e czp!~:;;d there c h n n g t d j o b s a t the e n d of the s e v e r a l vcbeks. 'w'e io iio: knov vhy o u r p a t l e n t r e m i n e d t h e r e for five years. . Ifowever, t h v r c Is more. A t f i r s t g l a n c e . our c a s e o f a c u t e leukfsmir a - p e a r s t o b e t h e cmnplcte o p p o s i t e o f p r e v i o u s o b s e r v a t i o n s on b e n z e n e p o i s o n i n g . w h e w l e u k o p e n i a was c o n s t a n t l y o b s e r v e d . However, i f we take i n t o c o n w l d r r n t i n n the c l i i i l c n l f c a t i i r e s a n d n o t t h e h c m a t o l o g f c a l paramters. we mnv u r l l b c s u r p r i s e d b y t h e i r s f c i i l a r i t l c s . T h e r e are many a n a l o g t a s : t h e acute anemia, p u r p u r a , various h c m o r r h a g c s . a n d especially t h e I: l n g I v n 1 hemorrhaged. v i t h psetido-scorbiit i c s t o m i t 1t is, f e v e r , and r a p i d l y f a t a l roiirsv o f tlie discasc-. In a d d l t l o i i , in t h c case d e s c r i b e d by CREXIEU as U C I I as I n our p a t i e n t , a d e n o p a t h i e s were p r e s e n t . O v e r a l l . tlic p o s t moretcm f i n d i n g s uere similar i n b o t h CJSC'S. Therefore, o u r c a s e d i f f e r s from the other s o l e t y i n r e g a r d s to t h c b l o o d p l c t u r e . Our case is o n c of acute leuki*ni;l. w h t l c t h e o t h e r o n e i n v o l v e d p c r n i c i o u s a n e m i a w i t h l c i i k c i p c ~ ~ i n .Thus, we a r c Led ,to q u e s t -i o n i f t h c s r . o p p o l s i t e f i n d l n g s a r c SO i r r r d u c t i h l c . . Uc s h a l l d i s c u s s t h e r e l a t i o n s h i p s b e t v e e n acute leukemia and p c r n i c i o u s anemia. . Such r t * l t l t i o n s h f p s a r c m a l . .JOLY s t a t e s that r e r c a l n f e a t u r e s of a c u t e l e u k c m l i i s rr*sc*mhIr th;it nf s e v c r e p c r n f c i o c i s a n e m i a . f n JOLY'S o p l n i c i n , i t miv bt- t h a t p r r v i o u s l v d c s c r i b c d rases of p e r n i c i o u s anemia were a c t u a l l y c h r ) s r o f ;II.UCCl*c*iikc*rnIa. T h i s may be t r u e o f t h e case c i t e d previously h y 1.E SoIR ;irid CLAUDE (Ref. 10). M i a t c o m p t f c a t e i the q u c s t l o n is t h a t c;isvs or a t - u t v I c u k c m i a w i t h o r i t hlaod l e u k e m i a hnvc been d c s c r i b c d , for uliorn t h e tvrm ; i c u t c "iipls?st i c Iciikvmias" or b e t t e r "leuk o p e n i c , " h a s h e m p r o p o s i d (C1,EKC). T h u s . o n e rnov w e l l ask i f s u c h forms o f 1cukrni;i v v r e n o t c n i v u n t e r e d i n some nf the p r e v f o i i s l y reported rases o f hcnxwic p i ~ l r o n t n ~o,b s r r v n t i o n s of a c u t e .?iicnia v l t h p u r p u r a . w h e r e there. was a disc1uit.t iiig frcqrwncv o f t h e p s c t t t l o - s c o r b u t i c buccal . l e s i o n s t h a t a r c f a i r l y f . h , i r a c t c r i s t i c of a c u t e l e u k e m i a . -10- * The cases of " a c u t c a p l a a t i c l r u k r n l a " or " I r u k o p c n i c Lcuktrf8" art very s t m i l n r t o Casea o f p e r n i c i o u s a n e m i a . Hotcover, d e r p l t e t h . ttnorctlral o p p o s t t t o n t h a t e x l s t s b e t w e e n t h e a n e m i c a n d the Icukrric p r o c c s 8 e n . t h e i r a s s o c i a t i o n 1s n o t rare (RXEUX). Ilony cases of 1etbkd8 are a c t o r p a n i e d b y q e v e r e a n e m i a s . Some authors h a v e p r o p o s e d t h e Cera % ? u c a n e m i a * ' f o r t h e c o m b t n a t i o n of l o u k e s l a a n d pernicloun a n e u i s . The q u e s t i o n vas ratscd a n d c r l t i c t z r d i n 1 9 2 5 by C I U L i E R a n d CHEVALIER (Ref. 11) a n d by RlEUX ( R e f . 13). In t h l s r e q p e c t . *de would llke ta a e n t f o n tvo f a i r l y r e c e n t o b s e r v a t l o n s , o n e by HOBECOL'R?, GIRAUD a n d CH. RIQIET J u n l o r ( R e f . 1 8 ) d e a l i n g w i t h a c l l n l c a l s v n d r o n e L n t e r m c d i a t e between a c u t e pernicious J n e m i a ,ind a c u t e l e u k e m i a . The o t h c r o b s e r v a t i o n b y CIMUFFARD a n d BERNARD ( R e f . 1 9 ) i n v o l v e d a case of petnf2ious a n c l f a t h a t eoded i n a c u t e myeloid leukemia. Perhaps m r e s u g g e s t i v e a r c t h e o b s e r v a c i o n a r e p o r t e d b v P . E. IREILL (Ref. ' 2 2 ) . Thc s t u d i e s d e m o n s t r a t e d how r a d i o a c t t v e s u b s t a n c e s may I n d u c e p=ir;ic!c?us a n e m i a s IS well a s l e u k e m i a s . Tvo i n d i v i d u a l s were e x p o s e d f e r nearly t h e same l e n g t h of t i m e t o t h o r i u m r a d i a t i o n . ' One d e v e l o p e d p e r n i c i o u s anemia while t h e other had nyeloqeno-Js leukemia. F i n a l l y . i t 1s known t h a t t h e r a d i a t i o n t h e r a p y u s e d t o t r e a t c h r o n i c leukemias. especial ly the myeloid leukcmias, m y induce the appearance of a s e v e r e a n e m i c svndrome o n d a c u t c l e u k e m i a , t h a t is, in e f f e c t , d ' "Ieukanemia" syndrome. C o n s e q u e n t l y , p e r n i c i o u s a n c m i a a n d a c u t e l e u k e m i a s h o u l d n o t be c o n s i d e r e d t o b e two a u t n o m o u s a n d i n d e p e n d e n t d i s e a s e s . I n cases of b e n , z e n e poisoning. VI- g c n c r n l l v s c v .I clinical p i r t u r c of w v v r r n n c m t a v l t h .leukopenia. i l o w c v c r , o u r C;ISC i n d 1 c a t c . s t I u L bcritenc- p o i s o n i i i K m y also result I n a c u t e leukemia. The c l . i s s i r n 1 f I n d i n g s rcpurting aciice a n e m f a w i t h l e u k o p e n i a i n c a s e s o f b e n z e n e p o i s o n i n g d o n o t exclude t h e possib i l i t y of aciitc Bcnzcne I n d u c e d l e u k e m i a . The two s v n d r o m e s m y be i n d u c e d b y the same p o i s o n i n g . . nir n e x t q u e s t i o n is, "Wiv'i:, i t t h a t i n c.ertairi c a s e s , uliich are f n d e e d t h e mort' f r c q u c n t oncs, d o e s b e n z e n e p o i s o n i n g l e n d t o I e u k o p e n l a ? " - . And, "Uhy, In o t h e r c a s e s , whfch u n t i L now uere i n f r c q u e n t , d o e s b e n z e n e p r o d u c e lrukcmfa?" Wc miy a n s u e r t h i s q u e s t i o n b y referring t o t h e effect hf b c n z l n c on l t s u k o p o l c s i s . Benzine h a s n p p o s i t c e f f e c t s d e p c n d l n g on t h e dose. Wc may a l s o m v n t f o n i n d [ v i d u ; i l s u s c e p t i b i l i t y w h i c h .ippcars t o p l a y an i m p o r t a n t r o l e I n tllc b e n z e n e ; i c r l d e n t s . b o t h i p 1ittm:iri c - i f n l c a l sLt113t l o n s as well ;IS i n animal e x p e r i m e n t a t i o n . l'ol.ICnHf) a n d RERNHEIH have d e m o n s t r a t e d t l ~ a ta n i m n l s h v c v a r l n h i c s e n s i t i v i t y t c i b e n z o l (Ref. 23). . . -11- - -- .. ..... .. Our o b s e r v a t i o n raises a n 0 t h t . r question. T h l n Is t h e porrsible t o x i c e t i o l o g y n f c c r t n t n .?cute lcukealas. I t t o r e a d i l y sdrlsslblc thrt s e v e r e anemla w i t h hemorrhagic purpura MV be caused by t h e tarin In question h e r c . n n c r l y b e n z i n e . Then, ' 2 % ~d o e s n o t t h e s a w poSs i b i l i t y h o l d Cure or a c u t e leukenla!" W l t h o u t d e n y i n g t h a t i n .OI cases, t h e l u c k e a i a may be o f an i n f e c t i o u s etiology, i t may b e Cac l u d d t h a t i n o t h e r c a s e s , che Ierlkernla m.iy be of a t o x i c o r g i n , t h e same as is t r u e f o r p e r n i c i o u s a n e m i a a n d p u r p u r a . .And going s t i l l f u r t l t c r I n o u r d t s c u s s i o n . ve would l i k e t o d l s c w s some of t h e n e o p l a s t ! c f e a t u r e s of l e u k e m t a t h a t d e v e l o p , as Ln o u r caSc, a f t e r p r o l o n p e d exposure t o b e n z e n e . : t is well-known that c o a l t a r and s e v e r a l oi L t s ' d e r i v a t l v c s arc c a r c i n o g e n i c . A t t h i s p o i n t , w e vould like to r e c a l l BARD'S vords who s t a t e d t h a t l e u k e m i a is c a n c e r of the b l o o d , JOLY (Ref. 2 1 ) wrote.... " I n c e r t a l n a c u t e l e u k e n t a s , t h e b l o o d l e u k o c y t e s are c o n s i d e r a b l e tn number and are composed n e a r l y e x c l u s i v e l y of u n d i f f e r e n t i a t e d lymphofd cells, w h t c h a r e n e i t h e r l y m p h o c y t e s nor a y e l o c v t e s , b u t u h i r h u n q u e s t i c m a b l y r e s e m b l e t h e c c l Ln o f many t n v a d i n g lymphadenomxi. These arc n e o p l a s t i c c e l l s . " We beltcve t h a t our o b s e r v a t i o n v e r y d e f i n i t e l y raises t h e q u e s t ion r c g a r d i n p : t h e ? e l a t i o n s h i p b e t v e e n cr-rtain a c u t e Leukemias and s a r c o m t t o s e s , b c c a u s e t h e toxic agenc . .1; q u e s t i o n . b e n z e n e , i s Y. coal t a r d e r t v a t t v e . T h e o r ~ t i c a l l y , i n antnmls, t h e leukemic s y n d r o m can b e produced by t h e a d m i n i s t r a t i o n of very l n w d o s e s of b e n z c n e . doses t h a t a r e much lover t h a n t h e 0nc.s i n d i i c i n g lriiknpcwia b u t g i v c n f o r n c o n t i n u o u s l y length o f timc. We a r c c u r r e n t l v n t t c m p t i n p s u c h r x p c r i m e n t u . F i n a l l y . from t h e - practical p o i n t o f v i e w . o n e may vel1 ask i f b e n z o l ' t h e r a p y i s n o t somctimvs c . i p n h t c o f t r a n s f o r m i n g chronic l e u k e r n l a i n t o a c u t c l e u k e m i a . T h i s p o s s i b i l i t y is c r i r r c n t l v r e c o g n i z e d i n r a d l a t i o n t h e r a p y . We d i d n o t f i n d any r e p o r t s a b o u t leukemia being t r a n s f o r m e d I n t o on a c u t e s t a g e f o l L o u i n g t h e a d m i n i s t r a t i o n of b e n z e n e . H o v e v e r , Ye s h o u l d mention t h a t t h e t h e r a p e u t i c d o s e s of b e n z e n e are much higher than the d o s c r t h a t , i n our o b s e r v a t i o n s , a r c r a p n P l e of l n c r c a s i n g t h e numb e r of w h i t e b l o o d c e l l s . As w e h a v e a l r e a d y m e n t i o n e d , d i f f e r e n t d o s c s of b c n z e n e can p r o d u c e opposLtc P f f e c t s . Th;js. s u c h a r e t h e v a r i o u s p r o b l e m s t h a t a r i a c From our case of ben- z e n e polnoning u h e r e t)w nrrrtc l e u k e m i a d i d riot f c t l l o w the classic coiirse. As ClUUFFARD a n d BERNARD wrote ( R t - f . 19). " l n hcmatolop;y, t h e n t y p f c a l . case, comply poorly t o our c l ~ s s i f i r n t i o n sv h i r h arc a l w a y s too r c s t r i c - .*." . .tive..... In f a c t . these arc the most l n t e r r s c l n g a n d t h e most v o r t h v h l l e cascs t o study.. ' . ' *This conunent shn1'1 h e d l s c i i s s e d n t I c i i R t t i m d I n mire d r t n l l i n t h e n e x t t h c s l s w r 1 t t r . n by (itit? o f US, Thc s t u d v w L l l i i l w i n c l u d e t h e r e s u l t s of c u r r e n t r x p e r l w n t a l studle!, vlicrc wv art- a t t e m p t l n g to i n d u c e l e u k e m i a in animals b y t h e a d m i n t s t r a t i o n of b e n z e n e . -1 2- -... .- :.. . 'C i 1. Crerniru. Severe anemia t n benzene poisonfng. Jo-1 de Lyon, 1926, p. 251. & Wdrcw 2 . Kohn-Abrest. Toxtcology t r e a t i s e . . 3 . LanRluio arid Desbouls. Thc e f f e c t of bcenzoi vapors on thc b 1 d . General and Jpplied hyglene, 1307. 4. Pajaud. C o n t r t b u t i o n to the pharmacodvnaaic and t o l d c o l o % u l s t u d y of b e n z i n e s . T`nesib a~ k r i e r ? * ? x ,1907. 5 . S e l l l n g . A p r e i l m i i i a r j <,;or: -6 cases of purpura hewrrhagfu d u e t o b e n z o l p o i s o n l n g . I r h - t s Hookins H o s p i t a l B u l i e t r n . h i L i - more,. 19iO. XXI, p . 3i-;- 6 . PappenheLm. p . 39). .;Benzui I ::.:k~-:-z+. !?`tit*. t , e x o . ?a:h... 1??4, 7 . Hasntoshi T.ihara. A n a t o m i c o - p a t h o l o ~ i c a l contributions on che e f f e c t of b e n z o l on the vartori:; o r g a n s and on t h e b l o o d . S c i e n t i f i c r e p o r t r o m t h e F e d e r a l I n s t i t u t e o f I n f e c t i o u s Dlseases a t the U n i v e r s l t y of Tokyo. 1 9 2 3 . 11. p. G59-62. 8 . H u l t g r e n . S O C . d e Btol. de S u e d e , 3 September 1926. 9. L e c o n t e . Arch. maladies d u coeur f e v r f e t 1918, p . 120. 1Q. L e Nolr and Claude. A rnsc of p u r p u r a a t t r i b u t e d t o benzine poism* l n g . N e d i c a l S o c i e t y of H o s p i t a l s , Paris. 1897. 1I. Chaiier and ClievaLier. Ancmir syndromc I n l e u k e m i a s . J o u r n a l d e Medectnc de J.yon. 1924, p. 2 2 9 . 12. J u l i r n and Bonn. A c.ist' of f a t a l p o i s o n l n g w i t h b e n z i n e vapors. Revue d e Elcd. L e g a l e . Paris. 1914. 13. R i c u x . Leucancmia. 1.a Mcdccfne. ?larch 1926, p. 4 6 3 . 14. F1aiidln a n d R o h c s r t i . Fit31 p u r p u r a hemotrhagica c a u s e d by occupat loiinl p o i s m i n f i w i t h bcnteol v a p o r s . He-dical Saciety ot H o s p i t a l s . Parls, 1922. 15. Chhambovrt. B e n z c n c poisoning: Thcsia a t [.yon. 1922. 16. O e t t l n g r r . Rcnzirl p o i s o n l n g . Bu1lc.t i n of t h e French Medical Legal S o c i e t y , 1922. - 13- -I(*-